1,2-substituted 3-oxopyrazolidine 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. An exemplary compound is, for instance, 4-(2-(2-(3-hydroxy-3-(4'-hydroxy-2'-methyl-[1,1'-biphenyl]-3-yl)propyl)-5-oxopyrazolidin-1-yl)ethyl)benzoic acid (Example 1). Pharmacological data are provided, for example

Description

1,2-Substituted 3-oxopyrazolidine derivatives as prostaglandin E2 receptor 4 (EP4) agonists for the treatment of gastrointestinal and pulmonary diseases 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 compounds and compositions for use 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 a key role 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) and leads to the generation of prostaglandins, including PGE2, the most widely produced prostanoid. PGE2's 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 protein-coupled receptors (activation of adenylate cyclase and production of cyclic adenosine monophosphate (cAMP)), EP2 and EP4; ii) Gq protein-coupled receptor (activation by PLC), EP1; and iii) Gi protein-coupled receptor (inhibition of adenylate cyclase), EP3. The EP4 receptor signals through the Gs protein and positively couples to adenylate cyclase to increase cAMP levels. The receptor was originally described in 1993 with the identification of an EP2-like receptor that positively couples 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 is 1–8% 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 complete 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. Prostaglandin E2 (PGE2) is a well-established secretagogue that can directly promote chloride secretion from intestinal epithelial cells. The secretory effects of PGE2 are mediated, in part, by the EP4 receptor, which can stimulate chloride anion 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 conditions of 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 range of compounds are used to induce and maintain remission, depending on the severity of the disease. These include aminosalicylates, corticosteroids, immunosuppressants, antibiotics, and biologics. Treatment may be administered in a stepwise fashion, with intensification of therapy according to the severity and progression of the disease. However, it is clear that some patients do not respond to or tolerate medical treatment 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 there is emerging interest in developing agents that restore barrier function (mucosal healing). The EP4 receptor 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 phase II study, the EP4 agonist, ONO-4819CD, was evaluated in patients with mild to moderate ulcerative colitis resistant to 5-aminosalicylic acid (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. An estimated 300 million people have asthma, making it 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 for long-term management are still needed. Progesterone 2 (PGE2) is known to have bronchodilatory and anti-inflammatory effects on isolated airway smooth muscle in 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 receptor agonists induced 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. Document WO 03 / 035064 describes a group of substituted pyrazolidinone compounds with activity on EP2 and EP4 receptors. 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 with the EP4 gene inactivated. 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 patients with IBD treated with ONO-4819CD (Nakase, H. et al. Inflamm. Bowel Dis. 2010, 16, 731-733). 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. Safe and effective EP4 receptor-selective agents need to be discovered. Compendium of the invention The present invention provides compounds that have activity as prostaglandin E2 receptor 4 (EP4) agonists. In one respect, a compound of Formula I is provided in this memorandum: or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or optical isomer thereof, wherein; A is R, C (O) R, CO2R, C (O) N (R) 2, C (O) N (R) S (O) 2R3, S (O) 2R, S (O) 2OR, SO2N (R) 2, C1-8 alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; X is halo, OR', COOR' or C1-6 alkyl; L and L' are each independently a C2-4 alkylene; R1 is H, halo, CN, NO2, OR, SR, COOR, C1-6 alkoxy or C1-6 alkyl; R2 is OR, OC (O) R3, OC (O) OR3, CO2R, CON (R) 2, SO2N (R) 2, SO2R3, OSO2R3 or OSO2N (R) 2; R3 is C1-6 alkyl, C3-6 cycloalkyl or a phenyl; R' is H, C1-6 alkyl or C3-6 cycloalkyl; and n is 0, 1, 2 or 3; wherein, in each case, alkyl, alkylene, alkoxy and cycloalkyl are optionally and independently substituted with up to 3 instances of OH, SH, CN, NO2, COOH, halo or COOC 1-4 alkyl; wherein, in each case, the heterocycloalkyl, aryl and heteroaryl are optionally and independently substituted with up to 3 instances of OR', SR', CN, NO2, CO2R', halo, C1-4 alkyl or oxo. 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 described herein, a composition described herein, or a kit described herein for use as a medicament. In another aspect, the invention includes a compound described herein, a composition described herein, or a 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, a 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 to a patient in need a compound or composition described herein. 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 food 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, gastrointestinal diseases of immune origin, Crohn's disease, ulcerative colitis, inflammatory bowel disease, and ischemic colitis. The compounds, compositions, or medicines may 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 the compounds of the invention for use in treatment methods comprising administering a compound of the invention as an EP4 receptor agonist. The compounds in Formula (I) may be used to treat, prevent, improve, control, or reduce the risk of diseases or disorders involving EP4 receptors. The compounds in Formula (I) 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 food intolerance, celiac disease, gastrointestinal motility disorders, functional gastrointestinal disorders, drug-induced enteropathy, and 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 in 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 studies in Caco-2 cells. 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 includes a compound of Formula I: or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or optical isomer thereof, wherein; A is R, C (O) R, CO2R, C (O) N (R) 2, C (O) N (R) S (O) 2R3, S (O) 2R, S (O) 2OR, SO2N (R) 2, C1-8 alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; X is halo, OR', COOR' or C1-6 alkyl; L and L' are each independently a C2-4 alkylene; R1 is H, halo, CN, NO2, OR, SR, COOR, C1-6 alkoxy or C1-6 alkyl; R2 is OR, OC (O) R3, OC (O) OR3, CO2R, CON (R) 2, SO2N (R) 2, SO2R3, OSO2R3 or OSO2N (R) 2; R3 is C1-6 alkyl, C3-6 cycloalkyl or a phenyl; R' is H, C1-6 alkyl or C3-6 cycloalkyl; and n is 0, 1, 2 or 3; wherein, in each case, alkyl, alkylene, alkoxy and cycloalkyl are optionally and independently substituted with up to 3 instances of OH, SH, CN, NO2, COOH, halo or COOC 1-4 alkyl; wherein, in each case, the heterocycloalkyl, aryl and heteroaryl are optionally and independently substituted with up to 3 instances of OR', SR', CN, NO2, CO2R', halo, C1-4 alkyl or oxo. In some embodiments, the compound is a compound of Formula (I) , Formula (Ia) , Formula (Ib) , Formula (Ic) , Formula (1) , Formula (1a) , Formula (1b) , Formula (1c) , Formula (2a) , Formula (2b) , Formula (2c) , Formula (2d) , Formula (3a) , Formula (3b) , Formula (3c) , Formula (3d) , Formula (3e) , Formula (3f) , Formula (5) , Formula (5a) , Formula (5b) , Formula (6) , Formula (6a) , Formula (6b) or a pharmaceutically acceptable salt or tautomer thereof. In some embodiments, the compound is a compound of formula (I), formula (Ia), formula (lb), formula (Ic), formula (1), formula (1a), formula (1b), formula (1c), formula (2a), formula (2b), formula (2c), formula (2d), formula (3a), formula (3b), formula (3c), formula (3d), formula (3e), formula (3f), formula (5), formula (5a), formula (5b), formula (6), formula (6a), formula (6b) or a pharmaceutically acceptable salt thereof. In some realizations, L' is the group In some realizations, L is the group In one embodiment of this aspect, the compound is a compound of Formula (1): or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or optical isomer thereof. In some embodiments, A is selected from C(O)OR', C(O)N(R')S(O)2R3, S(O)2OR', C1-8 alkyl, heterocycloalkyl or heteroaryl, wherein the heterocycloalkyl and heteroaryl are optionally and independently substituted with up to 3 cases of OR', SR', halo, C1-4 alkyl or oxo. In some realizations, A is selected from C(O)OR' and heteroaryl. In some embodiments, A is selected from the group consisting of: In some realizations, A is: In some areas, it is In some embodiments, the compound of Formula (I) is a compound of Formula (Ia), (Ib) or (Ic): or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or optical isomer thereof. In some embodiments, the compound of Formula (I) is a compound of Formula (1a), (1b) or (1c): or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or optical isomer thereof. In some embodiments, the compound of Formula (I) is a compound of Formula (3a), (3b), (3c), (3d), (3e) or (3f): or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or optical isomer thereof. In some embodiments, X is halo or OR'. In some embodiments, X is F, Cl or OH. In some realizations, X is F or OH, and yn is 0, 1, or 2. In some embodiments, X is F, Cl or OH, and n is 1 or 2. In some realizations, X is F or OH, and yn is 1 or 2. In some realizations, n is 0. In some embodiments, R1 is H, OH, halo, CN, C1-6 alkoxy optionally substituted with 1-3 fluorine atoms or C1-6 alkyl optionally substituted with 1-3 fluorine atoms. In some embodiments, R, 1 is H, OH, halo, CN, C1-6 alkyl optionally substituted with 1-3 fluorine atoms or C1-6 alkyl optionally substituted with 1-3 fluorine atoms. In some embodiments, R1 is methyl. In some realizations, R2 is OR', CON (R') 2, SO2N (R') 2 or OSO2N (R') 2. In some embodiments, R2 is OH, CONH2, SO2NH2u OSO2NH2. In some embodiments, R2 is CON (R) 2, SO2N (R) 2, OSO2R3 or OSO2N (R) 2. In some embodiments, R2 is CONH2, SO2NH2 or OSO2NH2. In some implementations, R2 is CONH2. In some embodiments, a compound of Formula (2a), (2b), (2c) or (2d) is provided in this document: or a pharmaceutically acceptable salt, solvate, hydrate or tautomer thereof. In some embodiments, R1 is H or C1-6 alkyl. In a further embodiment, R1 is methyl. In another embodiment, n is 0. In some embodiments, a compound of Formula (5), (5a), (5b), (6), (6a), (6b) is provided in this memory: or a pharmaceutically acceptable salt, solvate, hydrate or tautomer thereof. In some embodiments, R2 is CO2R, CON (R) 2, SO2N (R) 2 or OSO2N (R) 2. In a further embodiment, R2 is CONH2, SO2NH2 or OSO2NH2. In some embodiments, selected compounds from the group consisting of the following are provided in this document: or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or optical isomer thereof; or a pharmaceutically acceptable salt thereof. In some embodiments, the invention includes a pharmaceutical composition comprising a compound 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, the invention includes a compound or composition as 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 some embodiments, the invention includes a compound or composition as described herein, for use in a method of treating an EP4 receptor-mediated disease, the method comprising administering to a patient in need a compound or composition described herein. In some embodiments, EP4 receptor-mediated disease is a gastrointestinal disorder. In another embodiment, 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, gastrointestinal diseases of immune origin, 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 is a compound listed in Table 1 or a pharmaceutically acceptable salt, solvate, hydrate, or tautomer thereof. In some embodiments, this specification provides selected compounds from the compounds listed in Table 1 or a pharmaceutically acceptable salt thereof: Table 1: Exemplary Compounds of Formula (I) or a pharmaceutically acceptable salt thereof. ABBREVIATIONS aqueous acid Bn benzyl DCM dichloromethane DMA dimethylacetamide DMF dimethylformamide dppf 1,1'-bis(diphenylphosphino)ferrocene EDCI 1-ethyl-3-(3--dimethylaminopropyl)carbodiimide EtOAc ethyl acetate FA formic acid HATU 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium,3-oxide hexafluorophosphate HOBt hydroxybenzotriazole HPLC high-performance liquid chromatography h hour h hours LCMS liquid chromatography and mass spectrometry M Molar MeCN acetonitrile MeOH methanol Normal N NBS N-bromosuccinimide high-performance liquid chromatography (HPLC) TA ambient temperature saturated sat THF tetrahydrofuran UPLC ultra-high-performance liquid chromatography Definitions In this application, the following definitions apply, unless otherwise stated. The term "treatment", in relation to the uses of any of the compounds described herein, including those in Formula (I), Formula (Ia), Formula (Ib), Formula (Ic), Formula (1), Formula (1a), Formula (1b), Formula (1c), Formula (2a), Formula (2b), Formula (2c), Formula (2d), Formula (3a), Formula (3b), Formula (3c), Formula (3d), Formula (3e), Formula (3f), Formula (5), Formula (5a), Formula (5b), Formula (6), Formula (6a) and Formula (6b) is used to describe any form of intervention in which a compound is administered to a subject who has, is at risk of having or may be at risk of having 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" (for example, in relation to 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 a quantity sufficient to provide a desired level of pain relief. The desired level of pain relief might be, for example, the complete elimination of pain or a reduction in the intensity of the pain. As used in this dissertation, the term "hydroxyl" or "hydroxy" refers to an -OH group. As used in this dissertation, an "alkyl" group refers to a saturated aliphatic hydrocarbon group containing 1 to 12 (e.g., 1 to 8, 1 to 6, or 1 to 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 can be substituted (i.e., optionally substituted) with one or more substituents such as halo, phospho, cycloaliphatic [e.g., cycloalkyl or cycloalkenyl], heterocycloaliphatic [e.g., heterocycloalkyl or heterocycloalkenyl], aryl, heteroaryl, alkoxy, aroyl, heteroaroyl, acyl [e.g., carbonyl (aliphatic), carbonyl (cycloaliphatic), or carbonyl (heterocycloaliphatic)], nitro, cyano, amido [e.g., (cycloalkylalkyl) carbonylamino, arylcarbonylamino, aralkylcarbonylamino, (heterocycloalkyl) carbonylamino, (heterocycloalkylalkyl) carbonylamino, heteroarylcarbonylamino, heteroaralkylcarbonylamino, alkylaminocarbonyl, cycloalkylaminocarbonyl, heterocycloalkylaminocarbonyl, arylaminocarbonyl or heteroarylaminocarbonyl], amino [e.g., aliphaticamino, cycloaliphaticamino or heterocycloaliphaticamino], sulfonyl [e.g., aliphatic SO2], finyl, 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, alkyl (cycloaliphatic) or haloalkyl. As used in this dissertation, 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 moieties. 