Pyrrolidine-2-carboxamide derivatives as prostaglandin E2 receptor 4 (EP4) agonists for the treatment of gastrointestinal and pulmonary diseases

Abstract

The present invention relates to compounds of formula I as prostaglandin E2 receptor 4 (EP4) agonists for use in the treatment of gastrointestinal and pulmonary diseases or disorders. This disclosure provides exemplary compounds and pharmacological data.

Description

Pyrrolidine-2-carboxamide derivatives as prostaglandin E2 receptor 4 (EP4) agonists for the treatment of gastrointestinal and pulmonary diseases Technical field of the invention This application relates to novel compounds and their use as prostaglandin E2 receptor 4 (EP4) agonists. The compounds described herein may be useful in the treatment or prevention of diseases involving EP4 receptors. The application also covers pharmaceutical compositions comprising these compounds and the manufacture and use of these compounds and compositions in the prevention or treatment of such diseases involving EP4 receptors. Background of the invention Prostanoids, including prostaglandins and thromboxanes, are metabolites derived from arachidonic acid that play key roles in cellular physiological function. Arachidonic acid is an integral component of membrane phospholipids, released through the activity of phospholipase A2 (PLA2). Prostaglandin biosynthesis is mediated by cyclooxygenase (COX), which catalyzes the conversion of arachidonic acid into an unstable intermediate (PGH2), leading to the generation of prostaglandins, including PGE2. PGE2 is the most widely produced prostanoid, and its activity is mediated by its action on four functionally distinct receptor subtypes, EP1–4. EP receptors belong to a family of G protein-coupled receptors (GPCRs), which are integral membrane proteins with seven transmembrane domains. This class of receptors can be broadly classified according to their signaling pathways: i) Gs-coupled receptors (activation of adenylate cyclase and production of cyclic adenosine monophosphate (cAMP)), EP2 and EP4; ii) Gq-coupled receptor (activation by PLC), EP1; and iii) Gi-coupled receptor (inhibition of adenylate cyclase), EP3. The EP4 receptor sends signals through Gs and is positively coupled to adenylate cyclase to increase cAMP levels. The receptor was originally described in 1993 with the identification of an EP2-like receptor that is positively coupled to adenylate cyclase but does not bind to butaprost (A Honda et al. J. Biol. Chem. 1993, 268.7759-7762). The EP4 receptor plays a key role in various physiological functions, including gastrointestinal homeostasis, regulation of vascular tone, renal function, inflammation, fever, and carcinogenesis. The potent biological activity of PGE2 has spurred interest in developing selective agonists and antagonists of the EP4 subtype for the treatment of a wide range of conditions. Functional gastrointestinal disorders (FGIDs), including chronic constipation, are common gastrointestinal conditions encountered by primary care physicians and gastroenterologists. The prevalence of chronic constipation ranges from 1% to 8% and can negatively impact quality of life (QoL), resulting in a significant social and economic burden. Chronic constipation can cause discomfort and affect patients' daily lives. Symptoms include hard, lumpy stools, straining during defecation, and a feeling of incomplete evacuation. The use of laxatives and stool softeners remains high, even though many patients do not experience substantial benefit. There is a continued need for treatments that can provide comprehensive and sustainable symptomatic relief. The intestinal mucosa plays an important role in maintaining the homeostasis of anions and body fluids.These functions are mediated by the coordinated transport of ions through membrane-bound transporters and channels located in the apical and basolateral membranes of intestinal epithelial cells. PGE2 is a well-established secretagogue that can directly promote chloride secretion from intestinal epithelial cells. The secretory effects of PGE2 are partly mediated by the EP4 receptor, which can stimulate anionic chloride secretion in the intestinal mucosa. Lubiprostone, a bicyclic fatty acid derived from PGE1 and clinically approved for the treatment of chronic constipation and IBS-C, has been shown to promote fluid secretion and gastrointestinal motility by activating prostaglandin receptors (EP4). Selective EP4 agonists may have therapeutic value in promoting intestinal fluid homeostasis in chronic constipation. Inflammatory bowel disease (IBD) is a chronic, debilitating gastrointestinal disorder that includes ulcerative colitis and Crohn's disease. Patients with IBD typically present with symptoms including diarrhea, abdominal pain, weight loss, rectal bleeding, and fever. Clinical management involves strategies to control the abnormal, dysregulated immune response in the intestinal mucosa. A wide variety of agents are used to induce and maintain remission, depending on the severity of the disease. These include aminosalicylates, corticosteroids, immunosuppressants, antibiotics, and biologics. These may be administered in a stepwise fashion, with therapy intensified according to disease severity and progression. However, it is clear that some patients are refractory to medical treatment or do not tolerate it due to systemic side effects.Only a subset of patients achieve long-term remission with current therapeutic strategies, suggesting a need for improved therapies. Intestinal barrier dysfunction plays a key pathogenic role in IBD, and interest is growing in the development of agents that restore barrier function (mucosal healing). EP4 is expressed in several cell types, including gastrointestinal (GI) epithelial cells, lamina propria mononuclear cells, and sensory neurons innervating the colon, and may offer benefits in buffering inappropriate mucosal immune responses and protecting the GI mucosal barrier. PGE2 signaling via EP4 promotes cell differentiation toward a wound-associated epithelial cell phenotype that is important for wound repair (Miyoshi, H. et al. EMBO J). 2017, 36. 5-24) . Administration of EP4 agonists provides benefits in chemically induced colitis models (Kabashima, K. et al. J. Clin. Invest. 2002, 109, 883-893; Watanabe, Y. et al. Eur. J. Pharmacol. 2015, 754, 179-189; Nitta, M. et al. Scand. J. Immunol. 2002, 56, 66-75), whereas mutant mice lacking EP4 develop severe dextran sodium sulfate-induced colitis, characterized by impaired mucosal barrier function, increased epithelial cell loss, crypt damage, and increased immune cell infiltration (Kabashima, K. et al. J. Clin. Invest. 2002, 109, 883-893). In a small study in PhII, the EP4 agonist, ONO-4819CD, was evaluated in patients with mild to moderate ulcerative colitis refractory to 5-ASA (Nakase, H. et al. Inflamm. Bowel Dis. 2010, 16, 731-733).Although the study was not based on efficacy, patients treated with ONO-4819CD showed signs of improvement in Disease Activity Index (DAI) scores and histological scores. These data support a potential clinical benefit of EP4 agonist therapy in IBD. Asthma and chronic obstructive pulmonary disease (COPD) are inflammatory airway diseases characterized by airflow limitation. It is estimated that approximately 300 million people have asthma, and it is the most common chronic disease in children. Despite advances in asthma treatment, a significant proportion of patients have uncontrolled disease, which can lead to mortality and morbidity. Therapies that can effectively control asthma symptoms and reduce the risk of future exacerbations are still needed for long-term management. Progesterone 2 (PGE2) is known to have bronchodilatory and anti-inflammatory effects on airway smooth muscle isolated from rodents and humans. Inhaled PGE2 has been shown to be beneficial for reducing airway inflammation and caliber in patients with chronic bronchitis and asthma.However, PGE2 also induces a reflex cough, possibly through upper airway irritation mediated by the EP3 receptor. This has led to efforts to discover EP receptor-selective agents for the treatment of airway disorders. Interestingly, key species differences have been described in the receptor subtype responsible for mediating airway smooth muscle relaxation. In guinea pigs, monkeys, and mice, EP2 agonists can induce airway smooth muscle relaxation, whereas in humans, this is mediated by the EP4 receptor (Buckley, J. et al. Thorax 2011, 66, 1029-1035). Selective EP4 receptor agonists may have potential therapeutic value in airway diseases. The EP4 receptor has been shown to play a role in blood pressure regulation. EP4 is expressed in smooth muscle and endothelial cells and can induce vasodilatory effects through nitric oxide (NO) production mediated by endothelial nitric oxide synthase (eNOS). PGE2 has been shown to relax the smooth muscle of the aortic rings in a dose-dependent manner, an effect that is abolished in mice that do not receive EP4. In dogs anesthetized with halothane, the selective EP4 agonist, ONO-AE1-329, induces a vasodepressor response (Honda, A. et al. Eur. J. Pharmacol. 2016, 775, 130-137) and, similarly, hypotension was reported as one of the adverse drug reactions in IBD patients receiving ONO-4819CD (Nakase, H. et al. Inflamm. Bowel Dis.2010, 16, 731-733). The international publication WO 2013 / 004291 Al describes a group of cyclic amine derivatives that have EP4 receptor agonist activity. EP4 agonists that can be used to treat a variety of gastrointestinal and respiratory disorders without systemic cardiovascular side effects may have potential therapeutic value. In particular, EP4 agonists that can be used to treat a variety of gastrointestinal disorders without systemic cardiovascular side effects may have potential therapeutic value. There is a need to discover safe and effective selective EP4 agents. Compendium of the invention The present invention provides compounds that have activity as prostaglandin E2 receptor 4 (EP4) agonists. In one aspect, the invention provides a compound of formula I: or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or optical isomer thereof, wherein: A is OR, C(O)R, CO2R, C(O)N(R)2, C(O)N(R)S(O)2R, S(O)2R, S(O)2OR, SO2N(R)2, C1-8 alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; ring B is aryl or heteroaryl; X and Y are each independently CR" or N, where at least one of X and Y is CH; R1 and R2 are each independently H, C1-6 alkyl, C1-6 alkoxy or R1 and R2, together with the carbon atom to which they are attached, form a C3-6 cycloalkane-1, 1-diyl; each R3 is independently selected from H, OR', COOR', C (O) R', halogen or C1-6 alkyl; R4 is H, C1-6 alkyl, halogen, CN, NO2 or OR'; R5 is H or C1-6 alkyl; or R4 and R5, together with the pyrrolidine ring to which they are attached, form a C1-6 alkylene connector; R6 is H, C1-6 alkyl, C1-3 alkoxy optionally substituted with 1-3 atoms of fluorine, halogen, CN, NO2, OR', COOR' or C (O) R', R7 is OR, OC (O) R, OC (O) OR, CO2R, CON (R) 2, SO2N (R) 2, SO2R, OSO2R or OSO2N (R) 2; each R' is independently H, C1-6 alkyl or C3-6 cycloalkyl; each R" is H, C1-6 alkyl, halogen or OR'; and nym are each independently 0, 1, 2 or 3; wherein in each case, the alkyl, alkylene and cycloalkyl are each optionally and independently substituted up to 3 times with OH', SH, CN, NO2, COOH, halogen or C1-4 COO-alkyl; wherein the heterocycloalkyl, aryl and heteroaryl groups are each optionally and independently substituted up to 3 times with OR', SR', CN, NO2, COOR', halogen, C1-4 alkyl or oxo. In another aspect, the invention provides a compound of formula (1): or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or optical isomer thereof, wherein; A is selected from the group consisting of: U, V, W and Z are each independently selected from the group consisting of CH, COH, N or N+-O-, wherein at least three of U, V, W and Z are CH; X and Y are each selected independently of the group consisting of CH, CF, COH or N; R1 is H, C1-3 alkyl optionally substituted with 1-3 fluorine atoms or is attached to R2 to form a C3-6 cycloalkyl ring that is optionally substituted with 1-3 fluorine atoms; R2 is H, C1-3 alkyl optionally substituted with 1-3 fluorine atoms or is attached to R1 to form a C3-6 cycloalkyl ring that is optionally substituted with 1-3 fluorine atoms; R3 is H, OH or F; R4 is H, OH, F or is bonded to R5 to form a CH2 bridge; R5 is H or is joined to R4 to form a CH2 bridge; R6 is H, OH, CN, halogen, C1-3 alkoxy optionally substituted with 1-3 fluorine atoms or C1-3 alkyl optionally substituted with 1-3 fluorine atoms; R7 is OH, CO2H, CONH2, SO2NH2 or OSO2NH2; and R9 is a C1-3 alkyl or a C3-6 cycloalkyl ring. In another aspect, the invention includes a pharmaceutical composition comprising a compound described herein and a pharmaceutically acceptable excipient. In another aspect, the invention includes a kit comprising a compound described herein and at least one additional therapeutic agent selected from the group consisting of aminosalicylates, corticosteroids, immunomodulators, and combinations thereof. In another aspect, the invention includes a compound, composition, or kit described herein for use as a medicament. In another aspect, the invention includes a compound, composition, or kit described herein for use in the treatment of an EP4 receptor-mediated disease. In another aspect, the invention includes a compound or composition described herein for use in a method of modulating the agonist activity of the EP4 receptor in a biological sample, the method comprising contacting said EP4 receptor with a compound or composition described herein. In another aspect, the invention includes a compound or composition described herein for use in a method of treating an EP4 receptor-mediated disease, the method comprising administering a compound or composition described herein to a patient in need. The compounds herein may be used as EP4 receptor agonists. The compounds herein may act selectively on the EP4 receptor. The compounds may be used in the manufacture of compositions or medicaments. The compounds, compositions, or medicaments may be used to treat, prevent, improve, control, or reduce the risk of diseases or disorders in which EP4 receptors are involved. The compounds, compositions, or medicaments may be used to treat, prevent, improve, control, or reduce the risk of gastrointestinal disorders and conditions, including, but not limited to, constipation disorders.Irritable bowel syndrome with constipation predominance, mixed type irritable bowel syndrome, chronic idiopathic constipation, gastrointestinal symptoms associated with Parkinson's disease, gastrointestinal symptoms associated with cystic fibrosis, intestinal dysmotility, postoperative ileus, food allergy or intolerance, celiac disease, gastrointestinal motility disorders, functional gastrointestinal disorders, drug-induced enteropathy, NSAID-induced gastric and intestinal injury, chemotherapy-induced mucositis, gastroesophageal reflux disease (GERD), duodenogastric reflux, diarrheal diseases, immune-mediated gastrointestinal diseases, Crohn's disease, ulcerative colitis, inflammatory bowel disease, and ischemic colitis. The compounds, compositions, or medicines can also be used to treat, prevent, improve, control, or reduce the risk of lung diseases and conditions such as chronic obstructive pulmonary disease, asthma, chronic bronchitis, cystic fibrosis, emphysema, chronic idiopathic cough, hyperactive airway disorder, and idiopathic pulmonary fibrosis. Detailed description of the invention The invention relates to novel compounds. The invention also relates to the use of novel compounds as EP4 receptor agonists. The invention further relates to the use of novel compounds in the manufacture of medicaments for use as EP4 receptor agonists and to the compounds of the invention for use in treatment methods comprising administering a compound of the invention as an EP4 receptor agonist. Formula I compounds may be used to treat, prevent, improve, control, or reduce the risk of diseases or disorders in which EP4 receptors are involved. Formula I compounds may be used to treat, prevent, improve, control, or reduce the risk of gastrointestinal disorders and conditions, including, but not limited to, constipation disorders, irritable bowel syndrome with constipation predominance, mixed-type irritable bowel syndrome, chronic idiopathic constipation, gastrointestinal symptoms associated with Parkinson's disease, gastrointestinal symptoms associated with cystic fibrosis, intestinal dysmotility, postoperative ileus, food allergy or intolerance, celiac disease, gastrointestinal motility disorders, functional gastrointestinal disorders, drug-induced enteropathy, NSAID-induced gastric and intestinal injury, and chemotherapy-induced mucositis.Gastroesophageal reflux disease (GERD), duodenogastric reflux, diarrheal diseases, immune-mediated gastrointestinal diseases, Crohn's disease, ulcerative colitis, inflammatory bowel disease, and ischemic colitis. The compounds, of formula I, can also be used to treat, prevent, improve, control or reduce the risk of lung diseases and conditions such as chronic obstructive pulmonary disease, asthma, chronic bronchitis, cystic fibrosis, emphysema, chronic idiopathic cough, hyperactive airway disorder and idiopathic pulmonary fibrosis. Certain novel compounds of the invention exhibit particularly high activities as EP4 receptor agonists. The compounds of the invention have been shown to have EP4 receptor agonist activity. The compounds of the invention also possess low gastrointestinal permeability, as demonstrated by Caco-2 studies. Therefore, it is believed that the compounds of the invention exhibit low systemic bioavailability when administered orally. Functional agonism of EP4 receptors expressed in the gastrointestinal tract has the potential to treat a variety of gastrointestinal disorders. The combination of EP4 receptor agonist activity and low gastrointestinal permeability suggests that the compounds of the invention are useful for the treatment of a variety of gastrointestinal disorders without cardiovascular side effects resulting from systemic distribution. In one aspect, the invention provides a compound of formula I: or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or optical isomer thereof, wherein; A is OR, C(O)R, CO2R, C(O)N(R)2, C(O)N(R)S(O)2R, S(O)2R, S(O)2OR, SO2N(R)2, C1-8 alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; ring B is aryl or heteroaryl; X and Y are each independently CR" or N, where at least one of X and Y is CH; R1 and R2 are each independently H, C1-6 alkyl, C1-6 alkoxy or R1 and R2, together with the carbon atom to which they are attached, form a C3-6 cycloalkane-1, 1-diyl; each R3 is independently selected from H, OR', COOR', C (O) R', halogen or C1-6 alkyl; R4 is H, C1-6 alkyl, halogen, CN, NO2 or OR'; R5 is H or C1-6 alkyl; or R4 and R5, together with the pyrrolidine ring to which they are attached, form a C1-6 alkylene connector; R6 is H, C1-6 alkyl, C1-3 alkoxy optionally substituted with 1-3 atoms of fluorine, halogen, CN, NO2, OR', COOR' or C (O) R', R7 is OR, OC (O) R, OC (O) OR, CO2R, CON (R) 2, SO2N (R) 2, SO2R, OSO2R or OSO2N (R) 2; each R' is independently H, C1-6 alkyl or C3-6 cycloalkyl; each R" is H, C1-6 alkyl, halogen or OR'; and nym are each independently 0, 1, 2 or 3; wherein in each case, the alkyl, alkylene and cycloalkyl are each optionally and independently substituted up to 3 times with OH', SH, CN, NO2, COOH, halogen or C1-4 COO-alkyl; wherein the heterocycloalkyl, aryl and heteroaryl groups are each optionally and independently substituted up to 3 times with OR', SR', CN, NO2, COOR', halogen, C1-4 alkyl or oxo. In some embodiments, the compound is a compound of formula I: or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or optical isomer thereof, wherein; A is OR, C(O)R, CO2R, C(O)N(R)2, C(O)N(R)S(O)2R, S(O)2R, S(O)2OR, SO2N(R)2, C1-8 alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; ring B is aryl or heteroaryl; X and Y are each independently CR" or N, where at least one of X and Y is CH; R1 and R2 are each independently H, C1-6 alkyl, C1-6 alkoxy or R1 and R2, together with the carbon atom to which they are attached, form a C3-6 cycloalkane-1, 1-diyl; each R3 is independently selected from H, OR', COOR', C (O) R', halogen or C1-6 alkyl; R4 is C1-6 alkyl, halogen, CN, NO2 or OR'; R5 is H or C1-6 alkyl; or R4 and R5, together with the pyrrolidine ring to which they are attached, form a C1-6 alkylene connector; R6 is H, C1-6 alkyl, halogen, CN, NO2, OR', COOR' or C (O) R', R7 is OR, OC (O) R, OC (O) OR, CO2R, CON (R) 2, SO2N (R) 2, SO2R, OSO2R or OSO2N (R) 2; each R' is independently H, C1-6 alkyl or C3-6 cycloalkyl; each R" is H, C1-6 alkyl, halogen or OR'; and nym are each independently 0, 1, 2 or 3; wherein in each case, the alkyl, alkylene and cycloalkyl are each optionally and independently substituted up to 3 times with OH', SH, CN, NO2, COOH, halogen or C1-4 COO-alkyl; wherein the heterocycloalkyl, aryl and heteroaryl groups are each optionally and independently substituted up to 3 times with OR', SR', CN, NO2, COOR', halogen, C1-4 alkyl or oxo. In some embodiments, the compound is a compound of formula I, formula IIa, formula IIb, formula IIc, formula IId, formula IIe, formula (1), formula (1a), formula (1b), formula (2), formula (2a), formula (2b), formula (3), formula (3a), formula (3b), formula (4), formula (4a), formula (4b), formula (5), formula (5a), formula (5b), formula (6), formula (6a), formula (6b), formula (7), formula (7a), formula (7b), formula (8), formula (8a), formula (8b), formula (9), formula (9a), formula (9b), formula (10), formula (10a), formula (10b) or a pharmaceutically acceptable salt or tautomer thereof. In some embodiments, the compound is a compound of formula I, formula IIa, formula IIb, formula IIc, formula IId, formula IIe, formula (1), formula (1a), formula (1b), formula (2), formula (2a), formula (2b), formula (3), formula (3a), formula (3b), formula (4), formula (4a), formula (4b), formula (5), formula (5a), formula (5b), formula (6), formula (6a), formula (6b), formula (7), formula (7a), formula (7b), formula (8), formula (8a), formula (8b), formula (9), formula (9a), formula (9b), formula (10), formula (10a), formula (10b) or a pharmaceutically acceptable salt thereof. In some embodiments, A is CO2R', C (O) N (R) S (O) 2R, S (O) 2R or heteroaryl. In some embodiments, A is a COOH or 5-membered heteroaryl optionally substituted with OR' or SR'. In some embodiments, ring B is a 5-6-membered aryl or a 5-6-membered heteroaryl, each of which is optionally and independently substituted up to 3 times with alkyl OR', SR', CN, NO2, CO2R', halogen, or C1-4 alkyl. In some embodiments, ring B is a 5-6 membered aryl or a 5-6 membered heteroaryl. In some embodiments, ring B is phenyl, which is optionally substituted up to three times with OH. In some embodiments, ring B is a 6-membered heteroaryl comprising one or two nitrogen atoms, and each nitrogen is optionally substituted with oxo. In some embodiments, ring B is pyridine N-oxide. In some embodiments, each R3 is selected independently of OR', halogen, or C1-6 alkyl. In some embodiments, each R3 is selected independently of OR' or alkyl; yn is 0 or 1. In some embodiments, n is 0. In some realizations, n is 1. In some realizations, n is 0 or 1. In some embodiments, R4 is selected independently of OR' or halogen and; m is 0 or 1. In some embodiments, m is 0. In some realizations, m is 1. In some realizations, m is 0 or 1. In some implementations, R5 is H. In some embodiments, R4 and R5, together with the pyrrolidine ring to which they are attached, form a CH2 connector. In some embodiments, R4 is attached to the carbon atom to which R5 is attached, to form, together with the pyrrolidine ring to which R4 is attached, a C5 bridged bicyclic ring. In some embodiments, R4 and R5, together with the pyrrolidine ring to which they are attached, form a C5 bridged bicyclic ring. In some embodiments, R6 is H, C1-6 alkyl, halogen or OR'. In some embodiments, R6 is H, methyl, or OH. In some embodiments, R7 is OR, OC (O) R, CO2R, CON (R) 2, SO2N (R) 2, SO2R or OSO2N (R) 2. In some embodiments, R7 is OR, CO2R, CON (R) 2, SO2N (R) 2 or OSO2N (R) 2. In some embodiments, R' is H. In some embodiments, R7 is OH, CO2H, CONH2, SO2NH2 or OSO2NH2. In some implementations, R7 is CONH2. In some embodiments, when R7 is OH, then U, V and Z are CH and W is COH. In some embodiments, a compound of formula IIa, IIb, IIc, IId, and IIe is provided herein: or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or optical isomer thereof, wherein A, X, Y, R1, R2, R3, R4, R5, R6 and R7 are as defined above. In one embodiment, a compound of formula (1) is provided herein: or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or optical isomer thereof, wherein U, V, W and Z are each independently selected from the group consisting of CH, COH, N or N+-O-, and at least three of U, V, W and Z are CH. In some embodiments, R4 is H, OH, F or is bonded to R5 to form a CH2 bridge. In some embodiments, R5 is H or is joined to R4 to form a CH2 bridge. In some embodiments, A is selected from the group consisting of: e R9 es C1-3 alkyl or a C3-6 cycloalkyl ring. In one embodiment, a compound of formula (1) is provided herein: or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or optical isomer thereof, wherein; A is selected from the group consisting of: U, V, W and Z are each selected independently from the group consisting of CH, COH, N or N+-O-, and at least three of U, V, W and Z are CH; X and Y are each selected independently of the group consisting of CH, CF, COH or N; R1 is H, C1-3 alkyl optionally substituted with 1-3 fluorine atoms or is attached to R2 to form a C3-6 cycloalkyl ring that is optionally substituted with 1-3 fluorine atoms; R2 is H, C1-3 alkyl optionally substituted with 1-3 fluorine atoms or is attached to R1 to form a C3-6 cycloalkyl ring that is optionally substituted with 1-3 fluorine atoms; R3 is H, OH or F; R4 is H, OH, F or is joined to R5 to form a CH2 connector; R5 is H or is joined to R4 to form a CH2 bridge; R6 is H, OH, CN, halogen, C1-3 alkoxy optionally substituted with 1-3 fluorine atoms or C1-3 alkyl optionally substituted with 1-3 fluorine atoms; R7 is OH, CO2H, CONH2, SO2NH2 or OSO2NH2; R9 is a C1-3 alkyl or a C3-6 cycloalkyl ring. In some embodiments, compounds of formula (1a) or (1b) are provided in this document: or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or optical isomer thereof, wherein U, V, W, X, Y, Z, R1, R2, R3, R4, R5, R6 and R7 are as defined above. In some embodiments, compounds of Formula (2), (2a) or (2b) are provided in this document: or a pharmaceutical salt, solvate, hydrate or tautomer thereof, wherein A, U, V, W, X, Y, Z, R1, R2, R3, R4, R6 and R7 are as defined above. In some embodiments, the compound is a compound of formula (2a): or a pharmaceutically acceptable salt, solvate, hydrate or tautomer thereof, wherein U, V, W, X, Y, Z, R1, R2, R3, R4, R6 and R7 are as defined herein. In some embodiments, the compound is a compound of formula (2a): or a pharmaceutically acceptable salt, solvate, hydrate or tautomer thereof, wherein: U, V, W and Z are each selected independently from the group consisting of CH, COH, N or N+-O-, and at least three of U, V, W and Z are CH; X and Y are each selected independently of the group consisting of CH, CF, COH or N; R1 is H, C1-3 alkyl optionally substituted with 1-3 fluorine atoms or is attached to R2 to form a C3-6 cycloalkyl ring that is optionally substituted with 1-3 fluorine atoms; R2 is H, C1-3 alkyl optionally substituted with 1-3 fluorine atoms or is attached to R1 to form a C3-6 cycloalkyl ring that is optionally substituted with 1-3 fluorine atoms; R3 is H, OH or F; R4 is H, OH, F or is joined to R5 to form a CH2 connector; R6 is H, OH, CN, halogen, C1-3 alkoxy optionally substituted with 1-3 fluorine atoms or C1-3 alkyl optionally substituted with 1-3 fluorine atoms; and R7 is OH, CO2H, CONH2, SO2NH2 or OSO2NH2. In some embodiments, R1 and R2 are independently C1-3 alkyl optionally substituted with 1-3 fluorine atoms or R1 is attached to R2 to form a C3-6 cycloalkyl ring that is optionally substituted with 1-3 fluorine atoms. In some embodiments, R1 is H or methyl or is bonded to R2 to form a cyclopropane-1,1-diyl ring. In some embodiments, compounds of Formula (3), (3a), or (3b) are provided herein: or a pharmaceutically acceptable salt, solvate, hydrate or tautomer thereof, wherein A, U, V, W, X, Y, Z, R3, R4, R6 and R7 are as defined above. In some embodiments, the compound is a compound of formula (3a): or a pharmaceutically acceptable salt, solvate, hydrate or tautomer thereof, wherein U, V, W, X, Y, Z, R3, R4, R6 and R7 are as defined herein. In some embodiments, the compound is a compound of formula (3a): or a pharmaceutically acceptable