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

Abstract

The present invention relates to compounds of Formula I as prostaglandin:E2 receptor 4 (EP4) agonists for use in methods for treating gastrointestinal and pulmonary diseases or disorders. The disclosure provides exemplary compounds and pharmacological data. JPEG2025525894000085.jpg50170

Description

[Technical Field]

[0001] 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 in which the EP4 receptor is involved. This application is also directed to pharmaceutical compositions containing these compounds, as well as the manufacture and use of these compounds and compositions in the prevention or treatment of diseases in which the EP4 receptor is involved. [Background technology]

[0002] Prostanoids, including prostaglandins and thromboxanes, are metabolite derivatives of arachidonic acid that play important roles in cellular physiology. Arachidonic acid is an essential component of membrane phospholipids, liberated via the activity of phospholipase A2 (PLA2). Prostaglandin biosynthesis is mediated by cyclooxygenase (COX), which converts arachidonic acid to an unstable intermediate (PGH2), generating prostaglandins, including PGE2. PGE2 is the most widely produced prostanoid, whose activity is mediated through action at four functionally distinct receptor subtypes, EP1-EP4.

[0003] EP receptors belong to the G protein-coupled receptor (GPCR) family, which are integral membrane proteins with seven transmembrane domains. This receptor class can be broadly categorized according to their signaling pathways: i) Gs-coupled receptors (activating adenylate cyclase and producing cyclic adenosine monophosphate (cAMP)) EP2 and EP4, ii) Gq-coupled receptors (activating PLC) EP1, and iii) Gi-coupled receptors (inhibiting adenylate cyclase) EP3.

[0004] The EP4 receptor signals through Gs, positively couples to adenylate cyclase, and increases cAMP levels. This receptor was originally described in 1993 with the identification of an EP2-like receptor that positively couples to adenylate cyclase but does not bind butaprost (A Honda et al. J. Biol. Chem. 1993, 268, 7759-7762).

[0005] The EP4 receptor plays an important role in various physiological functions, including gastrointestinal homeostasis, regulation of vascular tone, renal function, inflammation, fever, and carcinogenesis. The potent biological actions of PGE2 have stimulated interest in developing subtype-selective EP4 agonists and antagonists for the treatment of a wide range of indications.

[0006] Functional gastrointestinal disorders (FGIDs), including chronic constipation, are common gastrointestinal conditions encountered by primary care physicians and gastroenterologists. The prevalence of chronic constipation ranges from 1% to 8%, can adversely affect quality of life (QoL), and imposes 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 common, despite many patients not achieving adequate relief. There remains a need for treatments that can provide complete and sustainable symptom relief.

[0007] The intestinal mucosa plays an important role in anion homeostasis and fluid maintenance. These functions are mediated through coordinated ion transport via membrane-bound transporters and channels located on the apical and basolateral membranes of intestinal epithelial cells. PGE2 is a known secretagogue that can directly promote chloride ion secretion from intestinal epithelial cells. The secretory action of PGE2 is regulated in part via the EP4 receptor, which can stimulate chloride anion secretion across the intestinal mucosa. Lubiprostone, a bicyclic fatty acid derivative of PGE1 clinically approved for the treatment of chronic constipation and IBS-C, has been shown to promote fluid secretion and gastrointestinal motility through activation of prostaglandin (EP4) receptors. EP4-selective agonists may be of therapeutic value in promoting intestinal fluid homeostasis in chronic constipation.

[0008] Inflammatory bowel disease (IBD) is a chronic, debilitating gastrointestinal disorder that includes ulcerative colitis and Crohn's disease. Patients with IBD typically experience symptoms including diarrhea, abdominal pain, weight loss, rectal bleeding, and fever. Clinical management involves strategies to control abnormal, dysregulated immune responses in the intestinal mucosa. Depending on the severity of the disease, a wide range of medications are used to induce and maintain remission. These medications include aminosalicylates, corticosteroids, immunosuppressants, antibiotics, and biologic agents. This may be done in a stepwise approach, with treatment intensification depending on the severity and progression of the disease. However, it is clear that some patients are refractory to drug therapy or cannot tolerate it due to systemic side effects. With current treatment strategies, only a small proportion of patients achieve long-term remission, suggesting the need for improved treatment.