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 in this dissertation, 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), amido (heterocycloaliphatic), (heteroaralkyl) amido, (heteroaryl) amido, (heterocycloalkyl) alkylamido, arylamido, aralkylamido, (cycloalkyl) alkylamido, or cycloalkylamido. As used in this dissertation, an "amino" group refers to -NRXRY, in which each of Rx and RY is independently hydrogen, aliphatic, cycloaliphatic, (cycloaliphatic)aliphatic, araliphatic, heterocycloaliphatic, (heterocycloaliphatic)aliphatic, heteroaryl, carboxyl, sulfinyl, sulfonyl, carbonyl (aliphatic), carbonyl (cycloaliphatic), carbonyl ((cycloaliphatic)aliphatic), arylcarbonyl, (araliphatic) carbonyl, (heterocycloaliphatic) carbonyl, (heterocycloaliphatic) aliphatic) carbonyl, (heteroaryl) carbonyl, or carbonyl (heteroaraliphatic), each of which is defined in this dissertation 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 in this dissertation, 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, or tetrahydroanthracenyl, anthracenyl) ring systems in which the monocyclic ring system is aromatic or at least one of the rings of a bicyclic or tricyclic ring system is aromatic. Bicyclic and tricyclic groups include benzofused 2- to 3-membered carbocyclic rings. For example, a benzofused group includes phenyl fused to 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; oxy (cycloaliphatic); oxy (heterocycloaliphatic); aryloxy; heteroaryloxy; oxy (araliphatic); oxy (heteroaraliphatic); aroyl; heteroaroyl; amino; oxo (on a non-aromatic carbocyclic ring of a benzofused bicyclic or tricyclic aryl group); nitro; carboxy; amido; acyl [e.g., carbonyl (aliphatic); carbonyl (cycloaliphatic)]; carbonyl (araliphatic); carbonyl (heterocycloaliphatic); carbonyl ( (heterocycloaliphatic) aliphatic); or carbonyl (heteroaraliphatic) ]; sulfonyl [e.g., SO2-aliphatic- or -SO2-amino]; sulfinyl [e.g., S (O) -aliphatic- or -S (O) -cycloaliphatic]; sulfanyl [e.g., S-aliphatic]; cyano; halo; 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)alkylaminocarbonyl)aryl, (alkylcarbonyl)aminoaryl, (arylaminocarbonyl)aryl and (heteroaryl)amino)carbonyl)aryl]; aminoaryl [e.g., (alkylsulfonyl)amino)aryl or (dialkylamino)aryl]; (cyclyanoalkyl)aryl; (alkoxy)aryl; (sulfamoyl)aryl [e.g., (aminosulfonyl) aryl]; (alkylsulfonyl) aryl; (cyano) aryl; (hydroxyalkyl) aryl; ( (alkoxy) alkyl) aryl; (hydroxy) aryl, ( (carboxy) alkyl) aryl; ( (dialkyl) amino) alkyl) aryl; ( ( (alkylsulfonyl) amino) alkyl) aryl; (heterocyclochloro) aryl aliphatic) 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 in this dissertation, a "cycloalkyl" group refers to a saturated (fused or bridged) mono- or bicyclic carbocyclic ring of 3 to 10 (e.g., 5 to 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)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, oxy (cycloaliphatic), oxy (heterocycloaliphatic), aryloxy, heteroaryloxy, oxy (araliphatic), oxy (heteroaraliphatic), aroyl, heteroaroyl, amino, amido [e.g., carbonylamino (aliphatic) , 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, carbonyl ( (cycloaliphatic) aliphatic) , carbonyl (araliphatic) , carbonyl (heterocycloaliphatic) , carbonyl ( (heterocycloaliphatic) aliphatic) carbonyl or (heteroaraliphatic) carbonyl], cyano, halo, hydroxy, mercapto, sulfonyl [e.g. e.g., alkyl-SO2 and aryl-SO2], sulfinyl [e.g. e.g., alkyl-S(O)-], sulfanyl [e.g. e.g., alkyl-S-], sulfoxy, urea, thiourea, sulfamoyl, sulfamide, oxo or carbamoyl. As used in this memory, a "heterocycloalkyl" group refers to a saturated 3- to 10-membered mono- or bicyclic (fused or bridged) ring structure (e.g., 5- to 10-membered mono- or bicyclic), in which 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, morpholinol, thiomorpholyl, octahydrobenzofuryl, octahydrochromenyl, octahydrothiochromenyl, octahydrothiochromenyl, octahydrothiochromenyl, octahydrothiochromenyl, octahydrothiochromenyl, octahydrothiochromenyl, octahydrothiochromenyl, octahydrothiochromenyl, octahydrothiochromenyl, octahydrothiochromenyl, octahydrothiochromenyl, octahydrothiochromenyl, octahydrothiochromenyl, octahydrothiochromenyl, octahydrothiochromenyl, octahydrothiochromenyl, octahydrothiochromenyl, hydroindolyl, octahydropyrindinyl, decahydroquinolinyl, octahydrobenzo[ / ?]thiopheneyl, 2-oxabicyclo[2.2.2]octyl, 1-aza-bicyclo [2.2.2]octyl, 3-aza-bicyclo[3.2.2]octyl and 2,6-dioxa-tricyclo[3.3.1.03'7]nonyl. A monocyclic heterocycloalkyl group can fuse 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, oxy (cycloaliphatic), (heterocycloaliphatic) oxy, aryloxy, heteroaryloxy, oxy (araliphatic), oxy (heteroaraliphatic), aroyl, heteroaroyl, amino, amido [e.g., carbonylamino (aliphatic), carbonylamino (cycloaliphatic) aliphatic), carbonylamino, (aryl) carbonylamino, (cycloaliphatic) aliphatic) 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, carbonyl ( (cycloaliphatic) aliphatic) , carbonyl (araliphatic) , carbonyl (heterocycloaliphatic) , carbonyl ( (heterocycloaliphatic) aliphatic) or carbonyl (heteroaraliphatic) ], nitro, cyano, halo, hydroxy, mercapto, sulfonyl [e.g., alkylsulfonyl or arylsulfonyl], sulfinyl [e.g. e.g., alkylsulfinyl], sulfanyl [e.g. e.g., alkylsulfanyl], sulfoxy, urea, thiourea, sulfamoyl, sulfamide, oxo or carbamoyl. A "heteroaryl" group, as used in this dissertation, refers to a monocyclic, bicyclic, or tricyclic ring system having 4 to 15 ring atoms, in which one or more of the ring atoms is a heteroatom (e.g., N, O, S, or combinations thereof), and in which 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 fused benzo ring system having 2 to 3 rings. For example, a fused benzo group includes benzo fused with one or two 4- to 8-membered heterocycloaliphatic residues (e.g., indolizyl, indolyl, isoindolyl, 3H-indolyl, indolinyl, benzo[b]furyl, benzo[b]thiophenyl, quinolinyl, or isoquinolinyl).Some examples of heteroarilo son azetidinilo, piridilo, IH-indazolilo, furilo, pirrolilo, tienilo, tiazolilo, oxazolilo, imidazolilo, tetrazolilo, benzofurilo, isoquinolinilo, benzotiazolilo, xanteno, tioxanteno, fenotiazina, dihidroindol, benzo [l, 3]dioxol, benzo[b]furilo, benzo[b]tiofenilo, indazolilo, bencimidazolilo, benztiazolilo, purilo, cinolilo, quinolilo, quinazolilo, cinolilo, ftalazolilo, quinazolilo, quinoxalilo, isoquinolilo, 4H-quinolizilo, benzo-1, 2, 5-tiadiadiazolilo o 1, 8-naftiridilo. Sin limitación, los heteroarilos monocíclicos incluyen furilo, tiofeno-ilo, 2H-pirrolilo, pirrolilo, oxazolilo, tazolilo, imidazolilo, pirazolilo, isoxazolilo, isotiazolilo, 1, 3, 4-tiadiazolilo, 2H-piranilo, 4-H-pranilo, piridilo, piridilo, dazilo, pirimidilo, pirazolilo, pirazilo o 1, 3, 5-triazilo. Los heteroarilos monocíclicos se numeran según la nomenclatura química estándar. Without limitation, bicyclic heteroaryls include indolyl, indolyl, isoindolyl, 3H-indolyl, indolynyl, benzo[b]furyl, benzo[b]thiophenyl, quinolynyl, isoquinolinyl, indolylyl, indolyl, indolyl, indolyl, benzofuryl, bephenyl, indazolyl, benzimidazyl, benziazolyl, purinyl, 4H-quinolyl, quinolyl, isoquinolyl, cinolyl, phthalazyl, quinazolyl, quinoxalyl, 1, 8-naphthyridyl or pteridyl. Bicyclic heteroaryls are numbered according to standard chemical nomenclature. A heteroaryl is optionally substituted with one or more substituents such as aliphatic [e.g., alkyl, alkenyl, or alkynyl]; cycloaliphatic; (cycloaliphatic) aliphatic; heterocycloaliphatic; aliphatic (heterocycloaliphatic); aryl; heteroaryl; alkoxy; oxy (cycloaliphatic); oxy (heterocycloaliphatic); aryl; heteroaryl; alkoxy (cycloaliphatic); oxy; arylaliphatic; oxy; heteroaryloxy; oxy (araliphatic); oxy (heteroaraliphatic); aroyl; heteroaroyl; amino; oxo (on a carbocyclic or non-aromatic heterocyclic ring of a bicyclic or tricyclic heteroaryl); carboxy; amido; acyl [e.g., aliphatic / carbonyl]; (cycloaliphatic) carbonyl; carbonyl ( (cycloaliphatic) aliphatic) ; carbonyl (araliphatic) ; carbonyl (heterocycloaliphatic) ; carbonyl ( (heterocycloaliphatic) aliphatic) ; or carbonyl (heteroaraliphatic) ]; sulfonyl [e.g., aliphatic sulfonyl or aminosulfonyl]; sulfinyl [e.g., aliphatic sulfinyl]; sulfanyl [e.g.[, aliphatic sulfanyl]; nitro; cyano; halo; 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]; (amido)heteroaryl [e.g., aminocarbonylheteroaryl, ( (alkylcarbonyl) amino) heteroaryl, ( ( (alkyl) amino) alkyl) aminocarbonyl) heteroaryl, ( ( (heteroaryl) amino) carbonyl) heteroaryl, ( (heterocycloaliphatic) carbonyl) heteroaryl and ( (alkylcarbonyl) amino) heteroaryl 1]; (cyanoalkyl) heteroaryl; (alkoxy) heteroaryl; (sulfamoyl) heteroaryl [for example, (aminosulfonyl) heteroaryl]; (sulfonyl) heteroaryl [for example, (alkylsulfonyl) heteroaryl]; (hydroxyalkyl) 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) aryl]; (alkyl) heteroaryl; or (haloalkyl) heteroaryl [e.g., trihaloalkylheteroaryl]. As used in this memory, an "alkoxy" group refers to an alkyl-O- group in which "alkyl" has been previously defined. As used in this memory, 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 in this memory, a "mercapto" group refers to -SH. As used in this memory, a "sulfo" group refers to -SO3H or -SO3RX when used terminally or -S(O)3- when used internally. As used in this memory, a "sulfamide" group refers to the structure -NRX-S(O)2-NRYRZ when used terminally and -NRX-S(O)2-NRY- when used internally, where Rx, RY, and Rz have been defined above. As used in this memory, a "sulfamoyl" group refers to the structure -OS(O)2-NRYRZ where RY and Rz have been defined above. As used in this memory, 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 in this dissertation, 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 S-aliphatic, -S-cycloaliphatic, -S-aryl, or similar groups. As used in this dissertation, a "halogen" or "halo" group refers to fluorine, chlorine, bromine, or iodine. As used in this dissertation, an "oxo" refers to =O. As used in this memory, the term "neighborly" generally refers to the placement of substituents in a group that includes two or more carbon atoms, in which the substituents are attached to adjacent carbon atoms. As used in this memory, the term "geminal" generally refers to the placement of substituents on a group that includes two or more carbon atoms, where the substituents are attached to the same carbon atom. The terms "terminal" and "internal" refer to the location of a group within a substituent. A group is terminal when it is located at the end of the substituent and is not further bonded to the rest of the chemical structure. The carboxyalkyl group, RxO(O)C, is an example of a terminally used carboxyl group. 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 alkylcarboxyl groups (e.g., alkyl-C(O)O-aryl- or alkyl-O(CO)-aryl-) are examples of internally used carboxyl groups. As used in this thesis, 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-, in which 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 above. The phrase "optionally substituted" is used interchangeably with "substituted or unsubstituted" in this specification. 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 the particular classes, subclasses, and species of the invention. Unless otherwise stated, each of the groups specific to the variables listed herein may be optionally substituted with one or more of the substituents described herein. Each substituent of a specific group is further optionally substituted with one or three of the following: halo, 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 of the following: halo, cyano, oxo, alkoxy, hydroxy, amino, nitro, aryl, haloalkyl, and alkyl. As a further example, the cycloalkyl portion of a (cycloalkyl)carbonylamino can be optionally substituted with one to three of the following: halo, cyano, alkoxy, hydroxy, nitro, haloalkyl, and alkyl. 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 or atoms to which they are attached. As used in this dissertation, 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 specific 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 specific 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 in this specification, 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 cases, 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. The invention described herein further relates to all tautomers of the compounds presented herein. For pharmaceutical uses, the salt should be considered 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 in a medium where the salt is insoluble, followed by removal of the solvent or medium using standard techniques (e.g., under vacuum, by lyophilization, or by 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, and arylsulfonic acids (e.g., benzenesulfonic, naphthalene-2-sulfonic, naphthalene-1,5-disulfonic, and p-toluenesulfonic), ascorbic (e.g., L-ascorbic), L-aspartic, benzoic, 4-acetamidobenzoic, butanoic, (+) camphoric, camphorsulfonic, (+)-(1S)-camphor-10-sulfonic, capric, caproic, caprylic, 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), α-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-hydroxy-2-naphthoic, nicotinic, nitric, oleic, orotic, oxalic, palmitic, pamoic, phosphoric, propionic, L-pyroglutamic, salicylic, 4-aminosalicylic, sebacic, stearic, succinic, sulfuric, tannic, tartaric acids (e.g., (+) -L-tartaric), thiocyanic, undecylenic and valeric. Also included are all solvates of the compounds and their salts. The 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 manufacture 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 carriers or excipients. The composition may further contain ingredients selected from, for example, diluents, adjuvants, excipients, vehicles, preservatives, fillers, disintegrants, wetting agents, emulsifying agents, suspending agents, sweeteners, flavoring agents, perfumes, antibacterial agents, antifungal agents, lubricants, and dispersing agents, depending on the nature of the route 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 and should not place an undue burden on them.In general, the daily dose range can be approximately between 10 µg and 30 mg per kg of body weight in humans and other mammals, if possible approximately between 50 µg and 30 mg per kg of body weight in humans and other mammals, for example, approximately between 50 µg and 10 mg per kg of body weight in humans and other mammals, for example, approximately between 100 µg and 30 mg per kg of body weight in humans and other mammals, for example, approximately between 100 µg and 10 mg per kg of body weight in humans and other mammals, and, if possible, approximately between 100 µg and 1 mg per kg of body weight in humans and other mammals. Combination therapy An effective amount in the pharmaceutical composition of the invention can be achieved 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 amount can be achieved by using a first amount of a compound of the invention and a second amount 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 amount (i.e., each in an amount 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 an amount 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 in this dissertation, the terms "in combination" or "co-administration" can 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 may 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, 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 (by for example, a prophylactic or therapeutic agent such as an anticancer agent) to a subject. It is understood that the method of jointly administering a first quantity of a compound of the invention and a second quantity of an additional therapeutic agent can 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 can result in improved efficacy of 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) can avoid or reduce adverse or unwanted side effects associated with the use of any of the therapies separately. 