salt, solvate, hydrate or tautomer thereof, wherein: U, V, W and Z are each selected independently from the group consisting of CH, COH, N or N+-O-, and at least three of U, V, W and Z are CH; X and Y are each selected independently of the group consisting of CH, CF, COH or N; R3 is H, OH or F; R4 is H, OH, F or is joined to R5 to form a CH2 connector; R6 is H, OH, CN, halogen, C1-3 alkoxy optionally substituted with 1-3 fluorine atoms or C1-3 alkyl optionally substituted with 1-3 fluorine atoms; and R7 is OH, CO2H, CONH2, SO2NH2 or OSO2NH2. In some implementations, R3 is H, OH or F. In some implementations, R3 is H or OH. In some implementations, R4 is H, OH or F. In some embodiments, R6 is H, OH, CN, halogen, C1-3 alkoxy optionally substituted with 1-3 fluorine atoms or C1-3 alkyl optionally substituted with 1-3 fluorine atoms. In some embodiments, R6 is H, OH, CN or methyl. In some embodiments, R6 is OH, CN or methyl. In some embodiments, R6 is methyl. In some embodiments, R7 is OH, CO2H, CONH2, SO2NH2 or OSO2NH2. In some embodiments, R7 is CO2H, CONH2, SO2NH2 or OSO2NH2. In some embodiments, R7 is CONH2 or SO2NH2. In some embodiments, X and Y are each selected independently of the group consisting of CH, CF, COH or N. In some embodiments, compounds of Formula (4), (4a) or (4b) are provided in this document: or a pharmaceutically acceptable salt, solvate, hydrate or tautomer thereof, wherein A, U, V, W, Z, R3, R4, R6 and R7 are as defined above. In some embodiments, compounds of formula (5), (5a) or (5b) are provided herein: or a pharmaceutically acceptable salt, solvate, hydrate or tautomer thereof, wherein A, R8 is H or OH and R3, R4, R6 and R7 are as defined above. In some embodiments, compounds of Formula (6), (6a) or (6b) are provided in this document: or a pharmaceutically acceptable salt, solvate, hydrate or tautomer thereof, wherein A, R3, R6, R7 and R8 are as defined above. In some embodiments, compounds of formula (7), (7a) or (7b) are provided herein: or a pharmaceutically acceptable salt, solvate, hydrate or tautomer thereof, wherein A, U, V, W, X, Y, Z, R3, R6 and R7 are as defined above. In some embodiments, compounds of formula (8), (8a) or (8b) are provided herein: or a pharmaceutically acceptable salt, solvate, hydrate or tautomer thereof, wherein A, U, V, W, X, Y, Z, R3, R4, R6 and R7 are as defined above. In some embodiments, compounds of formula (9), (9a) or (9b) are provided in this document: or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or optical isomer thereof, wherein A, U, V, W, X, Y, Z, R1, R2, R3, R6 and R7 are as defined herein. In some embodiments, compounds of formula (10), (10a) or (10b) are provided in this document: or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or optical isomer thereof, wherein A, U, V, W, X, Y, Z, R3, R6 and R7 are as defined herein. In some embodiments, the compound is a compound of formula (1) or formula (9) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or optical isomer thereof, wherein; A is OR, C(O)R, CO2R, C(O)N(R)2, C(O)N(R)S(O)2R, S(O)2R, S(O)2OR, SO2N(R)2, C1-8 alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; U, V, W and Z are each independently selected from the group consisting of CH, COH, N or N+-O-, wherein at least three of U, V, W and Z are CH; X and Y are each independently CR" or N, where at least one of X and Y is CH; R1 and R2 are each independently H, C1-6 alkyl, C1-6 alkoxy or R1 and R2, together with the carbon atom to which they are attached, form a C3-6 cycloalkane-1,1-diyl ring; each R3 is independently selected from H, OR', COOR', C (O) R', halogen or C1-6 alkyl; R4 is C1-6 alkyl, halogen, CN, NO2 or OR'; R5 is H or C1-6 alkyl; R6 is H, C1-6 alkyl, halogen, CN, NO2, OR', CO2R' or C (O) R'; R7 is OR, OC (O) R, OC (O) OR, CO2R, CON (R) 2, SO2N (R) 2, SO2R, OSO2R or OSO2N (R) 2; each R' is independently H, C1-6 alkyl or C3-6 cycloalkyl; each R" is H, C1-6 alkyl, halogen or OR'; and nym are each independently 0, 1, 2 or 3; wherein in each case, the alkyl, alkylene and cycloalkyl are each optionally and independently substituted up to 3 times with OH, SH, CN, NO2, COOH, halogen or C1-4 COO-alkyl; wherein in each case, the heterocycloalkyl, aryl and heteroaryl is each optionally and independently substituted up to 3 times with OR', SR', CN, NO2, CO2R', halogen, C1-4 alkyl or oxo. In some embodiments, the compound is a compound of formula (1) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or optical isomer thereof, wherein: A is COOH; U is CH; V is CH; W is CH, COH, N, or N-O'; Z is CH or COH; X is CH; Y is CH or COH; R1 is H or methyl and R2 is H or R1 is bonded to R2 to form a cyclopropane-1,1-diyl ring; R3 is H or OH; R4 is H or OH and R5 is H or R4 is bonded to R5 to form a CH2 bridge; R6 is H, OH, CN, or methyl; and R7 is OH, CO2H, CONH2, SO2NH2, or OSO2NH2. In some cases, the compound is a compound of formula (1) or formula (9) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or optical isomer thereof, wherein: A is COOH; U is CH; V is CH; W is CH, COH, N or N-O'; Z is CH or COH; X is CH; Y is CH or COH; R1 is H or methyl and R2 is H or R1 is attached to R2 to form a cyclopropane-1,1-diyl ring; R3 is H or OH; R4 is H or OH; R5 is H; R6 is H, OH, CN or methyl; and R7 is OH, CO2H, CONH2, SO2NH2 or OSO2NH2. In some embodiments, A is selected from CO2H, tetrazole, 1,2,4-oxadiazol-5(2H)-one, 13,4-oxadiazol-2(3H)-one, CONHSO2R6, CONHSO2Me, SO3H, 1,3,4-oxadiazol-2(3H)-thione, 1,2,4-oxadiazol-5(2H)-thione, 1,2,4-thiadiazol-5(2H)-one, 1,1-dioxide of 1,2,5-thiadiazolidin-3-one and 2,4-oxazolidindione. In some realizations, A is selected from: In some embodiments, A is selected from CO2H and a tetrazole ring. A can be CO2H. A can be a tetrazole ring. In some embodiments, U can be CH. PU can be COH. U can be N. U can be N+-O-. In some embodiments, U is CH. In some embodiments, V can be CH. V can be COH. V can be N. V can be N+-O-. In some realizations, V is CH. In some embodiments, W can be CH. W can be COH. W can be N. W can be N+-O-. In some embodiments, W is CH, COH, N or N+-O-. In some embodiments, W is CH or COH. In some embodiments, Z can be CH. Z can be COH. Z can be N. Z can be N+-O-. In some realizations, Z is CH or COH. In some embodiments, at least three of U, V, W, and Z are CH. U, V, and W can be CH. U, V, and Z can be CH. U, W, and Z can be CH. V, W, and Z can be CH. U, V, W, and Z can be CH. U, V, and Z can be CH, and W can be COH. In some embodiments, X can be CH. X can be CF. X can be COH. X can be N. In some embodiments, Y can be CH. Y can be CF. Y can be COH. Y can be N. In some embodiments, Y can be CH or COH. In the compounds in this document, at least one of X and Y is CH. Both X and Y can be CH. In some embodiments, X can be CH and Y can be CH or COH. In some embodiments, R1 can be H or a C1-3 alkyl optionally substituted with 1-3 fluorine atoms. R1 can be H. R1 can be a C1-3 alkyl optionally substituted with 1-3 fluorine atoms. R1 can be a C1-3 alkyl. R1 can be attached to R2 to form a C3-6 cycloalkyl ring that is optionally substituted with 1-3 fluorine atoms. R1 can be attached to R2 to form a C3-6 cycloalkyl ring. R1 can be H or methyl or can be attached to R2 to form a cyclopropane ring. R1 can be methyl optionally substituted with 1-3 fluorine atoms. R1 can be methyl. R1 can be attached to R2 to form a cyclopropane ring that is optionally substituted with 1-3 fluorine atoms. R1 can be attached to R2 to form a cyclopropane ring. In some embodiments, R2 can be H. R2 can be a C1-3 alkyl optionally substituted with 1-3 fluorine atoms. R2 can be a C1-3 alkyl. R2 can be attached to R1 to form a C3-6 cycloalkyl ring that is optionally substituted with 1-3 fluorine atoms. R2 can be attached to R1 to form a C3-6 cycloalkyl ring. R2 can be attached to R1 to form a cyclopropane ring that is optionally substituted with 1-3 fluorine atoms. R2 can be attached to R1 to form a cyclopropane ring. In some implementations, R3 can be H. R3 can be OH. R3 can be F. In some embodiments, R4 can be H. R4 can be OH. R4 can be F. R4 can be bonded to R5 to form a CH2 bridge. In some embodiments, R5 may be H. R5 may be joined to R4 to form a CH2 bridge. In some embodiments, R6 and R7 together with the ring to which they are attached may be the group consisting of: In some embodiments, R6 can be H, OH, CN, or methyl. R6 can be H. R6 can be OH. R6 can be CN. R6 can be a halogen. R6 can be F. R6 can be Cl. R6 can be Br. R6 can be a C1-3 alkoxy optionally substituted with 1-3 fluorine atoms. R6 can be a C1-3 alkoxy. R6 can be a methoxy optionally substituted with 1-3 fluorine atoms. R6 can be a methoxy. R6 can be a C1-3 alkyl optionally substituted with 1-3 fluorine atoms. R6 can be a C1-3 alkyl. R6 can be H or methyl. R6 can be methyl optionally substituted with 1-3 fluorine atoms. R6 can be methyl. In some embodiments, R7 can be OH. R7 can be CO2H. R7 can be CONH2. R7 can be SO2NH2. R7 can be OSO2NH2. In some implementations, R8 may be H. R8 may be OH. In some embodiments, R9 can be a C1-3 alkyl. R9 can be a C3-6 cycloalkyl ring. R9 can be methyl. In some embodiments, A can be CO2H; U, V, and Z can be CH; W can be COH; R1 can be methyl; R2 can be H; and R6 can be methyl. In some embodiments, the pharmaceutically acceptable compound or salt described herein possesses EP4 receptor agonist activity. In some embodiments, the invention includes a pharmaceutical composition comprising a pharmaceutically acceptable compound, salt, solvate, hydrate, tautomer or optical isomer described herein and a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition further comprises at least one additional therapeutic agent selected from the group consisting of aminosalicylates, corticosteroids, immunomodulators, and combinations thereof. In some embodiments, a pharmaceutically acceptable compound or salt described herein is described for use in a method of treating an EP4 receptor-mediated disease, the method comprising administering to a patient in need a pharmaceutically acceptable compound or salt described herein. In some realizations, EP4 receptor-mediated disease is a gastrointestinal disorder. In some embodiments, the gastrointestinal disorder is selected from the group consisting of constipation disorders, irritable bowel syndrome with predominant constipation, mixed-type irritable bowel syndrome, chronic idiopathic constipation, gastrointestinal symptoms associated with Parkinson's disease, gastrointestinal symptoms associated with cystic fibrosis, intestinal dysmotility, postoperative ileus, food allergy or intolerance, celiac disease, gastrointestinal motility disorders, functional gastrointestinal disorders, drug-induced enteropathy, NSAID-induced gastric and intestinal lesions, chemotherapy-induced mucositis, gastroesophageal reflux disease (GERD), duodenogastric reflux, diarrheal diseases, immune-mediated gastrointestinal diseases, Crohn's disease, ulcerative colitis, inflammatory bowel disease, and ischemic colitis.or lung diseases and conditions such as chronic obstructive pulmonary disease, asthma, chronic bronchitis, cystic fibrosis, emphysema, chronic idiopathic cough, hyperactive airway disorder, and idiopathic pulmonary fibrosis. In some embodiments, the compound of formula I or formula (1) is the compound listed in Table 1 or a pharmaceutically acceptable salt, solvate, hydrate, or tautomer thereof. In some embodiments, the compound of formula I or formula (1) are the compounds indicated in Table 1, or a pharmaceutically acceptable salt thereof: Table 1: Example Formula Compounds (I) Abbreviations aqueous acid Bn benzyl DCM dichloromethane DMA dimethylacetamide DMF dimethylformamide dppf 1, 1'-bis(diphenylphosphino)ferrocene EDCI 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide FA formic acid EtOAc ethyl acetate HATU 1-[bis(dimethylamino)methylene]-1H-1, 2, 3-triazolo[4, 5-b]pyridinium hexafluorophosphate 3-oxide, HOBt hydroxybenzotriazole HPLC High-performance liquid chromatography h hour h hours LC / MS Liquid Chromatography and Mass Spectrometry M Molar MeCN Acetonitrile MeOH methanol Normal N HPLC prep. preparative high-performance liquid chromatography TA ambient temperature sat. saturated THF tetrahydrofuran UPLC Ultra-high performance liquid chromatography Definitions In this application, the following definitions apply, unless otherwise stated. The term "treatment", in connection with the uses of any of the compounds described herein, including those in formulas I, IIa, IIb, IIc, IId, IIe, (1), (1a), (1b), (2), (2a), (2b), (3), (3a), (3b), (4), (4a), (4b), (5), (5a), (5b), (6), (6a), (6b), (7), (7a), (7b), (8), (8a), (8b), (9), (9a), (9b), (10), (10a) and (10b), is used to describe any form of intervention where a compound is administered to a subject who is suffering from, or at risk of suffering from, or is at risk of potential to develop the disease or disorder in question. Therefore, the term "treatment" covers both preventive (prophylactic) treatment and treatment where measurable or detectable symptoms of the disease or disorder are present. The expression "effective therapeutic amount" (e.g., in relation to the compound for use in methods of treating a disease or condition) refers to an amount of the compound that is effective in producing a desired therapeutic effect. For example, if the condition is pain, then the effective therapeutic amount is an amount sufficient to provide a desired level of pain relief. The desired level of pain relief might be, for example, complete elimination of the pain or a reduction in the severity of the pain. As used herein, the term "hydroxyl" or "hydroxy" refers to an -OH group. As used herein, an "alkyl" group refers to a saturated aliphatic hydrocarbon group containing 1-12 (e.g., 1-8, 1-6, or 1-4) carbon atoms. An alkyl group may be linear or branched. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-heptyl, or 2-ethylhexyl. An alkyl group may be substituted (i.e., optionally substituted) with one or more substituents such as halogen, phosphorus, cycloaliphatic (e.g., cycloalkyl or cycloalkenyl), heterocycloaliphatic (e.g., heterocycloalkyl or heterocycloalkenyl), aryl, heteroaryl, alkoxy, aroyl, heteroaroyl, acyl (e.g., chlorophyll ... e.g., (aliphatic) carbonyl, (cycloaliphatic) carbonyl or (heterocycloaliphatic) carbonyl], nitro, cyano, amido [e.g., (cycloalkylalkyl) carbonylamino, arylcarbonylamino, aralkylcarbonylamino, (heterocycloalkyl) carbonylamino, (heterocycloalkylalkyl) carbonylamino, heteroarylcarbonylamino, heteroaralkylcarbonylamino, alkylaminocarbonyl, cycloalkylaminocarbonyl, heterocycloalkylaminocarbonyl, arylaminocarbonyl or heteroarylaminocarbonyl], amino [e.g., aliphatic amino, cycloaliphatic amino or heterocycloaliphatic amino], sulfonyl [e.g., aliphatic-SO2-], sulfinyl, sulfanyl, sulfoxy, urea, thiourea, sulfamoyl, sulfamide, oxo, carboxy, carbamoyl, cycloaliphaticoxy, heterocycloaliphaticoxy, aryloxy, heteroaryloxy, aralkyloxy, heteroarylalkoxy, alkoxycarbonyl, alkylcarbonyloxy or hydroxy.Without limitation, some examples of substituted alkyls include carboxyalkyl (such as HOOC-alkyl, alkoxycarbonylalkyl and alkylcarbonyloxyalkyl), cyanoalkyl, hydroxyalkyl, alkoxyalkyl, acylalkyl, aralkyl, (alkoxyaryl)alkyl, (sulfonylamino)alkyl (such as (alkyl-SO2-amino)alkyl), aminoalkyl, amidoalkyl, (cycloaliphatic)alkyl or haloalkyl. As used herein, an "alkylene" group refers to a branched or linear bivalent alkyl group containing 2–12 (e.g., 2–8, 2–6, or 2–4) carbon atoms and serving to connect two chemical residues. Examples of alkylene groups include, but are not limited to, methylene, ethylene, propylene, butylene, isopropylene (methylethylene), and isobutylene (2-methylpropylene). An alkylene group may be substituted (i.e., optionally replaced) with one or more substituents as defined for the alkyl group. As used herein, an "amido" encompasses both "aminocarbonyl" and "carbonylamino". These terms, when used alone or in relation to another group, refer to an amido group such as -N(RX)-C(O)-RY or -C(O)-N(Rx)2, when used terminally, and -C(O)-N(RX)- or -N(RX)-C(O)- when used internally, wherein Rx and RY may be aliphatic, cycloaliphatic, aryl, araliphatic, heterocycloaliphatic, heteroaryl, or heteroaraliphatic. Examples of amido groups include alkylamido (such as alkylcarbonylamino or alkylaminocarbonyl), (heterocycloaliphatic)amido, (heteroaralkyl)amido, (heteroaryl)amido, (heterocycloalkyl)alkylamido, arylamido, aralkylamido, (cycloalkyl)alkylamido, or cycloalkylamido. As used herein, an "amino" group refers to -NRXRY where each of RX and RY is independently hydrogen, aliphatic, cycloaliphatic, (cycloaliphatic)aliphatic, aryl, araliphatic, heterocycloaliphatic, (heterocycloaliphatic)aliphatic, heteroaryl, carboxy, sulfanyl, sulfinyl, sulfonyl, (aliphatic) carbonyl, (cycloaliphatic) carbonyl, ((cycloaliphatic)aliphatic) carbonyl, arylcarbonyl, (araliphatic) carbonyl, (heterocycloaliphatic) carbonyl, ((heterocycloaliphatic)aliphatic) carbonyl, (heteroaryl) carbonyl, or (heteroaraliphatic) carbonyl, each of which is defined herein and is optionally substituted. Examples of amino groups include alkylamino, dialkylamino, or arylamino. When the term "amino" is not the terminal group (e.g., alkylcarbonylamino), it is represented by -NRX-, where RX has the same meaning as defined above. As used herein, an "aryl" group used alone or as part of a larger moiety as in "aralkyl," "aralkoxy," or "aryloxyalkyl" refers to monocyclic (e.g., phenyl), bicyclic (e.g., indenyl, naphthalenyl, tetrahydronaphthyl, tetrahydroindenyl), and tricyclic (e.g., fluorenyl, tetrahydrofluorenyl, tetrahydroanthracenyl, anthracenyl) ring systems in which the monocyclic ring system is aromatic or at least one of the rings in a bicyclic or tricyclic ring system is aromatic. Bicyclic and tricyclic groups include benzocondensed 2-3 membered carbocyclic rings. For example, a benzocondensed group includes phenyl condensed with two or more C4-8 carbocyclic moieties. An aryl group is optionally substituted with one or more substituents, including aliphatic [e.g., alkyl, alkenyl or alkynyl]; cycloaliphatic; (cycloaliphatic) aliphatic; heterocycloaliphatic; (heterocycloaliphatic) aliphatic; aryl; heteroaryl; alkoxy; (cycloaliphatic) oxy; (heterocycloaliphatic) oxy; aryloxy; heteroaryloxy; (araliphatic) oxy; (heteroaraliphatic) oxy; aroyl; heteroaroyl; amino; oxo (in a non-aromatic carbocyclic ring of a benzocondensed bicyclic or tricyclic aryl); nitro; carboxy; amido; acyl [e.g., (aliphatic) carbonyl; (cycloaliphatic) carbonyl; ((cycloaliphatic) aliphatic) carbonyl; (araliphatic) carbonyl; (heterocycloaliphatic) carbonyl; ((heterocycloaliphatic) aliphatic) carbonyl; or (heteroaraliphatic) carbonyl]; sulfonyl [e.g., aliphatic-SO2- or amino-SO2-]; sulfinil [e.g., aliphatic-S(O)- or cycloaliphatic-S(O)-]; sulfanyl [e.g., aliphatic-S-]; cyano; halogen; hydroxy; mercapto; sulfoxy; urea; thiourea; sulfamoyl; sulfamide; or carbamoyl. Alternatively, an aryl group may be unsubstituted. Non-limiting examples of substituted aryls include haloaryl [e.g., mono, di (such as p, m-dihaloaryl), and (trihalo)aryl]; (carboxy)aryl [e.g., (alkoxycarbonyl)aryl, ((aralkyl)carbonyloxy)aryl, and (alkoxycarbonyl)aryl]; (amido)aryl [e.g., (aminocarbonyl)aryl, (((alkylamino)alkyl)aminocarbonyl)aryl, (alkylcarbonyl)aminoaryl, (arylaminocarbonyl)aryl, and (((heteroaryl)amino)carbonyl)aryl]; aminoaryl [e.g., ((alkylsulfonyl)amino)aryl or ((dialkyl)amino)aryl]; (cyanoalkyl)aryl; (alkoxy)aryl; (sulfamoyl)aryl [e.g. e.g., (aminosulfonyl) aryl]; (alkylsulfonyl) aryl; (cyano) aryl; (hydroxyalkyl) aryl; ( (alkoxy) alkyl) aryl; (hydroxy) aryl, ( (carboxy) alkyl) aryl; ( ( (dialkyl) amino) alkyl) aryl; (nitroalkyl) aryl; ( ( (alkylsulfonyl) amino) alkyl) aryl; ( (heterocycloaliphatic) carbonyl) aryl; ( (alkylsulfonyl) alkyl) aryl; (cyanoalkyl) aryl; (hydroxyalkyl) aryl; (alkylcarbonyl) aryl; alkylaryl; (trihaloalkyl) aryl; p-amino-m-alkoxycarbonyl aryl; p-amino-m-cyanoaryl; p-halo-m-aminoaryl; or (m- (heterocycloaliphatic) - o- (alkyl) ) aryl. As used herein, a "cycloalkyl" group refers to a saturated (condensed or bridged) mono- or bicyclic carbocyclic ring of 3–10 (e.g., 5–10) carbon atoms. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, norbornyl, cubyl, octahydroindenyl, decahydronaphthyl, bicyclo[3.2.1]octyl, bicyclo[2.2.2]octyl, bicyclo[3.3.1]nonyl, bicyclo[3.3.2]decyl, bicyclo[2.2.2]octyl, adamantyl, or (aminocarbonyl)cycloalkyl. A cycloalkyl group may be optionally substituted with one or more substituents such as phosphorus, aliphatic [e.g., alkyl, alkenyl, or alkynyl], cycloaliphatic, (cycloaliphatic)aliphatic, heterocycloaliphatic, (heterocycloaliphatic)aliphatic, aryl, heteroaryl, alkoxy, (cycloaliphatic)oxy, (heterocycloaliphatic)oxy, aryloxy, heteroaryloxy, (araliphatic)oxy, (heteroaraliphatic)oxy, aroyl, heteroaroyl, amino, amido [e.g. e.g., (aliphatic) carbonylamino, (cycloaliphatic) carbonylamino, ((cycloaliphatic) aliphatic) carbonylamino, (aryl) carbonylamino, (araliphatic) carbonylamino, (heterocycloaliphatic) carbonylamino, ((heterocycloaliphatic) aliphatic) carbonylamino, (heteroaryl) carbonylamino, or (heteroaraliphatic) carbonylamino], nitro, carboxy [e.g., HOOC-, alkoxy carbonyl, or alkylcarbonyloxy], acyl [e.g., (cycloaliphatic) carbonyl, ( (cycloaliphatic) aliphatic) carbonyl, (araliphatic) carbonyl, (heterocycloaliphatic) carbonyl, ( (heterocycloaliphatic) aliphatic) carbonyl, or (heteroaraliphatic) carbonyl], cyano, halogen, hydroxy, mercapto, sulfonyl [e.g., alkyl-SO2- and aryl-SO2-], sulfinil [e.g., alkyl-S (O) -], sulfanyl [e.g., alkyl-S-], sulfoxy, urea, thiourea, sulfamoyl, sulfamide, oxo, or carbamoyl. As used herein, a "heterocycloalkyl" group refers to a 3-10 membered mono- or bicyclic (condensed or bridged) saturated ring structure (e.g., 5- or 10 membered mono- or bicyclic), wherein one or more of the ring atoms is a heteroatom (e.g., N, O, S, or combinations thereof). Examples of a heterocycloalkyl group include piperidyl, piperazyl, tetrahydropyranyl, tetrahydrofuryl, 1,4-dioxolanyl, 1,4-dithianyl, 1,3-dioxolanyl, oxazolidyl, isoxazolidyl, morpholinyl, thiomorpholyl, octahydrobenzofuryl, octahydrochromenyl, octahydrothiochromenyl, octahydroindolyl, octahydropyrindinyl, decahydroquinolinyl, octahydrobenzo[b]thiophenyl, 2-oxa-bicyclo[2.2.2]octyl, 1-aza-bicyclo[2.2.2]octyl, 3-azabicyclo[3.2.1]octyl, and 2,6-dioxa-tricyclo[3.3.1.03,7]nonyl.A monocyclic heterocycloalkyl group can be condensed with a phenyl moiety to form structures, such as tetrahydroisoquinoline, which would be classified as heteroaryls. A heterocycloalkyl group may be optionally substituted with one or more substituents such as phosphorus, aliphatic [e.g., alkyl, alkenyl, or alkynyl], cycloaliphatic, (cycloaliphatic)aliphatic, heterocycloaliphatic, (heterocycloaliphatic)aliphatic, aryl, heteroaryl, alkoxy, (cycloaliphatic)oxy, (heterocycloaliphatic)oxy, aryloxy, heteroaryloxy, (araliphatic)oxy, (heteroaraliphatic)oxy, aroyl, heteroaroyl, amino, amido [e.g. e.g., (aliphatic) carbonylamino, (cycloaliphatic) carbonylamino, ((cycloaliphatic) aliphatic) carbonylamino, (aryl) carbonylamino, (araliphatic) carbonylamino, (heterocycloaliphatic) carbonylamino, ((heterocycloaliphatic) aliphatic) carbonylamino, (heteroaryl) carbonylamino or (heteroaraliphatic) carbonylamino], nitro, carboxy [e.g., HOOC-, alkoxycarbonyl, or alkylcarbonyloxy], acyl [e.g., (cycloaliphatic) carbonyl, ( (cycloaliphatic) aliphatic) carbonyl, (araliphatic) carbonyl, (heterocycloaliphatic) carbonyl, ( (heterocycloaliphatic) aliphatic) carbonyl, or (heteroaraliphatic) carbonyl], nitro, cyano, halogen, hydroxy, mercapto, sulfonyl [e.g., alkylsulfonyl or arylsulfonyl], sulfinil [e.g., alkylsulfinyl], sulfanyl [e.g., alkylsulfanyl], sulfoxy, urea, thiourea, sulfamoyl, sulfamide, oxo or carbamoyl. A "heteroaryl" group, as used herein, refers to a monocyclic, bicyclic, or tricyclic ring system having 4 to 15 ring atoms, wherein one or more of the ring atoms is a heteroatom (e.g., N, O, S, or combinations thereof), and wherein the monocyclic ring system is aromatic, or at least one of the rings in the bicyclic or tricyclic ring systems is aromatic. A heteroaryl group includes a system of benzocondensed rings containing 2 to 3 rings. For example, a group of benzocondensates includes benzo condensed with one or two heterocycloaliphatic residues of 4 to 8 members (p. ej., indolizilo, indolilo, isoindolilo, 3H-indolilo, indolinilo, benzo[b]furilo, benzo[b]thiofenilo, quinolinilo or isoquinolinilo). Some examples of heteroarilo son azetidinilo, piridilo, 1H-indazolilo, furilo, pirrolilo, tienilo, tiazolilo, oxazolilo, imidazolilo, tetrazolilo, benzofurilo, isoquinolinilo, benzotiazolilo, xanteno, tioxanteno, fenotiazina, dihidroindol, benzo[1, 3]dioxol, benzo[b]furilo, benzo[b]tiofenilo, indazolilo, bencimidazolilo, benzotiazolilo, purilo, cinolilo, quinolilo, quinazolilo, cinolilo, ftalazilo, quinazolilo, quinoxalilo, isoquinolilo, 4H-quinolizilo, benzo-1, 2, 5-tiadiazolilo, o 1, 8-naftiridilo. A heteroaryl group includes heteroaryl N-oxide compounds, such as pyridine, pyrimidine, pyrazine, pyrrole, imidazole, thyzol, quinoline, or isoquinoline, which are oxidized at the nitrogen atom. An example of a heteroaryl N-oxide is pyridine N-oxide with the formula C5H5N-O+. Without limitation, monocyclic heteroaryls include furyl, thiophene-yl, 2H-pyrrolyl, pyrrolyl, oxazolyl, tazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, 1, 3, 4-thiadiazolyl, 2H-pyranyl, 4-H-pranyl, pyridyl, pyridazolyl pyrimidyl, pyrazolyl, pyrazyl or 1, 3, 5-triazil. Monocyclic heteroaryls are numbered according to conventional chemical nomenclature. Without limitation, the bicyclic heteroaryls include indolyl, indolyl, isoindolyl, 3H-indolyl, indolynyl, benzo[b]furyl, benzo[b]thiophenyl, quinolynyl, isoquinolinyl, indolylyl, isoindolyl, indolyl, benzo[bixofuryl, biophenyl,[] indazolyl, benzimidazyl, benzothiazolyl, purinyl, 4H-quinolyl, quinolyl, isoquinolyl, cinolyl, phthalazyl, quinazolyl, quinoxalyl, 1, 8-naphthyridyl or pteridyl. Bicyclic heteroaryls are numbered according to conventional chemical nomenclature. A heteroaryl group is optionally substituted with one or more substituents such as aliphatic [e.g., alkyl, alkenyl, or alkynyl]; cycloaliphatic; (cycloaliphatic)aliphatic; heterocycloaliphatic; (heterocycloaliphatic)aliphatic; aryl; heteroaryl; alkoxy; (cycloaliphatic)oxy; (heterocycloaliphatic)oxy; aryloxy; heteroaryloxy; (araliphatic)oxy; (heteroaraliphatic)oxy; aroyl; heteroaroyl; amino; oxo (on a carbocyclic or non-aromatic heterocyclic ring of a bicyclic or tricyclic heteroaryl group); carboxy; amido; acyl [e.g., aliphatic carbonyl; (cycloaliphatic) carbonyl; (cycloaliphatic) aliphatic) carbonyl; (araliphatic) carbonyl; (heterocycloaliphatic) carbonyl; ( (heterocycloaliphatic) aliphatic) carbonyl; or (heteroaraliphatic) carbonyl]; sulfonyl [e.g., aliphatic sulfonyl or aminosulfonyl]; sulfinyl [e.g., aliphatic sulfinyl]; sulfanyl [e.g.[aliphatic sulfanyl]; nitro; cyano; halogen; hydroxy; mercapto; sulfoxy; urea; thiourea; sulfamoyl; sulfamide; or carbamoyl. Alternatively, a heteroaryl may be unsubstituted. Non-limiting examples of substituted heteroaryls include (halo)heteroaryl [e.g., mono- and di-(halo)heteroaryl]; (carboxy)heteroaryl [e.g., (alkoxycarbonyl)heteroaryl]; cyanoheteroaryl; aminoheteroaryl [e.g., ((alkylsulfonyl)amino)heteroaryl and ((dialkyl)amino)heteroaryl]; (amido)heteroaryl [e.g., aminocarbonylheteroaryl, ((alkylcarbonyl)amino)heteroaryl, (((alkyl)amino)alkyl)aminocarbonyl)heteroaryl, (((heteroaryl)amino)carbonyl)heteroaryl, ((heterocycloaliphatic)carbonyl)heteroaryl, and ((alkylcarbonyl)amino)heteroaryl]; (cyanoalkyl)heteroaryl; (alkoxy)heteroaryl; (sulfamoyl)heteroaryl [e.g. e.g., (aminosulfonyl)heteroaryl]; (sulfonyl)heteroaryl [e.g. e.g.