[0009] Intestinal barrier dysfunction plays an important pathogenic role in IBD, and there is growing interest in developing drugs that restore barrier function (mucosal healing). EP4 is expressed in several cell types, including gastrointestinal (GI) epithelial cells, lamina propria mononuclear cells, and colonic innervating sensory neurons, and may provide benefits by protecting the GI mucosal barrier in addition to suppressing inappropriate mucosal immune responses. EP4-mediated PGE2 signaling promotes cell differentiation into wound-associated epithelial cell phenotypes, which are important for wound repair (Miyoshi, H. et al. EMBO J. 2017, 36, 5-24). Administration of an EP4 agonist is effective 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 EP4-deficient mutant mice develop severe dextran sulfate sodium-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). A small Phase II study evaluated the EP4 agonist ONO-4819CD in patients with mild to moderate ulcerative colitis refractory to 5-ASA (Nakase, H. et al. Inflamm. Bowel Dis. 2010, 16, 731-733). Although the study was not powered for efficacy, patients treated with ONO-4819CD showed signs of improvement in Disease Activity Index (DAI) scores and histological scores. These data support the potential clinical benefit of EP4 agonist therapy in IBD.

[0010] Asthma and chronic obstructive pulmonary disease are inflammatory airway disorders characterized by airway limitation. It is estimated that approximately 300 million people have asthma, making it the most common chronic disease in children. Despite advances in asthma management, a significant proportion of patients experience uncontrolled disease, which may lead to mortality and morbidity. There remains a need for treatments that can achieve effective control of asthma symptoms and reduce the risk of future exacerbations with long-term management. PGE2 is known to have bronchodilatory and anti-inflammatory effects in isolated airway smooth muscle of rodents and humans. Inhaled PGE2 has been shown to be beneficial for inflammation and airway dilation in patients with chronic bronchitis and asthma. However, PGE2 also induces reflex coughing, likely via stimulation of the upper airway via the EP3 receptor. This has led to ongoing efforts to discover EP receptor-selective drugs for the treatment of airway disorders. Interestingly, significant interspecies differences have been reported in the receptor subtypes that mediate airway smooth muscle relaxation. In guinea pigs, monkeys, and mice, EP2 agonists can induce relaxation of airway smooth muscle, while in humans, relaxation of airway smooth muscle is mediated by EP4 receptors (Buckley, J. et al. Thorax 2011, 66, 1029-1035). Selective EP4 receptor agonists may have promising therapeutic effects in airway diseases.

[0011] The EP4 receptor has been shown to play a role in blood pressure regulation. EP4 is expressed on smooth muscle cells and endothelial cells and can induce vasodilatory effects through endothelial nitric oxide synthase (eNOS)-mediated nitric oxide (NO) production. PGE2 has been shown to dose-dependently relax smooth muscle in aortic rings, and this effect is abolished in EP4 knockout mice. In halothane-anesthetized dogs, the EP4-selective agonist ONO-AE1-329 induced a vasopressor response (Honda, A. et al. Eur. J. Pharmacol. 2016, 775, 130-137). Similarly, hypotension was reported as a side effect in IBD patients receiving ONO-4819CD (Nakase, H. et al. Inflamm. Bowel Dis. 2010, 16, 731-733).

[0012] EP4 agonists that can be used to treat various gastrointestinal disorders and airway disorders without causing systemic side effects on the cardiovascular system may have promising therapeutic effects.In particular, EP4 agonists that can be used to treat various gastrointestinal disorders without causing systemic side effects on the cardiovascular system may have promising therapeutic effects.There is a need to discover safe and effective EP4 selective drugs. Summary of the Invention

[0013] The present invention provides compounds that have activity as prostaglandin E2 receptor 4 (EP4) agonists.