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 may 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, food allergy or intolerance, celiac disease, gastrointestinal motility disorders, functional gastrointestinal disorders, drug-induced enteropathy.Food allergy or intolerance induced by NSAIDs, 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. At least one additional therapeutic agent may be a corticosteroid. The corticosteroid may be budesonide. At least one additional therapeutic agent may be an immunomodulator. The immunomodulator may be iopurin. The immunomodulator may be methotrexate. Pharmaceutical formulations Although it is possible for the active compound to be administered alone, it is preferable to present it as a pharmaceutical composition (e.g., a formulation). Accordingly, in another embodiment of the invention, a pharmaceutical composition is provided comprising at least one compound of Formula (I) as defined above together with at least one pharmaceutically acceptable excipient. When the pharmaceutical composition comprises at least one additional therapeutic agent, the pharmaceutically acceptable compound, salt, solvate, hydrate, tautomer or optical isomer of the invention and the at least one additional therapeutic agent may be formulated together or the pharmaceutically acceptable compound, salt, solvate, hydrate, tautomer or optical isomer of the invention and the at least one additional therapeutic agent may be formulated separately. The composition may be a composition of tablets. The composition may be a composition in capsules. Pharmaceutically acceptable excipients may be selected from, for example, carriers (e.g., a solid, liquid, or semi-solid carrier), adjuvants, diluents (e.g., solid diluents as filler material; and liquid diluents 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 in this document, 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 (I) 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. Suitable pharmaceutical dosage forms for oral administration include tablets (coated or uncoated), capsules (hard or soft coated), caplets, 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 an inert diluent or carrier, 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.Tablets may also contain conventional ingredients such as binding and granulating agents like 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 juices (immediate-release tablets) or to be released in a controlled manner (controlled-release tablets) over a prolonged period or in a specific region of the gastrointestinal tract. The pharmaceutical compositions typically comprise from approximately 1% (w / w) to approximately 95%, preferably with a certain percentage (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 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 95%, preferably from approximately 20% to 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, tablets, or capsules. Tablets and capsules may contain, for example, 0–20% disintegrants, 0–5% lubricants, 0–5% fluidizers, and 0–99% (w / w) fillers (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 also typically contain 0–99% (w / w) release-controlling polymers (e.g., retardants) (depending on the dosage). Film coatings of tablets or capsules 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) cosolvents, and / or 0-99% (w / w) water for injection (WFI) (depending on the dose and whether they are lyophilized). Intramuscular injectable 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. The compounds in Formula (I) will generally be presented in unit dosage form and, as such, will normally 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, for example, from 50 milligrams to 1 gram, for example, 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 amounts of compound administered may be determined by a supervising physician according to standard procedures. Synthesis of compounds of formula (1) Method 1 using LC / MS Instruments: Acquity UPLC with photodiode array detector and QDA mass detector; Column: AcquityC-18, 1.6 microns, 50 x 2.1 mm; gradient [time (min) / solvent B in A (%)]: 0.00 / 10, 0.75 / 10, 2.80 / 90, 4.50 / 100, 4.60 / 100, 4.70 / 10; 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 0.8 mL / min. Method 2 using LC / MS Instruments: Acquity UPLC with photodiode array detector and QDA mass detector; Column: Acquity C-18, 1.6 microns, 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. Method 3 using LC / MS Instruments: Water 2690 with photodiode array detector and QDA mass detector; column: X-Bridge C-18, 5 microns, 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. General synthetic strategies Compounds of formula G-4 can be synthesized according to Scheme 1 by either 1) alkylating tert-butyl carbazate with a bromide compound of formula G-1a, or 2) contacting tert-butyl carbazate with an aldehyde of formula G-1b under reducing amination conditions to give the hydrazine compound G-2. Contacting G-2 with the divalent compound, 3-bromopropionyl chloride, gives the cyclized, BOC-protected compound of formula G-3. Deprotection of G-4 gives a compound of formula G-4. Scheme 1 Compounds of formula G-4 can be alkylated according to Scheme 2, by a conjugate addition reaction with a compound of formula G-5 to give a compound of formula G-6. G-6 can then be coupled with an aryl bromide of formula G-7, wherein Rx and Rx are each independently a lower alkyl group, or both Rx and Rx, together with the boron atom and the oxygen atoms to which they are attached, form a 5- or 6-membered heterocyclic ring. The coupling of G-6 to G-7 usually takes place in the presence of a palladium catalyst, such as PdCl2(dppf)·DCM, to give a biaryl compound of formula G-8. G-8 can be further reduced to give a compound of G-10. Other functional group interconversions are possible at this point in the synthesis, such as when A is an ester group, the compound G-8 or G-10 can be further hydrolyzed.Furthermore, the reduction (and / or other FGI, e.g., hydrolysis) can be carried out prior to the Pd-catalyzed coupling according to Scheme 2, by means of a compound of formula G-9. Scheme 2 Phenolic compounds of formula G-11 can be further derivatized to obtain compounds of formula G-12 according to Scheme 3, by reaction with a sulfonamidating reagent such as sulfamoyl chloride. Scheme 3 Examples Further embodiments are described in more detail in the following examples. In the chiral separations of racemic compounds exemplified in the following examples, "isomer 1" refers to the isomer that was eluted first from the chiral column and "isomer 2" refers to the isomer that was eluted second from the chiral column. Synthetic preparation of intermediate products Intermediate Product 1: Synthesis of 4-(2-(5-oxopyrazolidin-1-yl)ethyl) methyl benzoate (Intermediate Product 1) Intermediate product 1 Step (i): Methyl 4-(2-bromoethyl)benzoate (20.00 g, 82.65 mmol), tert-butyl carbazate (12.01 g, 90.92 mmol), NaHCO3 (27.78 g, 330.60 mmol), and NaI (1.24 g, 8.27 mmol) were suspended in MeCN (200 mL) at room temperature, and the reaction mixture was stirred at 80 °C for 24 h. The reaction mixture was concentrated under vacuum, and the residue was partitioned between water (1000 mL) and EtOAc (800 mL). The aqueous layer was further extracted with EtOAc (3 x 300 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 (normal phase, silica). The product was eluted with 0% to 18% EtOAc in hexane to yield the impure product, which was further purified by reversed-phase gradient ultrafast column chromatography (reversed phase, C18 silica). The product was eluted from 0% to 55% MeCN in water to yield tert-butyl 2-(4-(methoxycarbonyl)phenethyl)hydrazyl)-1-carboxylate (5.6 g, 23%) as a yellow oil. The product was confirmed by LCMS (Method_3), m / z 239 (ES+, M+H-tBu), at 2, 20 min. Step (ii): 2-(4-(methoxycarbonyl)phenethyl)hydrazine-1-carboxylate (5.60 g, 19.04 mmol) was dissolved in MeCN (60 mL) and potassium carbonate (13.16 g, 95.19 mmol) was added to the reaction mixture at room temperature. The reaction mixture was stirred at room temperature for 10 min. After this, 3-bromopropionyl chloride (2.90 mL, 28.56 mmol) was added dropwise at room temperature, and the reaction mixture was stirred at room temperature for 24 h. The reaction mixture was concentrated under vacuum, and the resulting residue was partitioned between water (800 mL) and EtOAc (500 mL). The aqueous layer was further extracted with EtOAc (2 x 200 mL). The organic layers were combined and dried (Na2SO4).The solvent was removed under vacuum, and the product was purified by gradient column chromatography (normal phase, silica). The product was eluted with 0% to 22% EtOAc in hexane to yield the impure product, which was further purified by reversed-phase gradient ultrafast column chromatography (reversed phase, C18 silica). The product was eluted with 0% to 45% MeCN in water to yield tert-butyl 2-(4-(methoxycarbonyl)phenethyl)-3-oxopyrazolidin-1-carboxylate (6.5 g, 98%) as a yellow oil. The product was confirmed by LC-MS (Method 3), m / z 293 (ES+, M+HtBu), at 2.43 min. Step (iii): tert-butyl 2-(4-(methoxycarbonyl)phenethyl)-3-oxopyrazolidin-1-carboxylate (6.5 g, 18.7 mmol) was dissolved in dioxane (70 mL) and 4 N HCl in dioxane (70 mL) was added dropwise to the reaction mixture at 0 °C and the reaction mixture was left to stir at room temperature for 4 h. The solvent was removed under vacuum to obtain the crude product which was purified by trituration with 20% MeOH in diethyl ether to give methyl 4-(2-(5-oxopyrazolidin-1-yl)ethyl)benzoate (4.8 g, 90%) in the form of a whitish powder. The product was confirmed by LCMS (Method_3), m / z 249 (ES+, M+H), at 1.57 min. 1H NMR: (400 MHz, DMSO) : 2.62-2.58 (t, 2H, J=8.2 Hz) , 3.06-3.02 (t, 2H, J=7.4 Hz) , 3.58-3.56 (t, 2H, J=4.4 Hz) , 3.74-3.70 (t, 2H, J=7, 2 Hz), 7, 46-7, 44 (d, 2H, J=8, 4 Hz), 7, 90-7, 89 (d, 2H), J=8, 0 Hz). Intermediate Product 2: Synthesis of methyl 4-(2-(2-(3-(3-bromophenyl)-3-hydroxypropyl)-5-oxopyrazolidin-1-yl)ethyl)-2,6-difluorobenzoate (Intermediate Product 2) Step (i): Methyl 4-bromo-2,6-difluorobenzoate (40.00 g, 159.36 mmol), potassium vinyltrifluoroborate (32.00 g, 239.04 mmol), and TEA (42 mL, 318.72 mmol) were dissolved in IPA (400 mL), and nitrogen gas was purged for 30 minutes at room temperature. Following this, PdCl2 (dppf)·DCM (13.01 g, 15.93 mmol) was added, and the reaction mixture was stirred at 80 °C for 3 h. The reaction mixture was then partitioned between water (1000 mL) and EtOAc (1000 mL). The aqueous layer was further extracted with EtOAc (2 x 500 mL). The organic layers were combined and dried (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 0% to 5% EtOAc in hexane to give methyl 2,6-difluoro-4-vinylbenzoate (25.0 g, 79%) as a yellow oil. Step (ii) Methyl 2,6-difluoro-4-vinylbenzoate (25.0 g, 126.19 mmol) was dissolved in a mixture of Z-butanol (130 mL) and water (175 mL) at room temperature. Following this, NBS (26.94 g, 151.43 mmol) was added in portions at room temperature and the mixture was stirred at 40 °C for 16 h. After cooling to 5 °C, a solution of NaOH (10.09 g, 252.23 mmol) was used, and the mixture was stirred at room temperature for 30 min. The reaction mixture was then partitioned between water (800 mL) and EtOAc (500 mL), and the aqueous layer was further extracted with EtOAc (2 x 300 mL). The organic layers were combined and dried (Na2SO4). The solvent was removed under vacuum to provide crude methyl 2,6-difluoro-4-(oxiran-2-yl)benzoate (22.8 g, 84%) in the form of a yellow oil. Step (iii): Methyl 2,6-difluoro-4-(oxiran-2-yl)benzoate (22.8 g, 106.54 mmol) was dissolved in methanol (500 mL) and 10% palladium on carbon with 50% moisture (6.9 g) was added. Ammonium formate (67.22 g, 1065.42 mmol) was then added at room temperature, and the reaction mixture was stirred for 16 h at room temperature. Once complete, the reaction mixture was filtered through a Celite bed, washed with MeOH (3000 mL), and the filtrate was concentrated under vacuum. The reaction mixture was then partitioned between water (1000 mL) and EtOAc (500 mL). The aqueous layer was further extracted with EtOAc (2 x 300 mL). The organic layers were combined and dried (Na2SO4). The solvent was removed under vacuum to provide the crude product, which was purified by ultrafast gradient column chromatography (normal phase, silica).The product was eluted with EtOAc from 0% to 26% in hexane to provide methyl 2,6-difluoro-4-(2-hydroxyethyl)benzoate (11 g, 47, 80%) in the form of a yellow oil. Step (iv): Methyl 2,6-difluoro-4-(2-hydroxyethyl)benzoate (11.00 g, 50.87 mmol) was dissolved in DCM (300 mL) at room temperature. Dess-Martin periodinane (32.36 g, 76.31 mmol) was then added in portions at room temperature, and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was then partitioned between a saturated aqueous solution of NaHCO3 (500 mL) and