[(alkylsulfonyl) heteroaryl]; (hydroxyalkyl) heteroaryl; (alkoxyalkyl) heteroaryl; (hydroxy) heteroaryl; ((carboxy)alkyl) heteroaryl; (((dialkyl)amino)alkyl]heteroaryl; (heterocycloaliphatic) heteroaryl; (cycloaliphatic) heteroaryl; (nitroalkyl) heteroaryl; (((alkylsulfonyl)amino)alkyl) heteroaryl; ((alkylsulfonyl)alkyl) heteroaryl; (cyanoalkyl) heteroaryl; (acyl) heteroaryl [e.g., (alkylcarbonyl) heteroaryl]; (alkyl) heteroaryl; or (haloalkyl) heteroaryl [e.g., trihaloalkylheteroaryl]. As used herein, an "alkoxy" group refers to an alkyl-O- group where "alkyl" has been previously defined. As used herein, a "carboxy" group refers to -COOH, -COORX, -OC(O)H, -OC(O)RX, when used as a terminal group; or -OC(O) or -C(O)O- when used as an internal group. As used herein, a "mercapto" group refers to -SH. As used herein, a "sulfo" group refers to -SO3H or -SO3Rx when used terminally or -S(O)3- when used internally. As used herein, a "sulfamide" group refers to the structure -NRX-S(O)2-NRYRZ when used terminally and -NRX-S(O)2-NRY- when used internally, wherein RX, RY, and RZ have been defined above. As used herein, a "sulfamoyl" group refers to the structure -OS(O)2-NRYRZ where RY and RZ have been defined above. As used herein, a "sulfonamide" group refers to the structure -S(O)2-NRXRY or -NRX-S(O)2-RZ when used terminally; or -S(O)2-NRX- or -NRX-S(O)2- when used internally, wherein Rx, Ry, and Rz are defined above. As used herein, a "sulfanyl" group refers to -S-RX when used terminally and -S- when used internally, where Rx has been defined above. Examples of sulfanyls include aliphatic-S-, cycloaliphatic-S-, aryl-S-, or similar groups. As used herein, a "halogen" or "halo" group refers to fluorine, chlorine, bromine, or iodine. As used herein, an "oxo" refers to =O. As used herein, the term "neighborly" generally refers to the position of substituents in a group that includes two or more carbon atoms, where the substituents are attached to adjacent carbon atoms. As used herein, the term "geminal" generally refers to the position of substituents in a group that includes two or more carbon atoms, where the substituents are attached to the same carbon atom. The terms "terminally" and "internally" refer to the position of a group within a substituent. A group is terminal when it is located at the end of the substituent and is not further attached to the rest of the chemical structure. The carboxyalkyl group, i.e., RXO(O)C-alkyl, is an example of a carboxy group used terminally. A group is internal when it is located in the middle of a substituent within the chemical structure. Alkylcarboxyl groups (e.g., alkyl-C(O)O- or alkyl-OC(O)-) and alkylcarboxyaryl groups (e.g., alkyl-C(O)O-aryl- or alkyl-O(CO)-aryl-) are examples of carboxyl groups used internally. As used herein, an "aliphatic chain" refers to a branched or linear aliphatic group (e.g., alkyl groups, alkenyl groups, or alkynyl groups). A linear aliphatic chain has the structure -[CH2]v-, where v is 1-12.A branched aliphatic chain is a linear aliphatic chain that is substituted with one or more aliphatic groups. A branched aliphatic chain has the structure -[CQQ]v- where Q is either hydrogen or an aliphatic group; however, Q will be an aliphatic group in at least one case. The term aliphatic chain includes alkyl chains, alkenyl chains, and alkynyl chains, where alkyl, alkenyl, and alkynyl have been defined previously. The phrase "optionally substituted" is used interchangeably with "substituted or unsubstituted" herein. As described herein, the compounds of the invention may be optionally substituted with one or more substituents, as generally illustrated above, or as exemplified by particular classes, subclasses, and species of the invention. Unless otherwise stated, each of the groups specific to the variables indicated herein may be optionally substituted with one or more substituents described herein. Each substituent of a specific group is further optionally substituted with one to three of the following groups: halogen, cyano, oxo, alkoxy, hydroxy, amino, nitro, aryl, cycloaliphatic, heterocycloaliphatic, heteroaryl, haloalkyl, and alkyl.For example, an alkyl group can be substituted with alkylsulfanyl, and the alkylsulfanyl can be optionally substituted with one to three halogen, cyano, oxo, alkoxy, hydroxy, amino, nitro, aryl, haloalkyl, and alkyl groups. As a further example, the cycloalkyl portion of a (cycloalkyl)carbonylamino can be optionally substituted with one to three halogen, cyano, alkoxy, hydroxy, nitro, haloalkyl, and alkyl groups. When two alkoxy groups are attached to the same atom or adjacent atoms, the two alkoxy groups can form a ring together with the atom(s) to which they are attached. As used herein, the term "substituted," whether or not preceded by "optionally," generally refers to the substitution of hydrogen atoms in a given structure by the radical of a specified substituent. Specific substituents are described earlier in the definitions and later in the descriptions of compounds and examples thereof. Unless otherwise stated, an optionally substituted group may have a substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be the same or different at each position. A ring substituent, such as a heterocycloalkyl, may be attached to another ring, such as a cycloalkyl, to form a spirobicyclic ring system, for example, with both rings sharing a common atom.As a person skilled in the art will recognize, the combinations of substituents provided for by this invention are those combinations that result in the formation of stable or chemically feasible compounds. As used herein, the phrase "stable or chemically feasible" refers to compounds that do not substantially change when subjected to conditions that permit their production, detection, and preferably their recovery, purification, and use for one or more of the purposes described herein. In some embodiments, a stable or chemically feasible compound is one that does not substantially change when maintained at a temperature of 40°C or lower, in the absence of moisture or other chemically reactive conditions, for at least one week. To the extent that any of the described compounds have chiral centers, the present invention extends to all optical isomers of said compounds, whether in the form of racemates or resolved enantiomers. The invention described herein relates to all crystalline forms, solvates, and hydrates of any of the described compounds, regardless of how they are prepared. To the extent that any of the described compounds have acidic or basic centers such as carboxylate or amino groups, then all salt forms of said compounds are included herein. For pharmaceutical uses, the salt shall be considered to be a pharmaceutically acceptable salt. Pharmaceutically acceptable salts include acid addition salts and base addition salts. Such salts can be formed by conventional means, for example, by reacting a free acid or free base form of a compound with one or more equivalents of an appropriate acid or base, optionally in a solvent or medium in which the salt is insoluble, followed by removal of the solvent or medium using conventional techniques (e.g., vacuum distillation, freeze-drying, or filtration). Salts can also be prepared by exchanging a counterion of a compound in the form of a salt with another counterion, for example, using a suitable ion-exchange resin. Examples of pharmaceutically acceptable salts include acid addition salts derived from mineral acids and organic acids, and salts derived from metals such as sodium, magnesium, potassium, and calcium. Examples of acid addition salts include acid addition salts formed with acetic, 2,2-dichloroacetic, adipic, alginic, arylsulfonic acids (e.g., benzenesulfonic, naphthalene-2-sulfonic, naphthalene-1,5-disulfonic, and p-toluenesulfonic), ascorbic acids (e.g., L-ascorbic), L-aspartic, benzoic, 4-acetamidobenzoic, butanoic, (+) camphoric, camphorsulfonic, (+)-(1S)-camphor-10-sulfonic, capric, caproic, aprilic, cinnamic, citric, cyclamic, dodecylsulfuric, ethane-1,2-disulfonic, ethanesulfonic, 2-hydroxyethanesulfonic, formic, fumaric, galactaric, gentisic, glucoheptonic, gluconic (e.g., D-gluconic), glucuronic (e.g., D-glucuronic), glutamic (e.g., L-glutaric), -oxoglutaric, glycolic, hippuric, bromhydric, hydrochloric, iodidric, isethionic, lactic (e.g., (+) -L-lactic and (±) -DL-lactic), lactobionic, maleic, malic (e.g.(-) -L-malic) , malonic, (±) -DL-mandelic, metaphosphoric, methanesulfonic, 1-hydroxynaphthoic, nicotinic, nitric, oleic, orotic, oxalic, palmitic, pamoic, phosphoric, propionic, L-pyroglutamic, salicylic, 4-aminosalicylic, sebacic, stearic, succinic, sulfuric, tannic, tartaric (e.g., (+) -L-tartaric) , thiocyanic, undecylenic and valeric. This also includes any solvate of the compounds and their salts. Preferred solvates are those formed by incorporating molecules of a pharmaceutically acceptable, non-toxic solvent (referred to hereafter as the solvation solvent) into the solid-state structure (e.g., crystalline structure) of the compounds of the invention. Examples of such solvents include water, alcohols (such as ethanol, isopropanol, and butanol), and dimethyl sulfoxide. Solvates can be prepared by recrystallizing the compounds of the invention with a solvent or solvent mixture containing the solvation solvent. Whether or not a solvate has formed in any given case can be determined by subjecting the crystals of the compound to analysis using conventional and well-known techniques, such as thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), and X-ray crystallography. Solvates can be stoichiometric or non-stoichiometric. Particular solvates can be hydrates, and examples of hydrates include hemihydrates, monohydrates, and dihydrates. For a more detailed discussion of solvates and the methods used to prepare and characterize them, see Bryn et al., Solid-State Chemistry of Drugs, second edition, published by SSCI, Inc. of West Lafayette, IN, USA, 1999, ISBN 0-967-06710-3. The term "pharmaceutical composition" in the context of this invention means a composition comprising an active agent and further comprising one or more pharmaceutically acceptable vehicles or excipients. The composition may further contain ingredients selected from, for example, diluents, adjuvants, excipients, vehicles, preservatives, fillers, disintegrating agents, wetting agents, emulsifying agents, suspending agents, sweetening agents, flavoring agents, perfuming agents, antibacterial agents, antifungal agents, lubricating agents, and dispersing agents, depending on the nature of the mode of administration and the pharmaceutical forms.The compositions may take the form, for example, of tablets, coated tablets, powders, elixirs, syrups, liquid preparations, including suspensions, aerosols, inhalants, lozenges, tablets, pastilles, emulsions, solutions, seals, granules, capsules and suppositories, as well as liquid preparations for injection, including liposomal preparations. The compounds of the invention may contain one or more isotopic substitutions, and a reference to a particular element includes within its scope all isotopes of that element. For example, a reference to hydrogen includes within its scope 1H, 2H(D), and 3H(T). Similarly, references to carbon and oxygen include within their scope, respectively 12C, 13C, and 14C, and 16O and 18O. Analogously, a reference to a particular functional group also includes within its scope isotopic variations, unless the context indicates otherwise. For example, a reference to an alkyl group, such as an ethyl group, or an alkoxy group, such as a methoxy group, also covers variations in which one or more of the hydrogen atoms of the group are in the form of an isotope of deuterium or tritium, e.g., as in an ethyl group in which the five hydrogen atoms are in the deuterium isotopic form (a perdeuteroethyl group) or a methoxy group in which the three hydrogen atoms are in the deuterium isotopic form (a trideuteromethoxy group). Isotopes can be radioactive or non-radioactive. Therapeutic doses may vary depending on the patient's needs, the severity of the condition being treated, and the compound being used. Determining the appropriate dose for a particular situation is a matter of expertise. Generally, treatment begins with the smallest doses, which are lower than the optimal dose of the compound. The dose is then increased in small increments until the optimal effect is achieved under the given circumstances. For convenience, the total daily dose may be divided and administered in portions throughout the day if desired. The magnitude of an effective dose of a compound will, of course, vary with the nature and severity of the condition being treated, as well as with the specific compound and its route of administration. Selecting appropriate doses is within the competence of a skilled practitioner, without placing an undue burden on them.In general, the daily dose range can be from approximately 10 µg to approximately 30 mg per kg of body weight of a human and non-human animal, preferably from approximately 50 µg to approximately 30 mg per kg of body weight of a human and non-human animal, for example from approximately 50 µg to approximately 10 mg per kg of body weight of a human and non-human animal, for example from approximately 100 µg to approximately 30 mg per kg of body weight of a human and non-human animal, for example from approximately 100 µg to approximately 10 mg per kg of body weight of a human and non-human animal, and most preferably from approximately 100 µg to approximately 1 mg per kg of body weight of a human and non-human animal. Combination therapy An effective quantity can be achieved in the pharmaceutical method or composition of the invention by employing a compound of the invention (including a pharmaceutically acceptable salt or solvate (e.g., hydrate)) alone or in combination with an additional suitable therapeutic agent, for example, an antiviral agent or a vaccine. When a "combination therapy" is employed, an effective quantity can be achieved by using a first quantity of a compound of the invention and a second quantity of an additional suitable therapeutic agent. In another embodiment of this invention, a compound of the invention and the additional therapeutic agent are each administered in an effective quantity (i.e., each in a quantity that would be therapeutically effective if administered alone). In another embodiment, a compound of the invention and the additional therapeutic agent are each administered in a quantity that alone does not provide a therapeutic effect (a subtherapeutic dose).In another embodiment, a compound of the invention can be administered in an effective amount, while the additional therapeutic agent is administered in a subtherapeutic dose. In yet another embodiment, a compound of the invention can be administered in a subtherapeutic dose, while the additional therapeutic agent, for example, a suitable anticancer agent, is administered in an effective amount. As used herein, the terms "in combination" or "co-administration" may be used interchangeably to refer to the use of more than one therapy (e.g., one or more prophylactic and / or therapeutic agents). The use of these terms does not restrict the order in which the therapies (e.g., prophylactic and / or therapeutic agents) are administered to a subject. Co-administration encompasses the administration of the first and second quantities of the co-administered compounds in an essentially simultaneous manner, such as in a single pharmaceutical composition, for example, a capsule or tablet containing a fixed ratio of the first and second quantities, or in multiple separate capsules or tablets for each compound. Furthermore, such co-administration also encompasses the sequential use of each compound in any order. In one embodiment, a compound of the invention and an additional therapeutic agent are administered separately, sequentially, or simultaneously to the subject. When co-administration involves the separate administration of the first quantity of a compound of the invention and a second quantity of an additional therapeutic agent, the compounds are administered close enough in time to produce the desired therapeutic effect. For example, the time interval between each administration that can result in the desired therapeutic effect may vary from minutes to hours and can be determined by considering the properties of each compound, such as potency, solubility, bioavailability, plasma half-life, and kinetic profile. For example, a compound of the invention and the second therapeutic agent may be administered in any order with a 24-hour, 16-hour, 8-hour, 4-hour, 1-hour, or 30-minute interval between them. More specifically, a first therapy (e.g., a prophylactic or therapeutic agent such as a compound of the invention) can be administered before (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 ​​hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks before), concomitantly with, or after (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 ​​hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks after) the administration of a second therapy (e.g., a prophylactic or therapeutic agent such as an anticancer agent) to a subject. It is understood that the method of co-administration of a first quantity of a compound of the invention and a second quantity of an additional therapeutic agent may result in an enhanced or synergistic therapeutic effect, wherein the combined effect is greater than the additive effect that would result from the separate administration of the first quantity of a compound of the invention and the second quantity of an additional therapeutic agent. As used herein, the term "synergistic" refers to a combination of a compound of the invention and another therapy (e.g., a prophylactic or therapeutic agent) that is more effective than the additive effects of the therapies. A synergistic effect of a combination of therapies (e.g., a combination of prophylactic or therapeutic agents) may permit the use of lower doses of one or more of the therapies and / or less frequent administration of such therapies to a subject. The ability to use lower doses of a therapy (e.g., a prophylactic or therapeutic agent) and / or to administer such therapy less frequently may reduce the toxicity associated with administering such therapy to a subject without reducing the efficacy of such therapy in the prevention, management, or treatment of a disorder. Furthermore, a synergistic effect may result in enhanced efficacy of the agents in the prevention, management, or treatment of a disorder.Finally, a synergistic effect of a combination of therapies (e.g., a combination of prophylactic or therapeutic agents) may avoid or reduce adverse or unwanted side effects associated with the use of any of the therapies alone. The presence of a synergistic effect can be determined using appropriate methods for evaluating drug interactions. Suitable methods include, for example, the Sigmoid Emax equation (Holford, NHG and Scheiner, LB, Clin. Pharmacokinet. 6: 429-453 (1981)), the Loewe additivity equation (Loewe, S. and Muischnek, H., Arch. Exp. Pathol Pharmacol. 114: 313-326 (1926)), and the median effect equation (Chou, TC and Talalay, P., Adv. Enzyme Regul. 22: 27-55 (1984)). Each of the above equations can be applied with experimental data to generate a corresponding graph that helps evaluate the effects of the drug combination. The corresponding graphs associated with the equations mentioned above are the concentration-effect curve, the isobologram curve, and the combination index curve, respectively. In one aspect, the invention provides a pharmaceutical composition comprising a pharmaceutically acceptable compound, salt, solvate, hydrate, tautomer, or optical isomer of the invention, a pharmaceutically acceptable excipient, and at least one additional therapeutic agent. In some embodiments, the pharmaceutically acceptable compound, salt, solvate, hydrate, tautomer, or optical isomer of the invention, and the at least one additional therapeutic agent are formulated together. In some embodiments, the pharmaceutically acceptable compound, salt, solvate, hydrate, tautomer, or optical isomer of the invention, and the at least one additional therapeutic agent are formulated separately. In another aspect, the invention provides a kit comprising a pharmaceutically acceptable compound, salt, solvate, hydrate, tautomer, or optical isomer of the invention and at least one additional therapeutic agent. The kit may include instructions for administering the pharmaceutically acceptable compound, salt, solvate, hydrate, tautomer, or optical isomer of the invention and the at least one additional therapeutic agent to a subject in need. In another aspect, the invention provides a combination therapy for use as a medicament, wherein the combination therapy comprises administering a pharmaceutically acceptable compound, salt, solvate, hydrate, tautomer, or optical isomer of the invention to a subject in need and administering an additional therapeutic agent to the subject in need. The pharmaceutically acceptable compound, salt, solvate, hydrate, tautomer or optical isomer of the invention and the additional therapeutic agent can be administered to the subject separately, sequentially or simultaneously. The pharmaceutical composition, kit and / or combination therapy may be used in the treatment of a gastrointestinal disorder or a pulmonary disease or condition.The gastrointestinal disorder can be selected from the group consisting of constipation disorders, irritable bowel syndrome with predominant constipation, mixed type irritable bowel syndrome, chronic idiopathic constipation, gastrointestinal symptoms associated with Parkinson's disease, gastrointestinal symptoms associated with cystic fibrosis, intestinal dysmotility, postoperative ileus, food allergy or intolerance, celiac disease, gastrointestinal motility disorders, functional gastrointestinal disorders, drug-induced enteropathy, NSAID-induced gastric and intestinal injury, chemotherapy-induced mucositis, gastroesophageal reflux disease (GERD), duodenogastric reflux, diarrheal diseases, immune-mediated gastrointestinal diseases, Crohn's disease, ulcerative colitis, inflammatory bowel disease, and ischemic colitis.The pulmonary disease or condition may be selected from the group consisting of chronic obstructive pulmonary diseases, asthma, chronic bronchitis, cystic fibrosis, emphysema, chronic idiopathic cough, hyperactive airway disorder, and idiopathic pulmonary fibrosis. At least one additional therapeutic agent may be selected from the group consisting of aminosalicylates, corticosteroids, immunomodulators, and combinations thereof. Aminosalicylates are also known as 5-aminosalicylates (5-ASA). The at least one additional therapeutic agent may be an aminosalicylate. The aminosalicylate may be mesalamine. The aminosalicylate may be sulfasalazine. The at least one additional therapeutic agent may be a corticosteroid. The corticosteroid may be budesonide. The at least one additional therapeutic agent may be an immunomodulator. The immunomodulator may be thiopurine. The immunomodulator may be methotrexate. Pharmaceutical compositions Although it is possible to administer the active compound alone, it is preferable to present it as a pharmaceutical composition (e.g., formulation). Accordingly, in another embodiment of the invention, a pharmaceutical composition is provided comprising at least one compound of formula (1) as defined above together with at least one pharmaceutically acceptable excipient. When the pharmaceutical composition comprises at least one additional therapeutic agent, the compound of the invention and the at least one additional therapeutic agent may be co-formulated or the compound of the invention and the at least one additional therapeutic agent may be formulated separately. The composition may be a tablet composition. The composition may be a composition in capsules. The pharmaceutically acceptable excipient(s) may be selected from, for example, vehicles (e.g., a solid, liquid, or semi-solid vehicle), adjuvants, diluents (e.g., solid diluents such as fillers or bulking agents; and liquid diluents such as solvents and co-solvents), granulating agents, binders, flow agents, coating agents, release control agents (e.g., polymers or waxes that retard or delay release), binding agents, disintegrants, buffering agents, lubricants, preservatives, antifungal and antibacterial agents, antioxidants, buffering agents, tonicity-adjusting agents, thickening agents, flavoring agents, sweeteners, pigments, plasticizers, flavor-masking agents, stabilizers, or any other excipient conventionally used in pharmaceutical compositions. The term "pharmaceutically acceptable," as used herein, means compounds, materials, compositions, and / or dosage forms that, to the best of medical judgment, are suitable for use in contact with the tissues of a subject (e.g., a human subject) without undue toxicity, irritation, allergic response, or other problems or complications, in proportion to a reasonable benefit-risk ratio. Each excipient must also be "acceptable" in the sense of being compatible with the other ingredients of the formulation. Pharmaceutical compositions containing compounds of formula (1) can be formulated according to known techniques, see, for example, Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, PA, USA. Pharmaceutical compositions may be in any form suitable for oral, parenteral, topical, intranasal, intrabronchial, sublingual, ophthalmic, otic, rectal, intravaginal, or transdermal administration. Pharmaceutical forms suitable for oral administration include tablets (coated or uncoated), capsules (hard or soft), oblong tablets, pills, lozenges, syrups, solutions, powders, granules, elixirs, and suspensions, sublingual tablets, wafers, or patches such as buccal patches. Tablet compositions may contain a unit dosage of the active compound together with a diluent or inert vehicle, such as a sugar or sugar alcohol, e.g., lactose, sucrose, sorbitol, or mannitol; and / or a non-sugar-derived diluent, such as sodium carbonate, calcium phosphate, calcium carbonate, or a cellulose or cellulose derivative, such as microcrystalline cellulose (MCC), methylcellulose, hydroxypropyl methylcellulose, and starches such as corn starch. The tablets may also contain conventional ingredients such as binding and granulating agents such as polyvinylpyrrolidone, disintegrants (e.g., swellable crosslinked polymers such as crosslinked carboxymethylcellulose), lubricating agents (e.g., stearates), preservatives (e.g., parabens), antioxidants (e.g., BHT), buffering agents (e.g., phosphate or citrate buffers) and effervescent agents such as citrate / bicarbonate mixtures.These excipients are well known and do not need to be discussed in detail here. Tablets can be designed to release the drug upon contact with gastric fluids (immediate-release tablets) or to release it in a controlled manner (controlled-release tablets) over a prolonged period or to a specific region of the GI tract. The pharmaceutical compositions typically comprise from approximately 1% (w / w) to approximately 95%, preferably % (w / w) of active ingredient and from 99% (w / w) to 5% (w / w) of a pharmaceutically acceptable excipient (e.g., as defined above) or a combination of such excipients. Preferably, the compositions comprise from approximately 20% (w / w) to approximately 90% (w / w) of active ingredient and from 80% (w / w) to 10% of a pharmaceutical excipient or combination of excipients. The pharmaceutical compositions comprise from approximately 1% to approximately 95%, preferably from approximately 20% to approximately 90%, of active ingredient. The pharmaceutical compositions according to the invention may be, for example, in unit-dose form, such as in the form of ampoules, vials, suppositories, pre-filled syringes, coated tablets, powders, caplets, or capsules. Tablets and capsules may contain, for example, 0–20% disintegrants, 0–5% lubricants, 0–5% flow aids, and / or 0–99% (w / w) fillers or bulking agents (depending on the drug dosage). They may also contain 0–10% (w / w) polymeric binders, 0–5% (w / w) antioxidants, and 0–5% (w / w) pigments. Slow-release tablets typically also contain 0–99% (w / w) release-controlling (e.g., retarding) polymers (depending on the dosage). Tablet or capsule film coatings typically contain 0–10% (w / w) polymers, 0–3% (w / w) pigments, and / or 0–2% (w / w) plasticizers. Parenteral formulations typically contain 0-20% (w / w) buffers, 0-50% (w / w) co-solvents, and / or 0-99% (w / w) water for injection (WFI) (depending on the dose and whether they are lyophilized). Intramuscular depot formulations may also contain 0-99% (w / w) oils. Pharmaceutical formulations may be presented to a patient in "patient packs" that contain a complete course of treatment in a single package, usually a blister pack. Compounds of formula (1) will generally be presented in unit dosage form and, as such, will typically contain sufficient compound to provide a desired level of biological activity. For example, a formulation may contain from 1 nanogram to 2 grams of active ingredient, e.g., from 1 nanogram to 2 milligrams of active ingredient. Within these ranges, particular subranges of the compound are from 0.1 milligrams to 2 grams of active ingredient (more commonly from 10 milligrams to 1 gram, e.g., from 50 milligrams to 500 milligrams), or from 1 microgram to 20 milligrams (e.g., from 1 microgram to 10 milligrams, e.g., from 0.1 milligrams to 2 milligrams of active ingredient). For oral compositions, a unit dosage form may contain from 1 milligram to 2 grams, more typically from 10 milligrams to 1 gram, e.g., from 50 milligrams to 1 gram, e.g., from 100 milligrams to 1 gram, of active compound. The active compound will be administered to a patient in need (e.g., a human or animal patient) in a quantity sufficient to achieve the desired therapeutic effect (effective dose). The precise quantities of compound administered may be determined by a supervising physician according to conventional procedures. Methods for the preparation of formula compounds (I) General synthetic schemes Scheme 1 With reference to Scheme 1, compounds of general formula G-5 can be synthesized from proline derivatives of formula G-1a, where PG is a protecting group, such as BOC. Amine compounds of general formula G-2 are coupled with G-1a, followed by deprotection of the amine protecting group, PG, to yield amides of general formula G-3. Common coupling reagents for achieving this transformation are well known to those skilled in the art, e.g., EDC, DCC, BOP, etc. Compounds of formula G-3 can be reacted with benzylic compounds of general formula G-4a to produce compounds of general formula G-5 under SN-2 reaction conditions, where the bromide is the leaving group, or with aldehyde compounds of general formula G-4b to produce compounds of general formula G-5 under reductive amination conditions. Scheme 2 With reference to Scheme 2, compounds of general formula G-5 can also be prepared from proline derivatives of general formula G-1b, where the carboxylic acid of G-1b is protected by a simple ester, such as a methyl ester. Compounds of general formula G-8 can be synthesized by reacting G-1b with a benzylic compound of general formula G-4a under SN-2 conditions, where the bromide is the leaving group, or with an aldehyde compound of general formula G-4b under reductive amination conditions. Compounds of general formula G-8 can then be coupled with an amine compound of general formula G-2 using the coupling conditions described above to yield compounds of general formula G-5. Scheme 3 With reference to Scheme 3, compounds of formula (1) can be synthesized from organoboronate compounds of general formula G-6 under palladium-catalyzed coupling conditions, using a palladium catalyst selected from those known to the art, e.g., PdCl2(dppf) DCM. Compounds of general formula G-6 can be coupled with aryl bromide compounds of general formula G-4a or benzaldehyde compounds of general formula G-4b to produce compounds of general formula G-7a or G-7b, respectively. Benzyl compounds of general formula G-7a, where bromide is the leaving group, react with amine compounds of general formula G-3 under SN-2 reaction conditions to produce compounds of formula (1).Benzaldehyde compounds of general formula G-7b react with amine compounds of general formula G-3 under reducing amination conditions to produce the compounds of formula (1). Scheme 4 With reference to Scheme 4, compounds of general formula G-5 can be coupled with organoboronate compounds of general formula G-6 using the palladium-catalyzed coupling chemistry discussed above to provide the compounds of formula (1). Those skilled in the art also know that some compounds of formula (1) will have the capacity to undergo further derivatization. For example, compounds of formula (1), where R7 is OH, can be further derivatized by reaction with a suitable electrophile, such as sulfamyl chloride to produce a sulfamyloxy derivative, carbamic chloride to produce a carbamate derivative, and so forth. Chromatographic methods LC / MS Method A Instruments: Acquity UPLC with photodiode array detector and QDA mass detector; Column: Acquity C-18, 1.6 micrometers, 50 x 1.6 mm; Gradient [time (min) / solvent B in A (%)]: 0.00 / 3, 0.20 / 3, 2.70 / 98. 