[0014] In one embodiment, the present invention provides a compound of formula I: [ka] or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or optical isomer thereof, A is OR', C(O)R', CO2R', C(O)N(R')2, C(O)N(R')S(O)2R', S(O)2R', S(O)2OR', SO2N(R')2, C1-8 alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; Ring B is aryl or heteroaryl; X and Y are each, independently of each other, CR″ or N, and at least one of X and Y is CH; R 1 and R 2 are, independently of each other, H, C 1-6 Alkyl, C 1-6 Alkoxy or R 1 and R 2 together with the carbon atoms to which they are attached, form C 3-6 forming cycloalkane-1,1-diyl; Each R 3 are, independently of each other, H, OR', COOR', C(O)R', halo, and C 1-6 alkyl; R 4 is H, C 1-6 alkyl, halo, CN, NO2, or OR'; R 5 is H or C 1-6 alkyl; or R 4 and R 5 together with the pyrrolidine ring to which they are attached, form C 1-6 forming an alkylene linker; R 6 is H, C 1-6 Alkyl, C optionally substituted with 1 to 3 fluorine atoms 1-3 alkoxy, halo, CN, NO2, OR', COOR', or C(O)R'; R 7 is OR', OC(O)R', OC(O)OR', COR', CON(R')2, SON(R')2, SOR', OSOR', or OSON(R')2; Each R' is independently H, C 1-6 Alkyl or C 3-6 is cycloalkyl; Each R" is H, C 1-6alkyl, halo, or OR'; n and m are each, independently of one another, 0, 1, 2, or 3; Each occurrence of alkyl, alkylene, and cycloalkyl optionally, and independently of one another, may include up to three of OH', SH, CN, NO2, COOH, halo, or COOC. 1-4 is substituted with alkyl; Heterocycloalkyl, aryl, and heteroaryl each optionally, and independently of one another, may be selected from up to three of OR', SR', CN, NO2, COOR', halo, C 1-4 substituted with alkyl or oxo; Provided are compounds of Formula I, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or optical isomer thereof:

[0015] In another aspect, the present invention provides a compound of formula (1): [ka] or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or optical isomer thereof; A is, [ka] selected from the group consisting of: U, V, W, and Z are each independently CH, COH, N, or N + -O - wherein at least three of U, V, W, and Z are CH; X and Y are each, independently of one another, selected from the group consisting of CH, CF, COH, or N; R 1 is H, C optionally substituted with 1 to 3 fluorine atoms 1-3 alkyl or R 2 C optionally substituted with 1 to 3 fluorine atoms by bonding to 3-6 forming a cycloalkyl ring; R 2is H, C optionally substituted with 1 to 3 fluorine atoms 1-3 alkyl or R 1 C optionally substituted with 1 to 3 fluorine atoms by bonding to 3-6 forming a cycloalkyl ring; R 3 is H, OH, or F; R 4 is H, OH, F, or R 5 It forms a CH2 bridge by binding to R 5 is H or R 4 It forms a CH2 bridge by binding to R 6 is H, OH, CN, halo, C optionally substituted with 1 to 3 fluorine atoms 1-3 Alkoxy or C optionally substituted with 1 to 3 fluorine atoms 1-3 is alkyl; R 7 is OH, CO2H, CONH2, SO2NH2, or OSO2NH2; R 9 is C 1-3 Alkyl or C 3-6 is a cycloalkyl ring, Provided is a compound of formula (1), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or optical isomer thereof:

[0016] In another aspect, the present invention includes pharmaceutical compositions comprising a compound described herein and a pharmaceutically acceptable excipient.

[0017] 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 an aminosalicylates, corticosteroids, immunomodulators, and combinations thereof.

[0018] In another aspect, the invention includes a compound described herein, a composition described herein, or a kit described herein for use as a medicament.

[0019] In another aspect, the invention includes a compound described herein, a composition described herein, or a kit described herein for use in treating an EP4 receptor-mediated disease.

[0020] In another aspect, the present invention includes a method for modulating EP4 receptor agonist activity in a biological sample, comprising contacting the EP4 receptor with a compound or composition described herein.

[0021] In another aspect, the present invention includes a method for treating an EP4 receptor-mediated disease, comprising administering to a patient in need of treatment for an EP4 receptor-mediated disease a compound or composition described herein.