DCM (800 mL). The aqueous layer was further extracted with EtOAc (2 x 500 mL). The organic layers were combined and dried (Na2SO4). The solvent was removed under vacuum to provide crude methyl 2,6-difluoro-4-(2-oxoethyl)benzoate (7.96 g, 73%) as a white solid. It was used in the next step without further purification. Step (v): Methyl 2,6-difluoro-4-(2-oxoethyl)benzoate (7.92 g, 37.00 mmol) and tert-butyl carbazate (4.89 g, 37.00 mmol) were dissolved in methanol (100 mL) under a nitrogen atmosphere, and 4 Å molecular sieves were added to maintain a moisture-free environment. Glacial acetic acid (0.3 mL, 3.70 mmol) was then added at room temperature, and the mixture was stirred for 3 h at room temperature. Afterward, the reaction mixture was cooled to 0 °C, and sodium cyanoborohydride (2.78 g, 44.40 mmol) was added in portions and stirred at room temperature for 12 h. The reaction mixture was concentrated under vacuum to obtain a residue. It was partitioned between a saturated aqueous solution of NaHCO3 (500 mL) and EtOAc (300 mL). The aqueous layer was further extracted with EtOAc (2 x 200 mL). The organic layers were combined and dried (Na2SO4).The solvent was removed under vacuum to obtain the crude product, which was purified by gradient column chromatography (normal phase, silica). The product was eluted with 0% to 3% EtOAc in DCM to yield crude tert-butyl 2-(3,5-difluoro-4-(methoxycarbonyl)phenethyl)hydrazine-1-carboxylate (9.10 g, 65%) as a white solid. The product was confirmed by LCMS (Method 2), m / z 275 (ES+, M+H-tBu), at 2.32 min. Step (vi): 2-(3,5-difluoro-4-(methoxycarbonyl)phenethyl)hydrazin-1-carboxylate tert-butyl (9.00 g, 27.26 mmol) was dissolved in DMF (20 mL) and potassium carbonate (18.83 g, 136.30 mmol) was added to the reaction mixture at room temperature and left to stir at room temperature for 10 min. After this, 4-bromobutanoyl chloride (3.4 mL, 40.89 mmol) was added dropwise at room temperature and the reaction mixture was left to stir at room temperature for 3 h and then at 40 °C for 16 h. The reaction mixture was divided between water (500 mL) and EtOAc (700 mL), the aqueous layer was further extracted with EtOAc (2 x 250 mL). The organic layers were combined and dried (Na2SO4).The solvent was removed under vacuum and the product was purified by gradient column chromatography (reversed phase, C18 silica). The product was eluted from a MeCN concentration of 0% to 50% in water to yield 3.5 g (33%) as a yellow oil. The product was confirmed by LCMS (Method 2) m / z 329 (ES+, M+H-tBu) at 2.48 min. Step (vii): 2-(3,5-difluoro-4-(methoxycarbonyl)phenethyl)-3-oxopyrazolidin-1-carboxylate (3.5 g, 9.11 mmol) was dissolved in dioxane (40 mL) and 4 N HCl in dioxane (20 mL) was added dropwise to the reaction mixture at 0 °C. The reaction mixture was stirred at room temperature for 18 h. The solvent was removed under vacuum to obtain the crude product, which was purified by trituration with 20% MeOH in diethyl ether to provide the HCl salt of methyl 2,6-difluoro-4-(2-(5-oxopyrazolidin-1-yl)ethyl)benzoate (2.62 g, 79%) as a whitish amorphous powder. The product was confirmed by LCMS (Method 2), m / z 285 (ES+, M+H), at 1.67 min. Step (vii): 2-(3,5-difluoro-4-(methoxycarbonyl)phenethyl)-3-oxopyrazolidin-1-carboxylate (3.5 g, 9.11 mmol) was dissolved in dioxane (40 mL) and 4 N HCl in dioxane (20 mL) was added dropwise to the reaction mixture at 0 °C. The reaction mixture was stirred at room temperature for 18 h. The solvent was removed under vacuum to obtain the crude product, which was purified by trituration with 20% MeOH in diethyl ether to provide the HCl salt of methyl 2,6-difluoro-4-(2-(5-oxopyrazolidin-1-yl)ethyl)benzoate (2.62 g, 79%) as a whitish amorphous powder. The product was confirmed by LCMS (Method 2), m / z 285 (ES+, M+H), at 1.67 min. Step (viii): The HCl salt of 2,6-difluoro-4-(2-(5-oxopyrazolidin-1-yl)ethyl)methyl benzoate (0.80 g, 2.81 mmol) and 1-(3-bromophenyl)prop-2-en-1-one (1.60 g, 14.08 mmol) were suspended in MeOH (10 mL) at room temperature, and the reaction mixture was stirred at room temperature for 15 min. After this, TEA (0.70 mL, 5.27 mmol) was added at room temperature, and the mixture was stirred at 60 °C for 4 h. The reaction mixture was partitioned between water (200 mL) and EtOAc (200 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 further purified by reversed-phase gradient ultrafast column chromatography (reversed phase, C18 silica). The product was eluted with 0% to 58% ACN in water to yield methyl 4-(2-(2-(3-(3-bromophenyl)-3-oxopropyl)-5-oxopiolyrazdin-1-yl)ethyl)-2,6-difluorobenzoate (0.65 g, 47%) as a colorless sticky material. The product was confirmed by LCMS (Method 2), m / z 495 (ES+, M+H), at 2.58 min. Step (ix): Methyl 4-(2-(2-(3-(3-bromophenyl)-3-oxopropyl)-5-oxopyrazolidin-1-yl)ethyl)-2,6-difluorobenzoate (0.650 g, 1.31 mmol) was dissolved in ethanol (4 mL) and water (2 mL), and CeCl3 (0.97 g, 3.94 mmol) was added. The reaction mixture was stirred at 0 °C for 5 min. Sodium borohydride (0.20 g, 0.5.26 mmol) was then added at 0 °C, and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was then partitioned between water (100 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). The solvent was removed under vacuum to provide Intermediate Product 2: methyl 4-(2-(2-(3-(3-bromophenyl)-3-hydroxypropyl)-5-oxopyrazolidin-1-yl)ethyl)-2,6-difluorobenzoate (0.620 g, 95%) as a brown solid. The product was confirmed by LCMS (Method 2), m / z 497 (ES+, M+H), at 2.04 min.RMN 1H: (400 MHz, DMSO): 1, 74-1, 73 (d, 2H, J=4, 8 Hz) , 2, 88-2, 76 (m, 4H) , 3, 12-3, 10 (d, 2H, J=7, 2 Hz) , 3, 86 (s, 3H) , 4, 66 (s, 1H) , 5, 44-5, 43 (d, 1H, J= 4, 4 Hz) , 7, 12-7, 10 (d, 2H, J= 9, 6 Hz) , 7, 36-7, 27 (m, 2H) , 7, 43-7, 41 (d, 1H, J= 8, 0 Hz), 7, 55 (s.1H). Producto intermedio B; Síntesis de 1-(3-bromofenil) prop-2-en-1-ona (Producto intermedio B) Step (i): 3-Bromobenzaldehyde (12.0 g, 56.6 mmol) was dissolved in diethyl ether (30 mL) at 0 °C, vinylmagnesium bromide (1 M in THF) (200 mL) was added dropwise at 0 °C in a nitrogen atmosphere and the mixture was stirred at room temperature for 3 h. The reaction mixture was partitioned between saturated aqueous NH4Cl (1000 mL) and EtOAc (800 mL); the aqueous layer was further extracted with EtOAc (2 x 300 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 (normal phase, silica). The product was eluted with EtOAc from 0% to 14% in hexane to provide 1-(3-bromophenyl)prop-2-en-1-ol (A) (12.0 g, 94%) in the form of a colorless oil. Step (ii): [1-(3-bromophenyl)prop-2-en-1-ol A) (12.0 g, 57.1 mmol) was dissolved in acetone (30 mL) at room temperature. Jones reagent (39 mL) was added dropwise at -25 °C and stirred at -25 °C for 30 min. The reaction mixture was then heated to 0 °C and stirred for 30 min. The reaction mixture was partitioned between saturated aqueous NaHCO3 (100 mL) and EtOAc (800 mL), and the aqueous layer was further extracted with EtOAc (2 x 250 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 (normal phase, silica). The product was eluted with 0% to 8% EtOAc in hexane to yield 1-(3-bromophenyl)prop-2-en-1-one (8.0 g, 97%) as a yellow gum. The product was confirmed by LCMS with no ionic mass at 2.39 min. Intermediate Product 3; synthesis of methyl 4-(2-(2-(3-(3-bromophenyl)-3-hydroxypropyl)-5-oxopyrazolidin-1-yl)ethyl)-2-hydroxybenzoate (Intermediate Product 3) Step (i): Methyl 4-bromo-2-methoxybenzoate (30.00 g, 156.07 mmol), potassium vinyltrifluoroborate (41.81 g, 312.16 mmol), and TEA (64.93 mL, 468.21 mmol) were dissolved in isopropyl alcohol (300 mL), and nitrogen gas was purged for 30 minutes at room temperature. Afterward, pDCI2 (dppf) DCM (20.09 g, 24.60 mmol) was added, and the reaction mixture was stirred at 80 °C for 3 h. The reaction mixture was then partitioned between water (1200 mL) and EtOAc (700 mL). The aqueous layer was further extracted with EtOAc (2 x 500 mL). The organic layers were combined and dried (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 0% to 14% EtOAc in hexane to give methyl 2-methoxy-4-vinylbenzoate (20.00 g, 84%) as a yellow oil.The product was confirmed by LCMS (Method 1), m / z 193 (ES+, M+H) at 2, 18 min. Step (ii): Methyl 2-methoxy-4-vinylbenzoate (20.00 g, 104.05 mmol) was dissolved in a mixture of Z-butanol (15 mL) and water (30 mL) at room temperature. Following this, NBS (27.78 g, 156.08 mmol) was added in portions at room temperature, and the reaction mixture was stirred at 40 °C for 2 h. The reaction mixture was then partitioned between water (1000 mL) and EtOAc (800 mL). The aqueous layer was further extracted with EtOAc (2 x 300 mL). The organic layers were combined and dried (Na2SO4). The solvent was removed under vacuum to yield crude 2-methoxy-4-(oxiran-2-yl) methyl benzoate (20.00 g, quantitative yield) as a yellow oil. Note: As this product was not stable, it proceeded to the next stage without purification. Step (iii): Methyl 2-methoxy-4-(oxiran-2-yl)benzoate (20.00 g, 96.06 mmol) was dissolved in methanol (200 mL) and 10% palladium on carbon with 50% moisture (10.00 g) was added. Ammonium formate (60.57 g, 960.60 mmol) was then added at room temperature, and the reaction mixture was stirred at 60 °C for 4 h. Afterward, the reaction mixture was filtered through a Celite bed and washed with MeOH (2000 mL). The filtrate was then concentrated under vacuum. The crude product was purified by ultrafast gradient column chromatography (normal phase, silica) and eluted with 0% to 45% EtOAc in hexane to yield crude methyl 4-(2-hydroxyethyl)-2-methoxybenzoate (9.80 g, 49%) as a colorless oil. The product was confirmed by LCMS (Method 1), m / z 211 (ES+), at 1.60 min. Step (iv): Methyl 4-(2-hydroxyethyl)-2-methoxybenzoate (9.80 g, 46.62 mmol) was dissolved in DCM (100 mL) at room temperature. Dess-Martin periodinane (39.54 g, 93.24 mmol) was then added in portions at room temperature, and the reaction mixture was stirred at room temperature for 4 h. The reaction mixture was then partitioned between a saturated aqueous solution of NaHCO3 (800 mL) and EtOAc (500 mL). The aqueous layer was further extracted with EtOAc (2 x 200 mL). The organic layers were combined and dried (Na2SO4). The solvent was removed under vacuum to provide methyl 2-methoxy-4-(2-oxoethyl)benzoate (10.0 g, quantitative yield) in the form of a yellow oil, which was used in the next stage without further purification. Step (v): Methyl 2-methoxy-4-(2-oxoethyl)benzoate (10.0 g, 48.03 mmol) and tert-butyl carbazate (7.62 g, 57.63 mmol) were dissolved in methanol (100 mL) under a nitrogen atmosphere. A 4 Å molecular sieve (1.00 g) was also added to maintain a moisture-free environment. Glacial acetic acid (0.3 mL, 4.80 mmol) was then added at room temperature, and the reaction mixture was stirred for 3 h at room temperature. After this, the reaction mixture was cooled to 0 °C, and sodium cyanoborohydride (4.53 g, 72.05 mmol) was added in portions. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was filtered under reduced pressure and the filtrate was concentrated under vacuum. The resulting residue was divided between a saturated aqueous solution of NaHCO3 (700 mL) and EtOAc (500 mL). The aqueous layer was further extracted with EtOAc (3 x 200 mL). The organic layers were combined and dried (Na2SO4).The solvent was removed under vacuum to obtain the crude product, which was purified by gradient column chromatography (normal phase, silica). The product was eluted from 0% to 29% EtOAc in hexane to yield crude tert-butyl 2-(3-methoxy-4-(methoxycarbonyl)phenethyl)hydrazine-1-carboxylate (7.0 g, 45%) as a yellow sticky material. The product was confirmed by LCMS (Method 2), m / z 347 (ES+, M+Na), at 2.02. Step (vi): 2-(4-(methoxycarbonyl)phenethyl)hydrazine-1-carboxylate (7.00 g, 21.59 mmol) was dissolved in MeCN (70 mL) and potassium carbonate (14.92 g, 107.93 mmol) was added to the reaction mixture at room temperature. The reaction mixture was stirred at room temperature for 10 min. After this, 3-bromopropionyl chloride (3.26 mL, 32.39 mmol) was added dropwise at room temperature and the reaction mixture was stirred at room temperature for 24 h. After this, the reaction mixture was stirred at 40 °C for 4 h. The reaction mixture was concentrated under vacuum and the resulting residue was partitioned between water (700 mL) and EtOAc (500 mL). The aqueous layer was further extracted with EtOAc (2 x 200 mL). The organic layers were combined and dried (Na2SO4).The solvent was removed under vacuum and the product was purified by gradient column chromatography (normal phase, silica). The product was eluted from 0% to 32% EtOAc in hexane to yield tert-butyl 2-(3-methoxy-4-(methoxycarbonyl)phenethyl)-3-oxopyrazolidino-1-carboxylate (2.0 g, 24%) as a yellow oil. The product was confirmed by LCMS (method 2), m / z 323 (ES+, M+H-tBu), at 2.27 min. Step (vii): 2-(3-methoxy-4-(methoxycarbonyl)phenethyl)-3-oxopyrazolidin-1-carboxylate tert-butyl (2.00 g, 5.29 mmol) was dissolved in 1,4-dioxane (20 mL) and 4 N HCl in dioxane (20 mL) was added dropwise to the reaction mixture at 0 °C and the reaction mixture was left to stir at room temperature for 8 h. The solvent was removed under vacuum to obtain the crude product which was purified by grinding with 20% MeOH in diethyl ether to give the crude HCl salt of 2-methoxy-4-(2-(5-oxopyrazolidin-1-yl)ethyl) methyl benzoate (1.50 g, 90.36%) in the form of a whitish amorphous powder. The product was confirmed by LCMS, m / z 279, 10 (ES+) , at 1,415 min. Step (viii): Methyl 2-methoxy-4-(2-(5-oxopyrazolidin-1-yl)ethyl)benzoate hydrochloride (1.00 g, 3.18 mmol), 1-(3-bromophenyl)prop-2-en-1-one (3.33 g, 15.88 mmol), and TEA (2.2 mL, 15.88 mmol) were suspended in MeOH (10 mL) at room temperature, and the reaction mixture was stirred at 60 °C for 4 h. The reaction mixture was partitioned between a saturated aqueous solution of NH4Cl (300 mL) and EtOAc (200 mL). 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 further purified by reversed-phase gradient ultrafast column chromatography (reversed phase, C18 silica). The product was eluted with MeCN from 0% to 65% in water to provide methyl 4-(2-(2-(3-(3-bromophenyl)-3-oxopropyl)-5-oxopyrazolidin-1-yl)ethyl)-2-methoxybenzoate (1.20 g, 69%) in the form of a colorless sticky material.The product was confirmed by LCMS (Method 2), m / z 489 (ES+, M+H), at 2.38 min. Step (ix): Methyl (R)-4-((1-(3-bromobenzyl)pyrrolidine-2-carboxamido)methyl)-2-methoxybenzoate (0.25 g, 0.51 mmol) was dissolved in DCM (3 mL) and the reaction mixture was cooled to -78 °C. Following this, BBr3 (1 M solution in DCM) (2.5 mL, 2.56 mmol) was added and the reaction mixture was stirred at -78 °C for 1 h. The reaction mixture was then partitioned between a saturated aqueous solution of NaHCO3 (100 mL) and DCM (70 mL). 