3.00 / 100, 3.50 / 100, 3.51 / 3, 4.00 / 3; Solvents: solvent A = 0.1% formic acid in water; solvent B = 0.1% formic acid in water / acetonitrile (10:90); column temperature 35 °C; flow rate 0.9 ml / min. LC / MS Methods B and C Instruments: HP 1100 with DAD G1315A, Waters Micromass ZQ; Column: Phenomenex Gemini-NX C-18, 3 micrometers, 2.0 x 30 mm; Method B gradient [time (min) / solvent B in A (%)]: 0.00 / 2, 0.10 / 2, 2.50 / 95, 3.50 / 95; Method C gradient [time (min) / solvent B in A (%)]: 0.00 / 2, 0.01 / 2, 8.40 / 95, 10.00 / 95; Solvents: solvent A = 2.5 L of H2O + 2.5 ml of 28% ammonia in H2O solution; Solvent B = 2.5 L of MeCN + 135 ml of H2O + 2.5 ml of 28% ammonia in H2O solution. Injection volume 1 L; UV detection from 230 to 400 nm; mass detection from 130 to 800 AMU; column temperature 45 °C; flow rate 1.5 ml / min. LC / MS Method D Instruments: Agilent 1260 Infinity LC with diode array detector, MS with single quadrupole Agilent 6120B with API-ES source; column: Restek Penta Fluorophenylpropyl, 3 micrometers, 2, 1 x 30 mm. Gradient [time (min / solvent B in A (%)]: 0.00 / 2, 0.1 / 2, 8.4 / 95, 10 / 95, 10.1 / 2, 12 / 2; Solvents: solvent A = water (2.5 L) with 2.5 mL of formic acid; solvent B = MeCN (2.5 L) with 125 mL of water and 2.5 mL of formic acid. Injection volume 0.5 L; UV detection 190 to 400 nm; mass detection 130 to 800 AMU; column temperature 40 °C; flow rate 1.5 mL / min. LC / MS Method E Instruments: Agilent Technologies 1290 Series with binary pump, diode array detector and G6120A, MS with quadrupole. Column: Agilent Poroshell 120 EC-C18, 2.7 µm, 4.6 x 50 mm; gradient [time (min) / solvent B in A (%)]: 0.00 / 10, 0.50 / 10, 4.00 / 90, 4.50 / 100, 4.51 / 10, 5.00 / 10; Solvents: solvent A = 0.05% formic acid in water; solvent B = 0.05% formic acid in acetonitrile; column temperature 35 °C; flow rate 1.0 ml / min. LC / MS Method F Instruments: Water 2690 with photodiode array detector and QDA mass detector; Column: X-Bridge C-18, 5 micrometers, 100 x 1.6 mm; gradient [time (min) / solvent B in A (%)]: 0.01 / 10, 1.00 / 10, 5.00 / 100, 7.00 / 100, 7.50 / 10, 8.00 / 10; Solvents: solvent A = 0.1% formic acid and 10 mM ammonium carbonate in water; solvent B = acetonitrile; column temperature 35 °C; flow rate 0.9 ml / min. LC / MS Method G Instruments: Water 2690 with 996 photodiode array detector and Micromass ZQ mass spectrometer; Column: C-18, 3.5 micrometers, 50 x 4.6 mm; gradient [time (min) / solvent B in A (%)]: 0.00 / 10, 1.00 / 10, 4.00 / 100, 6.00 / 100, 6.50 / 10, 7.00 / 10; Solvents: solvent A = 10 mM ammonium bicarbonate in water; solvent B = methanol; flow rate 1.2 ml / min. LC / MS Method H Instruments: Agilent 1290 RRLC with Agilent 6120 mass spectrometer; Column: X-Bridge C1850 x 4.6 mm, 3.5 µm; Gradient: 95:5 at 0.01 min, 15:85 at 2.8 min, 5:95 at 3.5 min to 5.0 min, 95:5 at 5.01 min to 6.0 min; Solvents: Solvent A = 5 mM ammonium bicarbonate in water; Solvent B = acetonitrile; Flow rate 1 mL / min. LC / MS Method I Instruments: Agilent 1290 RRLC with Agilent 6120 mass spectrometer; Column: BEH C182, 1 x 50 mm, 1.7 µm; Gradient: 98:2 at 0.01 min to 0.5 min, 30:70 to 3.0 min (Flow rate: 0.45 mL / min), 5:95 from 4 min to 5.5 min (Flow rate: 0.50 mL / min), 98:2 at 5.51 min to 6.0 min (Flow rate: 0.45 mL / min); Solvents: Solvent A = 5 mM ammonium acetate and 0.1% FA in water; Solvent B = 0.1% FA in acetonitrile; Flow rate: 0.45 mL / min. LC / MS Method J Instruments: Waters Acquity H-Class LCMS, Mass Lynx software, PDA detector and QDa mass detector; Column: Gemini-NX C18, 3 µm, 30 x 2 mm; Gradient: [Time (min) / % A: % B] 3-minute analysis: [0, 00 / 100:0], [1, 30 / 0:100], [1, 55 / 0:100], [1, 60 / 100:0], [3, 00 / 100:0]; Solvents: (A) : 50 mM aqueous ammonium acetate solution at pH 7.40 (B) : acetonitrile; column temperature 40 °C; Flow rate 0.5 ml / min; mass spec solvent: 0.1% formic acid solution in 90% v / v methanol:water; injection of 1.0 l; range 200 nm to 500 nm. LC / MS K method Instruments: Waters Acquity Class H and SQ Mass Detector; Column: BEH C182, 1 x 50 mm, 1.7 µm; Gradient: 95:5 from 0.01 min to 0.6 min (Flow rate: 0.55 ml / min), 30:70 to 0.6 min (Flow rate: 0.60 ml / min), 10:90 to 0.80 min (Flow rate: 0.65 ml / min), 0:100 to 1.1 min to 1.70 min (Flow rate: 0.65 ml / min), 95:5 to 1.71 min to 2.0 min (Flow rate: 0.55 ml / min); Solvents: solvent A = 2 mM ammonium acetate and 0.1% FA in water; solvent B = 0.1% FA in acetonitrile; flow rate 0.55 ml / min. LC / MS Method L Instruments: Waters Acquity Class H with SQ mass spectrometer; Column: BEH C182, 1 x 50 mm, 1.7 µm; Gradient: 98:2 at 0.01 min to 0.5 min, 30:70 to 3.0 min (Flow rate: 0.45 ml / min), 5:95 from 4 min to 5.5 min (Flow rate: 0.50 ml / min), 98:2 at 5.51 min to 6.0 min (Flow rate: 0.45 ml / min); Solvents: Solvent A = 5 mM ammonium acetate and 0.1% FA in water; Solvent B = 0.1% FA in acetonitrile; Flow rate 0.45 ml / min. Purification by HPLC prep. Where indicated, intermediate or final compounds were purified by preparative reversed-phase HPLC using the instruments and methods described below: HPLC Method A Gilson semi-preparative HPLC system – including a 321 pump, a 171 diode array detector, and a GX-271 liquid handler with Gilson Trilution software. Phenomenex Kinetix C18 column, 100 x 30 mm, 5 µm. Flow rate 30 ml / min, solvent B in solvent A gradient: 5% to 35% solvent B (over 10 min), 100% solvent B (for 2 min); Solvent A: Water with 0.1% TFA. Solvent B: MeCN. HPLC Method B Gilson semi-preparative HPLC system – including a 321 pump, a 171 diode array detector, and a GX-271 liquid handler with Gilson Trilution software. Gemini-NX C18 column, 100 x 30 mm, 5 µm. Flow rate 30 ml / min. Solvent B in solvent A gradient: 5% to 35% solvent B (over 10 min), 100% solvent B (for 2 min); Solvent A: Water with 0.2% 28% aqueous ammonia. Solvent B: MeCN. HPLC Method C Gilson semi-preparative HPLC system – including twin-piston pumps 331 and 332, a diode array detector 171, and a GX-271 liquid handler with Gilson Trilution software. Gemini-NX C18 column, 100 x 30 mm, 5 µm. Flow rate 30 ml / min, solvent B in solvent A gradient: 5% to 35% solvent B (over 10 min), 100% solvent B (for 2 min); Solvent A: Water with 0.2% 28% aqueous ammonia. Solvent B: MeCN. HPLC Method D Agilent Preparative 1200 Infinite Series Sunfire C18250 column x 19 mm 5 µm. Flow rate 17 ml / min, solvent B gradient in solvent A 0.00 / 10. 17, 00 / 16, 17, 01 / 98, 19, 00 / 98, 19, 01 / 10, 21 / 10. Solvent A: Water with 0.1% FA, solvent B: MeCN. HPLC Method E SHIMADZU preparative HPLC system – including an LC-20AP pump, an SPD-20A detector, and Labsolutions software (version 5.90). Column: Agilent 10, Prep-C18, 250 x 21.2 mm. Solvent / Gradient: 10–80% acetonitrile in water containing 0.1% TFA. Flow rate: 20 mL / min. HPLC Method F A Shimadzu LC-20AP and UV detector were used. The column used was a Sunfire C18 (250*19) mm, 5 µm. The column flow rate was 12.0 ml / min. The mobile phases used were (A) 0.1% formic acid in water and (B) 100% acetonitrile. The solvent B gradient was 0-20% for 30 min, 100% for 2 min, and then 100-0% for 5 min. HPLC Method G Waters Xbridge C18150 * 50mm * 10um; mobile phase: [water (NH4HCO310 mM) - ACN]; B%: 33%-63%, min. HPLC Method H Phenomenex luna C18150 * 25mm * 10um; mobile phase: [water (0.225% FA) - ACN]; % of B: 3.- 33%, 10 min. HPLC Method I A Shimadzu LC-20AP and UV detector were used. The column was a Sunfire c18 (250 x 19) mm, 5 micrometers, with a column flow rate of 14.0 mL / min. The mobile phases used were (A) 0.1% formic acid in water and (B) 100% acetonitrile. The solvent B gradient was 0–20% over 23 minutes, then 20–20% over 2 minutes, 100% over 2 minutes, and then 100–0% over 6 minutes. Examples Compounds of formula (1) can be prepared according to synthetic methods known to the person skilled in the art. The following examples are provided to help the invention be more fully understood. When preparation routes are not included, the relevant intermediate compound is commercially available. Commercial reagents were used without further purification. Final compounds and intermediates are named using ChemDraw Professional, version 17.0.0.206 (121). Room temperature (TA) refers to approximately 20–27 °C. 1H NMR spectra were recorded at 400 or 500 MHz on a Bruker, Varian, or Jeol instrument. Chemical shift values ​​are expressed in parts per million (ppm), i.e., relative to a deuterated solvent such as d-chloroform (7.26 ppm), d6-DMSO (2.50 ppm), or d4-methanol (3.31 ppm). The following abbreviations are used for the multiplicity of NMR signals: s = singlet, br = wide, d = doublet, t = triplet, c = quartet, m = multiplet. Coupling constants are given as J values, measured in Hz.NMR and mass spectrometry results were corrected to account for background peaks. Chromatography refers to column chromatography performed on 6–120 or 4–633 µm mesh, 60 Å silica gel, and carried out under nitrogen pressure (ultrafast chromatography) or automated ultrafast chromatography using a Biotage Isolera instrument. Microwave-mediated reactions were performed in Biotage Initiator or CEM Discover microwave reactors. Synthetic preparation of intermediate compounds Intermediate compound 1: 4-((S)-1-((R)-pyrrolidine-2-carboxamido)ethyl) methyl benzoate hydrochloride (Intermediate compound 1-HCl) Step (i): To a mixture of N-Boc-D-proline (2.0 g, 9.29 mmol) in DMF (43.85 ml), diisopropylethylamine (4.82 ml, 27.87 mmol), HATU (4.25 g, 11.15 mmol), and methyl 4-[(1S)-1-aminoethyl]benzoate (2.0 g, 11.15 mmol) were added. The mixture was stirred at room temperature overnight, after which it was diluted with EtOAc and water (1:1), and the organic layers were separated. The organic phase was washed with brine (2 x 50 ml) and dried (fried) before vacuum concentration. The residue was purified by ultrafast column chromatography (normal phase, 25 g of Biotage® SNAP KP-Sil, 70 mL / min, ethyl acetate gradient in isohexane from 0% to 100%) to yield tert-butyl (2R)-2-[[(1S)-1-(4-methoxycarbonylphenyl)ethyl]carbamoyl]pyrrolidine-1-carboxylate (3.383 g, 9.0 mmol, 97% yield) as a pale yellow solid. LC / MS (Method B) 2.05 min [M+H]+ 377 Step (ii): To a solution of (2R)-2-[[(1S)-1-(4-methoxycarbonylphenyl)ethyl]carbamoyl]pyrrolidine-1-carboxylate tert-butyl (4.03 g, 10.71 mmol) in 1,4-dioxane (20.2 mL), 4 M HCl was added to 1,4-dioxane (20.2 mL, 10.71 mmol), and the mixture was stirred for 3 hours at room temperature. Once the reaction was complete, 1,4-dioxane (20.2 mL) was added to the mixture under LC / MS monitoring. The reaction mixture was then concentrated under vacuum to give the intermediate compound 1-HCl (3.39 g, 101%) as a white solid. LC / MS (Method B) 1, 73 min [M+H]+ 277. Intermediate compound 2: 4- ( (S) -1- ( (R) -1- (3-bromobenzyl)pyrrolidine-2-carboxamido) ethyl) methyl benzoate (Intermediate compound 2) Potassium carbonate (1.1 g, 7.99 mmol) and 3-bromobenzyl bromide (1.6 g, 6.39 mmol) were added to a solution of the intermediate compound 1-HCl (1.0 g, 3.2 mmol) in MeCN (96 mL). The resulting mixture was heated to 70 °C overnight, then filtered through a phase separator and washed with EtOAc before vacuum concentration. The residue was resuspended in EtOAc, and the organic phase was washed with water and brine, dried through a hydrophobic frit, and vacuum concentration. The residue was purified by ultrafast column chromatography (10 g of Biotage® SNAP KP-Sil, 30 mL per min, ethyl acetate gradient in isohexane from 30 to 100%) to give intermediate compound 2 (1.18 g, 83%) as a white solid. LC / MS (Method B) 1.73 min [M+H]+ 445 Intermediate Compound 3: 4-((S)-1-((2R,4R)-4-hydroxypyrrolidine-2-carboxamido)ethyl) methyl benzoate hydrochloride (Intermediate Compound 3) The intermediate compound 3-HCl was synthesized in a procedure analogous to intermediate compound 1, using (2R, 4R)-1-tert-butoxycarbonyl-4-hydroxypyrrolidine-2-carboxylic acid. LC / MS (Method B) 1, 47 min [M+H]+ 293 Intermediate compound 4: 4-((S)-1-((2R, 4R)-1-(3-bromobenzyl)-4-hydroxypyrrolidine-2-carboxamido)ethyl) methyl benzoate (Intermediate compound 4) Intermediate compound 4 was synthesized in a procedure analogous to intermediate compound 2, using the intermediate compound 3-HCl. LC / MS (Method B) 2, 17 min [M+H]+ 463 Intermediate compound 5: 4-((S)-1-((R)-1-(3-bromo-4-methoxybenzyl)pyrrolidine-2-carboxamido)ethyl) methyl benzoate (Intermediate compound 5) To a mixture of the intermediate compound 1-HCl (300 mg, 0.96 mmol) and 3-bromo-4-methoxybenzaldehyde (412.49 mg, 1.92 mmol) in DCM (5 mL) sodium triacetoxyborohydride (426.87 mg, 2.01 mmol) was added. The mixture was stirred at room temperature for 16 hours, after which it was diluted with saturated NaHCO3 solution. The organic layers were separated, washed with brine, dried (by passing them through a hydrophobic frit), and concentrated. The residue was purified by ultrafast column chromatography (normal phase, 10 g of Biotage® SNAP KP-Sil, 30 mL / min, ethyl acetate gradient in isohexane from 30% to 100%) to provide intermediate compound 5 (380 mg, 0.80 mmol, 83% yield) as a clear gum, which was sonicated in Et₂O to provide a white, fluffy solid. LC / MS (Method B) 2, 36 min [M+H]+ 475. Intermediate compound 6: 4-((S)-1-((R)-1-(3-bromo-5-methoxybenzyl)pyrrolidine-2-carboxamido)ethyl) methyl benzoate (Intermediate Compound 6) To a solution of the intermediate compound 1-HCl (300 mg, 0.96 mmol) in MeCN (10.8 ml) were added 1-bromo-3-(bromomethyl)-5-methoxybenzene (0.15 ml, 1.92 mmol) and potassium carbonate (331.4 mg, 2.4 mmol). The resulting mixture was heated under reflux for 16 hours, after which it was partitioned between EtOAc and water. The organic layers were separated, washed with brine, dried (fried), and concentrated. The residue was purified by ultrafast column chromatography (25 g Biotage® SNAP KP-Sil, 60 mL / min, EtOAc gradient in isohexane from 0% to 90%) to provide intermediate compound 6 (300 mg, 0.63 mmol, 66% yield) as a white solid. LC / MS (Method B) 2, 44 min [M+H]+ 475 Intermediate compound 7: (3-bromobenzyl)-D-proline (Intermediate compound 7) Step (i): Methyl D-prolinate hydrochloride (10.00 g, 60.38 mmol) was dissolved in ACN (120 ml) and Na2CO3 (12.80 g, 120.77 mmol) was added. The reaction mixture was stirred at room temperature for 15 min. Then, 1-bromo-3-(bromomethyl)benzene (18.11 g, 72.46 mmol) was added and the reaction mixture was stirred at 800 °C for 16 hours. The reaction mixture was then partitioned between water (300 ml) and EtOAc (200 ml), and the aqueous layer was extracted again with EtOAc (2 x 100 ml). The organic layers were combined and dried (Na₂SO₄), the solvent was removed under vacuum, and the crude product was purified by gradient column chromatography. The product was eluted with EtOAc in 0% to 20% hexane to yield pure methyl (3-bromobenzyl)-D-prolinate (11.00 g, 61.34%) as a yellow sticky material. LC / MS: (Method A): m / z 298 [M+H]+ at 1.35 min. Step (ii): Methyl (3-bromobenzyl)-D-prolinate (10.60 g, 35.68 mmol) was dissolved in dioxane (50 ml) and water (30 ml), LiOH monohydrate (7.48 g, 178.42 mmol) was added at room temperature and the reaction mixture was left to stir at room temperature for 6 hours. Glacial acetic acid (20 mL) was then added to bring the solution to pH ~6. The reaction mixture was then concentrated under vacuum to obtain the crude product, which was purified by reversed-phase gradient ultrafast column chromatography (reversed phase, C18 silica). The product eluted from 0% to 13% MeCN in water (0.1% FA as a modifier) ​​to yield pure (3-bromobenzyl)-D-proline (7.8 g, 77%) as a white solid. LC / MS: (Method A): m / z 284 [M+H]+ at 1.28 min. Intermediate Compound 8: (R)-4-((1-(3-bromobenzyl)pyrrolidine-2-carboxamido)methyl)-2-hydroxybenzoate (Intermediate Compound 8) Step (i): Intermediate compound 7 (2.50 g, 8.83 mmol) was dissolved in MeCN (15 mL) and methyl 4-(aminomethyl)-2-methoxybenzoate (1.90 g, 9.71 mmol) was added to the mixture at room temperature. Then, propylphosphonic anhydride (50% solution in EtOAc) (11.42 mL, 17.66 mmol) was added and the reaction mixture was stirred at room temperature for 30 min. Next, TEA (3.88 mL, 26.54 mmol) was added at 0 °C and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was then partitioned between saturated aqueous NaHCO3 solution (100 mL) and EtOAc (100 mL). The aqueous layer was further extracted with EtOAc (2 x 70 ml).The organic layers were combined and dried on Na2SO4, the solvent was removed under vacuum, and the crude product was purified by ultrafast gradient column chromatography (normal phase, silica). The product was eluted with EtOAc in 0% to 64% hexane to yield pure methyl (R)-4-((1-(3-bromobenzyl)pyrrolidine-2-carboxamido)methyl)-2-methoxybenzoate (2.50 g) as a yellow sticky material. LC / MS: (Method A): m / z 461 [M+H]+, at 1.56 min. Step (ii): Methyl (R)-4-((1-(3-bromobenzyl)pyrrolidine-2-carboxamido)methyl)-2-methoxybenzoate (0.30 g, 0.65 mmol) was dissolved in DCM (30 mL) and the reaction mixture was cooled to -78 °C. BBr3 was added as a 1 M solution in DCM (3.3 mL, 3.26 mmol) and the reaction mixture was stirred at -78 °C for 1 hour. The reaction mixture was then partitioned between saturated aqueous NaHCO3 solution (70 mL) and DCM (70 mL), and the aqueous layer was extracted again with DCM (2 x 40 mL). The organic layers were combined and dried (Na2SO4), and the solvent was separated under vacuum to provide the pure intermediate compound 8 (0.25 g, 86%) as a whitish solid. LC / MS: (Method A): m / z 447 [M+H]+ at 1.67 min. Intermediate compound 9: (S)-4-(1-aminoethyl)-2-methoxybenzoate (Intermediate compound 9) (S)-4-(1-aminoethyl)-2-methoxybenzoic acid (2.00 g, 10.25 mmol) was dissolved in methanol (20 mL) at room temperature. HCl, as a 4 N solution in dioxane (10 mL, 40 mmol), was added, and the reaction mixture was stirred at 70 °C for 8 hours. The reaction mixture was concentrated under vacuum, and the resulting residue was purified by grinding with diethyl ether to yield intermediate compound 9 (2.1 g, quantitative) as a white solid. LC / MS: (Method A) 0.93 min, no ionic mass. Intermediate compound 10: 4-((S)-1-((R)-1-(3-bromobenzyl)pyrrolidine-2-carboxamido)ethyl)-2-hydroxybenzoate methyl (Intermediate compound 10) Step (i): Intermediate compound 9 (1.5 g, 7.71 mmol) was dissolved in MeCN (15 mL) and intermediate compound 7 (2.23 g, 7.89 mmol) was added to the reaction mixture at room temperature. HATU (4.09 g, 10.75 mmol) was then added and the mixture was stirred for 30 min. Next, N,N-diisopropylethylamine (2.50 mL, 14.34 mmol) was added at 0 °C and the mixture was stirred at room temperature for 2 hours. The reaction mixture was then divided between saturated aqueous NaHCO3 (250 mL) and EtOAc (250 mL). The aqueous layer was further extracted with EtOAc (2 x 150 ml) and the organic layers were combined and dried over Na2SO4. The solvent was removed under vacuum and the crude product was purified by gradient ultrafast column chromatography (reversed-phase followed by normal-phase). First, the reversed-phase ultrafast column chromatography product eluted from 0% to 68% using MeCN in water as the mobile phase.Second, the normal-phase chromatography product was eluted using a gradient of EtOAc in hexane from 0% to 78% to provide methyl 4-((S)-1-((R)-1-(3-bromobenzyl)pyrrolidine-2-carboxamido)ethyl)-2-methoxybenzoate (1.50 g, 44.11%) as a white solid. LC / MS (method G): The product was confirmed m / z 475.1 (ES+, M+2) at 1.438 min. Step (ii): Methyl 4-((S)-1-((R)-1-(3-bromobenzyl)pyrrolidine-2-carboxamido)ethyl)-2-methoxybenzoate (1.50 g, 3.16 mmol) was dissolved in DCM (30 mL) and the mixture was cooled to -78 °C. BBr3 was added as a 1 M solution in DCM (3.79 mL, 3.79 mmol) and the reaction mixture was stirred at -78 °C for 1 hour. The reaction mixture was then partitioned between saturated aqueous NaHCO3 solution (200 mL) and DCM (250 mL). The aqueous layer was again extracted with DCM (2 x 150 mL), and the organic layers were combined and dried (Na2SO4). The solvent was separated under vacuum and the crude product was purified by reversed-phase gradient ultrafast column chromatography (reversed phase, C18 silica). The product eluted from a MeCN concentration in water of 0% to 65% to yield the pure intermediate compound 10 (0.99 g, 68%) as a white solid. LC / MS: (Method G): m / z 461 [M+H]+ at 5.43 min. Intermediate compound 11: 3'-(bromomethyl)-5'-hydroxy-2-methyl-[1,1'-biphenyl]-4-carboxamide (Intermediate compound 11) Step (i): 3-bromo-5-hydroxybenzaldehyde (4.00 g, 20.00 mmol), 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (5.74 g, 22.00 mmol) and K2CO3 (3.20 g, 60.01 mmol) were dissolved in 1,4-dioxane (15 mL) and water (15 mL). Nitrogen gas was then purged through the mixture for 20 minutes at room temperature, followed by the addition of PdCl2 (dppf) DCM (1.63 g, 2.00 mmol). The reaction mixture was then stirred at 80 °C for 2 hours. The reaction mixture was then divided between water (400 ml) and EtOAc (250 ml), and the aqueous layer was further extracted with EtOAc (2 x 100 ml).The organic layers were combined and dried (Na2SO4), the solvent was removed under vacuum, and the crude product was purified by reversed-phase ultrafast column chromatography (reversed phase, C18 silica) with a gradient. The product was eluted in MeCN in water from 0% to 35% to give 3'-formyl-5'-hydroxy-2-methyl-[1,1'-biphenyl]-4-carboxamide (3.60 g, 71%) as a brown solid. LC / MS: (Method A): m / z 256 [M+H]+, at 1.09 min. Step (ii): 3'-Formyl-5'-hydroxy-2-methyl-[1,1'-biphenyl]-4-carboxamide (1.50 g, 5.88 mmol) was dissolved in methanol (15 mL) at room temperature. The reaction mixture was cooled to 0 °C, sodium borohydride (0.44 g, 11.76 mmol) was added at 0 °C, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was partitioned between saturated aqueous NaHCO3 solution (100 mL) and EtOAc (80 mL), and the aqueous layer was further extracted with EtOAc (3 x 50 mL). The organic layers were combined and dried (Na2SO4), and the solvent was removed under vacuum to provide 3'-hydroxy-5'-(hydroxymethyl)-2-methyl-[1,1'-biphenyl]-4-carboxamide (1.36 g, 90%) as a whitish solid. LC / MS: (Method A): m / z 258 [M+H]+, at 0.94 min. Step (iii): 3'-Hydroxy-5'-(hydroxymethyl)-2-methyl-[1,1'-biphenyl]-4-carboxamide (1.36 g, 5.29 mmol) was dissolved in 33% HBr in CH3COOH (12 ml) at room temperature, and the resulting reaction mixture was allowed to stir at room temperature for 16 hours. The reaction mixture was then partitioned between saturated aqueous NaHCO3 solution (200 ml) and EtOAc (150 ml), and the aqueous layer was further extracted with EtOAc (2 x 50 ml). The organic layers were combined and dried (Na2SO4), and the solvent was removed under vacuum to provide 3'-(bromomethyl)-5'-hydroxy-2-methyl-[1,1-biphenyl]-4-carboxamide (1.59 g, 94%) as a reddish-brown solid. LC / MS: (Method A): m / z 320 [M+H]+, at 1.23 min. Intermediate compound 12: 3-(bromomethyl)-2-methyl-[1,1-biphenyl]-4-sulfonamide (Intermediate compound 12) Step (i): 4-Bromo-3-methylbenzenesulfonamide (1.00 g, 3.99 mmol), bis(pinacolate)diboron (2.02 g, 7.98 mmol), and KOAc (1.17 g, 11.97 mmol) were dissolved in dioxane (10 mL) at room temperature. For this purpose, nitrogen gas was purged for 30 min at room temperature. After this, PdCl2 (dppf) DCM (0.325 g, 0.399 mmol) was added, and the reaction mixture was stirred at 80°C for 2 h. The reaction mixture was then partitioned between water (100 mL) and EtOAc (100 mL), and the aqueous layer was further extracted with EtOAc (2 x 100 mL). The organic layers were combined and dried (Na2SO4). The solvent was separated under vacuum and the crude product was purified by gradient ultrafast column chromatography (normal phase, silica). The product was eluted with EtOAc in 0% to 30% hexane to provide pure 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide (1.0 g, 85%) as a yellow solid.LC / MS: (Method F): The m / z of the product was not compatible at the main peak (ES+), at 0.46 min. Step (ii): 3-Bromobenzaldehyde (4.50 g, 24.46 mmol), 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide (8.72 g, 29.35 mmol), and K₂CO₃ (10.20 g, 73.38 mmol) were dissolved in 1,4-dioxane (18 mL) and water (12 mL). Gaseous nitrogen was purged for 30 minutes at room temperature. Then, PdCl₂(dppf) DCM (1.99 g, 2.44 mmol) was added, and the reaction mixture was stirred at 80 °C for 2 h. The reaction mixture was divided between water (500 ml) and EtOAc (150 ml). The aqueous layer was further extracted with EtOAc (2 x 150 ml). The organic layers were combined and dried (Na2SO4). The solvent was separated under vacuum and the crude product was purified by gradient column chromatography (normal phase, silica). The product was eluted with EtOAc in 0% to 40% hexane to give pure 3'-formyl-2-methyl-[1,1'-biphenyl]-4-sulfonamide (4.5 g, 67%) as a whitish solid.LC / MS: (Method A): The desired mass was compatible at the main peak at 1.74 min. Step (iii): 3'-Formyl-2-methyl-[1,1'-biphenyl]-4-sulfonamide (4.00 g, 14.54 mmol) was dissolved in methanol (30 mL) at room temperature. The reaction mixture was cooled to 0 °C and sodium borohydride (1.65 g, 43.62 mmol) was added in portions. The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with cold water (50 mL). A solid precipitated, which was filtered and vacuum dried to give 3'-(hydroxymethyl)-2-methyl-[1,1-biphenyl]-4-sulfonamide (3.6 g, 79%) as a whitish solid. LC / MS: (Method A): 260. [M+H-H2O]+, at 1.51 min. Step (iv): 3'-(Hydroxymethyl)-2-methyl-[1,1'-biphenyl]-4-sulfonamide (3.60 g, 12.99 mmol) was dissolved in HBr (64% in water) (35 mL) and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with cold water (50 mL). A solid precipitated, which was filtered and vacuum dried to give 3'-(Bromomethyl)-2-methyl-[1,1'-biphenyl]-4-sulfonamide (3.7 g, 84%) as a yellow solid. LC / MS: (Method A): The mass was not compatible at 1.51 min. Intermediate compound 13: 3'-(bromomethyl)-2-methyl-[1,1'-biphenyl]-4-carboxamide (Intermediate compound 13) Intermediate compound 13 was synthesized by a procedure analogous to intermediate compound 12 using 4-bromo-3-methylbenzamide to give intermediate compound 13. LC / MS: (Method A): m / z 305 [M+H]+, at 2.02 min. Intermediate compound 14 Step (i): To a solution of compound a1 (2.4 g, 11.16 mmol, 1 eq) and compound a2 (1.62 g, 13.39 mmol, 1.2 eq) in THF (50 mL), Ti(OEt)4 (5.09 g, 22.32 mmol, 4.63 mL, 2 eq) was added. The mixture was stirred at 30 °C for 5 h. TLC (PE:EA = 5:1) indicated that compound a1 had been completely consumed and a new spot had formed. The reaction mixture was diluted with H2O (50 mL) and extracted with EA (100 mL * 2). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by ultrafast silica gel chromatography (ISCO®; SepaFlash® 20 g ultrafast silica column, eluent of a 0-30% ethyl acetate / petroleum ether gradient at 50 ml / min) to give compound a3 (3.5 g, 11.00 mmol, 98.55% yield) in the form of a yellow oil, which was confirmed by 1H NMR. RMN 1H (CDCl3, 400 MHz) 8, 54 (s, 1H) , 7, 67 (d, J = 8, 0 Hz, 1 H) , 7, 40 (d, J = 1, 6 Hz, 1H) , 7, 30 (dd, J = 1, 6, 8, 0 Hz, 1 H) , 3, 98 (s, 3 H) , 1, 28 (s, 9 H) . Step (ii): Dimethylzinc (1 M, 13.36 mL, 1.7 eq) was dissolved in THF (50 mL), and MeMgBr (3 M, 3.93 mL, 1.5 eq) was added dropwise at 10 °C. The mixture was then stirred at 10 °C for 30 min. The reaction solution was then cooled to 0 °C, and a solution of compound a3 (2.50 g, 7.86 mmol, 1 eq) in THF (12.5 mL) was added dropwise. The reaction mixture was then stirred at 10 °C for 1 h. TLC (PE:EA = 1:1) indicated that compound a3 had been completely consumed. The reaction mixture was diluted with H2O (30 mL) and extracted with EA (50 mL * 2). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue.The residue was purified by ultrafast silica gel chromatography (ISCO®; 20 g SepaFlash® ultrafast silica column, 30-60% ethyl acetate / petroleum ether gradient eluent at 50 ml / min) to give compound a4 (1.2 g, 3.52 mmol, 44.83% yield, 98.1% purity) as a white solid, which was confirmed by 1H NMR. SFC: Rt = 1, 220 min, ee: 97, 1% 1H NMR (CDCl3, 400 MHz) 7.49 (d, J = 8.4 Hz, 1H) , 6.90 (s, 1H) , 6.82 (d, J = 8.0 Hz, 1H) , 4.55 (dd, J = 2.0.6.4 Hz, 1H) , 3.90 (s, 3H), 3.32 (s, 1H), 1.52 (d, J = 6.8 Hz, 3H), 1.22 (s, 9H). Step (iii): A solution of compound a4 (1.4 g, 4.19 mmol, 1 eq) in EtOH (40 mL) was mixed with TEA (1.27 g, 12.56 mmol, 1.75 mL, 3 eq) and Pd(dppf)Cl2.CH2Cl2 (342.03 mg, 418.82 µmol, 0.1 eq). The mixture was stirred at 80 °C for 16 h under CO2 (3.5 bar (50 psi)). LC-MS showed that compound a4 had been completely consumed and a main peak with the desired mass was detected. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2). Petroleum ether / ethyl acetate = 3 / 1 to 1 / 1) to give compound a5 (1.35 g, 4.09 mmol, 97.65% yield, 99.2% purity) in the form of a yellow oil, which was confirmed by H NMR LCMS: [M+1]+= 328, 4. SFC: Rt = 0.901 min, ee = 97.9%. 1H NMR (CDCl3, 400 MHz) 7.77 (d, J = 7.6 Hz, 1 H) , 7.0.- 6.90 (m, 2 H) , 4.6.- 4.57 (m, 1 H) , 4.36 (q, J = 7.2 Hz, 2 H) , 3.91 (s, 3 H), 3.33 (d, J = 1.6 Hz, 1 H), 1.54 (d, J = 6.8 Hz, 3 H), 1.38 (t, J = 7.2 Hz, 3 H), 1.23 (s, 9 H). Step (iv): To a solution of compound a5 (1.35 g, 4.12 mmol, 1 eq) in DCM (15 mL), HCl / dioxane (4 M, 20 mL) was added at 0°C. The mixture was stirred at 15°C for 12 h. LC-MS showed that compound a5 had been completely consumed. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was ground with PE:EA = 5:1 (10 mL) at 15°C for 10 min to give compound a6 (920 mg, 3.54 mmol, 85.91% yield, HCl) as a yellow solid, which was confirmed by ¹H NMR 1H NMR (DMSO-d6, 400 MHz) 8.67 (s, 3 H) , 7.64 (d, J = 8.0 Hz, 1 H) , 7.44 (s, 1 H) , 7.13 (d, J = 8.0 Hz, 1 H) , 4.5.- 4.36 (m, 1 H) , 4.24 (q, J = 6.8 Hz, 2 H) , 3.85 (s, 3 H) , 1.52 (d, J = 6.4 Hz, 3 H) , 1.27 (t, J = 7.2 Hz, 3 H) . Step (v): HATU (1.87 g, 4.93 mmol, 2 eq) and DIEA (1.59 g, 12.32 mmol, 2.15 ml, 5 eq) were added to a solution of compound a7 (795.58 mg, 3.70 mmol, 1.5 eq) in DMF (8 ml). The mixture was stirred at 25 °C for 0.5 h. Compound a6 (640 mg, 2.46 mmol, 1 eq, HCl) was added, and the resulting mixture was stirred at 25 °C for 1 h. LC-MS showed that compound a6 had been completely consumed, and a main peak with the desired mass was detected. The reaction mixture was diluted with H2O (30 ml) and extracted with EA (50 ml * 2). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue.The residue was purified by ultrafast silica gel chromatography (ISCO®; SepaFlash® 20 g ultrafast silica column, 0-50% ethyl acetate / petroleum ether gradient eluent at 40 ml / min) to give compound a8 (1.26 g, crude) in the form of a yellow oil, which was confirmed by LCMS H NMR: [M-Boc]+ = 321.5. SFC: Rt=0.926 min, ee: 100% 1H NMR (DMSO-d6, 400 MHz) 8, 3.- 8, 23 (m, 1 H) , 7, 56 (d, J = 7, 6 Hz, 1 H) , 7, 12 (s, 1 H) , 6, 97 (d, J = 7, 6 Hz, 1 H) , 5, 0.- 4, 81 (m, 1 H) , 4, 23 (q, J = 7, 2 Hz, 2 H) , 4, 1.- 4, 05 (m, 1 H) , 3, 8.- 3, 78 (m, 3 H) , 3, 4.- 3, 35 (m, 1 H) , 3, 2.- 3, 22 (m, 1 H), 2, 2.- 2, 03 (m, 1 H), 1, 9.- 1, 71 (m, 3H), 1, 4.- 1, 29 (m, 8 H), 1, 24- 1, 11 (m, 7 H). Step (vi): To a solution of compound a8 (1.2 g, 2.85 mmol, 1 eq) in DCM (10 mL), HCl / dioxane (4 M, 10 mL) was added. The mixture was stirred at 15 °C for 1 h. LC-MS showed that compound a8 had been completely consumed and a main peak with the desired mass was detected. The reaction mixture was concentrated under reduced pressure to give intermediate compound 14 (830 mg, crude, HCl) as a yellow oil. LCMS: [M+1]+= 321, 2 Intermediate compound 15 Step (i): A mixture of compound b1 (1 g, 4.65 mmol, 1 eq), NH4Cl (373.12 mg, 6.98 mmol, 1.5 eq), HATU (2.65 g, 6.98 mmol, 1.5 eq), and DIEA (1.20 g, 9.30 mmol, 1.62 ml, 2 eq) in DMF (25 ml) was degassed and purged with N2 three times, and then the mixture was stirred at 30 °C for 12 h in an N2 atmosphere. LCMS indicated that compound b1 had been completely consumed. The mixture was added dropwise slowly to the water (35 ml). The precipitate was filtered and the filter cake was concentrated to give compound b2 (600 mg, 2.80 mmol, 60.28% yield) as a brown solid, which was confirmed by H NMR LCMS: m / z= 213.7 [M+1]. 1H NMR (DMSO-d6, 400 MHz) 8.00 (s, 1 H) , 7.85 (d, J= 1.6 Hz, 1 H) , 7.6.- 7.65 (m, 1 H) , 7.6.- 7.59 (m, 1 H) , 7.42 (s, 1 H) , 2, 38 (s, 3 H) . Step (ii): A mixture of compound b2 (450 mg, 2.10 mmol, 1 eq) , 4,4,5,5-tetramethyl-2- (4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl) -1,3,2-dioxaborolane (640.60 mg, 2.52 mmol, 1.2 eq) , AcOK (412.63 mg, 4.20 mmol, 2 eq) , Pd (dppf) Cl2 (153.82 mg, 210.22 umol, 0.1 eq) in dioxane (12 ml) was degassed and purged with N23 times, and then the mixture was stirred at 85 °C for 12 h in an atmosphere of N2. LC-MS indicated that compound b2 was completely consumed, and a main peak with the desired mass was detected. TLC (petroleum ether:ethyl acetate = 1:1) also indicated that compound b2 was completely consumed. The reaction mixture was concentrated under reduced pressure to give a residue.The residue was purified by ultrafast silica gel chromatography (ISCO®; SepaFlash® 20 g ultrafast silica column, 0-65% ethyl acetate / petroleum ether gradient eluent at 45 ml / min) to give compound b3 (440 mg, 1.69 mmol, 80.15% yield) as a white solid, which was confirmed by H NMR. LCMS: m / z= 261.9 [M+1]. 1H NMR (CDCl3, 400 MHz) 7.82 (d, J= 7.6 Hz, 1H), 7.6.- 7.54 (m, 2H), 6.2.- 5.84 (m, 2H), 2.58 (s, 3H), 1.36 (s, 12H). Step (iii): To a solution of compound b3 (1 g, 3.83 mmol, 1 eq) and compound b4 (1.07 g, 4.98 mmol, 1.3 eq) in dioxane (30 mL) and H2O (3 mL), K2CO3 (1.06 g, 7.66 mmol, 2 eq) and Pd(dppf)Cl2 (280.21 mg, 382.96 µmol, 0.1 eq) were added. The mixture was stirred at 80 °C for 12 h in a N2 atmosphere. TLC (PE:EA = 1:1) indicated that compound b3 had been completely consumed and a new spot had formed. The reaction mixture was diluted with H2O (30 mL) and extracted with EA (50 mL * 2). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 3:1 to 1:2) to give intermediate compound 15 (550 mg, 2.04 mmol, 53.33% yield) as a yellow solid, which was confirmed by ¹H NMR 1H NMR (CDCl3, 400 MHz) 10.03(s,1H), 7.80(s,1H), 7.69(d,J=4.4Hz,1H), 7.42(s,2H), 7.33(d,J=4.8Hz,1H), 7, 13 (s, 1 H), 6, 5.- 5, 32 (m, 2 H), 3, 92 (s, 3 H), 2, 34 (s, 3 H). Intermediate compound 16: (S)-1-(4-bromo-3-methoxyphenyl)ethane-1-amine (Intermediate compound 16) Step (i): To a solution of 4-bromo-3-methoxybenzaldehyde (31.16 g, 0.14 mol, 1 eq) dissolved in THF (240 ml) at room temperature, Ti(OEt)4 (66.10 g, 0.28 mol, 61.20 ml, 2 eq) was added to a reaction mixture and the reaction mixture was stirred at room temperature for 15 minutes. (R)-2-methylpropan-2-sulfinamide (28.09 g, 0.23 mol, 1.6 eq) previously dissolved in THF (60 ml) was added to a reaction mixture and the mixture was stirred at 30 °C overnight. The TLC (EA:hexane = 2:8) indicated that the 4-bromo-3-methoxybenzaldehyde had been completely consumed and a new spot had formed. The reaction mixture was diluted with H₂O (300 mL), but a salt formed and was filtered through a vacuum pump. The filtrate was extracted with EA (3 x 500 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue.The residue was purified by ultrafast silica gel chromatography (normal phase silica with EA / hexane from 0 to 15.0%) to give (R, E)-N-(4-bromo-3-methoxybenzylidene)-2-methylpropane-2-sulfinamide (35.9 g, yield of 77.85%) as a white solid. TLC: (EtOAc / Hexane, 2, 0:8, 0, RF: 0, 40). Mass (ESI +vo) : 318, 0 [M]. LCMS: 100.0% (LCMS method H), RT: 3.545 min, 280.0 mm. 1H NMR (400 MHz, CDCl3) : 8.57 (s, 1 H), 7.69-7.71 (d, 1 H), 7.44 (d, 1 H), 7.30-7.33 (dd, 1 H), 4.01 (s, 3 H), 1.31 (s, 9 H). Step (ii): Dimethylzinc (1.5 M in toluene, 269.66 mL, 3.7 eq) was dissolved with THF (150 mL) and MeMgBr (3.0 M in diethyl ether, 116.6 mL, 3.2 eq) was added dropwise at 15-20 °C, and then the mixture was stirred at 15-20 °C for 45 min. Afterwards, the reaction solution was cooled to 0 °C, and a solution of (R, E)-N-(4-bromo-3-methoxybenzylidene)-2-methylpropane-2-sulfamide (34.79 g, 0.034 mol, 1 eq) predissolved in THF (150 mL) was added dropwise, and then the reaction mixture was stirred at 0 °C for 30 min. The TLC (EA:hexane = 5:5) indicated that the (R, E)-N-(4-bromo-3-methoxybenzylidene)-2-methylpropane-2-sulfinamide had been completely consumed. The reaction mixture was diluted with cold H₂O (1000 mL) and a solid formed. It was then acidified with 1 N HCl (pH = 2 to 3) and extracted with EA (800 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue.The residue was purified by ultrafast silica gel chromatography (normal phase silica with EA / hexane from 0 to 45.0%) to give (R) -N- ( (S) -1- (4-bromo-3-methoxyphenyl) ethyl) -2-methylpropane-2-sulfamid (25.57 g, yield of 69.97%, purity of 97.20%) in the form of a whitish solid. TLC: (EtOAc / Hexane, 5, 0:5, 0, RF: 0, 25). Mass (ESI +vo) : 335.8 [M+1]. LCMS: 100.0% (LCMS method H), RT: 3.067 min, 254.0 mm. 1H NMR (400 MHz, CDCl3): 7.50-7.52 (s, 1H), 7.01 (s, 1H), 6.82-6.84 (dd, 1H), 4.77-4.78 (s, 1H), 4.42 (s, 1H), 3.93 (s, 3H), 1, 58-1, 62 (t, 6 H), 1, 29 (s, 9 H). Step (iii): To a solution of (R)-N-((S)-1-(4-bromo-3-methoxyphenyl)ethyl)-2-methylpropane-2-sulfinamide (25.57 g, 0.07 mol, 1 eq) in dioxane (20 mL) HCl in dioxane (4.0 M, 125 mL) at 0°C was added. The mixture was stirred at room temperature for 3 h. The TLC (EA:hexane = 5:5) indicated that the (R)-N-((S)-1-(4-bromo-3-methoxyphenyl)ethyl)-2-methylpropane-2-sulfinamide had been completely consumed. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was washed with dioxane (40 ml) and concentrated under reduced pressure to give a residue to give (S) -1- (4-bromo-3-methoxyphenyl) ethan-1-amine (intermediate compound 16) (18, 73 g, HCl salt) in the form of a white solid. TLC: (EtOAc / Hexane, 5, 0:5, 0, RF: 0, 25). LCMS: 100.0% (LCMS method H), RT: 2.371 min, 230.0 mm. 1H NMR (400 MHz, DMSO-D2O) : 8.75 (s, 3H) , 7.59-7.68 (d, 1 H) , 7.49 (s, 1 H) , 7.02-7.04 (d, 1 H) , 4.3.- 4.39 (s, 1 H) , 3. 88 (s, 3 H), 3, 56 (s, 1 H), 1, 51-152 (t, 3 H). Intermediate compound 17: 4'-hydroxy-5-methoxy-2'-methyl-[1,1'-biphenyl]-3-carbaldehyde (Intermediate compound 17) To a solution of (4-hydroxy-2-methylphenyl)boronic acid (3.5 g, 0.02 mol, 1 eq) , 3-bromo-5-methoxybenzaldehyde (4.95 g, 0.020 mol, 1.0 eq) in dioxane (35 ml) and H2O (11 ml) K2CO3 (6.35 g, 0.046 mol, 2 eq) was added, the mixture was degassed for 10 min and, after degassing, Pd (dppf) Cl2 (1.6 g, 0.002 mol, 0.1 eq) was added to a reaction mixture. The reaction mixture was then stirred at 80 °C overnight. The TLC (EA:hexane = 5:5) indicated that the (4-hydroxy-2-methylphenyl)boronic acid had been completely consumed and a new stain had formed. The reaction mixture was diluted with H₂O (300 mL) and extracted with EA (3 x 150 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue.The residue was purified by column chromatography (normal phase silica with EA / hexane from 0 to 46.0%) to give 4'-hydroxy-5-methoxy-2'-methyl-[1,1'-biphenyl]-3-carbaldehyde (intermediate compound 17) (4.0 g, yield of 71.68%) as a brown solid. TLC: (EtOAc / Hexane, 5, 0:5, 0, RF: 0, 25). Mass (ESI +vo) : 243.0 [M+1]. LCMS: 95.66% (LCMS method H), RT: 3.029 min, 254.0 mm. 1H NMR (400 MHz, DMSO-D2O): 10.01 (s, 1H), 9.48 (s, 1H), 7.43-7.36 (d, 2H), 7.16 (s, 1H), 7.08-7.06 (d, 1H), 6.67-6, 71 (m, 2H), 3, 86 (s, 3 H), 2, 18 (s, 3 H). Synthetic preparation of compounds of formula I Example 1: 4-((1S)-1-((2R)-1-((4'-hydroxy-2'-methyl-1',2',3',4',5',6'-hexahydro-[1,1'-biphenyl]-3-yl)methyl)pyrrolidine-2-carboxamido)ethyl)benzoic acid (Compound 1) Step (i): A mixture of intermediate compound 2 (150 Mg, 0.3400 mmol), (4-hydroxy-2-methylphenyl)boronic acid (56.3 mg, 0.3700 mmol), potassium carbonate (0.09 g, 0.67 mmol), and tetrakis(triphenylphosphine) palladium (0) (11.68 mg, 0.01 mmol) in 1,4-dioxane (1.4 mL) and water (0.3 mL) was heated to 100 °C for 1 hour in a microwave reactor. An additional addition of (4-hydroxy-2-methylphenyl)boronic acid (56.3 mg, 0.3700 mmol) was made, and the mixture was placed in the microwave reactor for a further 1 hour. The crude product was diluted with water and EtOAc and the organic layers were separated, washed with water and brine and dried by passing them through a hydrophobic frit before vacuum concentration.The residue was purified by ultrafast column chromatography (normal phase, 10 g, Biotage® SNAP KP-Sil, 30 ml per min, ethyl acetate gradient in isohexane from 30 to 100%) to give methyl 4-[(1S)-1-[(2R)-1-[[3-(4-hydroxy-2-methylphenyl)phenyl]methyl]pyrrolidine-2-carbonyl]amino]ethyl]benzoate (148 mg, 93%), in the form of a pale yellow gum. LC / MS (Method B) 2, 36 min [M+H]+ 473. Step (ii): To a solution of methyl 4-[(1S)-1-[[(2R)-1-[[3-(4-hydroxy-2-methylphenyl)phenyl]methyl]pyrrolidine-2-carbonyl]amino]ethyl]benzoate (148 Mg, 0.31 mmol) in 1,4-dioxane (2.62 mL) and water (2.62 mL), lithium hydroxide monohydrate (59.13 mg, 1.41 mmol) was added. The reaction was stirred at room temperature for 3 hours before checking for completion by LC / MS and then concentrated under vacuum. The crude residue was purified by reversed-phase HPLC (HPLC method A) to give compound 1 (52.5 mg, 36%) as a white solid. LC / MS (Method C) : m / z 459 [M+H]+ 2, 30 min. 1H NMR (400 MHz, DMSO-d6) 7.91 (m, 1H), 7.74 (m, 2H), 7.33 (dd, J = 7.5 Hz, 1H), 7.2.- 7.21 (m, 2H), 7.1.- 7.08 (m, 3H), 6, 98 (m, 1H), 6, 6.- 6, 61 (m, 2H), 4, 8.- 4.76 (m, 1H) , 3.80 (d, J = 12.9 Hz, 1H) , 3.52 (d, J =12.9 Hz, 1H) , 3.08 (dd, J = 9.5.4.1 Hz, 1H) , 2.99-2.93 (m, 1H) , 2, 39-2, 29 (m, 1H), 2, 13 (s, 3H), 2, 09- 1, 97 (m, 2H), 1, 72-1, 61 (m, 3H), 1, 24 (d, J=7, 0 Hz, 3H). Exchangeable acidic proton not observed in the spectra. Example 2: 4-((S)-1-((R)-1-((2'-methyl-4'-sulfamoyl-[1,1'-biphenyl]-3-yl)methyl)pyrrolidine-2-carboxamido)ethyl)benzoic acid (Compound 2) Compound 2 was synthesized by a procedure analogous to Example 1, using intermediate compound 2 and (2-methyl-4-sulfamoylphenyl)boronic acid, wherein only the addition of boronic acid in step (i) of the procedure is required. The crude product was purified by HPLC preparation (HPLC Method A) to yield compound 2 (48.5 mg, 0.09 mmol, 34%) as a white foam. LC / MS (Method C): m / z 522 [M+H]+ 2, 28 min. 1H NMR (400 MHz, DMSO-d6) 7, 94 (d, J =8, 0 Hz, 1H) , 7, 71 (s, 1H) , 7, 67 (m, 3H) , 7, 47 (br s, 2H) , 7, 39 (dd, J= 7, 6 Hz, 1H) , 7, 3.- 7, 27 (m, 3H) , 7, 23 (m, 1H) , 7, 17 (m, 2H) , 4, 8.- 4, 74 (m, 1H) , 3, 84 (d, J= 13, 2 Hz, 1H) , 3, 52 (d, J= 13, 1 Hz, 1H), 3, 08 (dd, J= 7, 8 Hz, 1H) , 2, 9.- 2, 88 (m, 1H) , 2, 3.- 2, 26 (m, 1H) , 2, 23 (s, 3H) , 2, 0.- 1, 96 (m, 1H) , 1, 7.- 1, 57 (m, 3H) , 1, 24 (d, J= 6, 9 Hz, 3H) . Exchangeable acidic proton not observed in the spectra. Example 3: 4-((S)-1-((R)-1-((4'-carbamoyl-2'-methyl-[1,1'-biphenyl]-3-yl)methyl)pyrrolidine-2-carboxamido)ethyl)benzoic acid (Compound 3) Compound 3 was synthesized by a procedure analogous to that of Example 1, using intermediate compound 2 and 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide, wherein only a boronic acid addition is required in step (i) of the procedure. The crude product was purified by HPLC (HPLC Method C) to give compound 3 (71 mg, 0.15 mmol, 43%) as a white foam. LC / MS (Method C): m / z 486 [M+H]+ 2, 36 min. 1H NMR (400 MHz, DMSO-d6) 8, 0.- 7, 96 (m, 2H) , 7, 8.- 7, 74 (m, 3H) , 7, 72 (m, 1H) , 7, 38 (m, 1H) , 7, 3.- 7, 18 (m, 7H) , 4, 85-4, 76 (m, 1H) , 3, 82 (d, J= 13, 0 Hz, 1H) , 3, 52 (d, J= 13, 0 Hz, 1H) , 3, 07 (dd, J= 9, 8, 4, 1 Hz, 1H) , 2, 9.- 2, 90 (m, 1H) , 23.- 2.27 (m, 1H) , 2.21 (s, 3H) , 2.0.- 1.96 (m, 1H) , 1.7.- 1.59 (m, 3H) , 1.25 (d, J= 7, 0 Hz, 3H) . Exchangeable acidic proton not observed in the spectra Example 4: 4-((S)-1-((2R,4R)-4-hydroxy-1-((2'-methyl-4'-sulfamoyl-[1,1'-biphenyl]-3-yl)methyl)pyrrolidine-2-carboxamido)ethyl)benzoic acid (Compound 4) Compound 4 was synthesized by a procedure analogous to Example 1, using intermediate compound 4 and (2-methyl-4-sulfamoylphenyl)boronic acid, wherein only one addition of boronic acid is required in step (i) of the procedure. The crude residue was purified by HPLC (HPLC Method C) to give compound 4 (73.1 mg, 0.14 mmol, 60%) as a white foam. LC / MS (Method C): m / z 538 [M+H]+ 2, 12 min. 1H NMR (400 MHz, DMSO-d6) 7.86 (d, J= 8.0 Hz, 2H) , 7.81 (s, 1H) , 7.75 (m, 1H) , 7.4.- 7.34 (m, 4H) , 7.32 (d, J= 8.0 Hz, 2H) , 7, 25 (m, 1H) , 4, 75-5, 00 (m, 1H) , 4, 3.- 4, 25 (m, 1H) , 3, 87 (d, J= 12, 9 Hz, 1H) , 3, 69 (d, J= 12, 9 Hz, 1H) , 3, 23 (dd, J= 10, 6, 4, 6 Hz, 1H) , 3, 10 (d, J= 10, 3 Hz, 1H) , 2, 6.- 2, 58 (m, 1H) , 2, 5.- 2, 43 (m, 1H) , 2, 31 (s, 3H) , 1, 8.- 1, 74 (m, 1H) , 1, 31 (d, J= 7, 0 Hz, 3H) . Exchangeable protons not observed in the spectra. Example 5: 4-((S)-1-((2R,4R)-4-hydroxy-1-((4'-hydroxy-2'-methyl-[1,1'-biphenyl]-3-yl)methyl)pyrrolidine-2-carboxamido)ethyl)benzoic acid (Compound 5) Compound 5 was synthesized by a procedure analogous to Example 1, using intermediate compound 4 and (4-hydroxy-2-methylphenyl)boronic acid, wherein only one addition of boronic ester is required in step (i) of the procedure. The crude residue was purified by HPLC (HPLC Method B) to give compound 5 (63.6 mg, 0.13 mmol, 65%) as a white solid. LC / MS (Method C): m / z 475 [M+H]+ 2, 11 min. 1H NMR (400 MHz, DMSO-d6) 9, 72 (br s, 1H) , 8, 73 (br s, 1H) , 7, 78 (m, 2H) , 7, 43 (s, 1H) , 7, 3.- 7, 28 (m, 2H) , 7, 2.- 7, 16 (m, 1H) , 7, 1.- 7, 02 (m, 2H) , 6, 84 (d, J= 8, 3 Hz, 1H) , 6, 6.- 6, 62 (m, 1H) , 6, 58 (dd, J= 8, 2, 2, 5 Hz, 1H) , 5, 36 (br s, 1H), 4, 8.- 4, 74 (m, 1H) , 4, 5.- 4, 37 (m, 2H) , 4, 3.- 4, 15 (m, 2H) , 3, 6.- 3, 52 (m, 1H) , 3, 5.- 3, 16 (m, 2H, under the water peak) , ), 2, 7.- 2, 63 (m, 1H), 2, 02 (s, 3H), 1, 9.- 1, 85 (m, 1H), 1, 30 (d, J= 7, 0 Hz, 3H). Example 6: 4-((S)-1-((2R,4R)-1-((4'-carbamoyl-2'-methyl-[1,1'-biphenyl]-3-yl)methyl)-4-hydroxypyrrolidine-2-carboxamido)ethyl)benzoic acid (Compound 6) Compound 6 was synthesized by a procedure analogous to that of Example 1, using intermediate compound 4 and 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide, wherein only a boronic ester addition is required in step (i) of the procedure. The crude residue was purified by HPLC (HPLC Method B) to give compound 6 (106.5 mg, 0.21 mmol, 86%) as a white foam. LC / MS (Method C): m / z 502 [M+H]+ 2, 12 min. 1H NMR (400 MHz, DMSO-d6) 9, 74 (br s, 1H) , 8, 74 (d, J= 7, 7 Hz, 1H) , 7, 92 (s, 1H) , 7, 7.- 7, 74 (m, 3H) , 7, 68 (dd, J= 7, 8, 1, 8 Hz, 1H) , 7, 52 (s, 1H) , 7, 4.- 7, 43 (m, 1H) , 7, 38 (m, 1H) , 7, 33 (s, 1H) , 7, 25 (dt, J=7, 6, 1, 5 Hz, 1H) , 7, 07 (m, 3H), 5, 36 (br s, 1H), 4, 82-4, 74 (m, 1H), 4, 52- 4, 41 (m, 2H), 4, 33-4, 25 (m, 1H), 4, 25-4, 18 (m, 1H), 3, 65-3, 54 (m, 1H), 3, 43-3, 30 (m, 1H), 2, 76-2, 64 (m, 1H), 2, 11 (s, 3H), 1, 97- 1, 89 (m, 1H), 1, 30 (d, J=7, 0 Hz, 3H). Example 7: 4-((S)-1-((R)-1-((4'-hydroxy-[1,1'-biphenyl]-3-yl)methyl)pyrrolidine-2-carboxamido)ethyl)benzoic acid (Compound 7) Compound 7 was synthesized by a procedure analogous to that of Example 1, using intermediate compound 2 and 4-hydroxybenzeneboronic acid. The crude residue was purified by HPLC (HPLC method C) to give compound 7 (49.2 mg, 0.11 mmol, 56%) as a white foam. LC / MS (method D): m / z 445 [M+H]+ 1, 82 min. 1H NMR (400 MHz, DMSO-d6) 8, 07 (d, J= 8, 2 Hz, 1H) , 7, 8.- 7, 79 (m, 2H) , 7, 5.- 7, 49 (m, 1H) , 7, 4.- 7, 42 (m, 3H) , 7, 3.- 7, 29 (m, 3H) , 7, 2.- 7, 20 (m, 1H) , 6, 8.- 6, 79 (m, 2H) , 4, 8.- 4, 79 (m, 1H) , 3, 79 (d, J= 12, 8 Hz, 1H) , 3, 54 (d, J = 12, 8Hz, 1H), 3, 09 (dd, J=9, 7, 4, 4 Hz, 1H) , 3, 0.- 2, 95 (m, 1H) , 2, 36 (dd, J = 8, 2 Hz, 1H) , 2, 0.- 1, 98 (m, 1H) , 1, 7.- 1, 62 (m, 3H) , 1, 27 (d, J= 7, 0 Hz, 3H) . Acid and exchangeable hydroxyl protons not observed in the spectra. Example 8: 4-((S)-1-((R)-1-((2'-cyano-4'-hydroxy-[1,1'-biphenyl]-3-yl)methyl)pyrrolidine-2-carboxamido)ethyl)benzoic acid (Compound 8) Compound 8 was synthesized by a procedure analogous to that of Example 1, using intermediate compound 2 and 5-hydroxy-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenitrile, wherein only a boronic ester addition is required in step (i) of the procedure. The crude residue was purified by HPLC (HPLC Method C) to give compound 8 (22 mg, 0.05 mmol, 32%) as a white foam. LC / MS (Method C): m / z 470 [M+H]+ 1, 60 min. 1H NMR (400 MHz, DMSO-d6) 8, 04 (d, J= 8, 2 Hz, 1H) , 7, 8.- 7, 76 (m, 2H) , 7, 48 (br s, 1H) , 7, 4.- 7, 33 (m, 4H) , 7, 28-7, 23 (m, 2H) , 7, 22 (d, J=2, 6 Hz, 1H) , 7, 17 (dd, J= 8, 6, 2, 6 Hz, 1H) , 4, 89-4, 80 (m, 1H) , 3, 85 (d, J= 13, 0 Hz, 1H) , 3, 53 (d, J= 13, 0 Hz, 1H) , 3, 10 (dd, J= 9, 7, 4, 3 Hz, 1H) , 3, 0.- 2, 94 (m, 1H) , 2, 3.- 2, 29 (m, 1H) , 2, 0.- 1, 98 (m, 1H) , 1, 7.- 1, 61 (m, 3H) , 1, 28 (d, J = 6, 9 Hz, 3H) . Acid and exchangeable hydroxyl protons not observed in the spectra. Example 9: 3'-(((R)-2-(((S)-1-(4-carboxyphenyl)ethyl) carbamoyl) pyrrolidine-1-yl) methyl)-2-methyl-[1,1'-biphenyl]-4-carboxylic acid (Compound 9) Compound 9 was synthesized by a procedure analogous to Example 1, using intermediate compound 2 and 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid, wherein only a boronic acid addition is required in step (i) of the procedure. The crude residue was purified by HPLC (HPLC Method B) to give compound 9 (34.7 mg, 0.07 mmol, 34%), as a white foam. LC / MS (Method C): m / z 487 [M+H]+, 1.29 min. 1H NMR (400 MHz, DMSO-d6) 12.88 (br s, 1H) , 9.67 (br s, 1H) , 8.93 (d, J= 7.7 Hz, 1H) , 7.8.- 7.82 (m, 1H) , 7.8.- 7.77 (m, 2H) , 7, 7.- 7, 73 (m, 1H) , 7, 4.- 7, 41 (m, 3H) , 7, 3.- 7, 30 (m, 1H) , 7, 1.- 7, 10 (m, 3H) , 4, 8.- 4, 79 (m, 1H) , 4, 4.- 4, 31 (m, 2H) , 4, 2.- 4, 13 (m, 1H) , 3, 6.- 3, 56 (m, 1H) , 3, 3.- 3, 23 (m, 1H) , 2, 5.- 2, 51 (m, 1H) , 2, 16 (s, 3H) , 2, 1.- 2.04 (m, 1H), 1. 9.- 1.81 (m, 2H), 1.31 (d, J = 6.9 Hz, 3H). Example 10: 4-((S)-1-((R)-1-((2'-methyl-4'-(sulfamoyloxy)-1',2',3',4',5',6'-hexahydro-[1,1'-biphenyl]-3-yl)methyl)pyrrolidine-2-carboxamido)ethyl)benzoic acid (Compound 10) To a solution of compound 1 (74.0 mg, 0.16 mmol) in DMA (1.4 mL), sulfamyl chloride (46.61 mg, 0.40 mmol) was added, and the mixture was stirred at room temperature for 18 hours and confirmed complete by LC / MS. An additional addition of sulfamyl chloride (46.61 mg, 0.40 mmol) was made, and the reaction mixture was stirred for another 18 hours. Afterward, 0.5 mL of water was added to inactivate the reaction. The mixture was purified by reversed-phase HPLC (HPLC method B) to yield compound 10 (68.4 mg, 0.127 mmol, 79% yield) as a colorless glass. LC / MS (Method C): m / z 538 [M+H]+, 1.88 min. 1H NMR (400 MHz, MeOD-d4) 7, 8.- 7, 83 (m, 2H) , 7, 4.- 7, 37 (m, 3H) , 7, 3.- 7, 26 (m, 1H) , 7, 2.- 7, 17 (m, 1H) , 7, 1.- 7, 09 (m, 3H) , 7, 0.- 6, 96 (m, 1H) , 4, 91 (q, J= 7, 0 Hz, 1H) , 4, 50 (d, J= 12, 8 Hz, 1H) , 4, 29 (d, J= 12, 8 Hz, 1H) , 4, 22 (dd, J= 9, 4, 6, 1 Hz, 1H), 3, 8.- 3, 74 (m, 1H), 3, 4.- 3, 35 (m, 1H), 2, 6.- 2, 57 (m, 1H) , 2, 2.- 2, 18 (m, 1H) , 2, 14 (s, 3H) , 2, 1.- 1, 99 (m, 2H) , 1, 40 (d, J= 7, 0 Hz, 3H) . Exchangeable protons not observed. Example 11: 4-( (S) -1- ( (R) -1- ( (4'-carbamoyl-2'-hydroxy-[1, 1'-biphenyl]-3-yl) methyl) pyrrolidine-2-carboxamido) ethyl) benzoic acid (compound 11). Step (i): A mixture of 4-bromo-3-hydroxybenzamide (204.79 mg, 0.95 mmol), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (200.00 mg, 0.86 mmol), potassium carbonate (238.21 mg, 1.72 mmol), and tetrakis(triphenylphosphine) palladium (0) (99.58 mg, 0.09 mmol) in 1,4-dioxane (4.5 mL) and water (1 mL) was heated to 100 °C in a microwave reactor for 40 minutes. The mixture was diluted with EtOAc and 1 M HCl (aq). The organic layers were separated and dried over MgSO4, filtered, and concentrated. The gummy residue was suspended in Et2O and sonicated. The liquid was pipetted off to yield 4-(3-formylphenyl)-3-hydroxybenzamide (150 mg, 0.6218 mmol, 72% yield) as a yellow solid, which was used without further purification. Step (ii): A mixture of intermediate compound 1 (150.0 mg, 0.480 mmol) and 4-(3-formylphenyl)-3-hydroxybenzamide (138.83 mg, 0.58 mmol) in DMF (3 ml) was stirred at TA for 30 minutes, and then sodium triacetoxyborohydride (203.27 mg, 0.96 mmol) was added. The mixture was stirred at room temperature overnight, after which it was directly purified by HPLC (HPLC Method A) to provide methyl 4-[(1S)-1-[[(2R)-1-[[3-(4-carbamoyl-2-hydroxyphenyl)phenyl]methyl]pyrrolidine-2-carbonyl]amino]ethyl]benzoate (56.8 mg, 0.11 mmol, 23% yield) in the form of a clear gum. LC / MS (Method C): m / z 502 [M+H]+ 3.69 min. Step (iii): This was carried out analogously to Step (ii) of Example 1 to provide compound 11 (40.2 mg, 73%) in the form of a white foam.LC / MS (Método C) : m / z 488 [M+H]+ 1, 72 min RMN 1H (400 MHz, DMSO-d6) 12, 88 br (s, 1H) , 9, 87 (s, 1H) , 9, 73 (br s, 1H) , 8, 94 (d, J = 7, 8 Hz, 1H) , 7, 88 (s, 1H) , 7, 84 (d, J = 8, 0 Hz, 2H) , 7, 68 (s, 1H) , 7, 65-7, 59 (m, 1H) , 7, 46 (s, 1H) , 7, 4.- 7, 35 (m, 3H) , 7, 31 (br s, 1H) , 7, 25 (d, J = 7, 9 Hz, 1H) , 7, 18 (d, J = 8, 0 Hz, 2H) , 4, 87 (q, J = 7, 1 Hz, 1H) , 4, 43-4, 32 (m, 2H) , 4, 22-4, 14 (m, 1H) , 3, 36-3, 26 (m, 1H) , 3, 16 (s, 1H) , 2, 16-2, 05 (m, 1H) , 1, 96-1, 82 (m, 2H) , 1, 34 (d, J = 6, 9 Hz, 3H) . LC / MS (método C) : m / z 488 [M+H]+ 1, 72 min. Ejemplo 12: Ácido 4- ( (S) -1- ( (R) -1- ( (4'-carbamoil-6-hidroxi-[1, 1'-bifenil]-3-il) metil) pirrolidina-2-carboxamido) etil) benzoico (compuesto 12) Step (i): A mixture of intermediate compound 5 (100.0 mg, 0.21 mmol), (4-carbamoylphenyl)boronic acid (38.0 mg, 0.23 mmol), potassium carbonate (58.15 mg, 0.42 mmol), and tetrakis(triphenylphosphine) palladium (0) (24.31 mg, 0.02 mmol) in 1,4-dioxane (1.6 mL) and water (0.50 mL) was heated to 100 °C in a microwave reactor for 40 minutes, after which the mixture was diluted with EtOAc and water. The organic layers were separated, and the aqueous layer was washed with brine, dried over MgSO4, filtered, and concentrated. The residue was purified by ultrafast column chromatography (normal phase, 10 g of Biotage® SNAP KP-Sil, 30 ml per min, MeOH gradient in DCM from 0% to 8%), to provide methyl 4-[(1S)-1-[((2R)-1-[[3-(4-carbamoylphenyl)-4-methoxyphenyl]methyl]pyrrolidine-2-carbonyl]ethyl]benzoate (48 mg, 0.093 mmol, 44% yield). LC / MS (method B): m / z 516 [M+H]+2, 11 min. Step (ii): To a solution of methyl 4-[(1S)-1-[[(2R)-1-[[3-(4-carbamoylphenyl)-4-methoxyphenyl]methyl]pyrrolidine-2-carbonyl]amino]ethyl]benzoate (45.0 mg, 0.09 mmol) in DCM (1.5 mL) at -78 °C, a solution of boron tribromide in 1 M DCM (0.44 mL, 0.44 mmol) was added dropwise. The mixture was allowed to heat gradually to room temperature and stirred at room temperature overnight. The mixture was cooled to 0 °C and MeOH / H2O 1:1 (2 mL) was added dropwise. The mixture was stirred for 1 hour and then concentrated, and the crude material was purified by reversed-phase HPLC (HPLC method C) to give compound 12 (25 mg, 0.05 mmol, 59% yield) as a white foam. LC / MS (Method C): m / z 488 [M+H]+ 1, 64 min. NMR 1H (400 MHz, Methanol-d4) 7, 9.- 7, 87 (m, 2H) , 7, 8.- 7, 79 (m, 2H) , 7, 6.- 7.49 (m, 2H) , 7.41 (d, J = 2.3 Hz, 1H) , 7.26 (dd, J = 8.5, 2.3 Hz, 1H) , 7.13 (d, J = 8.2 Hz, 2H) , 6.91 (d, J = 8.3 Hz, 1H) , 4, 90 (q, J = 8, 5, 7, 1 Hz, 1H) , 4, 43 (d, J = 12, 9 Hz, 1H) , 4, 23-4, 11 (m, 2H) , 3, 76 (dt, J = 11, 6, 6, 0 Hz, 1H) , 3, 4.- 3, 33 (m, 1H) , 2, 6.- 2, 50 (m, 1H) , 2, 3.- 2, 14 (m, 1H) , 2, 1.- 1, 94 (m, 2H) , 1, 40 (d, J = 7, 0 Hz, 3H) . Exchangeable protons are absent. Example 13: 4-((S)-1-((R)-1-((4'-carbamoyl-5-hydroxy-2'-methyl-1,2,3,4,5,6-hexahydro-[1,1'-biphenyl]-3-yl)methyl)pyrrolidine-2-carboxamido)ethyl)benzoic acid (Compound 13) Step (i): A mixture of methyl 4-[(1S)-1-[[(2R)-1-[(3-bromo-5-methoxy-phenyl)methyl]pyrrolidine-2-carbonyl]amino]ethyl]benzoate compound intermediate 6 (250 mg, 0.53 mmol), 3-methyl-4-(4, 4, 5, 5-tetramethyl-1, 3,2-dioxaborolan-2-yl)benzamide (151.0 mg, 0.53 mmol, 58 mmol), potassium carbonate (145.4 mg, 1.05 mmol), and tetrakis(triphenylphosphine)palladium(0) (60.8 mg, 0.050 mmol) in 1,4-dioxane (3.5 mL) and water (0.8 ml) was heated to 100 °C in a Biotage microwave reactor for 1 hour, after which the mixture was diluted with EtOAc and water. The organic layer was separated and the aqueous layer was washed with brine, dried over MgSO4, filtered and concentrated.The residue was purified by ultrafast column chromatography (normal phase, 10 g, Biotage® SNAP KP-Sil - 50 µm irregular silica, 30 ml per min, [MeOH gradient in DCM 0% to 8%]. The resulting impure gum was sonicated in ether and the solids were separated by filtration to provide methyl 4-[(1S)-1-[[(2R)-1-[[3-(4-carbamoyl-2-methylphenyl)-5-methoxyphenyl]methyl]pyrrolidine-2-carbonyl]amino]ethyl]benzoate (174 mg, 0.33 mmol, 62% yield) as a cream-colored solid. LC / MS (method B): m / z 530 [M+H]+ 2, 16 min. Step (ii): To a solution of methyl 4-[(1S)-1-[[(2R)-1-[[3-(4-carbamoyl-2-methylphenyl)-5-methoxyphenyl]methyl]pyrrolidine-2 carbonyl]amino]ethyl]benzoate (170 mg, 0.32 mmol) in DCM (5 mL) at -78 °C, boron tribromide solution, 1 M in DCM (5 mL) (1.6 mL, 1.6 mmol), was added dropwise. The mixture was allowed to heat gradually to room temperature and stirred overnight. The mixture was cooled to 0 °C and MeOH / H2O 1:1 (2 mL) was added dropwise. The mixture was stirred for 1 hour, after which it became concentrated. The crude material was purified by reversed-phase HPLC (HPLC method C) to provide compound 13 (89 mg, 0.18 mmol, 55% yield) as a white foam. LC / MS (Method C): m / z 502 [M+H]+ 1, 66 min. 1H NMR (400 MHz, Methanol-d4) 8, 0.- 7, 85 (m, 2H) , 7, 73 (s, 1H) , 7, 63 (d, J = 8, 0 Hz, 1H) , 7, 19 (d, J = 8, 1 Hz, 2H) , 7, 00 (d, J = 7, 9 Hz, 1H) , 6, 9.- 6, 69 (m, 3H) , 4, 96 (q, J = 6, 7 Hz, 1H) , 4, 43 (d, J =12, 8 Hz, 1H) , 4, 2.- 4, 12 (m, 2H) , 3, 8.- 3, 71 (m, 1H) , 3, 4.- 3, 35 (m, 1H) , 2, 6.- 2, 55 (m, 1H) , 2, 3.- 2, 18 (m, 1H) , 2, 16 (s, 3H) , 2, 1.- 1, 97 (m, 2H) , 1, 42 (d, J = 7, 0 Hz, 3H) . Exchangeable protons are absent. Example 14: 4-((1S)-1-((2R)-1-((4'-carbamoyl-6-hydroxy-2'-methyl-1,2,3,4,5,6-hexahydro-[1,1'-biphenyl]-3-yl)methyl)pyrrolidine-2-carboxamido)ethyl)benzoic acid (Compound 14) Compound 14 was synthesized by a procedure analogous to that of Example 12, using the intermediate compound 5 and 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide to give compound 14. LC / MS (Method C): m / z 502 [M+H]+ 3, 69 min. 1H NMR (400 MHz, Methanol-d4) 7.94 (d, J = 8.2 Hz, 2H) , 7.73 (d, J = 1.8 Hz, 1H) , 7.6.- 7.54 (m, 1H) , 7.3.- 7.26 (m, 1H) , 7.21 (d, J = 8, 1 Hz, 2H) , 7, 16 (d, J = 2, 3 Hz, 1H) , 7, 0.- 6, 96 (m, 1H) , 6, 90 (d, J = 8, 3 Hz, 1H) , 4, 96 (q, J = 7, 0, 6, 5 Hz, 1H) , 4, 38 (d, J = 12, 8 Hz, 1H) , 4, 2.- 4, 11 (m, 2H) , 3, 78-3, 66 (m, 1H) , 3, 3.- 3, 31 (m, 1H) , 2, 64-2, 52 (m, 1H) , 2, 29-2, 15 (m, 1H) , 2, 11 (s, 3H) , 2, 0.- 1, 98 (m, 2H) , 1, 44 (d, J = 7, 0 Hz, 3H) . Exchangeable protons are absent. Example 15: Acid (R) -4- ( (1- ( (4'-carbamoyl-2'-methyl-[1, 1'-biphenyl]-3-yl) methyl) pyrrolidine-2-carboxamido) methyl) -2-hydroxybenzoic (compound 15) Step (i): The intermediate compound 8 (0.20 g, 0.45 mmol), 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (0.15 g, 0.58 mmol), and K₂CO₃ (0.123 g, 0.89 mmol) were dissolved in 6 mL of a dioxane:water (3:3) mixture and purged with nitrogen gas for 30 minutes at room temperature. Then, PdCl₂(dppf) DCM (0.036 g, 0.045 mmol) was added, and the reaction mixture was stirred at 80 °C for 4 hours. The reaction mixture was then partitioned between water (70 mL) and EtOAc (70 mL). The aqueous layer was further extracted with EtOAc (2 x 50 ml), and the organic layers were combined and dried (Na2SO4). The solvent was separated under vacuum, and the crude product was purified by gradient reversed-phase ultrafast column chromatography (reversed phase, C18 silica).The product eluted in MeCN in water from 0% to 55% to give (R)-4-((1-((4'-carbamoyl-2'-methyl-[1,1'-biphenyl]-3-yl)methyl)pyrrolidine-2-carboxamido)methyl)-2-hydroxybenzoate methyl (0.147 g, 65%) as a light brown solid. LC / MS: (Method A): m / z 502 [M+H]+ at 1.46 min. Step (ii): 4-((S)-1-((3R,6R)-6-methyl-4-(4-(trifluoromethyl)benzyl)morpholine-3-carboxamido)ethyl)methyl benzoate (0.147 g, 0.29 mmol) was dissolved in dioxane (2 ml) and water (1 ml). LiOH monohydrate (0.036 g, 0.88 mmol) was added at room temperature and the mixture was stirred at room temperature for 16 hours. The reaction mixture was then acidified with 4 N aqueous HCl (2 ml) to adjust the pH to ~1 and extracted with EtOAc (40 ml). The aqueous layer was further extracted with EtOAc (3 x 30 ml), and the organic layers were combined and dried (Na2SO4). The solvent was separated under vacuum and the crude product was purified by gradient reversed-phase ultrafast column chromatography (reversed phase, C18 silica). The product was eluted with MeCN in water from 0% to 26% to give compound 15 (0.10 g, 70%) as a whitish solid. LC / MS: (Method A): m / z 488 [M+H]+ at 1.34 min.RMN 1H: (400 MHz, DMSO) 1, 79 (s, 3H) , 2, 24 (s, 3H) , 3, 17 (s, 3H) , 3, 81 (s, 1H) , 4, 08 (s, 1H) , 4, 26- 4, 14 (m, 2H) , 6, 62-6, 60 (d, 1H, J= 8, 0 Hz) , 6, 66 (s, 1H) , 7, 34-7, 24 (m, 3H) , 7, 44-7, 401 (m, 3H) , 7, 64-7, 62 ( (d, 1H, J= 8, 0 Hz) , 7, 75-7, 73 (d, 1H, J= 7, 6 Hz) , 7, 80 (s, 1H) , 7, 97 (s, 1H) , 8, 53 (s, 1H) , 12, 97 (s, 2H) . Ejemplo 16: Ácido (R) -2-hidroxi-4- ( (1- ( (2'-metil-4'-sulfamoil-[1, 1'-bifenil]-3-il) metil) pirrolidina-2-carboxamido) metil) benzoico (Compuesto 16) Compound 16 was synthesized by a procedure analogous to that of Example 15, using intermediate compound 8 and 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-ylbenzenesulfonamide) to give compound 16. LC / MS: (Method A) m / z 524 [M+H]+ at 1, 40 min. 1H NMR: (400 MHz, DMSO) : 1.77-1.74 (t, 3H, J=6.6 Hz) , 2.17 (s, 1H) , 2.26 (s, 3H) , 3.05 (s, 1H) , 3.42-3.40 (m, 1H) , 3. 50-3, 47 (m, 1H) , 3, 68 (s, 1H) , 4, 00-3, 97 (d, 1H, J=12, 4 Hz) , 4, 25-4, 13 (m, 2H) , 6, 57-6, 56 (d, 1H, J=8, 0 Hz) , 6, 61 (s, 1H), 7, 28-7, 268 (d, 1H, J=6, 8 Hz) , 7, 44-7, 35 (m, 6H) , 7, 60-7, 58 (d, 1H, J=8, 0 Hz) , 7, 70-7, 67 (dd, 1H, J=1, 6 Hz & J=4, 0 Hz) , 7, 74-7, 74 (d, 1H, 1, 2 Hz), 8, 39 (s, 1H), 13, 62 (s, 2H). Example 17: 4-((S)-1-((R)-1-((4'-carbamoyl-2'-methyl-[1,1'-biphenyl]-3-yl)methyl)pyrrolidine-2-carboxamido)ethyl)-2-hydroxybenzoic acid (Compound 17) Compound 17 was synthesized by a procedure analogous to that of Example 15, using intermediate compound 10 and 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide to give compound 17. LC / MS: (Method A): The mass of the product was confirmed m / z 502 [M+H]+ at 1, 16 min. 1H NMR: (400 MHz, DMSO) 1.28-1.26 (d, 3H, J=7.2 Hz), 1.85-1.75 (m, 3H), 2.24 (s, 4H), 3.16 (s, 2H), 3.84 (s, 1H), 4.01 (s, 1H), 4, 79-4, 72 (m, 1H), 6, 66-6, 64 (d, 1H, J= 7, 2 Hz), 6, 72 (s, 1H), 7, 30-7, 23 (dd, 2H, J= 7, 6 Hz), 7, 45-7, 35. (m, 4H) , 7, 64-7, 62 (d, 1H, J= 8, 0 Hz) , 7, 75-7, 73 (d, 1H, J= 8, 0 Hz) , 7, 80 (s, 1H) , 7, 98 (s, 1H) , 8, 32 (s, 1H) , 12, 97 (s, 1H). Example 18: 2-hydroxy-4-((S)-1-((R)-1-((2'-methyl-4'-sulfamoyl-[1,1'-biphenyl]-3-yl)methyl)pyrrolidine-2-carboxamido)ethyl)benzoic acid (Compound 18) Compound 18 was synthesized by a procedure analogous to that of Example 15, using intermediate compound 10 and 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide to give compound 18. LC / MS: (Method A) m / z 538 [M+H]+ at 1, 22 min. 1H NMR: (400 MHz, DMSO) 1.27-1.26 (d, 3H, J=6.8 Hz), 1.84-1.75 (m, 3H), 2.26 (s, 4H), 3.20 (s, 1H), 3.87-3.80 (bs, 1H), 4, 02-3, 80 (bs, 1H) , 4, 77-4, 73 (t, 1H, J=7, 2 Hz) , 6, 65-6, 64 (d, 1H, J= 6, 4 Hz) , 6, 72 (s, 1H) , 7, 46-7, 29 (m, 7H) , 7, 62-7, 60 (d, 1H, J= 8, 0 Hz) , 7, 69- 7, 670 (d, 1H, J= 8, 0 Hz) , 7, 74 (s, 1H) , 8, 32-8, 31 (m, 1H) , 13, 08 (s, 1H) . (some aliphatic protons fused with the DMSO-d6 water peak) Example 19: 4-((S)-1-((R)-1-((6-hydroxy-4'-sulfamoyl-[1,1'-biphenyl]-3-yl)methyl)pyrrolidine-2-carboxamido)ethyl)cyclohex-3-ene-1-carboxylic acid (Compound 19) Compound 19 was synthesized by a procedure analogous to that of Example 12, using the intermediate compound 5 and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide to give compound 19. LC / MS (method D): m / z 524 [M+H]+1, 56 min. 1H NMR (400 MHz, Methanol-d4) 7.86 (d, J = 8.0 Hz, 2H) , 7.8.- 7.77 (m, 2H) , 7.5.- 7.54 (m, 2H) , 7.39 (d, J = 2.3 Hz, 1H) , 7.2.- 7, 23 (m, 1H) , 7, 08 (d, J = 8, 0 Hz, 2H) , 6, 89 (d, J = 8, 3 Hz, 1H) , 4, 9.- 4, 85 (m, 1H) , 4, 43 (d, J = 12, 9 Hz, 1H) , 4, 2.- 4, 07 (m, 2H) , 3, 75 (dt, J = 11, 6, 6, 0 Hz, 1H) , 3, 39-3, 32 (m, 1H) , 2, 65-2, 47 (m, 1H) , 2, 27-2, 13 (m, 1H) , 2, 1.- 1, 92 (m, 2H) , 1, 36 (d, J = 7, 0 Hz, 3H) . Exchangeable protons are absent Example 20: 4-((S)-1-((R)-1-((5-hydroxy-2'-methyl-4'-sulfamoyl-[1,1'-biphenyl]-3-yl)methyl)pyrrolidine-2-carboxamido)ethyl)benzoic acid (Compound 20) Compound 20 was synthesized by a procedure analogous to that of Example 12, using the intermediate compound 6 and 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide to give compound 20. LC / MS (method D): m / z 538 [M+H]+ 1, 69 min. 1H NMR (400 MHz, Methanol-d4) 7, 9.- 7, 83 (m, 2H), 7, 7.- 7, 71 (m, 1H), 7, 6.- 7, 59 (m, 1H), 7, 21-7, 13 (m, 2H), 7, 03 (d, J = 8, 1 Hz, 1H), 6, 93 (dd, J = 2, 3, 1, 6 Hz, 1H) , 6, 85 (t, J = 1, 5 Hz, 1H) , 6, 76 (dd, J = 2, 4, 1, 4 Hz, 1H) , 4, 94 (q, J = 7, 0 Hz, 1H), 4, 45 (d, J = 12.7 Hz, 1H) , 4.2.- 4.15 (m, 2H) , 3.8.- 3.72 (m, 1H) , 3.4.- 3.35 (m, 1H) , 2.6.- 2.55 (m, 1H) , 2.3.- 2.17 (m, 1H) , 2.17 (s, 3H) , 2.1.- 1.98 (m, 2H) , 1.41 (d, J = 7.0 Hz, 3H) . Exchangeable protons are absent. Example 21: 4-((S)-1-((2R,4R)-1-((4'-carbamoyl-5-hydroxy-2'-methyl-[1,1'-biphenyl]-3-yl)methyl)-4-hydroxypyrrolidine-2-carboxamido)ethyl)benzoic acid (Compound 21) Compound 21 was synthesized by a procedure analogous to that of Example 12, using the intermediate compound 6 and 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide to give compound 21. LC / MS (method D): m / z 518 [M+H]+ 1, 46 min. 1H NMR (400 MHz, Methanol-d4) 7, 9.- 7, 84 (m, 2H) , 7, 71 (dt, J = 2, 0, 0, 6 Hz, 1H) , 7, 6.- 7, 59 (m, 1H) , 7, 1.- 7, 12 (m, 2H) , 6.97 (d, J = 8.0 Hz, 1H) , 6.92 (dd, J = 2.3, 1.5 Hz, 1H) , 6.89 (t, J = 1.5 Hz, 1H) , 6.75 (dd, J = 2.3, 1.5 Hz, 1H) , 4.93 (q, J = 7, 0Hz, 1H) , 4, 5.- 4, 55 (m, 1H) , 4, 52 (d, J = 12, 6 Hz, 1H) , 4, 31 (dd, J =10, 8, 4, 2 Hz, 1H) , 4, 17 (d, J = 12, 7 Hz, 1H) , 3, 79 (d, J = 11, 8 Hz, 1H) , 3, 43 (dd, J= 11, 8, 3, 8 Hz, 1H) , 2, 83 (ddd, J= 14, 0, 10, 8, 4, 7 Hz, 1H) , 2, 19-2, 08 (m, 4H) , 1, 42 (d, J = 7, 0Hz, 3H). Exchangeable protons are absent. Example 22: 4-((1S)-1-((2R)-1-((2'-hydroxy-4'-sulfamoyl-1',2',3',4',5',6'-hexahydro-[1,1'-biphenyl]-3-yl)methyl)pyrrolidine-2-carboxamido)ethyl)benzoic acid (Compound 22) Step (i): The intermediate compound 1-HCl (0.35 g, 1.12 mmol) and 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (0.31 g, 1.34 mmol) were dissolved in DCM (4 mL) under a nitrogen atmosphere. 4 Å molecular sieves (300 mg) were also added to maintain moisture-free conditions. Potassium acetate (0.11 g, 1.68 mmol) was then added at room temperature, and the reaction mixture was stirred for 4 hours at room temperature. The reaction mixture was then cooled to 0°C and sodium triacetoxyborohydride (0.28 g, 1.34 mmol) was added in portions, and the reaction mixture was allowed to be stirred at room temperature for 16 hours.The solvent was separated under vacuum to obtain the crude product, which was purified by gradient reversed-phase ultrafast column chromatography (reversed phase, C18 silica). The product eluted in 0% to 22% MeCN to give 4-((S)-1-((R)-1-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)pyrrolidine-2-carboxamido)ethyl)methyl benzoate (0.26 g, 47.18%) as a yellow solid. LC / MS: (Method A): m / z 411 [M+H]+, (boronic acid) at 1.22 min and m / z 493 [M+H]+, at 1.81 min. Step (ii): 4-((S)-1-((R)-1-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)pyrrolidine-2-carboxamido)ethyl)methyl benzoate (0.16 g, 0.32 mmol), 4-bromo-3-hydroxybenzenesulfonamide (0.10 g, 0.39 mmol) and K2CO3 (0.13 g, 0.97 mmol) were dissolved in toluene (1 ml), ethanol (0.5 ml) and water (0.5 ml). The mixture was purged with nitrogen gas at room temperature for 20 minutes, then PdCl2 (dppf) DCM (0.014 g, 0.016 mmol) was added, and the reaction mixture was stirred at 90 °C for 1.5 hours. The reaction mixture was partitioned between water (70 mL) and EtOAc (70 mL), and the aqueous layer was further extracted with EtOAc (2 x 40 mL). The organic layers were combined and dried (Na2SO4), the solvent was removed under vacuum, and the crude product was purified by gradient reversed-phase ultrafast column chromatography (reversed phase, C18 silica).The product was eluted with MeCN in water from 0% to 24% to provide 4-((S)-1-((R)-1-((2'-hydroxy-4'-sulfamoyl-[1,1'-biphenyl]-3-yl)methyl)pyrrolidine-2-carboxamido)ethyl)methyl benzoate (0.08 g, 46.96%) as a yellow solid, which was used in the next step without further purification. LC / MS: (Method A): m / z 538 [M+H]+, at 1.33 min. Step (iii): 4-((S)-1-((R)-1-((2'-hydroxy-4'-sulfamoyl-[1,1'-biphenyl]-3-yl)methyl)pyrrolidine-2-carboxamido)ethyl)methyl benzoate (0.08 g, 0.15 mmol) was dissolved in dioxane (0.5 ml) and water (0.5 ml). LiOH (0.03 g, 0.76 mmol) was added at room temperature and the reaction mixture was allowed to stir at room temperature for 3 hours. The reaction mixture was concentrated under vacuum to provide the crude product, which was purified using preparative HPLC (HPLC method D). LC / MS: (Método A): m / z 524 [M+H]+, a 1, 18 min. RMN 1H: (400 MHz, CD3OD): 1, 34-1, 35 (d, 3H J= 6, 8 Hz), 2, 05-1, 89 (m, 3H), 2, 34 (s, 1H), 2, 82-2, 81 (d, 1H, J= 4, 8 Hz), 3, 38-3, 37 (d, 1H, J= 3, 2 Hz), 3, 55-3, 53 (d, 1H, J= 6, 0 Hz), 4, 00 (s, 2H), 7, 26-7, 25 (d, 2H, J= 7, 2 Hz), 7, 45-7, 34 (m, 5H) 7, 58-7, 56 (d, 1H, J= 7, 6 Hz), 7, 64 (s, 1H), 7, 91-7, 89 (d, 2H, J= 7, 2 Hz). Ejemplo 23: Acido (S)-4- (1- (2- ( (4'-carbamoil-5-hidroxi-2'-metil-[1, 1'-bifenil]-3-il) metil) -2-azabiciclo[2.1.1]hexano-1-carboxamido) etil) benzoico (Compuesto 23) Step (i): 2-(tert-butoxycarbonyl)-2-azabicyclo[2.1.1]hexane-1-carboxylic acid (0.25 g, 1.10 mmol) was dissolved in MeCN (3 ml) and methyl (S)-4-(1-aminoethyl)benzoate (0.23 g, 1.32 mmol) was added to the reaction mixture at room temperature. Then HATU (0.63 g, 1.65 mmol) was added and the reaction mixture was stirred at room temperature for 30 min. Next, N,N-diisopropylethylamine (0.6 ml, 3.30 mmol) was added at room temperature and stirred at room temperature for 2 hours. The reaction mixture was divided between water (60 ml) and EtOAc (50 ml), and the aqueous layer was further extracted with EtOAc (2 x 30 ml).The organic layers were then combined and dried (Na2SO4), the solvent was removed under vacuum, and the crude product was purified by gradient reversed-phase ultrafast column chromatography (C18 silica). The product was eluted with 100% MeCN to yield tert-butyl (S)-1-((1-(4-(methoxycarbonyl)phenyl)ethyl)carbamoyl)-2-azabicyclo[2,1,1]hexane-2-carboxylate (0.42 g, 98%) as a yellow solid. LC / MS: (Method A): m / z 289 [M+H-Boc]+ at 2.23 min. Step (ii): (S)-1-((1-(4-(methoxycarbonyl)phenyl)ethyl)carbamoyl)-2-azabicyclo[2.1.1]hexane-2-carboxylate tert-butyl (0.42 g, 1.08 mmol) was dissolved in dioxane (2 ml) under a nitrogen atmosphere, and then 4 N HCl was added to dioxane (4 ml) at room temperature and allowed to be stirred at room temperature for 3 hours. The solvent was separated under vacuum and the crude material was purified by trituration with diethyl ether (5 ml) to provide methyl (S)-4-(1-(2-azabicyclo[2.1.1]hexane-1-carboxamido)ethyl)benzoate hydrochloride (0.34 g, quantitative) as a pale yellow solid. LC / MS: (Method A) : m / z 289 (ES+) at 1, 00 min. Step (iii): Methyl (S)-4-(1-(2-azabicyclo[2,1,1]hexane-1-carboxamido)ethyl)benzoate hydrochloride (0.26 g, 0.80 mmol) and DIPEA (0.4 ml, 2.40 mmol) were dissolved in MeCN (3 ml) at room temperature. Following this, 3'-(bromomethyl)-5'-hydroxy-2-methyl-[1,1'-biphenyl]-4-carboxamide (0.30 g, 0.96 mmol) was added, and the reaction mixture was stirred at 80 °C for 16 hours. The reaction mixture was partitioned between water (80 ml) and EtOAc (80 ml), and the aqueous layer was further extracted with EtOAc (2 x 25 ml). The organic layers were combined and dried (Na2SO4), the solvent was removed under vacuum, and the crude product was purified by gradient reversed-phase ultrafast column chromatography (C18 silica). The product was eluted with MeCN in water from 0% to 59% to yield (S)-4-(1-(2-((4'-carbamoyl-5-hydroxy-2'-methyl-[1,1'-biphenyl]-3-yl)methyl)-2-azabicyclo[2.1.1]hexane-1-carboxamido) ethyl) methyl benzoate (0.20 g, 48%) in the form of a yellow solid. LC / MS (method A): m / z 528.17 (ES+) at 1.65 min. Step (iv): Methyl (S)-4-(1-(2-((4'-carbamoyl-5-hydroxy-2'-methyl-[1,1'-biphenyl]-3-yl)methyl)-2-azabicyclo[2.1.1]hexane-1-carboxamido)ethyl)benzoate (0.20 g, 0.39 mmol) was dissolved in dioxane (1 ml) and water (1 ml). Then, LiOH monohydrate (0.084 g, 1.99 mmol) was added at room temperature and the mixture was stirred at room temperature for 3 hours. The reaction mixture was acidified with glacial acetic acid (2 ml) to adjust the pH to ~4 and then concentrated under vacuum. The crude product was purified by ultrafast reversed-phase column chromatography (reversed phase, C18 silica) with gradient, and the product was eluted with ACN in water from 0% to 36% to give compound 23 (0.17 g, 85.19%) as a whitish solid. LC / MS (method A): m / z 514.2 (ES+) at 1.456 min.RMN 1H: (400 MHz, DMSO) 1, 373-1, 355 (d, 3H, J=7, 2 Hz) , 1, 791-1, 768 (d, 4H, J=9, 2 Hz) , 2, 267 (s, 3H) , 2, 619-2, 595 (d, 2H, J=9, 6 Hz) , 2, 686-2, 666 (d, 1H, J=8, 0 Hz) , 3, 475 (s, 2H) , 5, 041-4, 986 (m, 1H) , 6, 594 (s, 1H) , 6, 848-6, 822 (d, 2H, J=10, 4 Hz) , 7, 251-7, 231 (d, 1H, J=8, 0 Hz) , 7, 341 (s, 1H) , 7, 403-7, 383 (d, 2H, J=8, 0 Hz) , 7, 735-7, 716 (d, 1H, J=7, 6 Hz) , 7, 800-7, 780 (t, 3H, J=4, 0 Hz) , 7, 968 (s, 1H) , 8, 228- 8, 208 (d, 1H, J=8, 0 Hz) , 12, 979 (s, 1H) . Ejemplo 24: Ácido 4- ( (S) -1- ( (R) -1- ( (5- (2-metil-4-sulfamoilfenil) piridin-3il) metil) pirrolidina-2-carboxamido) etil) benzoico (compuesto 24) Step (i): A mixture of 5-bromonicotinaldehyde (356.81 mg, 1.92 mmol) and intermediate compound 1 (300.0 mg, 0.96 mmol) in DCM (4.5 ml) was stirred at room temperature for 1 hour, and then sodium triacetoxyborohydride (426.87 mg, 2.01 mmol) was added and the mixture was stirred at room temperature for 16 hours, after which it was diluted with saturated NaHCO3. The organic layers were separated, washed with water and brine, dried (fried), and concentrated. The residue was then purified by ultrafast column chromatography (25 g Biotage® SNAP KP-Sil, 30 ml per min, ethyl acetate gradient in isohexane from 30% to 100%) to provide methyl 4-[(1S)-1-[(2R)-1-[(5-bromo-3-pyridyl)methyl]pyrrolidine-2-carbonyl]amino]ethyl]benzoate (398.1 mg, 0.89 mmol, 93% yield), as a white solid. LC / MS (method B): m / z 446 [M+H]+, 2, 12 min.Step (ii): A mixture of methyl 4-[(1S)-1-[[(2R)-1-[(5-bromo-3-pyridyl)methyl]pyrrolidine-2-carbonyl]amino]ethyl]benzoate (200.0 mg, 0.45 mmol), 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide (173.11 mg, 58 mmol), potassium carbonate (123.86 mg, 0.90 mmol) and tetrakis(triphenylphosphine) palladium (0) (77.67 mg, 0.07 mmol) in 1,4-dioxane (1.8 ml) and water (0.45 ml) was heated to 100 °C for 30 minutes in a microwave reactor. The crude product was diluted with water and EtOAc and the organic layers were separated, washed with water and brine, and dried (fried) before being concentrated under vacuum.The residue was purified by ultrafast column chromatography (50 g of Biotage® SNAP KP-Sil, 80 ml per min, ethyl acetate gradient in isohexane from 30% to 100%) to give methyl 4-[(1S)-1-[[(2R)-1-[[5-(2-methyl-4-sulfamoylphenyl)-3-pyridyl]methyl]pyrrolidine-2-carbonyl]amino]ethyl]benzoate (231 mg, 96.065%), as a whitish solid. LC / MS (method B): m / z 537 [M+H]+, 1, 93 min. Step (iii): To a solution of lithium hydroxide monohydrate (63.22 mg, 1.51 mmol) in water (3.2 ml) and 1,4-dioxane (3.2 ml) 4-[(1S)-1-[[(2R)-1-[[5-methyl-4-sulfamoylphenyl)-3-pyridyl]methyl]pyrrolidine-2-carbonyl]amino]ethyl]methylbenzoate (231.0 mg, 0.43 mmol) was added and the resulting mixture was allowed to be stirred for 3 hours before checking that it was complete by LC / MS. The mixture was then concentrated under vacuum, and the residue was purified by reversed-phase HPLC (5–35%, low pH) to yield compound 24 (136.1 mg, 0.26 mmol, 60.5% yield) as a colorless glass. LC / MS (Method D): m / z 523 [M+H]+, 1, 51 min. 1H NMR (400 MHz, DMSO-d6) 9.83 (br s, 1H), 89.01 (d, J = 7.7 Hz, 1H), 8.66 (d, J = 2.0 Hz, 1H), 8.53 (d, J = 2.1 Hz, 1H), 7.92 (t, J = 2, 1 Hz, 1H), 7, 8.- 7, 78 (m, 2H), 7, 7.- 7, 73 (m, 1H), 7, 7.- 7.64 (m, 1H) , 7.36 (s, 2H) , 7.22 (d, J = 8.0 Hz, 1H) , 7.15 (d, J = 8.1 Hz, 2H) , 4.84 (p, J = 7.0 Hz, 1H) , 4.5.- 4.42 (m, 2H) , 4, 2.- 4, 22 (m, 1H) , 3, 6.- 3, 55 (m, 1H) , 3, 4.- 3, 25 (m, 1H) , 2, 17 (s, 3H) , 2, 15-2, 06 (m, 1H) , 1, 91 (tq, J= 15, 8, 8, 7, 8, 2 Hz, 2H) , 1, 31 (d, J = 7, 0 Hz, 3H) . Interchangeable proton absent. Example 25: 4-((S)-1-((2R,4R)-1-((5-(4-carbamoyl-2-methylphenyl)pyridin-3yl)methyl)-4-hydroxypyrrolidine-2-carboxamido)ethyl)benzoic acid (Compound 25) Compound 25 was synthesized by a procedure analogous to Example 24 using the intermediate compound 3 and 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide to provide compound 25. LC / MS (method D): m / z 503 [M+H]+, 1, 21 min. 1H NMR (400 MHz, DMSO-d6) 8.80 (d, J=7.8 Hz, 1H) , 8.64 (d, J = 2.0 Hz, 1H) , 8.43 (d, J = 2.1 Hz, 1H) , 8.00 (t, J = 2.1 Hz, 1H) , 7. 95 (s, 1H) , 7, 87-7, 56 (m, 4H) , 7, 37 (s, 1H) , 7, 11-6, 92 (m, 3H) , 4, 75 (p, J = 7, 1 Hz, 1H) , 4, 6.- 4, 33 (m, 4H) , 4, 26 (s, 1H), 3, 6.- 3.51 (m, 1H) , 3, 4.- 3.25 (m, 1H) , 2.84-2.60 (m, 1H) , 2.09 (s, 3H) , 1.95 (d, J = 13.9 Hz, 1H) , 1.28 (d, J = 7, 0Hz, 3H). Exchangeable proton absent Example 26: 1-oxide of 3-(4-carbamoyl-2-methylphenyl) -5- ( ( (R) -2- ( ( (S) -1- (4-carboxyphenyl) ethyl) carbamoyl) pyrrolidine-1-yl) methyl) pyridine (Compound 26) Step (i): To a suspension of (4-carbamoyl-2-methylphenyl)boronic acid, pinacol ester (4.00 g, 15.3 mmol, 1.0 eq), 5-bromo-3-pyridinemethanol (2.88 g, 15.3 mmol, 1 eq) and CH3COOK (4.50 g, 45.9 mmol, 3 eq) in dioxane / ELO (64 ml / 16 ml) in dioxane / H2O (64 ml / 16 ml) in an N2 atmosphere, Pd (dppf) Cl2 (1.12 g, 1.53 mmol, 0.1 eq) was added. The reaction mixture was stirred at 85 °C for 16 hours and then the mixture was filtered and concentrated. The residue was purified by silica gel column chromatography (eluent - DCM:MeOH = 20:1 10:1) to give 4-(5-(hydroxymethyl)pyridin-3-yl)-3-methylbenzamide (2.5 g, 68%) as a yellow solid. LC / MS: (Method E): m / z 243 [M+H]+, 0, 80 min. Step (ii): To a solution of 4-(5-(hydroxymethyl)pyridin-3-yl)-3-methylbenzamide (1.20 g, 4.9 mmol, 1.0 eq) in DCM (30.00 ml), SOCl2 (5.83 g, 49.0 mmol, 10.0 eq) was added. The mixture was stirred at TA for 1 hour, filtered and concentrated, and the residue was purified by silica gel column chromatography (eluent - DCM:MeOH = 20:1 10:1) to provide 4-(5-(chloromethyl)pyridin-3-yl)-3-methylbenzamide (1.0 g, 78.7%) as a yellow solid. LC / MS: (Method E) : m / z 261[M+H]+, 2, 73 min. Step (iii): To a suspension of 4-(5-(chloromethyl)pyridin-3-yl)-3-methylbenzamide (500.0 mg, 1.92 mmol, 1.0 eq) in DCM (15 ml), m-CPBA (663.5 mg, 3.84 mmol, 2.0 eq) was added. The reaction mixture was stirred at TA for 1 hour, concentrated under vacuum, and the residue was purified by silica gel column chromatography (eluent -DCM:MeOH = 20:1 15:1) to provide 3-(4-carbamoyl-2-methylphenyl)-5-(chloromethyl)pyridine 1-oxide (500 mg, 94%) as a light yellow solid. LC / MS: (Method E) : m / z 277 [M+H]+, 2, 30 min. Step (iv): To a solution of 1-oxide of 3-(4-carbamoyl-2-methylphenyl)-5-(chloromethyl)pyridine (200 mg, 0.72 mmol, 1.0 eq) in MeCN (12 ml) and DMF (2 ml) intermediate compound 1 (226 mg, 0.72 mmol, 1.0 eq), NaHCO3 (182 mg, 2.17 mmol, 3.0 eq) and NaI (108 mg, 0.72 mmol, 1.0 eq). The resulting mixture was stirred at 70 °C for 4 hours, then filtered and concentrated, and the residue was purified by silica gel column chromatography (eluent - DCM:MeOH = 30:1 15:1) to give 3-(4-carbamoyl-2-methylphenyl)-5-(chloromethyl)pyridine 1-oxide (311 mg, yield: 89%) as a white solid. LC / MS: (Method E): m / z 517 [M+H]+, 2, 50 min. Step (v): To a solution of the compound 3-(4-carbamoyl-2-methylphenyl)-5-(chloromethyl)pyridine 1-oxide (330 mg, 0.60 mmol, 1.0 eq) in methanol (10 mL), LiOH (1.8 mL, 1.80 mmol, 3.0 eq) was added. The mixture was stirred at room temperature for 2 days and then diluted with water (5 mL), acidified with 1 N HCl to pH ~ 5, and the solvent was removed under vacuum. The residue was purified by HPLC preparation (Method E) to give compound 26 (120 mg, yield: 40.0%) as a white solid. LC / MS: (Method E): m / z 503 [M+H]+, 1, 20 min. 1H NMR (400 MHz, Methanol-d4): 8.51-8.48 (m, 1H), 8.18 (s, 1H), 7.87 (dd, J = 8.0.2.0 Hz, 2H), 7.80 (s, 1H), 7.73 (d, J = 8.0 Hz, 1H) , 7.63-7.60 (m, 1H) , 7.23 (d, J = 8.0 Hz, 2H) , 6.98 (d, J = 7.6 Hz, 1H) , 4.65-4.59 (m, 1H) , 4.4.- 4.28 (m, 2H) , 3, 90 (s, 1H) , 3, 48-3, 43 (m, 1H) , 2, 76- 2, 69 (m, 1H) , 2, 34-2, 27 (m, 1H) , 2, 21-2, 14 (m, 4H) , 2, 13-2, 07 (m, 1H) , 1, 44 (d, J = 7, 2 Hz, 3H). Example 27: 4-(1-(2-((2'-methyl-4'-sulfamoyl-[1,1'-biphenyl]-3-yl)methyl)-2-azabicyclo[2.1.1]hexane-1-carboxamido)cyclopropyl)benzoic acid (Compound 27) Compound 27 was synthesized by a procedure analogous to Example 23 using methyl 4-(1-aminocyclopropyl)benzoate and intermediate compound 12 to give compound 27 LC / MS: (Method A): 546 [M+H]+ at 1, 40 min. Chiral HPLC: The purity of the product was confirmed at 11, 73 min. 1H NMR: (400 MHz, DMSO) 1.13 (m, 2H), 1.23 (m, 2H), 1.85-1.78 (m, 4H), 2.32 (s, 3H), 2.67 (s, 3H), 3.63 (s, 2H), 7. 17-7, 15 (d, 2H, J=8 Hz) , 7, 26-7, 25 (d, 1H, J=6, 4 Hz) , 7, 50-7, 37 (m, 6H) , 7, 76-7, 69 (m, 4H) , 8, 61 (s, 1H) , 12, 83 (bs, 1H) . Example 28: (S)-4-(1-(2-((4'-carbamoyl-2'-methyl-[1,1'-biphenyl]-3-yl)methyl)-2-azabicyclo[2.1.1]hexane-1-carboxamido)ethyl)benzoic acid (Compound 28) Compound 28 was synthesized by a procedure analogous to Example 23 using intermediate compound 13 to give compound 28 LC / MS: (Method A) : m / z 498 (ES+) at 1, 27 min. Chiral HPLC: Product purity was confirmed at 8.83 min. 1H NMR: (400 MHz, DMSO) : 1.39-1.37 (d, 3H, J= 7.2 Hz) , 1.79 (m, 4H) , 2.28 (s, 3H) , 2.70- 2.61 (m, 3H) , 3.57 (s, 2H) , 5. 06-5, 02 (t, 1H, J= 7, 4 Hz) , 7, 29-7, 24 (m, 2H) , 7, 46-7, 36 (m, 6H) , 7, 82-7, 75 (m, 4H) , 7, 97 (s, 1H) , 8, 30 (s, 1H) , 12, 80 (s, 1H) . Example 29: 4-(1-(2-((4'-carbamoyl-2'-methyl-[1,1'-biphenyl]-3-yl)methyl)-2-azabicyclo[2.1.1]hexane-1-carboxamido)cyclopropyl) benzoic acid (Compound 29) Compound 29 was synthesized by a procedure analogous to Example 23 using methyl 4-(1-aminocyclopropyl)benzoate and intermediate compound 13 to give compound 29 LC / MS: (Method A): m / z 510 [M+H]+ at 1, 23 min. 1H NMR: (400 MHz, DMSO) : 1.14 (s, 2H), 1.24 (s, 2H), 1.78 (d, 2H, J= 3.6 Hz), 1.85 (s, 2H), 2.29 (s, 3H), 2.61 (s, 1H), 2, 67 (s, 2H) , 3, 62 (s, 2H) , 7, 18-7, 30 (m, 4H) , 7, 36-7, 48 (m, 4H) , 7, 74 (d, 3H, J= 8, 0 Hz) , 7, 82 (s, 1H) , 7, 98 (s, 1H), 8, 65 (s, 1H), 12, 82 (s, 1H) . Example 30: (R)-4-(1-(1-(2'-methyl-4'-sulfamoyl-[1,1'-biphenyl]-3-yl)methyl)pyrrolidine-2-carboxamido)cyclopropyl)benzoic acid (Compound 30) Compound 30 was synthesized by a procedure analogous to Example 23 using (tert-butoxycarbonyl)-D-proline, methyl 4-(1-aminocyclopropyl)benzoate and intermediate compound 12 to give compound 30. LC / MS: (Method A): m / z 534 [M+H]+, at 1, 18 minutes. Chiral HPLC: Product purity was confirmed at 11, 23 min. 1H NMR: (400 MHz, DMSO) : 1.06-1.04 (d, 2H, J= 4.8 Hz) , 1.19-1.18 (m, 2H) , 1.78-1.77 (d, 3H, J=2.8 Hz) , 2.14-2.12 (m, 1H) , 2, 29 (s, 3H) , 2, 38-2, 36 (m, 1H) , 3, 12-3, 11 (m, 2H) , 3, 62- 3, 59 (d, 1H, J= 12, 8 Hz) , 3, 85-3, 82 (d, 1H, J= 13, 2 Hz), 7, 11-7, 09 (d, 2H, J= 8, 4 Hz) , 7, 28-7, 27 (d, 1H, J= 6, 8 Hz) , 7, 44-7, 35 (m, 6H) , 7, 7º-7, 67 (m, 1H) , 7, 78-7, 75 (q, 3H), 8, 48 (s, 1H), 12, 77 (s, 1H). Example 31: (R)-4-(1-(1-((4'-carbamoyl-2'-methyl-[1,1'-biphenyl]-3-yl)methyl)pyrrolidine-2-carboxamido)cyclopropyl)benzoic acid (Compound 31) Compound 31 was synthesized by a procedure analogous to Example 23 using (tert-butoxycarbonyl)-D-proline, methyl 4-(1-aminocyclopropyl)benzoate and intermediate compound 12 to give compound 31. LC / MS: (Method A): m / z 498 [M+H]+ at 1, 12 min. Chiral HPLC: Product purity was confirmed at 8, 98 min. 1H NMR: (400 MHz, DMSO) 1.20 (m, 1H), 1.23 (m, 1H), 1.77 (s, 3H), 2.08-2.10 (m, 1H), 2.27 (s, 3H), 2.67 (s, 2H), 3. 