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 to yield methyl 4-(2-(2-(3-(3-bromophenyl)-3-oxopropyl)-5-oxopyrazolidin-1-yl)ethyl)-2-hydroxybenzoate (0.18 g, 74%) as a yellow sticky material. The product was confirmed by LCMS (Method 2) m / z 475 (ES+, M+H) at 2.61 min. Step (x): Methyl 4-(2-(2-(3-(3-bromophenyl)-3-oxopropyl)-5-oxopyrazolidin-1-yl)ethyl)-2-hydroxybenzoate (0.16 g, 0.34 mmol) was dissolved in ethanol (2 mL) and water (2 mL). CeCl3 (0.25 g, 1.01 mmol) was added, and the reaction mixture was stirred at 0 °C for 5 min. After this, NaBH4 (0.085 g, 1.36 mmol) was added at 0 °C, and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was then divided between a saturated aqueous solution of NaHCO3 (30 mL) and EtOAc (30 mL). The aqueous layer was further extracted with EtOAc (2 x 20 mL). The organic layers were combined and dried (Na2SO4). The solvent was removed under vacuum to yield the intermediate product methyl 3,4-(2-(2-(3-(3-bromophenyl)-3-hydroxypropyl)-5-oxopyrazolidin-1-yl)ethyl)-2-hydroxybenzoate (0.15 g, 93%) as a whitish solid. The product was confirmed by LCMS (Method 2), m / z 478 (ES+, M+H) at 2.46 min. Synthetic preparation of Formula I compounds Example 1: Synthesis of 4-(2-(3-hydroxy-3-(4'-hydroxy-2'-methyl-[1,1'-biphenyl]-3-yl)propyl)-5-oxopyrazolidin-1-yl)ethyl)benzoic acid (Compound 1) Step (i): Intermediate product 1, methyl 4-(2-(5-oxopyrazolidin-1-yl)ethyl)benzoate hydrochloride (2.00 g, 7.26 mmol), and 1-(3-bromophenyl)prop-2-en-1-one (1.50 g, 14.52 mmol) were suspended in IPA (20 mL) at room temperature, and the reaction mixture was stirred at room temperature for 15 min. After this, TEA (2.5 mL, 36.30 mmol) was added at room temperature, and the mixture was stirred at 80 °C for 12 h. The reaction mixture was partitioned between a saturated aqueous solution of NH4Cl (500 mL) and EtOAc (300 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 further purified by reversed-phase gradient ultrafast column chromatography (reversed phase, C18 silica). The product was eluted with 0% to 75% MeCN in water to yield methyl 4-(2-(2-(3-(3-bromophenyl)-3-oxopropyl)-5-oxopyrazolidin-1-yl)ethyl)benzoate (0.80 g, 24%) as a colorless, sticky material. The product was confirmed by LCMS (Method 3), m / z 459 (ES+, M+H), at 2.48 min. Step (ii): 4-(2-(2-(3-(3-bromophenyl)-3-oxopropyl)-5-oxopyrazolidin-1-yl)ethyl)methyl benzoate (0.25 g, 0.55 mmol), 4-hydroxy-2-methylphenyl)boronic acid (0.99 g, 0.65 mmol), and potassium carbonate (0.23 g, 1.65 mmol) were suspended in dioxane (3 mL) and water (2 mL) at room temperature, and the reaction mixture was degassed with nitrogen at room temperature for 15 min. After this, PdCl2 (dppf) .DCM (0.04 g, 0.05 mmol) was added at room temperature, and the reaction mixture was left to stir at 100 °C for 4 h. The reaction mixture was divided between water (200 mL) and EtOAc (100 mL). The aqueous layer was further extracted with EtOAc (2 x 50 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 (normal phase, silica).The product was eluted with EtOAc from 0% to 80% in hexane to give the intermediate product 4,4-(2-(3-(4'-hydroxy-2'-methyl-[1,1'-biphenyl]-3-yl)-3-oxopropyl)-5-oxopyrazolidin-1-yl)ethyl) benzoate (0.21 g, 81%) , as a whitish solid. The product was confirmed by LCMS (Method 3), m / z 509 (ES+, M+Na) , at 2.33 min. Step (iii): 4-(2-(2-(3-(3-bromophenyl)-3-oxopropyl)-5-oxopyrazolidin-1-yl)ethyl)methyl benzoate (0.21 g, 0.43 mmol) and cerium chloride (iii) (0.32 g, 1.30 mmol) were dissolved in ethanol (3 mL) and water (3 mL) at room temperature and the reaction mixture was left to stir at room temperature for 5 min. After this, sodium borohydride (0.65 g, 1.73 mmol) was added at 0 °C and the reaction mixture was left to stir at room temperature for 2 h. The reaction mixture was partitioned between a saturated aqueous solution of NaHCO3 (100 mL) and EtOAc (50 mL), and the aqueous layer was further extracted with EtOAc (2 x 30 mL). The organic layers were combined and dried (Na2SO4). The solvent was removed under vacuum to provide 4-(2-(3-hydroxy-3-(4'-hydroxy-2'-methyl-[1,1'-biphenyl]-3-yl)propyl)-5-oxopyrazolidin-1-yl)ethyl) methyl benzoate (0.16 g, 76%) as a whitish solid.The product was confirmed by LCMS (Method 3), m / z 489 (ES+, M+H), at 2.19 min. Step (iv): 4-(2-(2-(3-hydroxy-3-(4'-hydroxy-2'-methyl-[1,1'-biphenyl]-3-yl)propyl)-5-oxopyrazolidin-1-yl)ethyl) methyl benzoate (0.16 g, 0.33 mmol) was dissolved in dioxane (2 mL) and water (2 mL). LiOH monohydrate (0.073 g, 1.75 mmol) was added at room temperature and the mixture was stirred at room temperature for 3 h. The reaction mixture was then partitioned between water (80 mL) and EtOAc (2 x 50 mL). The aqueous layer was further acidified with 1 N aqueous HCl (~20 mL), the pH was adjusted to ~3, and it was extracted with EtOAc (2 x 70 mL). The organic layers were combined and dried (Na2SO4). The solvent was removed under vacuum to provide 4-(2-(2-(3-hydroxy-3-(4'-hydroxy-2'-methyl-[1,1'-biphenyl]-3-yl)propyl)-5-oxopyrazolidin-1-yl)ethyl)benzoic acid) (0.125 g, 81%) as a brown solid. The product was confirmed by LCMS (Method 3), m / z 475 (ES+, M+H), at 1.97 min.RMN 1H: (400 MHz, DMSO) : 1, 26-1, 23 (m, 3H) , 1, 82-1, 80 (d, 2H, J=6, 4 Hz) , 2, 16 (s, 3H) , 2, 88-2, 85 (t, 3H, J=6, 0 Hz) , 3, 17 (s, 3H) , 4, 08 (s, 1H) , 4, 71-4, 69 (d, 1H, J=6, 0 Hz) , 6, 87-6, 83 (m, 2H) , 7, 01-6, 99 (d, 1H, J = 8, 4 Hz) , 7, 16-7, 14 (d, 1H, J = 7, 6 Hz) , 7, 37-7, 26 (m, 5H) , 7, 85-7, 83 (d, 2H, 8, 4 Hz) , 9, 43 (s, 2H) . Compounds 1R and 1S: Racemic compound 1 (0.12 g) was separated enantiomerically using a Shimadzu preparative HPLC system (PHENOMNENEX AMYLOSE-250*21, 2 mm, 5 µm column) with a mobile phase of 43.0% 10 mM DEA in heptane and 57.0% IPA, without a gradient, at a flow rate of 16.00 mL / min. Isomer 1: (0.004 g, 2.6%; whitish solid). The product was confirmed by LCMS (Method 3), m / z 475 (ES+, M+H), at 2.30 min. 1H NMR: (400 MHz, MeOD) : 2.03-1.93 (m, 2H) , 2.93-2.90 (t, 4H, J=6.8 Hz) , 3.07-3.03 (t, 3H, J=7.2 Hz) , 3.25 (s, 2H) , 3. 37-3, 32 (m, 1H) , 3, 59-3, 56 (m, 1H) , 3, 71-3, 69 (m, 2H) , 4, 87-4, 84 (t, 1H) , J=6, 0 Hz) , 6, 68-6, 66 (m, 1H) , 6, 73-6, 72 (d, 1H, J=2, 0 Hz) , 7, 02-7, 00 (d, 1H, J=8, 0 Hz) , 7, 25-7, 19 (m, 3H) , 7, 41-7, 32 (m, 5H) , 7, 91-7, 89 (d, 2H, J=8, 0 Hz) . Isomer 2: The product was confirmed by LCMS (Method 3) , m / z 475 (ES+, M+H) , at 2, 30 min.RMN 1H: (400 MHz, MeOD): 1, 97-1, 94 (t, 2H, J=6, 4 Hz) , 2, 93-2, 90 (t, 4H, J=6, 8 Hz) , 3, 07-3, 03 (m, 3H) , 3, 26 (s, 2H) , 3, 59-3, 57 (t, 2H J=4, 6 Hz) , 3, 71-3, 69 (t, 2H J=4, 6 Hz) , 4, 87-4, 84 (t, 1T H, J=6, 4 Hz) , 6, 68-6, 65 (dd, 1H J=2, 4 Hz y J=4, 0 Hz), 6, 72-6, 72 (d, 1H, J=2, 0 Hz) , 7, 02-7, 00 (d, 1H, J=8, 0 Hz) , 7, 24-7, 19 (m, 3H) , 7, 41-7, 32 (m, 5H) , 7, 91-7, 89 (d, 2H), J = 8, 0 Hz). Ejemplo 2; Síntesis del ácido 4- (2- (2- (3- (4'-carbamoil-2'-metil-[1, 1'-bifenil]-3-il) -3-hidroxipropil) -5-oxopyrazolidin-1-il) etil) benzoico (Compuesto 2) Step (i): Intermediate product 1, methyl 4-(2-(5-oxopyrazolidin-1-yl)ethyl)benzoate hydrochloride (2.00 g, 7.26 mmol), and 1-(3-bromophenyl)prop-2-en-1-one (1.50 g, 14.52 mmol) were suspended in IPA (20 mL) at room temperature, and the reaction mixture was stirred at room temperature for 15 min. After this, TEA (2.5 mL, 36.30 mmol) was added at room temperature, and the mixture was stirred at 80 °C for 12 h. The reaction mixture was partitioned between a saturated aqueous solution of NH4Cl (500 mL) and EtOAc (300 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 further purified by reversed-phase gradient ultrafast column chromatography (reversed phase, C18 silica). The product was eluted with 0% to 75% MeCN in water to provide 4-(2-(2-(3-(3-bromophenyl)-3-oxopropyl)-5-oxopyrazolidin-1-yl)ethyl) methyl benzoate (0.80 g, 24%) in the form of a colorless sticky material. The product was confirmed by LCMS (Method 3), m / z 459 (ES+, M+H), at 2, 48 min. Step (ii): 4-(2-(2-(3-(3-bromophenyl)-3-oxopropyl)-5-oxopyrazolidin-1-yl)ethyl) methyl benzoate (0.60 g, 1.30 mmol), 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzamide (1.36 g, 5.23 mmol) and K2CO3 (0.2554 g, 3.92 mmol) were dissolved in a dioxane in water (3:2.5 mL) mixture and nitrogen gas was purged for 20 minutes at room temperature. After this, PdCl2 (dppf) DCM (0.21 g, 0.26 mmol) was added and the reaction mixture was stirred at 80 °C for 8 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 70 mL). The organic layers were combined and dried (Na2SO4).The solvent was removed under vacuum and the crude product was purified by ultrafast gradient column chromatography (reversed phase, C18 silica). The product was eluted from a MeCN concentration of 0% to 38% in water to give 4-(2-(3-(4'-carbamoyl-2'-methyl-[1,1'-biphenyl]-3-yl)-3-oxopropyl)-5-oxopyrazolidin-1-yl)ethyl) methyl benzoate (0.60 g, 90%) as a white solid. LCMS: (Method 3): The product was confirmed m / z 536 (ES+, M+Na) at 2.16 min. Step (iii): 4-(2-(2-(3-(4'-carbamoyl-2'-methyl-[1,1'-biphenyl]-3-yl)-3-oxopropyl)-5-oxopyrazolidin-1-yl)ethyl) methyl benzoate (0.60 g, 1.16 mmol) was dissolved in ethanol (3 mL) and water (2 mL), and CeCl3 (0.86 g, 3.50 mmol) was added to the reaction mixture. The reaction mixture was stirred at 0 °C for 5 min. After this, sodium borohydride (0.17 g, 4.67 mmol) was added at 0 °C, and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was divided between a saturated aqueous solution of NaHCO3 (100 mL) and EtOAc (80 mL) and the aqueous layer was further extracted with EtOAc (2 x 50 mL). The organic layers were combined and dried (Na2SO4).The solvent was removed under vacuum and the crude product was purified by ultrafast gradient column chromatography (reversed phase, C18 silica), eluting the product from 0% to 35% MeCN in water to give 4-(2-(2-(3-(4'-carbamoyl-2'-methyl-[1,1'-biphenyl]-3-yl)-3-hydroxypropyl)-5-oxopyrazolidin-1-yl)ethyl) methyl benzoate (0.50 g, 83%) as a whitish solid. LCMS: (Method 3 by LCMS): The product was confirmed m / z 516 (ES+, M+H) at 2.78 min. Step (iv): 4-(2-(2-(3-(4'-carbamoyl-2'-methyl-[1,1'-biphenyl]-3-yl)-3-hydroxypropyl)-5-oxopyrazolidin-1-yl)ethyl) methyl benzoate (1.80 g, 3.49 mmol) was dissolved in dioxane (15 mL) and water (8 mL). LiOH monohydrate (0.73 g, 17.46 mmol) was added at room temperature, and the reaction mixture was stirred at room temperature for 3 h. The reaction mixture was then partitioned between water (250 mL) and EtOAc (2 x 350 mL). The aqueous layer was further acidified with 4 N aqueous HCl (60 mL) to adjust the pH to ~1 and extracted with EtOAc (2 x 300 mL). The organic layers were combined and dried (Na2SO4). The solvent was removed under vacuum to provide pure 4-(2-(2-(3-(4'-carbamoyl-2'-methyl-[1,1'-biphenyl]-3-yl)-3-hydroxypropyl)-5-oxopyrazolidin-1-yl)ethyl)benzoic acid (1.47 g, 83%) in the form of a whitish solid. LCMS (method 2): The product was confirmed m / z 502 (ES+, M+H) , at 1, 53 min. 1H NMR: (400 MHz, DMSO) : 1.76-1.84 (m, 2H, ) , 2.26 (s, 3H) , 2.70-2.90 (m, 4H) , 3.18 (s, 3H) , 4.72 (brs, 1H) , 5.37 (d, 1H, J=4, 0 Hz) , 7, 21-7, 45 (m, 8H) , 7, 74 (dd, 1H, J= 7, 9 and 1, 9 Hz) , 7, 80-7, 45 (m, 8H) , 7, 74 (dd, 1H, J= 7, 9 and 1, 9 Hz) , 7, 80-7, 45 (m, 8H) , 7, 74 (dd, 1H, J= 7, 9 and 1, 9 Hz) , 7, 80-7, 45 (m, 8H) , 7, 74 (dd, 1H, J= 7, 9 and 1, 9 Hz) , 7, 80-7, 45 (m, 8H) , 7, 74 86 (m, 3H) , 7, 98 (s, 1H) , 12, 86 (brs, 1H) Compounds 2R and 2S: Racemic compound 2 was separated enantiomerically in a Waters Prep-HPLC system using the following method: ADH column: 9.5 x 250 mm, 5 microns, solvents A: 0.1% TFA in n-heptane, B: IPA: methanol (70:30) isocratic 75% A / 25% B with variable flow rate (time / flow, 0, 01 / 4, 0, 5, 00 / 4, 0, 10, 00 / 8, 0, 100, 00 / 8, 0, min / mL per minute) Isomer 1 (0.489 g, 28%) in the form of a whitish solid. LCMS: (Method 2): The product was confirmed m / z 502 (ES+, M+H) at 1.56 min. 1H NMR: (400 MHz, DMSO) : 1.77-1.86 (m, 2H) , 2.27 (s, 3H) , 2.74-2.90 (m, 4H) , 3.14 (brs, 2H) , 4.73 (t, 1H, J=6.4 Hz) , 7. 21-7, 47 (m, 8H), 7, 75 (dd, 1H, J= 7, 9 Hz, 1, 9 Hz), 7, 80-7, 86 (m, 3H), 7, 98 (s, 1H), 12, 86 (brs, 1H). (Note: Some of the aliphatic protons obscured by DMSO and / or water) Isomer 2 (0.477 g, 27%) as a whitish solid. LCMS: (Method 2): The product was confirmed m / z 502 (ES+, M+H) at 1.56 min. 1H NMR: (400 MHz, DMSO) 1.77-1.86 (m, 2H), 2.27 (s, 3H), 2.76-2.90 (m, 4H), 3.14 (brs, 2H), 4.69-4.76 (m, 1H), 5.37 (brs, 1H) , 7, 22-7, 45 (m, 8H) , 7, 75 (dd, 1H, J= 7, 9 Hz, 1, 9 Hz) , 7, 81 to 7, 86 (m, 3H) , 7, 97 (s, 1H) , 12, 84 (brs, 1H) . (Note: Some of the aliphatic protons are obscured by DMSO and / or water) Example 3: Synthesis of 4-(2-(3-hydroxy-3-(2'-methyl-4'-sulfamoyl-[1,1'-biphenyl]-3-yl)propyl)-5-oxopyrazolidin-1-yl)ethyl)benzoic acid (Compound 3) It was synthesized by the method described in Example 1 using 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide, which was synthesized from 3-methyl-4-bromobenzsulfonamide, PdCI2 (dppf) .DCM and KOAc, in dioxane (80 °C; 2 h), and reversed-phase ultrafast chromatography in the final step to give 4-(2-(3-hydroxy-3-(2'-methyl-4'-sulfamoyl-[1,1'-biphenyl]-3-yl)propyl)-5-oxopyrazolidin-1-yl)ethyl)benzoic acid; (0.027 g, 28%) in the form of a whitish solid. The product was confirmed by LCMS (Method 3), m / z 538 (ES+, M+H), at 1, 90 min. 1H NMR: (400 MHz, DMSO) : 1.10-1.07 (t, 1H, J=7 Hz) , 1.82-1.80 (d, 2H, 5.6 Hz) , 2.08 (s, 1H) , 2.29 (s, 4H) , 2.87-2.85 (d, 4H, 6, 4 Hz) , 3, 13 (s, 3H) , 4, 73 (s, 1H) 5, 39-5, 38 (d, 1H, 4, 4 Hz) , 7, 35-7, 24 (m, 3H) , 7, 46-7, 37 (m, 6H) , 7, 71-7, 68 (m, 1H), 7, 75 (s, 1H), 7, 84-7, 82 (d, 2H, J=8, 4 Hz), 12, 85 (s, 1H). Compounds 3R and 3S: Racemic compound 3 was separated enantiomerically using a Waters Prep-HPLC system (CROMEGACHIRAL CCO 250*20 mm, 5 µm column) with a mobile phase consisting of 75% FA at 0.1% heptane and 25% a mixture of IPA and methanol (50:50), with a flow rate of 18.00 mL / min and no gradient. Isomer 1: (0.019 g, 6.5%; whitish solid) The product was confirmed by LCMS (Method 3), m / z 538 (ES+, M+H), at 1.90 min. 1H NMR: (400 MHz, DMSO) : 1.23 (s, 2H), 1.82-1.81 (d, 2H, J = 6.4 Hz), 2.33-2.29 (m, 4H), 2.83 (s, 4H), 3.16 (s, 5H), 4. 