04-3.34 (m, 3H) 7, 35-7, 42 (m, 4H), 7, 74 (d, 3H, J= 8 Hz), 7, 80 (s, 1H), 7, 99 (s, 1H), 8, 45 (s, 1H), 12, 78 (s, 1H). Example 32: (S)-4-(1-(2-((2'-methyl-4'-sulfamoyl-[1,1'-biphenyl]-3-yl)methyl)-2-azabicyclo[2,1,1]hexane-1-carboxamido)ethyl)benzoic acid (Compound 32) Compound 32 was synthesized by a procedure analogous to Example 23 using intermediate compound 12 to give compound 32. LC / MS: (Method A): Product m / z 534 (ES+) at 1, 27 min. Chiral HPLC: Product purity was confirmed at 12, 16 min. 1H NMR: (400 MHz, DMSO) 1, 39-1, 37 (d, 3H, J= 7, 2 Hz) , 1, 82-1, 79 (m, 4H) , 2, 31 (s, 3H) , 2, 18-2, 61 (m, 3H) , 3, 61-3, 53 (m, 2H) , 7, 26-7, 24 (m, 1H) , 7, 47-7, 37 (m, 8H) , 7, 72-7, 70 (m, 1H) , 7, 80-7, 76 (m, 3H) , 8, 28-8, 26 (d, 1H, J= 8, 4Hz), 12, 86 (s, 1H) . Example 33: 4-((S)-1-((R)-1-((4',5-dihydroxy-2'-methyl-[1,1'-biphenyl]-3-yl)methyl)pyrrolidine-2-carboxamido)ethyl)benzoic acid (Compound 33) Step (i): To a solution of (tert-butoxycarbonyl)-D-proline (5.0 g, 27.90 mmol) in DMF (50 ml) HATU (21.22 g, 55.8 mmol, 2 eq) and DIPEA (24.15 ml, 139.5 mmol, 5 eq) were added, and the mixture was stirred at 25 °C for 0.5 h. (S)-4-(1-aminoethyl) methyl benzoate (6.01 g, 27.90 mmol, 1 eq) was added and the resulting mixture was stirred at 25 °C for 1 h. Once completed, the reaction mixture was diluted with H2O (500 ml) and extracted with EA (2 x 150 ml). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by ultrafast silica gel chromatography, eluent with a 0-50% ethyl acetate / hexene gradient, to give tert-butyl (R)-2-((S)-1-(4-(methoxycarbonyl)phenyl)ethyl)carbamoyl)pyrrolidine-1-carboxylate (8.5 g, 79.31%) in the form of a yellow oil. TLC: (EA / hexene, 5, 0:5, 0, RF: 0, 7) . Mass (ESI +vo): 277.0 [M-100]. LCMS: 98.91% (method H de LCMS), RT: 2,949 min, 254 nm. 1H NMR: (400 MHz, DMSO) : 1.20-1.25 (m, 9H), 1.34-1.47 (m, 3H), 1.78-2.13 (m, 4H), 3.27-3.35 (m, 2H), 3.83 (m, 3H), 4, 06-4, 15 (m, 1H), 4, 93-5, 00 (m, 1H), 7, 4-7, 52 (m, 2H), 7, 8- 7, 90 (m, 2H), 8, 36-8, 38 (d, J=6, 8 Hz, 1H). Step (ii): To a solution of (R)-2-((S)-1-(4-(methoxycarbonyl)phenyl)ethyl)carbamoyl)pyrrolidine-1-carboxylate tert-butyl (8.5 g, 2.85 mmol, 1 eq) in DCM (100 mL) HCl in dioxane (4.0 M, 85 mL) was added. The mixture was stirred at 15 °C for 1 h. The starting material was completely consumed, then the reaction mixture was concentrated under reduced pressure to remove the HCl / dioxane. Dioxane (30 mL) was further added to the residue and concentrated under reduced pressure to give 4-((S)-1-((R)-pyrrolidine-2-carboxamido)ethyl)methyl benzoate (7.5 g, crude, HCl salt) as a brown solid. TLC: (EA / hexene, 5, 0:5, 0, RF: 0, 8) . Mass (ESI +vo) : 277.0 [M+1]. LCMS: 89, 10% (método H de LCMS) y RT: 2, 184 min, 230 nm. RMN 1H: (400 MHz, DMSO) : 1, 26-1, 41 (m, 6H) , 1, 89 (s, 3H) , 2, 33-2, 35 (m, 2H) , 3, 63- 3, 90 (m, 9H) , 3, 18 (m, 3H) , 4, 47-3, 84 (m, 6H) , 4, 21 (m, 1H) , 4, 97-5, 0 (m, 1H) , 7, 50-7, 52 (d, J=4, 4 Hz, 2H) , 7, 90-7, 94 (d J=16, 0 Hz, 2H) , 8, 51 (s, 1H) , 9, 29-9, 30 (d, 1H) , 10, 03 (s, 1H) . Análisis por HPLC: 99, 41% RT 5, 81, 240, 0 nm, 4, 0 nm Step (iii): To a solution of 4-((S)-1-((R)-pyrrolidine-2-carboxamido)ethyl) methyl benzoate (7.5 g, 27.14 mmol, 1 eq, HCl) , 3-bromo-5-methoxybenzaldehyde (7.01 g, 32.57 mmol, 1.2 eq) in DCE (40 ml) and DMF (40 ml) TEA (3.76 ml, 27.14 mmol) in DCE (40 ml) and DMF (40 ml) , 1 eq) was added and the mixture was stirred at 30 °C for 1 h. AcOH (1.63 mL, 27.14 mmol, 1 eq) and NaBH3CN (3.41 g, 54.28 mmol, 2 eq) were added, and the resulting mixture was stirred at 30 °C for 12 h. The starting material was completely consumed, and a main peak with the desired mass was detected. The mixture was then diluted with H2O (500 mL), the pH was adjusted to 9 with solid NaHCO3, and it was extracted with EA (2 x 200 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue.The residue was purified by ultrafast silica gel chromatography, eluent with 0-10% MEOH / DCM gradient to give the pure compound 4-((S)-1-((R)-1-(3-bromo-5-methoxybenzyl)pyrrolidine-2-carboxamido)ethyl)methyl benzoate (5, 40 g, 39, 76%) in the form of a white solid. TLC: (MeOH / DCM, 1, 0:9, 0, RF: 0, 2). Mass (ESI +vo) : 475.2 [M+1]. LCMS: 95.77% (LCMS method H), RT: 3.656 min, 202 nm. 1H NMR: (400 MHz, DMSO) : 6.92 (S, 1H), 7.038 (S, 1H), 7.14 (S, 1H), 7.42-7.44 (d, J = 8.0 Hz, 2 H), 7.89-7.91 (d, J= 8.0 Hz, 2 H), 8, 18-8, 20 (d, J= 8, 0 Hz, 1 H) , 1, 10-1, 14 (m, 4 H) , 1, 34-1, 36 (d, 3 H) , 1, 65-1, 73 (m, 3H) , 2, 020-2, 068 (m, 1 H), 2, 33-2, 36 (m, 1H) , 2, 72-3, 10 (m, 6H) , 3, 47-3, 50 (d, J =12, 0 Hz, 1H) , 2, 70-3, 85 (m, 6 H) , 4, 86-4, 90 (m, 1H) . RMN 1H: (400 MHz, CDCl3) : 6, 79 (s, 1H) , 7, 017 (s, 1H) , 7, 092 (s, 1H) , 7, 36-7, 39 (d, J = 8, 0 Hz, 2 H) , 7, 68 (s, 1H) , 8, 037-8, 058 (d, J= 8, 0 Hz, 2 H) , 1, 16-1, 35 (m, 6H) , 1, 36-1, 46 (s, 3H) , 1, 70-1, 84 (m, 3H) , 2, 24 (m, 1H) , 2, 44-2, 46 (s, 1H) , 2, 64 (s, 1H) , 2, 84-3, 14 (m, 5H) , 3, 26 (m, 1H) , 3, 54-3, 57 (m, 1H) , 3, 72-4, 002 (m, 7H) , 5, 056-5, 10 (m, 1H) . Análisis por HPLC: 99, 59%, RT, 6, 57 minutos, a 239, 0 nm. Step (iv): To a solution of 4-((S)-1-((R)-1-(3-bromo-5-methoxybenzyl)pyrrolidine-2-carboxamido)ethyl) methyl benzoate (5.3 g, 11.15 mmol 1 eq) , (4-hydroxy-2-methylphenyl)boronic acid (2.55 g, 16.72 mmol, 1.5 eq) in dioxane (70 ml) and H2O (15 ml) K2CO3 (3.078 g, 11.15 mmol, 2 eq) and Pd(dppf)Cl2 (0.816 g, 1.11 mmol, 0.1 eq) . The mixture was stirred at 90 °C for 12 h in an N2 atmosphere. The starting material was completely consumed and a new stain formed. The reaction mixture was diluted with H2O (100 ml) and extracted with EA (2 x 100 ml). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue.The residue was purified by ultrafast silica gel chromatography, eluting with 0–05% MeOH / DCM gradient to give 4- ( (S) -1- ( (R) -1- ( (4'-hydroxy-5-methoxy-2'-methyl-[1, 1'-biphenyl-3-methyl)] pyrrolidine-2-carboxamide) ethyl) methyl benzoate (3. 5 g, 66%) as a white solid. TLC: (EA / hexene, 5, 0:5, 0, RF: 0, 2) . Mass (ESI +vo) : 503, 2 [M+1]. LCMS: 92.39% (LCMS method H), RT: 3.296 min, 230 nm. 1H NMR: (400 MHz, DMSO) : 6, 62-6, 70 (m, 3H) , 6, 82-6, 85 (d, J= 11, 2 Hz, 2 H) , 7, 00-7, 02 (d, J= 8, 0 Hz, 7, 7, 42-4) (d, J= 8, 0 Hz, 2 H) , 7, 86-7, 88 (d, J= 8, 0 Hz, 2 H) , 8, 14-8, 16 (d, J= 8, 0 Hz, 1 H) , 1, 23-1, 33 (m, 4, 1, 3 H) (m, 1, 7 H) 2, 05 (m, 1H) , 2, 16 (s, 3H) , 2, 33- 2, 39 (m, 1 H) , 3, 087-3, 097 (m, 2H) , 3, 49-3, 52 (m, 1H) , 3, 76-3, 94 (m, 7H) 4, 85-4, 90 (m, 1H) . RMN 1H: (400 MHz, CDCl3) : 6, 75-6, 85 (m, 5H) , 7, 08-7, 10 (d, 1H) , 7, 30-7, 39 (m, 2H) , 7, 87-8, 06 (m, 3H) , 1, 30-1, 48 (m, 3H) , 1, 72-1, 89 (m, 4H) , 2, 24 (s, 4H) , 2, 48 (m, 1H) , 3, 18 (m, 1H) , 3, 34-3, 35 (m, 2H) , 3, 49-3, 52 (m, 1H) , 3, 62-3, 66 (m, 1H) , 3, 85-3, 95 (m, 6H) . Análisis por HPLC: 89, 40% RT 7, 31 minutos, a 239, 0 nm. Step (v): To a solution of 4-((S)-1-((R)-1-((4'-hydroxy-5-methoxy-2'-methoxy-2'-methyl-[1,1'-biphenyl]-3-yl)methyl)pyrrolidine-2-carboxamido)ethyl)methyl benzoate (3.7 g, 7.36 mmol, 1 eq) in DCM (100 ml) BBr3 (1.0 M solution in DCM) (40.52 ml, 5.5 eq) at -60 °C was added dropwise. After the addition, the mixture was stirred at this temperature for 30 min and then the resulting mixture was stirred at 15 °C for 2 h. The starting material was completely consumed. The reaction mixture was then inactivated by the addition of MeOH (200 mL) at -60 °C, and subsequently concentrated under reduced pressure to yield the residue. The residue was purified by ultrafast silica gel chromatography, eluent with a 0-20% MeOH / DCM gradient, to give 4-((S)-1-((R)-1-((4',5-dihydroxy-2'-methyl-[1,1'-biphenyl]-3-yl)methyl)pyrrolidine-2-carboxamido)ethyl)methyl benzoate (2.80 g, 77.85%) as a white solid. TLC: (EA / MEOH / DCM 4, 0:1, 0:5, 0, RF: 0, 4) . Masa (ESI +vo) : 489, 2 [M+1]. LCMS: 84, 75% (método H de LCMS) , RT: 2, 921 min, 254, 0 nm. RMN 1H: (400 MHz, DMSO) : 6, 57-6, 58 (m, 2H) , 6, 64 (d, 1H) , 6, 80-6, 84 (m, 3H) , 7, 17- 7, 23 (d, J= 8, 0 Hz, 2H) , 7, 81-7, 89 (d, J= 8, 0 Hz, 2 H) , 9, 01-9, 028 (d, J= 7, 2 Hz, 1 H) , 1, 35-1, 37 (m, 3 H) , 1, 90-1, 93 (m, 2 H) , 2, 05-2, 15 (m, 4H) , 2, 70 (m, 1H) , 3, 18 (s, 4 H) , 3, 32 (m, 1H) , 3, 60-3, 62 (S, 1H) , 4, 23-4, 31 (m, 3H) , 4, 88-4, 31 (m, 1H) . HPLC quiral: 85, 25%, RT 8, 23 min, a 234, 0 nm. Step (vi): To a solution of 4-((S)-1-((R)-1-((4',5-dihydroxy-2'-methyl-[1,1'-biphenyl]-3-yl)methyl)pyrrolidine-2-carboxamido)ethyl)methyl benzoate (2.80 g, 5.73 mmol) in EtOH (10 ml) and THF (30 ml) LiOH.H2O (2.40 g, 57.31 mmol) in H2O (30 ml) was added. The mixture was stirred at room temperature for 15 h. LCMS RM showed that starting material remained. Then, LiOH.H2O (2.65 g, 63.04 mmol) was added again and the mixture was stirred at room temperature for 24 h. The starting material was completely consumed, then the reaction mixture was concentrated under reduced pressure to remove EtOH and THF. The mixture was then diluted with H₂O (20 mL), the pH was adjusted to 5 with HCl solution (2.0 M), and the mixture was concentrated under reduced pressure to give the crude product. The crude product was purified by HPLC preparation.(Method F) to give 4-((S)-1-((R)-1-((4', 5-dihydroxy-2'-methyl-[1, 1'-biphenyl]-3-yl)methyl)pyrrolidine-2-carboxamido)ethyl)benzoic acid (compound 33) (500 mg, 18, 38%) in the form of a white solid. TLC: (Methanol / DCM, 1, 0:9, 0, RF: 0, 1) . Mass (ESI +vo) : 475.0 [M+H], LCMS: 100.0% (LCMS method I), RT: 2.747 min, 304.0 nm. LCMS: 100.0% (LCMS method H), RT: 2.080 min, 304.0 nm. HPLC analysis: 100.0% [RT 2.85 min, at 220.0 nm], 1H NMR: (400 MHz, MeOD) : 6.63-6.70 (m, 5H) , 6.95-6.98 (d, J=8.0 Hz, 1H) , 7.288-7.307 (d, J = 7.6 Hz, 2H) , 7.94-7.97 (d, J = 8.0 Hz, 2H) , 1.35-1.39 (m, 3H) , 1.87-1.97 (m, 3H) , 2.17 (m, 3H) , 2.34 (m, 1H) , 2.79-2.813 (m, 1H) , 3.40 (m, 1H), 3, 53-3, 55 (m, 1H), 3, 86-3, 95 (m, 1H). RMN 1H: (400 MHz, DMSO): 6, 57-6, 71 (m, 5H) , 6, 976-6, 996 (d, J=8, 0 Hz, 1H) , 7, 368-7, 388 (d, J =8, 0 Hz, 2H) , 7, 865-7, 885 (d, J = 8, 0 Hz, 2H) , 8, 052-8, 072 (d, J = 8, 0 Hz, 1H) , 9, 40 (s, 1H) , 1, 25-1, 33 (m, 3 H) , 1, 70-1, 73 (m, 3H) , 2, 066 (m, 2H) , 2, 166 (s, 3H), 3, 028 (s, 1H), 3, 08-3, 12 (m, 1H), 3, 70-3, 77 (m, 2H), 3, 86-4, 90 (m, 1H). Ejemplo 34: Acido 4- ( (S)-1- ( (R) -1- ( (4'-carbamoil-5-hidroxi-2'-metil-[1, 1'-bifenil]-3-il)metil)pirrolidina-2-carboxamido)etil) -2-hidroxibenzoico (Compuesto 34) Step (i): To a solution of intermediate compound 14 (160 mg, 448.38 umol, 1 eq, HCl), intermediate compound 15 (144.89 mg, 538.05 umol, 1.2 eq) in DCE (2.5 ml) and DMF (2.5 ml) TEA (45.37 mg, 448.38 umol, 62.41 ul, 1 eq) was added and the mixture was stirred at 30 °C for 1 h. AcOH (26.93 mg, 448.38 µmol, 25.64 µl, 1 eq) and NaBH3CN (56.35 mg, 896.75 µmol, 2 eq) were added, and the resulting mixture was stirred at 30 °C for 12 h. LC-MS showed that intermediate compound 14 had been completely consumed, and a main peak with the desired mass was detected. The combined mixture was then diluted with H2O (20 mL), the pH was adjusted to 9 with solid NaHCO3, and it was extracted with EtOAc (30 mL * 2). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by HPLC prep.(HPLC method G) to give compound c1 (102 mg, 174.07 umol, 38.82% yield, 97.9% purity) in the form of a yellow solid, which was confirmed by H NMR. LCMS: [M+1]+= 574, 2. SFC: Rt = 1, 404 min, ee = 100% 1H NMR: (MeOD, 400 MHz) 7.80 (s, 1 H) , 7.7.- 7.71 (m, 1 H) , 7.67 (d, J= 8.0 Hz, 1 H) , 7.29 (d, J=7.6 Hz, 1 H) , 6.98 (d, J= 11. 2 Hz, 2 H), 6, 9.- 6, 85 (m, 2 H) , 6, 79 (s, 1 H) , 4, 85-4, 81 (m, 1 H) , 4, 30 (q, J= 6, 8, 2 H) , 3, 86-3, 71 (m, 8 H) , 3, 27-3, 17 (m, 2 H), 2, 6.- 2, 49 (m, 1 H), 2, 30 (s, 3 H), 2, 27-2, 13 (m, 1 H), 1, 8.- 1, 74 (m, 3 H), 1, 3.- 1, 29 (m, 6 H). Step (ii): BBr3 (502.20 mg, 2.00 mmol, 193.15 µl, 5 eq) in DCM (2 mL) was added dropwise to a solution of compound c1 (230 mg, 400.92 µmol, 1 eq) in DCM (2 mL) at -60 °C. After the addition, the mixture was stirred at this temperature for 30 min, and then the resulting mixture was stirred at 15 °C for 2 h. LC-MS showed that compound c1 had been completely consumed. The reaction mixture was inactivated by the addition of MeOH (5 mL) at -60 °C, then the mixture was heated to room temperature and concentrated under reduced pressure to give compound c2 (220 mg, crude) as a yellow solid. LCMS: [M+1]+= 546, 2. Step (iii): To a solution of compound c2 (220 mg, 403.21 µmol, 1 eq) in EtOH (1 mL) and THF (5 mL), LiOH·H₂O (50.76 mg, 1.21 mmol, 3 eq) in H₂O (1 mL) was added. The mixture was stirred at 30 °C for 15 h. LC-MS showed that compound c2 remained. LiOH·H₂O (50.76 mg, 1.21 mmol, 3 eq) was added, and the mixture was stirred at 30 °C for 15 h. LC-MS showed that 9.1% of compound c2 remained, and a main peak with the desired mass was detected. The reaction mixture was concentrated under reduced pressure to remove the EtOH and THF. The mixture was then diluted with H2O (3 mL), the pH was adjusted to 5 using HCl (2 M), and the mixture was concentrated under reduced pressure to give a residue. The residue was purified by HPLC preparation.(HPLC method H) to give acid 4- ( (S) -1- ( (R) -1- ( (4'-carbamoyl-5-hydroxy-2'-methyl-[1, 1'-biphenyl]-3-yl) methyl) pyrrolidine-2-carboxamide) ethyl) -2-hydroxybenzoic acid (34, 71 mg 214.09 umol, 53, 10% yield, purity 99.2%) in the form of a white solid, which was confirmed by H NMR. LCMS (LCMS method J): 1.25 min, m / z 518.34 [MH+] SFC: Rt = 1, 499 min, ee = 100% 1H NMR (MeOD, 400 MHz) 7, 7.- 7, 71 (m, 2 H) , 7, 66 (dd, J= 1, 6, 8, 0 Hz, 1 H) , 7, 09 (d, J= 8, 0 Hz, 1 H) , 6, 6, 6, 8 H. , 6, 82 (s, 1 H) , 6, 7.- 6, 74 (m, 1 H) , 6, 69 (d, J = 1, 2 Hz, 1 H) , 6, 58 (dd, J= 1, 6, 8, 0 Hz, 1 H) , 4, 8, 4-4, 8, 8 H) (m 4, 28-4, 17 (m, 1 H) , 4, 1.- 4, 06 (m, 1 H) , 3, 92 (dd, J=4, 8, 8, 4 Hz, 1 H) , 3, 6.- 3, 56 (m, 1 H) , 3, 2. 0, 1 H (3, 6). 2, 5.- 2, 42 (m, 1 H) , 2, 22 (s, 3 H) , 2, 1.- 1, 91 (m, 3 H) , 1, 36 (d, J= 7, 2 Hz, 3 H) . Example 35: 4-((S)-1-((R)-1-((4',5-dihydroxy-2'-methyl-[1,1'-biphenyl]-3-yl)methyl)pyrrolidine-2-carboxamido)ethyl)-2-hydroxybenzoic acid (Compound 35) Step (i): To a solution of (tert-butoxycarbonyl)-D-proline (7.250 g, 0.027 mol, 1.0 eq) in DMF (72 ml), HATU (15.50 g, 0.04 mol, 1.5 eq) was added to a reaction mixture and the reaction mixture was stirred at 0°C for 15 min. DIPEA (13.94 ml, 0.08 mol, 3 eq) was added to a reaction mixture at 0°C, the mixture was stirred at TA for 30 min. The salt of (S)-1-(4-bromo-3-methoxyphenyl)ethan-1-amine.HCl (intermediate compound 16) (5.85 g, 0.027 mol, 1 eq, HCl) was added and the resulting mixture was stirred at 25°C for a night. LC-MS showed that intermediate compound 16 had been completely consumed and a main peak with the desired mass was detected. The reaction mixture was diluted with cooled H2O (800 ml) and extracted with EA (3 x 300 ml). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue.The residue was purified by ultrafast silica gel chromatography (normal phase silica with EA / hexane from 0 to 40.0%) to give tert-butyl (R)-2-((S)-1-(4-bromo-3-methoxyphenyl)ethyl)carbamoyl)pyrrolidine-1-carboxylate (11.4 g, 98.10% yield, 96% purity) in the form of a colorless gum. TLC: (Hexane / EtOAc, 5, 0:5, 0, RF: 0, 4). LCMS: 96.31% (LCMS method H), RT: 3.161 min, 254.0 nm. Chiral HPLC: 80.05% at RT 4.23. 1H NMR: (400 MHz, CDCl3) : 7.47-7.39 (s, 3H) , 6.91-6.73 (m, 3H) , 5.04 (s, 2H) , 4.34 (s, 2H) , 3.96-3.86 (s, 5H) , 3. 46-3, 3 (m, 4H), 2, 99 (s, 1H), 2, 9.- 2, 89 (s, 1H), 2, 84-2, 83 (s, 7H), 2, 40-2, 31 (m, 1H), 2, 19-2, 08 (m, 2H), 1, 89-1, 63 (s, 5H), 1, 58-1, 22 (m, 25H) . Step (ii): To a solution of (R) -2- ( ( (S) -1- (4-bromo-3-methoxyphenyl)ethyl) carbamoyl) tert-butyl pyrrolidine-1-carboxylate (11.4 g, 0.026 mol, 1 eq) in EtOH (120 ml) TEA (8.08 g, 0.08 mol, 11.1 ml, 3 eq) and Pd (dppf) Cl2.CH2Cl2 (22.12 g, 0.002 mol, 0.1 eq) were added. The mixture was stirred at 100 °C for 16 h under CO gas (8.6 bar (125 psi)). TLC showed that the (R)-2-(((S)-1-(4-bromo-3-methoxyphenyl)ethyl)carbamoyl)pyrrolidine-1-carboxylate of tert-butyl was completely consumed, and a main peak with the desired mass was detected. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue. The reaction mixture was diluted with H₂O (1200 mL) and extracted with EA (3 x 400 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue.The residue was purified by ultrafast silica gel chromatography (normal phase silica with EA / hexane from 0 to 49.0%) to give (R)-2-(((S)-1-(4-(ethoxycarbonyl)-3-methoxyphenyl)ethyl)carbamoyl)pyrrolidine-1-carboxylate tert-butyl (7.25 g, 59.37% yield) in the form of a colorless gum. TLC: (Hexane / EtOAc, 5, 0:5, 0, RF: 0, 4). Mass (ESI +vo) : 321.2 [M-100+1]. LCMS: 89.69% (LCMS H method), RT: 2.999 min, 254.0 mm. Chiral HPLC: 98.91% at RT 6.16. 1H NMR: (400 MHz, DMSO-D2O): 8.38-8.29 (m, 1H), 7.57-7.55 (s, 1H), 7.12-6.96 (m, 2H), 4.97-4.88 (m, 1H), 4.25-4.21 (d, 2H) , 4, 04-4, 02 (s, 1H) , 3, 85-3, 80 (d, 3H) , 2, 11 (m, 7H) , 1, 77 (s, 3H) , 1, 38 (s, 8H) , 1, 28-1, 17 (m, 11H) . Step (iii): To a solution of (R)-2-(((S)-1-(4-(ethoxycarbonyl)-3-methoxyphenyl)ethyl)carbamoyl)pyrrolidine-1-carboxylate tert-butyl (7.25 g, 0.017 mol, 1 eq) in dioxane (20 ml) HCl / dioxane (4.0 M, 120 ml) was added. The mixture was stirred at room temperature for 1.5 h. TLC showed that the (R)-2-(((S)-1-(4-(ethoxycarbonyl)-3-methoxyphenyl)ethyl)carbamoyl)pyrrolidine-1-carboxylate tert-butyl was completely consumed and a main peak with the desired mass was detected.The reaction mixture was concentrated under reduced pressure to remove the HCl / dioxane, dioxane (40 ml *2) was added, the reaction mixture was concentrated under reduced pressure to remove the HCl / dioxane and give 2-methoxy-4-((S)-1-((R)-pyrrolidine-2-carboxamido)ethyl) ethyl benzoate. HCl salt (5.5 g, crude) in the form of a brown gum. TLC: (Hexane / EtOAc, 5, 0:5, 0, RF: 0, 2). LCMS: 98.97% (LCMS K method), RT: 1.057 min, 254.0 nm. Chiral HPLC: 97.97% at RT 6.19. 1H NMR: (400 MHz, DMSO-D2O): 9.79 (s, 1H), 9.23-9.21 (d, 1H), 8.54 (s, 1H), 7.61-7.59 (d, 1H), 7.16 (s, 1H), 7.01-6, 99 (d, 1H), 4, 99-4, 95 (m, 1H), 4, 27-4, 21 (q, 3H), 3, 85 (s, 3H), 3, 58 (s, 2H), 3, 22-3, 18 (m, 3H), 2, 70 (s, 3H) , 2, 37-2, 35 (m, 1H), 1, 91 (s, 3H), 1, 42- 1, 40 (d, 3H), 1, 26-1, 32 (t, 4H). Step (iv): To a mixture of the salt 2-methoxy-4-((S)-1-((R)-pyrrolidine-2-carboxamido)ethyl) ethyl benzoate.HCl (5.50 g, 0.015 mol, 1 eq) in DCE (50 ml), TEA (4.66 g, 6.14 ml, 0.046 mol, 3 eq) was added at 0°C. The mixture was stirred at 0°C for 10 minutes. Then, after adding 4'-hydroxy-5-methoxy-2'-methyl-[1,1'-biphenyl]-3-carbaldehyde (intermediate compound 17) (3.73 g, 0.015 mol, 1 eq) to the reaction mixture, the mixture was stirred at 60°C for 3 h. After 3 h, NaBH3CN was added. (2.86 g, 0.046 mol, 3 eq) and then the resulting mixture was stirred at 30 °C overnight. LC-MS showed that the ethyl benzoate salt of 2-methoxy-4-((S)-1-((R)-pyrrolidine-2-carboxamido)ethyl) benzoate.HCl was completely consumed and a main peak with the desired mass was detected. The mixture was then diluted with H2O (600 ml) and extracted with EA (400 ml * 3).The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by normal-phase column chromatography (neutral activated alumina normal phase with 5.0% to 30.0% methanol / DCM) to give ethyl 4-((S)-1-((R)-1-((4'-hydroxy-5-methoxy-2'-methyl-[1,1'-biphenyl]-3-yl)methyl)pyrrolidine-2-carboxamido)ethyl)-2-methoxybenzoate (3.77 g, 44.72% yield, 81.66% purity) as a whitish solid. TLC: (Hexane / EtOAc, 7, 0:3, 0, RF: 0, 4). Mass (ESI +vo) : 547.33 (M+1) LCMS: 81.66% (LCMS method H), RT: 3.382 min, 254 nm. Chiral HPLC: 83.20% RT 8.08 min at 232.0 nm. RMN 1H: (400 MHz, DMSO-D2O) : 1, 21-1, 1, 32 (m, 6H) , 1, 72-1, 75 (m, 3H) , 2, 01- 2, 06 (m, 1H) , 2, 18 (s, 3H) , 2, 35-2, 39 (m, 1H) , 3, 05-3, 13 (m, 2H) , 3, 52-3, 56 (m, 1H) , 3, 79-3, 81 (m, 6H) , 4, 21-4, 26 (m, 2H) , 4, 83-4, 86 (m, 1H) , 6, 64-6, 69 (m, 2H) , 6, 73 (s, 1H) , 6, 84-6, 87 (d, 2H, J=10 Hz) , 6, 91-6, 93 (d, 1H, J=7, 6 Hz) , 7, 02-7, 07 (m, 2H) , 7, 55-7, 57 (d, 1H, J=7, 6 Hz) , 8, 14-8, 16 (d, 1H, J=7, 6 Hz) , 9, 37 (s, 1H) . Step (v): To a solution of 4-((S)-1-((R)-1-((4'-hydroxy-5-methoxy-2'-methyl-[1,1'-biphenyl]-3-yl)methyl)pyrrolidine-2-carboxamido)ethyl)-2-methoxybenzoate (3.77 g, 0.006 mol, 1 eq) in DCM (108 ml) BBr3 (1.0 M solution in DCM) (8.63 g, 34.42 ml, 0.034 mol, 5 eq) was added to a reaction mixture at -78 °C, the mixture was stirred at -78 °C for 1 h. Afterwards, the resulting mixture was stirred at TA for 2 h. The TLC showed that the 4-((S)-1-((R)-1-((4'-hydroxy-5-methoxy-2'-methyl-[1,1'-biphenyl]-3-yl)methyl)pyrrolidine-2-carboxamido)ethyl)-2-methoxybenzoate of ethyl had been completely consumed and a main peak with the desired mass was detected.The reaction mixture was inactivated by adding MeOH (197.5 ml) dropwise slowly at -78 °C, then the mixture was heated to room temperature and concentrated under reduced pressure to give ethyl 4-((S)-1-((R)-1-((4',5-dihydroxy-2'-methyl-[1,1'-biphenyl]-3-yl)methyl)pyrrolidine-2-carboxamido)-2-ethyl)-2-hydroxybenzoate (5.04 g, crude) as a yellow solid. TLC: (Hexane / EtOAc, 8, 0:20, RF: 0, 2). Mass (ESI +vo) : 519.4 [M+1]. LCMS: 52.0% (LCMS L method), RT: 2.838 min, 254 nm. Step (vi): To a solution of 4-((S)-1-((R)-1-((4',5-dihydroxy-2'-methyl-[1,1'-biphenyl]-3-yl)methyl)pyrrolidine-2-carboxamido)ethyl)-2-hydroxybenzoate (5.04 g, 0.009 mol, 1 eq) in EtOH (35 ml) and THF (170 ml) LiOH.H2O (3.05 g, 0.07 mol, 7.5 eq) in H2O (35 ml) was added. The mixture was stirred at 30 °C for 7 days. LC-MS showed that the ethyl 4-((S)-1-((R)-1-((4',5-dihydroxy-2'-methyl-[1,1'-biphenyl]-3-yl)methyl)pyrrolidine-2-carboxamido)ethyl)-2-hydroxybenzoate was completely consumed, and a main peak with the desired mass was detected. The reaction mixture was concentrated under reduced pressure to remove EtOH and THF. The mixture was then cooled to 0°C, diluted with H₂O (20 mL), and the pH was adjusted to 5 using HCl (2.0 M) at 0°C. A solid was formed, filtered through a vacuum pump, and the mixture was concentrated under reduced pressure to give a residue. The residue was purified by HPLC prep.(HPLC method 1) to give 4-((S)-1-((R)-1-((4',5-dihydroxy-2'-methyl-[1,1'-biphenyl]-3-yl)methyl)pyrrolidine-2-carboxamido)ethyl)-2-hydroxybenzoic acid (compound 35) (472.5 mg, 9.91% yield, 100.0% purity) in the form of a white solid. TLC: (Methanol / DCM, 1, 0:9, 0, RF: 0, 1) . Mass (ESI +vo) : - 491.2 (M+1) LCMS: 100.0% (LCMS L method), RT: 2.415 min, 304.0 nm. LCMS: 99.60% (LCMS method H), RT: 2.156 min, 304.0, nm. Chiral HPLC: 100.0% at RT 6.75. 1H NMR: (400 MHz, MeOD): 7.76-7.78 (d, 1H), 6.86-6.88 (d, 1H), 6.79-6.80 (d, 2H), 6.72 (s, 2H), 6.66 (s, 1H), 6.60 (s, 2H) , 4, 85-4, 87 (m, 1H) , 4, 18-4, 21 (d, 1H) , 4, 08-4, 11 (d, 1H) , 3, 94 (s, 1H) , 3, 60 (s, 1H) , 3, 15 (s, 1H) , 2, 49 (s, 1H), 2, 12 (s, 4H), 1, 99 (s, 2H), 1, 37- 1, 39 (d, 3H). RMN 1H: (400 MHz, DMSO-D2O) : 9, 52 (s, 1H) , 9, 35 (s, 1H) , 8, 14-8, 31 (m, 1H) , 7, 64-7, 66 (d, 1H) , 6, 93-6, 95 (d, 1H) , 6, 72 (s, 3H) , 6, 11-6, 65 (m, 4H) , 4, 76-4, 79 (m, 1H) , 3, 90 (s, 1H) , 3, 72 (s, 1H) , 3, 2-3, 5 (m, 3H) , 2, 33-2, 36 (s, 1H) , 2, 12 (s, 3H) , 1, 75-1, 85 (m, 3H) , 1, 29-1, 28 (d, 4H) . Ensayo de actividad biológica Cloning, baculovirus generation, large-scale infection of HEK293 cells, and membrane preparation: The human prostaglandin E2 receptor 4 (EP4) was cloned into the pBacMam expression vector (GeneScript, UK). EP4 DNA transposition was performed using Invitrogen's Bac-to-Bac baculovirus expression systems. Baculovirus P0 was generated by transfecting SF9 cells with acidophilic DNA using Cellfectin II transfection reagent (ThermoFisher Scientific, UK). Following P0 generation, P1 virus was then generated for large-scale infection and membrane preparation. HEK293 cells were cultured in DMEM (ThermoFisher Scientific, UK), supplemented with 10% heat-inactivated fetal bovine serum (FBS). Cells were infected at a seeding density of 3.5 million cells / ml in 500 cm3 flasks with 5% v / v EP4 Bacman. Expression was carried out for a period of 36 hours at 37°C with 5% CO2.The cells were separated using PBS and a cell scraper. The cell culture was centrifuged at 2500 rpm for 10 min at 4 °C. The supernatant was then discarded, and the pellet was stored at -80 °C. The pellet was thawed and resuspended in 15 mL of homogenization buffer (20 mM HEPES, 10 mM EDTA, pH 7.4). It was then homogenized in a mechanical homogenizer (VMR) for 10 seconds. The membrane was centrifuged in centrifuge tubes at 40,000 g for 15 min at 4 °C. The supernatant was discarded and resuspended in 15 mL of homogenization buffer and homogenized for 20 seconds. The membrane was then centrifuged at 40,000 g for 45 min at 4 °C. The membrane was then resuspended in 3 ml of storage buffer (HEPES 20 mM, EDTA 0.1 mM, pH 7.4) and mixed thoroughly. The resulting membranes were then stored at -80 °C. Functional assay of Gs cAMP: cAMP production following EP4 receptor activation was determined using the time-resolved homogeneous fluorescence dynamic-2 (HTRF) cAMP assay (Cisbio, France). HEK293 cells were transfected using 0.5% Bacmam EP4 virus for 36 hours, before dissociating the cells and freezing them at -150°C. On the day of the assay, increasing concentrations of the test compounds, along with positive controls (10 µM PGE2 (Tocris, Abingdon, UK)) and a negative control (DMSO (Sigma-Aldrich, UK)) were added to a ProxiPlate-384 Plus, white, shallow 384-well microplate (PerkinElmer, USA) using the ECHO dispenser. The cells were thawed in a water bath and resuspended in DMEM supplemented with 10% FBS before being centrifuged at 1200 RPM for 5 min to form a pellet. The pellet was resuspended in assay buffer (DMEM + 0.5 mM IBMX (Tocris, Abingdon, UK)) at 0.5 x 10⁶ cells / ml. The cell suspension, for a final assay concentration of 5000 cells / well, was added using the Multidrop to the pre-dispensed assay plate. The plate was then incubated at 37 °C for 30 min with 5% CO₂. cAMP production was determined according to the manufacturer's instructions before reading the plates on a PheraStar fluorescence plate reader (BMG LabTech, Germany). The pEC50 values ​​were calculated from the midpoint of the curve using Dotmatics, as shown in Table 2. Table 2: pEC50 and Emax values ​​of EP4 Unidirectional CACO-2 cell permeability assay Caco-2 cells (ECACC) were seeded in 24-well Transwell plates with 2 x 10⁵ cells per well and used in confluent monolayers after a 21-day culture at 37 °C with 5% CO₂. Assay compounds were incubated at 10 µM, 0.2% final DMSO, n = 2 in assay buffer (Hanks equilibrated saline supplemented with 25 mM HEPES, adjusted to pH 6.5). Hanks equilibrated saline supplemented with 25 mM HEPES, adjusted to pH 7.4 (0.2% final DMSO) was used for the basolateral chamber (as the receptor). Incubations were performed at 37 °C, with samples taken from the donor and acceptor chambers at T=0 and 1 hour, and the compound was analyzed by mass spectrometry (LC-MS / MS) which included an internal analytical standard (carbamazepine 0.5 µM). The apparent permeability (Pap) values ​​are shown in Table 3 and were determined from the relationship: Where V is the volume of each Transwell compartment (apical 125 l, basolateral 600 l) and the concentrations are the relative MS responses for the compound (normalized to the internal standard) in the donor chamber before incubation and in the acceptor chamber at the end of incubation. Area = area of ​​cells exposed to drug transfer (0.33 cm2). Lucifer Yellow (LY) was added to the apical buffer in all wells to assess cell layer viability. Because LY cannot freely permeate lipophilic barriers, a high degree of LY transport indicates poor cell layer integrity, and wells with a Pap of LY > 10 x 10⁻⁶ cm / s were rejected. The recovery of the compound from the wells was determined from the MS responses (normalized to the internal standard) in the donor and acceptor chambers at the end of incubation compared to the response in the donor chamber before incubation. Table 3 - Average values ​​of apparent permeability (Pap)