74 (s, 1H) , 5, 40 (s, 1H) , 7, 25-7, 23 (m, 3H) , 7, 44-7, 34 (m, 6 H) 71-7, 68 (m, 1H) , 7, 75-7, 75 (d, 1H, J=1, 6 Hz) , 7, 82-7, 8 (d, 2H, J=8 Hz). Isomer 2: (0.017 g, 5.8%; whitish solid). The product was confirmed by LCMS (Method 3), m / z 538 (ES+, M+H), at 1.93 min.RMN 1H: (400 MHz, DMSO): 1, 23-1, 16 (d, 3H, J= 28, 0 Hz) , 1, 82 (s, 2H) , 2, 29 (s, 4H) , 2, 82 (s, 4H) , 3, 14 (s, 2H) , 4, 74 (s, 1H) , 5, 39 (s, 1H) 7, 24-7, 21 (d, 3H, J= 12 Hz) , 7, 42-7, 35 (q, 5H) , 7, 80-7, 69 (m, 4H). Ejemplo 4; Síntesis de 4- (2- (2- (3- (4'-hidroxi-2'-metil-[1, 1'-bifenil]-3-il) -3-oxopropil) -5-oxopirazolidin-1-il) etil) benzoato (Compuesto 4) Step (i): The intermediate product 4 of Example 1 (4-(2-(3-(4'-hydroxy-2'-methyl-[1,1'-biphenyl]-3-yl)-3-oxopropyl)-5-oxopyrazolidin-1-yl)ethyl) methyl benzoate, 0.17 g, 0.34 mmol) was dissolved in dioxane (3 mL) and water (2 mL). LiOH monohydrate (0.073 g, 1.74 mmol) was added at room temperature and the mixture was stirred at room temperature for 3 h. The reaction mixture was then partitioned between water (80 mL) and EtOAc (2 x 50 mL). The aqueous layer was further acidified with 4 N aqueous HCl (3 mL) to adjust the pH to ~1 and extracted with EtOAc (2 x 50 mL). The organic layers were combined and dried (Na2SO4). The solvent was removed under vacuum to provide pure 4-(2-(2-(3-(4'-hydroxy-2'-methyl-[1,1'-biphenyl]-3-yl)-3-oxopropyl)-5-oxopyrazolidin-1-yl)ethyl)benzoic acid (0.13 g, 79%) as a white solid. The product was confirmed by LCMS (Method 1), m / z 473 (ES+, M+H), at 2.13 min. Step (ii): 4-(2-(3-(4'-hydroxy-2'-methyl-[1,1'-biphenyl]-3-yl)-3-oxopropyl)-5-oxopyrazolidin-1-yl)ethyl)benzoic acid (0.130 g, 0.27 mmol) was dissolved in DMA (3 mL). Sulfamoyl chloride (0.095 g, 0.82 mmol) was added at room temperature and the mixture was stirred at room temperature for 3 h. The reaction mixture was then partitioned between water (70 mL) and EtOAc (30 mL). The aqueous layer was further extracted with EtOAc (2 x 20 mL). The organic layers were combined and dried (Na2SO4). The solvent was removed under vacuum and the crude product was purified by ultrafast gradient column chromatography. The product was eluted with 0% to 5% methanol in DCM to provide pure 4-(2-(2-(3-(2'-methyl-4'-(sulfamoyloxy)-[1,1'-biphenyl]-3-yl)-3-oxopropyl)-5-oxopyrazolidin-1-yl)ethyl)benzoic acid (0.15 g, 99%) as a white solid. The product was confirmed by LCMS (Method 1), m / z 552 (ES+), at 2.14 min. Step (iiia) (racemic method): 4-(2-(3-(2'-methyl-4'-(sulfamoyloxy)-[1,1'-biphenyl]-3-yl)-3-oxopropyl)-5-oxopyrazolidin-1-yl)ethyl)benzoic acid (0.03 g, 0.054 mmol) was dissolved in methanol (3 mL) and 10% palladium on carbon with 50% moisture (0.02 g) was added. H2 gas was purged through the reaction mixture at room temperature for 2 h. Once complete, the reaction mixture was filtered through a celite bed, washed with MeOH (30 mL), and the filtrate was concentrated under vacuum. The crude product was purified by ultrafast gradient column chromatography (reversed phase, C18 silica). The product was eluted from 0% to 35% MeCN in water to yield 4-(2-(3-hydroxy-3-(2'-methyl-4'-(sulfamoyloxy)-[1,1'-biphenyl]-3-yl)propyl)-5-oxopyrazolidin-1-ethyl)benzoic acid (0.010 g, 33%) as a brown solid. The product was confirmed by LCMS (Method 1), m / z 554 (ES+, M+H), at 2.01 min.RMN 1H: (400 MHz, MeOD) : 1, 98 a 1, 95 (t, 3H, J = 6, 4 Hz) , 2, 26 (s, 3H) , 2, 95-2, 92 (m, 3H, J = 6, 8 Hz) , 3, 26 (s, 2H) , 3, 36 (s, 1H) , 3, 58-3, 56 (m, 1H) , 3, 70-3, 68 (m, 1H) , 4, 87-4, 85 (d, 2H) = 6, 4 Hz) , 7, 25-7, 12 (m, 5H) , 7, 25 (s, 1H) , 7, 46 a 7, 39 (m, 2H) , 7, 92 (s, 2H) , 12, 72 (s, 1H) . Step (iiib) (chiral separation method): 4-(2-(2-(3-(2'-methyl-4'-(sulfamoyloxy)-[1,1'-biphenyl]-3-yl)-3-oxopropyl)-5-oxopyrazolidin-1-yl)ethyl)benzoic acid (0.10 g, 0.18 mmol) was dissolved in ethanol (3 mL) and water (2 mL) and CeCl3 (0.13 g, 0.54 mmol) was added to the reaction mixture. The reaction mixture was stirred at 0 °C for 5 min. After this, sodium borohydride (0.027 g, 0.72 mmol) was added at 0 °C and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was then divided between water (30 mL) and EtOAc (2 x 20 mL). The aqueous layer was further acidified with 4 N aqueous HCl (3 mL), the pH was adjusted to ~1, and it was extracted with EtOAc (2 x 50 mL). The organic layers were combined and dried (Na2SO4). The solvent was removed under vacuum to provide the crude product. Compounds 4R and 4S: Racemic compound 4 was separated enantiomerically using a Schimadzu preparative HPLC system (CROMEGACHIRAL CCJ, 25 cm x 20 mm, 5 µm column) with a mobile phase consisting of 60% FA in 0.1% heptane and 40% of an IPA / methanol mixture (60:40) at a flow rate of 19.00 mL / min without a gradient. Isomer 1: (0.0057 g, 24%; white solid) The product was confirmed by LCMS (Method 1), m / z 554 (ES+, M+H), at 2.02 min. Chiral HPLC: Product purity was confirmed at 16.23 min. 1H NMR: (400 MHz, MeOD) : 1.98-1.93 (m, 2H), 2.27 (s, 3H), 2.97-2.91 (m, 4H), 3.27-3.27 (m, 2H), 4.88-4.85 (t, 2H, J= 6, 4 Hz) , 7, 23-7, 18 (m, 4H) , 7, 34-7, 31 (m, 3H) , 7, 46-7, 41 (m, 2H) , 7, 93-7, 92 (d, 2H, J= 6, 8 Hz) 7, 63-7, 61 (d, 2H, J= 8, 8 Hz) , 7, 73-7, 71 (d, 1H, J= 7, 6 Hz) , 7, 83-7, 78 (m, 3H) , 8, 58-8, 56 (t, 1H, J= 5, 2 Hz) .Isomer 2: (0.0047 g, 26%; white solid) The product was confirmed by LCMS (Method 1), m / z 554 (ES+, M+H), at 2.02 min. Chiral HPLC: the purity of the product was confirmed at 10.62 min. 1H NMR: (400 MHz, MeOD): 1.98-193 (m, 3H), 2.27 (s, 3H), 2.97-2.93 (m, 4H), 3.27 (s, 2H), 4.88-4.85 (t, 2H, J = 6.4 Hz), 7, 24-7, 25 (m, 4H) , 7, 31-7, 29 (m, 2H) , 7, 34 (s, 1H) , 7, 46-7, 39 (m, 2H) , 7, 46-7, 39 (m, 2H) , 7, 46-7, 39 (m, 2H) , 7, 46-7, 39 (m, 2H), 7, 46-7, 39 (m, 2H), 7, 46-7, 39 (m, 2H), 7, 46-7, 39 (m, 2H), 7, 9-37, 91 (d, 2H, J = 7, 6 Hz), 8, 51 (s, 1H) . Example 5: Synthesis of 4-(2-(2-(3-(4'-carbamoyl-2'-methyl-[1,1'-biphenyl]-3-yl)-3-hydroxypropyl)-5-oxopyrazolidin-1-yl)ethyl)-2,6-dihydroxybenzoic acid (Compound 5) Step (i): The intermediate product 2,4-(2-(2-(3-(3-bromophenyl)-3-hydroxypropyl)-5-oxopyrazolidin-1-yl)ethyl)-2,6-methyl difluorobenzoate (0.20 g, 0.60 mmol), 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (0.21 g, 0.79 mmol) and K2CO3 (0.17 g, 0.1.30 mmol) were dissolved in a dioxane:water (1:1.5 mL) and nitrogen gas mixture and purged for 30 minutes at room temperature. After this, PdCl2 (dppf) .DCM (0.099 g, 0.12 mmol) was added and the reaction mixture was stirred at 80 °C for 1 h. The reaction mixture was then partitioned between water (70 mL) and EtOAc (70 mL), and the aqueous layer was further extracted with EtOAc (2 x 30 mL). The organic layers were combined and dried (Na2SO4).The solvent was removed under vacuum and the crude product was purified by reversed-phase gradient ultrafast column chromatography (reversed phase, C18 silica). The product was eluted with 0% to 28% MeCN in water to give methyl 4-(2-(2-(3-(4'-carbamoyl-2'-methyl-[1,1'-biphenyl]-3-yl)-3-hydroxypropyl)-5-oxopyrazolidin-1-yl)ethyl)-2,6-difluorobenzoate (0.29 g, 87%) as a light brown solid. The product was confirmed by LCMS (Method 2), m / z 552 (ES+, M+H) at 1.92 min. Step (ii): Methyl 4-(2-(2-(3-(4'-carbamoyl-2'-methyl-[1,1'-biphenyl]-3-yl)-3-hydroxypropyl)-5-oxopyrazolidin-1-yl)ethyl)-2,6-difluorobenzoate (0.29 g, 0.29 mmol) was dissolved in dioxane (4 mL) and water (2 mL). LiOH (0.11 g, 0.88 mmol) was added at room temperature and the mixture was stirred at room temperature for 16 h. The reaction mixture was acidified with 4 N aqueous HCl (4 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). The organic layers were combined and dried (Na2SO4).The solvent was removed under vacuum and the crude product was purified by reversed-phase gradient ultrafast column chromatography (reversed phase, C18 silica). The product was eluted with 0% to 23% ACN in water to yield 4-(2-(2-(3-(4'-carbamoyl-2'-methyl-[1,1'-biphenyl]-3-yl)-3-hydroxypropyl)5-oxopyrazolidin-1-yl)ethyl)-2,6-difluorobenzoic acid (0.15 g, 53%) as a whitish solid. The product was confirmed by LCMS (Method 2), m / z 538 (ES+, M+H) at 1.49 min. 1H NMR (400 MHz, DMSO) : 1.23 (s, 2H), 1.81-1.80 (d, 2H, J=4.8 Hz), 2.26 (s, 3H), 2.75 (s, 3H), 3.17-3.16 (d, 4H, 3.6 Hz) , 4, 12-4, 11 (d, 1H, J=4, 8 Hz) , 4, 71 (s, 1H) , 5, 47-5, 46 (d, 1H, J= 3, 6 Hz) , 6, 75-6, 73 (d, 2H, J= 7, 2 Hz) , 7, 25-7, 22 (m, 2H) , 7, 37-7, 33 (m, 2H), 7, 43-7, 39 (m, 2H), 7, 76-7, 74 (m, 1H), 7, 82 (s, 1H), 8, 02 (s, 1H). Compounds 5R and 5S: The racemic mixture (70 mg) was separated enantiomerically using a Shimadzu Prep-HPLC system (CHROMEGACHIRAL CCO 250*25 mm, 5 µm column) with a mobile phase consisting of 80% FA at 0.1% heptane and 20% of a non-gradient mixture of IPA and methanol (70:30), at a flow rate of 20.00 mL / min. Isomer 1: (0.038 g, 13%; white solid) The product was confirmed by LCMS (Method 2), m / z 538 (ES+, M+H) at 1.59 min. Chiral HPLC: The purity of the product was confirmed at 14.48 min. 1H NMR: (400 MHz, DMSO) :1.81-1.80 (d, 2H, J = 6.4 Hz), 2.27 (s, 4H), 2.85 (s, 4H), 3.1-3.12 (d, 2H, J = 5.6 Hz), 4.73 (s, 1H), 5, 36 (s, 1H), 7, 10-7, 04 (m, 2H), 7, 27-7, 22 (m, 2H), 7, 43-7, 34 (m, 4H), 7, 76-7, 74 (m, 1H), 7, 82 (s, 1H) , 7, 97 (s, 1H) , 13, 78 (s, 1H) . Isomer 2: (0, 052 g, 18 %; whitish solid) The product was confirmed by LCMS (method 2) , m / z 538 (ES+, M+H) , at 1, 60 min.Chiral HPLC: Product purity was confirmed at 10, 50 min. 1H NMR (400 MHz, DMSO): 1.81-1.80 (d, 2H, J = 5.6 Hz), 2.27 (s, 3H), 2.85 (s, 3H), 3.14-3.12 (d, 2H, 7.6 Hz), 4.72 (s, 1H) , 5, 37 (s, 1H) , 7, 06-7, 04 (d, 2H, J = 8, 8 Hz) , 7, 27-7, 22 (m, 2H) , 7, 43-7, 34 (m, 4H) , 7, 76-7, 74 (m, 1H) , 7, 82 (s, 1H), 7, 97 (s, 1H), 13, 79 (s, 1H). Example 6: Synthesis of 2-hydroxy-4-(2-(2-(3-hydroxy-3-(2'-methyl-4'-sulfamoyl-[1,1'-biphenyl]-3-yl)propyl)-5-oxopyrazolidin-1-yl)ethyl) benzoic acid (Compound 6) Step (i): The intermediate product 3,4-(2-(2-(3-(3-bromophenyl)-3-hydroxypropyl)-5-oxopyrazolidin-1-yl)ethyl)-2-hydroxybenzoate methyl (0.15 g, 0.32 mmol), 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide (0.14 g, 0.47 mmol) and K2CO3 (0.89 g, 0.64 mmol) were dissolved in 4 mL of a 1:1 mixture of dioxane and water. Nitrogen gas was purged for 30 minutes at room temperature. After this, PdCl2 (dppf) .DCM (0.026 g, 0.032 mmol) was added and the reaction mixture was stirred at 80 °C for 1 h. The reaction mixture was then partitioned between water (50 mL) and EtOAc (50 mL). The aqueous layer was further extracted with EtOAc (2 x 20 mL). The organic layers were combined and dried (Na2SO4).The solvent was removed under vacuum and the crude product was purified by ultrafast gradient column chromatography (reversed phase, C18 silica). The product was eluted from 0% to 55% MeCN in water to yield methyl 2-hydroxy-4-(2-(2-(3-hydroxy-3-(2'-methyl-4'-sulfamoyl-[1,1'-biphenyl]-3-yl)propyl)-5-oxopyrazolidin-1-yl)ethyl)benzoate (0.13 g, 73%) as a white solid. The product was confirmed by LCMS (method 2) m / z 568 (ES+) at 1.86 min. Step (ii): 2-hydroxy-4-(2-(2-(3-hydroxy-3-(2'-methyl-4'-sulfamoyl-[1,1'-biphenyl]-3-yl)propyl)-5-oxopyrazolidin-1-yl)ethyl) methyl benzoate (0.13 g, 0.23 mmol) was dissolved in 4 mL of a 1:1 mixture of dioxane and water at room temperature, and LiOH monohydrate (0.048 g, 1.15 mmol) was added, and the reaction mixture was left to stir at room temperature for 3 h. The reaction mixture was partitioned between water (30 mL) and EtOAc (2 x 50 mL). The aqueous layer was further acidified with 4 N aqueous HCl (2 mL) to adjust the pH to ~1, and then extracted with EtOAc (2 x 50 mL). The organic layers were combined and dried (Na2SO4). The solvent was removed under vacuum to provide pure 2-hydroxy-4-(2-(2-(3-hydroxy-3-(2'-methyl-4'-sulfamoyl-[1,1'-biphenyl]-3-yl)propyl)-5-xopyrazolidin-1-yl)ethyl)benzoic acid (0.050 g, 39%) in the form of a whitish solid.The product was confirmed by LCMS (Method 2), m / z 554 (ES+, M+H), at 1, 90 min. Compounds 6R and 6S: Racemic compound 6 (50 mg) was separated enantiomerically using a Waters Prep-HPLC system (250 x 10 mm, 5 µm CHIRALPAK AD-H column) with a mobile phase consisting of 80% FA at 0.1% heptane and 20% of a non-gradient mixture of IPA and acetonitrile (70:30), at a flow rate of 7.00 mL / min. Isomer 1: (0.006 g, 4.7%; sticky solid) The product was confirmed by LCMS (method 2), m / z 554 (ES+, M+H), at 1.86 min. Chiral HPLC: The purity of the product was confirmed at 18.45 min. 1H NMR: (400 MHz, MeOD) : 1,971-1,955 (d, 3H, J=6, 4 Hz) , 2,331 (s, 3H) , 2,908-2,853 (m, 4H) , 3,59-3,56 (t, 3H, J= 4, 8 Hz) , 3, 70-3, 68 (t, 3H, J= 4, 6 Hz) , 6, 81 (s, 2H) , 7, 27-7, 25 (d, 1H, J= 7, 25 2 Hz) , 7, 38-7, 36 (d, 2H, J = 8, 0 Hz) , 7, 49-7, 43 (m, 2H) , 7, 78-7, 76 (d, 2H, J = 7, 6 Hz) , 7, 84 (s, 1H) .Isomer 2: (0.007 g, 4.0%; sticky solid) The product was confirmed by LCMS (Method 3), m / z 554 (ES+, M+H), at 1.87 min. Chiral HPLC: The purity of the product was confirmed at 29.47 min. 1H NMR: (400 MHz, MeOD) : 1.99-1.96 (m, 3H) , 2.33-2.30 (d, 3H, J= 10.4 Hz) , 2.91-2.86 (m, 4H) , 3.58-3.56 (t, 2H, J= 4.6 Hz) , 3, 70-3, 68 (t, 2H, J= 4, 6 Hz) , 6, 82 (s, 2H) , 7, 27-7, 25 (d, 1H, J= 7, 252 Hz) , 7, 38-7, 36 (d, 2H, J = 8, 0 Hz) , 7, 49-7, 43 (m, 2H), 7, 78-7, 76 (d, 2H, J = 8, 0 Hz), 7, 83 (s, 1H). Example 7: Synthesis of 4-(2-(2-(3-(4'-carbamoyl-2'-methyl-[1,1'-biphenyl]-3-yl)-3-hydroxypropyl)-5-oxopyrazolidin-1-yl)ethyl)-2-hydroxybenzoic acid (Compound 7) Compound 7 was synthesized by the method described in Example 6 using 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide to give 4-(2-(2-(3-(4'-carbamoyl-2'-methyl-[1,1'-biphenyl]-3-yl)-3-hydroxypropyl)-5-oxopyrazohdin-1-yl)ethyl)-2-hydroxybenzoic acid (0.075 g, 86%) as a whitish solid. The product was confirmed by LCMS (method 2) m / z 518 (ES+, M+H) at 1.62 min. Compounds 7R and 7S: Racemic compound 7 (75 mg) was separated using a Waters Prep-HPLC system (250 x 10 mm, 5 µm CHIRALPAK AD-H column) with a mobile phase consisting of 75% FA in 0.1% heptane and 25% of an IPA / acetonitrile mixture (70:30) at a flow rate of 8.00 mL / min, without a gradient. Isomer 1: (0.016 g, 19%; off-white solid) The product was confirmed by LCMS (Method 2), m / z 518 (ES+, M+H), at 1.74 min. Chiral HPLC: Product purity was confirmed at 11.21 min. 1H NMR (400 MHz, DMSO) : 1.81-1.80 (d, 2H, J= 6.0 Hz), 2.27 (s, 3H), 2.54 (s, 1H), 2.80-2.7 (d, 4H, J= 6.4 Hz), 3.153 (s, 3H) , 4, 74-4, 71 (t, 1H, J= 6, 0 Hz) , 5, 32 (s, 1H) , 6, 78-6, 74 (m, 2H) 7, 27-7, 22 (m, 2H) , 7, 36-7, 33 (m, 2H) , 7, 43-7, 38 (m, 2H) , 7, 68-7, 66 (d, 1H, J= 8, 0 Hz) , 7, 76-7, 73 (dd, 1H, J= 1, 6 Hz) , 7, 81 (s, 1H) , 7, 97 (s, 1H) , 11, 20 (s, LH) , 13, 84 (s, 1H) .Isomer 2: (0, 025 g, 29 %; white solid) The product was confirmed by LCMS (Method 2), m / z 518 (ES+, M+H), at 1, 73 min. HPLC quiral: the purity of the product was confirmed at los 9, 72 min. NMR 1H: (400 MHz, DMSO) : 1, 81-1, 80 (d, 2H, J= 6, 4 Hz) , 2, 27 (s, 4H) , 2, 80 (s, 4H) , 3, 15-3, 14 (d, 3H, J= 6, 4 Hz) , 4, 74-4, 72 (d, 1H, J= 6, 0 Hz) , 5, 31 (s, 1H) , 6, 76-6, 74 (d, 1H, J= 8, 4 Hz) , 6, 31 (s, 1H) , 6, 76-6, 74 (d, 1H, J= 8, 4 Hz) , 6, 31 (s, 1H) , 6, 76-6, 74 (d, 1H, J= 8, 4 Hz) , 6, 31 (s, 1H) , 6, 76-6, 74 (d, 1H, J= 8, 4 Hz) , 6, 31 (s, 1H) , 6, 76-6, 74 (d, 1H, 78 (s, 1H) , 7, 27-7, 22 (m, 2H) , 7, 36-7, 33 (m, 2H) , 7, 43-7, 38 (m, 2H) , 7, 68-7, 66 (d, 1H, J= 8, 0 Hz) , 7, 76-7, 73 (dd, 1H, J= 1, 6 Hz), 7, 81 (s, 1H) , 7, 97 (s, 1H) , 11, 20 (s, pH) , 13, 84 (s, 1H) . Example 8: Synthesis of 2,6-difluoro-4-(2-(3-hydroxy-3-(2'-methyl-4'-sulfamoyl-[1,1'-biphenyl]-3-yl)propyl)-5-oxopyrazolidin-1-yl)ethyl)benzoic acid (Compound 8) Compound (8) was synthesized by the method described in Example 5, using 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide to give 2,6-difluoro-4-(2-(2-(3-hydroxy-3-(2'-methyl-4'-sulfamoyl-[1,1'-biphenyl]-3-yl)propyl)-5-oxopyrazolidin-1-yl)ethyl)benzoic acid (0.040 g, 23%) as a white solid. The product was confirmed by LCMS (Method 2), m / z 574 (ES+, M+H) at 1.58 min. Compounds 8R and 8S: The racemic compound (8) (40 mg) was separated enantiomerically using a Shimadzu Prep-HPLC system (CHROMEGACHIRAL CCO 250*25 mm, 5 µm column) with a mobile phase consisting of 80% FA at 0.1% heptane and 20% of a non-gradient mixture of IPA and acetonitrile (70:30) at a flow rate of 22.00 mL / min. Isomer 1: (0.010 g, 5.7%; sticky gum) The product was confirmed by LCMS (Method 2), m / z 574 (ES+, M+H) at 1.58 min. Chiral HPLC: The purity of the product was confirmed at 28.03 min. 1H NMR: (400 MHz, MeOD) : 1.30 (s, 3H) , 1.98-1.96 (d, 3H, J= 6.0 Hz) , 2.34 (s, 4H) , 2.96-2.93 (t, 6H, J= 6.6 Hz) , 6.98-6, 95 (d, 2H, J= 9, 2 Hz) , 7, 28-7, 25 (m, 1H) , 7, 38-7, 36 (m, 2H) , 7, 50-7, 43 (m, 2H) , 7, 50-7, 43 (m, 2H) , 7, 78-7, 76 (dd, 1H, J = 1, 5Hz) , 7, 84-7, 84 (m, 1H) . Isomer 2: (0, 012 g, 6, 8 %; sticky gum) The product was confirmed by LCMS (Method 2) , m / z 574 (ES+, M+H) , at 1, 58 min.HPLC test: The pure product will be confirmed within 20 minutes. 6, 98-6, 95 (d, 2H, J= 9, 2 Hz) , 7, 28-7, 26 (m, 1H) , 7, 38-7, 36 (m, 2H) , 7, 48H-7, 45 (m, 2 Hz) , 7, 78-7, 76 (dd, 1H, J = 1, 5Hz), 7, 84 (s, 1H). Ejemplo 9: Synthesis of (3'- (3- (2- (4- (1H-tetrazol-5-il) fenetil) -3-oxopirazolidin-1-il) -1-hidroxipropil) -2-metil-[1, 1'-bifenil]-4-carboxamida (Compuesto 9) Step (i): 1-Bromo-4-(2-bromoethyl)benzene (10.00 g, 38.18 mmol), tert-butylhydrazine carboxylate (7.57 g, 57.27 mmol), NaHCO3 (12.84 g, 15.27 mmol), and NaI (0.57 g, 3.82 mmol) were suspended in MeCN (100 mL) at room temperature, and the reaction mixture was stirred at 70 °C for 72 h. The reaction mixture was concentrated under vacuum, and the residue was partitioned between water (1000 mL) and EtOAc (800 mL). The aqueous layer was further extracted with EtOAc (3 x 500 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 (normal phase, silica). The product was eluted from 0% to 15% EtOAc in hexane to yield tert-butyl 2-(4-bromophenethyl)hydrazine-1-carboxylate (5.0 g, 42%) as a whitish solid. The product was confirmed by LCMS (Method 2), m / z 260 (ES+, m+H-TBu) at 2.34 min. Step (ii): 2-(4-bromophenethyl) tert-butyl hydrazine-1-carboxylate (5.00 g, 15.89 mmol) was dissolved in DMF (50 mL) at room temperature, and potassium carbonate (10.98 g, 79.47 mmol) was added. The mixture was stirred at room temperature for 15 minutes. Then, 3-bromopropionyl chloride (2.40 mL, 23.56 mmol) was added dropwise at room temperature, and the reaction mixture was stirred at room temperature for 24 h. The reaction mixture was concentrated under vacuum. The resulting residue was partitioned between water (500 mL) and EtOAc (400 mL). The aqueous layer was further extracted with EtOAc (2 x 300 mL). The organic layers were combined and dried over Na2SO4, and the solvent was removed under vacuum.The crude product was purified by gradient column chromatography (normal phase, silica) with EtOAc from 0% to 30% in hexane, yielding tert-butyl 2-(4-bromophenethyl)-3-oxopyrazolidin-1-carboxylate (4.0 g, 68%) as a sticky yellow solid. The product was confirmed by LCMS (method 2), m / z 313 (ES+, M+H-tBu), at 2.65 min. Step (iii): 2.00 g (4-bromophenethyl)-3-oxopyrazolidine-1-carboxylate (tert-butyl) was dissolved in 20 mL of DMF. Nitrogen gas was purged at room temperature for 15 minutes. After this, zinc cyanide (1.28 g, 10.87 mmol) and tetraquistriphenylphosphine-palladium 0 (0.63 g, 0.54 mmol) were added, and the reaction mixture was stirred at 150 °C for 1 h in a microwave oven (the reaction was divided into 4 reaction vials). The reaction mixture was partitioned between water (400 mL) and EtOAc (300 mL). The aqueous layer was further extracted with EtOAc (2 x 200 mL). The organic layers were combined and dried (Na2SO4).The solvent was removed under vacuum and the crude product was purified by reversed-phase gradient ultrafast column chromatography (reversed phase, C18 silica), eluting the product from 0% to 68% MeCN in water to give 4-(2-(5-oxopyrazolidin-1-yl)ethyl)benzenitrile (0.65 g, 41%) as a yellow solid. The product was confirmed by LCMS (Method 2), m / z 216 (ES+, M+H), at 1.63 min. Step (iv): 4-(2-(5-oxopyrazolidin-1-yl)ethyl) (0.60 g, 2.79 mmol) and 1-(3-bromophenyl)prop-2-en-1-one (2.90 g, 13.95 mmol) were suspended in MeOH (6 mL) at room temperature, and the reaction mixture was stirred at room temperature for 15 min. After this, TEA (2.00 mL, 13.95 mmol) was added at room temperature, and the mixture was stirred at 60 °C for 4 h. The reaction mixture was partitioned between water (200 mL) and EtOAc (150 mL), and the aqueous layer was further extracted with EtOAc (2 x 120 mL). The organic layers were combined and dried (Na2SO4). The solvent was removed under vacuum and the crude product was purified by reversed-phase gradient ultrafast column chromatography (reversed phase, C18 silica), the product was eluted with 0% to 72% ACN in water to provide 4-(2-(2-(3-(3-bromophenyl)-3-oxopropyl)-5-oxopyrazolidin-1-yl)ethyl) benzoate (0.50 g, 49%) in the form of a yellow oil.The product was confirmed by LCMS (Method 2), m / z 426 (ES+, M+H), at 2.58 min. Step (v): 4-(2-(2-(3-(3-bromophenyl)-3-oxopropyl)-5-oxopyrazolidin-1-yl)ethyl)benzenitrile (0.50 g, 1.18 mmol), 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (0.46 g, 1.76 mmol) and K2CO3 (0.33 g, 2.35 mmol) were dissolved in 1,4-dioxane (5 mL) and water (5 mL). Nitrogen gas was purged at room temperature for 20 min. After this, PdCl2 (dppf) .DCM (0.096 g, 0.12 mmol) was added and the reaction mixture was stirred at 80 °C for 2 h. The reaction mixture was then divided between water (200 mL) and EtOAc (150 mL). 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 gradient ultrafast column chromatography (reversed phase, C18 silica). The product was eluted with 0% to 55% MeCN in water to give 3'-(3-(2-(4-cyanophenethyl)-3-oxopyrazolidin-1-yl)propanoyl)-2-methyl-[1,1'-biphenyl]-4-carboxamide (0.25 g, 44%) as a whitish solid. The product was confirmed by LCMS (Method 2), m / z 481 (ES+, M+H), at 2.18 min. Step (vi) 3'-(3-(2-(4-cyanophenethyl)-3-oxopyrazolidin-1-yl)propanoyl)-2-methyl-[1,1'-biphenyl]-4-carboxamide (0.20 g, 0.42 mmol) was dissolved in ethanol (2 mL) and water (2 mL). After this, NaBHI (0.03 g, 0.83 mmol) was added at 0 °C and the mixture was stirred at room temperature for 1 h. The reaction mixture was partitioned between water (50 mL) and EtOAc (50 mL), and the aqueous layer was further extracted with EtOAc (2 x 30 mL). The organic layers were combined and dried (Na2SO4). The solvent was removed under vacuum to yield pure 3'-(3-(2-(4-cyanophenethyl)-3-oxopyrazolidin-1-yl)-1-hydroxypropyl)-2-methyl-[1,1'-biphenyl]-4-carboxamide (0.17 g, 85%) as a whitish solid. The product was confirmed by LCMS (Method 2), m / z 483 (ES+, M+H), at 2.14 min. Step (vii): 3'-(3-(2-(4-cyanophenethyl)-3-oxopyrazolidin-1-yl)-1-hydroxypropyl)-2-methyl-[1,1'-biphenyl]-4-carboxamide (0.17 g, 0.35 mmol) was suspended in DMF (2 mL) at room temperature, and sodium azide (0.24 g, 3.50 mmol) and ammonium chloride (0.20 g, 3.50 mmol) were added and left to stir at 100 °C for 48 h. The reaction mixture was partitioned between water (70 mL) and EtOAc (50 mL) and the aqueous layer was further extracted with EtOAc (3 x 50 mL). The organic layers were combined and dried (Na2SO4). The solvent was removed under vacuum and the crude product was purified by reversed-phase gradient ultrafast column chromatography (reversed phase, C18 silica). The product was eluted with MeCN from 0% to 45% in water to provide (3'-(3-(2-(4-(1H-tetrazol-5-yl)phenethyl)-3-oxopyrazolidin-1-yl)-1-hydroxypropyl)-2-methyl-[1,1'-biphenyl]-4-carboxamide (0.10 g, 54%) as a whitish solid.The product was confirmed by LCMS (Method 2), m / z 526 (ES+), at 1.91 min. Chiral HPLC: The purity of the product was confirmed at 13.67 min and 15.68 min. 1H NMR (400 MHz, DMSO) : 1.85-1.83 (d, 2H, J = 6.4 Hz), 2.29 (s, 3H), 2.89-2.86 (m, 4H), 3.18 (S, 4H), 4.76 (S, 1H), 5. 40 (m, 1H) , 7, 29-7, 24 (m, 2H) , 7, 45-7, 36 (m, 6H) , 7, 76-7, 76 (d, 1H) , J=1, 2 Hz) , 7, 83 (s, 1H) , 7, 95-7, 93 (d, 2H, J=8, 0Hz), 8, 00 (s, 1H) . Compounds 9R and 9S: Racemic compound 9 (90 mg) was separated enantiomerically using a Waters 600 Controller HPLC system (Chiralpak_IG_SFC_21 mm*250 mm, 5 µm column) with a mobile phase of 90% heptane and 10% IPA and acetonitrile (70:30), without a gradient, at a flow rate of 23.00 mL / min. Isomer 1: (0.028 g, 31%; white solid) The product was confirmed by LCMS (Method 2), m / z 526 (ES+, M+H), at 1.75 min. Chiral HPLC: Product purity was confirmed at 13.19 min. 1H NMR: (400 MHz, DMSO) 1.82-1.81 (d, 2H, J = 5.6 Hz), 2.10 (s, 3H), 2.87-2.83 (t, 4H, J = 6.6 Hz), 3.15 (S, 4 h), 4.73 (s, 1H), 5, 36 (s, 1H), 7, 26-7, 22 (m, 2H), 7, 42-7, 33 (m, 6H), 7, 75-7, 73 (m, 1H), 7, 81 (s, 1H), 7, 92-7, 90 (d, 2H, J=8, 0Hz), 7, 97 (s, 1H) . Isomer 2: (0.025 g, 28%; white solid) The product was confirmed by LCMS (Method 2), m / z 526 (ES+, M+H), at 1.76 min. Chiral HPLC: the purity of the product was confirmed at 14.89 min (98%).RMN 1H:. (400 MHz, DMSO) : 1, 82-1, 81 (d, 2H, J = 6 Hz) , 2, 26 (s, 3H) , 2, 83-2, 66 (m, 4H) , 3, 07 (s, 4H) , 4, 73 (s, 1H) , 5, 37 (s, 1H) , 7, 43-7, 22 (m, 8H) , 7, 75-7, 73 (m, 1H) , 7, 80 (s, 1H) , 90-7, 89 (d, 2H, J = 8, 0 Hz) , 7, 98 (s, 1H) . Ejemplo 10: Ensayos biológicos Cloning, baculovirus generation, large-scale infection of HEK293 cells, and membrane preparation: The human prostaglandin E2 receptor (EP4) was cloned into the pBacMam expression vector (GeneScript, UK). EP4 DNA transposition was performed using Invitrogen's Bac-to-Bac baculovirus expression systems. P0 baculovirus was generated by transfecting SF9 cells with bacmido DNA using Cellfectin II transfection reagent (ThermoFisher Scientific, UK). Following P0 generation, P1 generation virus was then generated, ready 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). The cells were infected at a seeding density of 3.5 million cells / mL in 500 cm3 flasks containing 5% v / v EP4 Bacman.Expression was carried out for 36 hours at 37 °C with 5% CO2. Cells were removed 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 (HEPES 20 mm, MEDTA 10 mm, 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. It was then homogenized for 20 seconds. The membrane was centrifuged at 40,000 g for 45 min at 4 °C. The membrane was 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 proteins and cAMP: cAMP production after EP4 receptor activation was determined using the Homogeneous Time-Resolved Fluorescence (HTRF) cAMP dynamic-2 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 assay compounds, along with positive controls (PGE210 uM (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 minutes to form a pellet. The pellet was resuspended in assay buffer (DMEM + 0.5 mM IBMX (Tocris, Abingdon, UK)) to a density of 0.5 x 10⁶ cells / mL. The cell suspension, for a final assay concentration of 5000 cells / well, was added using a multidrop to the pre-dispensed assay plate. The plate was then incubated at 37 °C for 30 minutes with 5% CO₂. cAMP production was determined according to the manufacturer's instructions before reading the plates on a PheraStar fluorescence plate reader (BMGlabtech, Germany). The pEC50 (-Log M) values ​​were calculated from the midpoint of the curve using Dotmatics, as shown in Table 2. Table 2: Activity (pEC50 and Emax values) of selected compounds from Formula (1) for the prostaglandin E2 receptor 4 (human cAMP EP4) UNIDIRECTIONAL CELL PERMEABILITY TEST CACO-2 Caco-2 (ECACC) cells were seeded in 24-well Transwell plates at a rate of 2 x 10⁵ cells per well and used in confluent monolayers after a 21-day culture at 37 °C with 5% CO₂. The assay compounds were incubated at 10 µM, final 0.2% DMSO, n=2 in assay buffer (Hanks balanced salt supplemented with 25 mM HEPES, adjusted to pH 6.5). Hanks balanced salt supplemented with 25 mM HEPES, adjusted to pH 7.4 (final 0.2% DMSO), was used for the basolateral chamber (as the receptor). Incubations were performed at 37 °C, with samples taken from the donor and recipient chambers at T = 0 and 1 hour, and the compound was analyzed by mass spectrometry (LC-MS / MS), including 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 µl, basolateral 600 µl) and the concentrations are the relative mass spectrometry responses for the compound (normalized to the internal standard) in the donor chamber before incubation and in the recipient chamber at the end of the incubation area = cell area 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 cross lipophilic barriers, a high degree of LY transport indicates poor cell layer integrity, and wells with a Pap concentration >10 x 10⁻⁶ cm / s of LY were rejected. The recovery of the compound from the wells was determined from the mass spectrometry responses (normalized to the internal standard) in the donor and recipient 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 R, C(O)R, CO2R, C(O)N(R)2, C(O)N(R)S(O)2R3, S(O)2R, S(O)2OR, SO2N(R)2, C1-8 alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; X is halo, OR', COOR' or C1-6 alkyl; L and L' are each independently a C2-4 alkylene; R1 is H, halo, CN, NO2, OR', SR', COOR', C1-6 alkoxy or C1-6 alkyl; R2 is OR, OC(O)R3, OC(O)OR3, CO2R, CON(R)2, SO2N(R)2, SO2R3, OSO2R3, or OSO2N(R)2; R3 is C1-6 alkyl, C3-6 cycloalkyl, or a phenyl; R' is H, C1-6 alkyl, or C3-6 cycloalkyl; and n is 0, 1, 2, or 3; wherein, in each case, alkyl, alkylene, alkoxy, and cycloalkyl are optionally and independently substituted with up to 3 instances of OH, SH, CN, NO2, COOH, halo, or COOC1-4 alkyl; wherein, in each case, heterocycloalkyl, aryl, and heteroaryl are optionally and independently substituted with up to 3 instances of OR', SR', CN, NO2,CO2R', halo, C1-4 alkyl or oxo.