Claims

1. A compound of formula I: or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or optical isomer thereof, wherein; A is OR, C(O)R, CO2R, C(O)N(R)2, C(O)N(R)S(O)2R, S(O)2R, S(O)2OR, SO2N(R)2, C1-8 alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; ring B is aryl or heteroaryl; X and Y are each independently CR" or N, wherein at least one of X and Y is CH; R1 and R2 are each independently H, C1-6 alkyl, C1-6 alkoxy, or R1 and R2, together with the carbon atom to which they are attached, form a C3-6 cycloalkane-1,1-diyl ring; each R3 is independently selected from H, OR', COOR', C(O)R', halogen, or C1-6 alkyl; R4 is H, C1-6 alkyl, halogen, CN, NO2, or OR'; R5 is H or C1-6 alkyl; or R4 and R5, together with the pyrrolidine ring to which they are attached, form a C1-6 alkylene connective; R6 is H, C1-6 alkyl, C1-3 alkoxy optionally substituted with 1-3 atoms of fluorine, halogen, CN, NO2, OR',CO2R' or C (O) R'; R7 is OR, OC (O) R, OC (O) OR, CO2R, CON (R) 2, SO2N (R) 2, SO2R, OSO2R or OSO2N (R) 2; each R' is independently H, C1-6 alkyl or C3-6 cycloalkyl; Each R" is H, C1-6 alkyl, halogen, or OR'; and nym are each independently 0, 1, 2, or 3; wherein in each case, the alkyl, alkylene, and cycloalkyl groups are each optionally and independently substituted up to 3 times with OH, SH, CN, NO2, COOH, halogen, or C1-4 alkyl; wherein in each case, the heterocycloalkyl, aryl, and heteroaryl groups are each optionally and independently substituted up to 3 times with OR', SR', CN, NO2, CO2R', halogen, C1-4 alkyl, or oxo.

2. The compound according to claim 1, wherein: (i) ring B is a 6-membered aryl or a 5-6-membered heteroaryl; each optionally and independently substituted up to 3 times with OR', SR', CN, NO2, CO2R', halogen, or alkyl. C1-4; or (ii) ring B is phenyl, which is optionally substituted up to three times with OH,or a 6-membered heteroaryl comprising one or two nitrogen atoms, wherein each nitrogen atom is optionally oxidized.

3. The compound according to claim 1 or 2, which is a compound of formula (1): or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or optical isomer thereof, wherein; U, V, W, and Z are each independently selected from the group consisting of CH, COH, N, or N+-O-, wherein at least three of U, V, W, and Z are CH.

4. The compound according to any one of claims 1-3, wherein R4 is H, OH, F, or is bonded to R5 to form a CH2 bridge; preferably wherein R4 is H, OH, or is bonded to R5 to form a CH2 bridge.

5. The compound according to any one of claims 1-4, wherein R5 is H or is bonded to R4 to form a CH2 bridge; preferably where R5 is H.

6. The compound according to any one of claims 1-5,wherein A is selected from the group consisting of: 9 is a C1-3 alkyl or a C3-6 cycloalkyl ring; preferably wherein A is: or 7. The compound according to claim 3, which is a compound of formula (2a): or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or optical isomer thereof, wherein U, V, W, X, Y, Z, R1, R2, R3, R4, R6 and R7 are the same as defined in claim 3.

8. The compound according to any one of claims 1-7, wherein R1 and R2 are independently H or C1-3 alkyl optionally substituted with 1-3 fluorine atoms.

9. The compound according to any one of claims 1-7, wherein R1 is H or methyl or is attached to R2 to form a cyclopropane-1,1-diyl ring; more preferably wherein R1 is methyl; and / or where R2 is H.

10. The compound according to claim 3, which is a compound of formula (3a): or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or optical isomer thereof,wherein U, V, W, X, Y, Z, R3, R4, R6 and R7 are the same as defined in claim 3.

11. The compound according to any one of claims 1-10, wherein R3 is H, OH or F; preferably wherein R3 is H or OH; more preferably wherein R3 is H.

12. The compound according to any one of claims 1-11, wherein R4 is H, OH or F; preferably wherein R4 is H or OH; more preferably wherein R4 is H.

13. The compound according to any one of claims 1-12, wherein R6 is H, OH, CN, halogen, C1-3 alkoxy optionally substituted with 1-3 fluorine atoms or C1-3 alkyl optionally substituted with 1-3 fluorine atoms; preferably wherein R6 is H, OH, CN or methyl; more preferably wherein R6 is methyl.

14. The compound according to any one of claims 1-13, wherein R7 is OH, CO2H, CONH2, SO2NH2 or OSO2NH2; preferably wherein R7 is CONH2 or SO2NH2.

15. The compound according to any one of claims 1-14,wherein X and Y are each independently selected from the group consisting of CH, CF, COH, or N; preferably wherein X is CH and Y is CH or COH; more preferably wherein X and Y are both CH.

16. The compound according to any one of claims 3-15, wherein U, V, W, and Z are CH, or wherein U, V, and Z are CH and W is COH.

17. The compound according to claim 1, wherein the compound is selected from: or a pharmaceutically acceptable salt, solvate, hydrate, or tautomer thereof.

18. A pharmaceutical composition comprising a pharmaceutically acceptable compound, salt, solvate, hydrate, tautomer, or optical isomer according to any one of claims 1-17, and a pharmaceutically acceptable excipient; preferably wherein the composition further comprises at least one additional therapeutic agent selected from the group consisting of aminosalicylates, corticosteroids, immunomodulators, and combinations thereof.

19. A kit comprising a compound,A pharmaceutically acceptable salt, solvate, hydrate, tautomer, or optical isomer according to any one of claims 1-17 and at least one additional therapeutic agent selected from the group consisting of aminosalicylates, corticosteroids, immunomodulators, and combinations thereof.

20. A compound according to any one of claims 1-17, a composition according to claim 18, or a kit according to claim 19 for use in medicine.

21. A compound according to any one of claims 1-17, a composition according to claim 18, or a kit according to claim 19, for use in the treatment of an EP4 receptor-mediated disease, wherein the EP4 receptor-mediated disease is a gastrointestinal disorder or a pulmonary disease or condition.

22. The compound, composition, or kit for use according to claim 21, wherein: (i) the gastrointestinal disorder is selected from the group consisting of constipation disorders,irritable bowel syndrome with predominant constipation, mixed-type irritable bowel syndrome, chronic idiopathic constipation, gastrointestinal symptoms associated with Parkinson's disease, gastrointestinal symptoms associated with cystic fibrosis, intestinal dysmotility, postoperative ileus, food allergy or intolerance, celiac disease, gastrointestinal motility disorders, functional gastrointestinal disorders, drug-induced enteropathy, NSAID-induced gastric and intestinal injury, chemotherapy-induced mucositis, gastroesophageal reflux disease (GERD), duodenogastric reflux, diarrheal diseases, immune-mediated gastrointestinal diseases, Crohn's disease, ulcerative colitis, inflammatory bowel disease, and ischemic colitis; and / or (ii) the pulmonary disease or condition is selected from chronic obstructive pulmonary disease, asthma, chronic bronchitis, cystic fibrosis, emphysema,chronic idiopathic cough, hyperactive airway disorder, and idiopathic pulmonary fibrosis.