2. The compound according to claim 1, wherein (i) L is the group (ii) L is the group.

3. The compound according to claim 1 or 2, wherein the compound is a compound of Formula (1): OR a pharmaceutically acceptable salt, solvate, hydrate, tautomer or optical isomer thereof, wherein A, X, R1, R2 and n are the same as those defined in claim 1.

4. The compound according to any one of claims 1-3, wherein A is selected from C(O)OR', C(O)N(R')S(O)2R3, S(O)2OR', C1-8 alkyl, heterocycloalkyl or heteroaryl, wherein the heterocycloalkyl and the heteroaryl are each optionally and independently substituted with up to 3 instances of OR', SR', halo, C1-4 alkyl or oxo; preferably wherein A is selected from the group consisting of: more preferably wherein A is: most preferably wherein A is .

5. The compound according to any of claims 1-4, wherein: (i) X is halo or OR',preferably wherein X is F or OH; more preferably wherein X is F or OH, and n is 1 or 2; or (ii) n is 0.

6. The compound according to any one of claims 1-5, wherein R1 is H, OH, halo, CN, C1-6 alkoxy optionally substituted with 1-3 fluorine atoms or C1-6 alkyl optionally substituted with 1-3 fluorine atoms; preferably wherein R1 is C1-6 alkyl optionally substituted with 1-3 fluorine atoms; more preferably wherein R1 is methyl.

7. The compound according to any one of claims 1-6, wherein: (i) R2 is OR, CON(R)2, SO2N(R)2 or OSO2N(R)2, preferably wherein R2 is OH, CONH2, SO2NH2 or OSO2NH2; or (ii) R2 is CON(R)2, SO2N(R)2, OSO2R3 or OSO2N(R)2; preferably wherein R2 is CONH2, SO2NH2 or OSO2NH2.

8. The compound according to any one of claims 1-7, which is a compound of Formula (2a), (2b), (2c) or (2d): or a pharmaceutically acceptable salt, solvate, hydrate or tautomer thereof, wherein X, R1,R2 and n are the same as those defined in any preceding claim.

9. The compound according to claim 1, which is a compound of Formula (5), (5a), (5b), (6), (6a), (6b): or a pharmaceutically acceptable salt, solvate, hydrate, or tautomer thereof.

10. The compound according to claim 1, wherein the compound is selected from the group consisting of: or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or optical isomer thereof.

11. A pharmaceutical composition comprising a pharmaceutically acceptable compound, salt, solvate, hydrate, or tautomer, according to any one of claims 1 to 10, and a pharmaceutically acceptable excipient; and optionally wherein the composition further comprises at least one additional therapeutic agent selected from the group consisting of aminosalicylates, corticosteroids, immunomodulators, and combinations thereof.

12. A kit comprising a compound, a salt, a solvate,A pharmaceutically acceptable hydrate, tautomer, or optical isomer according to any one of claims 1 to 10, and at least one additional therapeutic agent selected from the group consisting of aminosalicylates, corticosteroids, immunomodulators, and combinations thereof.

13. A compound according to any one of claims 1 to 10, a composition according to claim 11, or a kit according to claim 12, for use as a medicament.

14. The compound according to any one of claims 1 to 10, the composition according to claim 11, or the kit according to claim 12, 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.

15. The compound, composition, or kit for use according to claim 14,where: (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, gastrointestinal diseases of immune origin, 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.