[0022] The above-mentioned compounds can be used herein as EP4 receptor agonists.The above-mentioned compounds can act selectively at the EP4 receptor.The above-mentioned compounds can be used in the manufacture of compositions or medicaments.The compounds, compositions, or medicaments can be used to treat, prevent, improve, control, or reduce the risk of diseases or disorders involving the EP4 receptor. The compounds, compositions, or medicaments described above may be used to treat, prevent, ameliorate, control, or reduce the risk of gastrointestinal disorders and conditions including, but not limited to, constipation, constipation-predominant irritable bowel syndrome, mixed irritable bowel syndrome, chronic idiopathic constipation, gastrointestinal symptoms associated with Parkinson's disease, gastrointestinal symptoms associated with cystic fibrosis, intestinal motility dysfunction, postoperative ileus, food allergy or food intolerance, celiac disease, gastrointestinal motility disorders, functional gastrointestinal disorders, drug-induced enteropathy, NSAID-induced gastrointestinal injury, chemotherapy-induced mucositis, gastroesophageal reflux disease (GERD), duodenogastric reflux, diarrhea, immune-mediated gastrointestinal diseases, Crohn's disease, ulcerative colitis, inflammatory bowel disease, and ischemic colitis.

[0023] The compounds, compositions, or medicaments described above may also be used to treat, prevent, ameliorate, 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, reactive airways disease, and idiopathic pulmonary fibrosis. DETAILED DESCRIPTION OF THE INVENTION

[0024] The present invention relates to novel compounds. The present invention also relates to the use of the novel compounds as agonists of the EP4 receptor. The present invention further relates to the use of the novel compounds in the manufacture of medicaments for use as EP4 receptor agonists, and to methods of treatment comprising administering the compounds of the present invention as EP4 receptor agonists.

[0025] The compounds of formula I can be used to treat, prevent, ameliorate, control, or reduce the risk of diseases or disorders in which the EP4 receptor is involved. The compounds of Formula I, such compounds, compositions, or medicaments, can be used to treat, prevent, ameliorate, control, or reduce the risk of gastrointestinal disorders and conditions including, but not limited to, constipation, constipation-predominant irritable bowel syndrome, mixed irritable bowel syndrome, chronic idiopathic constipation, gastrointestinal symptoms associated with Parkinson's disease, gastrointestinal symptoms associated with cystic fibrosis, intestinal motility dysfunction, postoperative ileus, food allergy or food intolerance, celiac disease, gastrointestinal motility disorders, functional gastrointestinal disorders, drug-induced enteropathy, NSAID-induced gastrointestinal injury, chemotherapy-induced mucositis, gastroesophageal reflux disease (GERD), duodenogastric reflux, diarrhea, immune-mediated gastrointestinal diseases, Crohn's disease, ulcerative colitis, inflammatory bowel disease, and ischemic colitis.

[0026] The compounds of formula I may also be used to treat, prevent, ameliorate, 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, reactive airways disease, and idiopathic pulmonary fibrosis.

[0027] Certain novel compounds of the present invention exhibit particularly high activity as EP4 receptor agonists.

[0028] The compounds of the present invention have been shown to have activity as EP4 receptor agonists.The compounds of the present invention also have low gastrointestinal permeability, as shown by Caco-2 studies.Therefore, it is believed that the compounds of the present invention have low systemic bioavailability when orally administered.The agonistic effect on the function of EP4 receptors expressed in the gastrointestinal tract may provide treatment for various gastrointestinal disorders.The combination of EP4 receptor agonist activity and low gastrointestinal permeability suggests that the compounds of the present invention are useful for treating various gastrointestinal disorders without causing adverse cardiovascular effects resulting from systemic distribution.

[0029] In one embodiment, the present invention provides a compound of formula I: [ka] or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or optical isomer thereof; A is OR', C(O)R', CO2R', C(O)N(R')2, C(O)N(R')S(O)2R', S(O)2R', S(O)2OR', SO2N(R')2, C 1-8 alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; Ring B is aryl or heteroaryl; X and Y are each, independently of each other, CR″ or N, and at least one of X and Y is CH; R 1 and R 2 are, independently of each other, H, C 1-6 Alkyl, C 1-6 Alkoxy or R 1 and R 2 together with the carbon atoms to which they are attached, form C 3-6 forming a cycloalkane-1,1-diyl; Each R3 are, independently of each other, H, OR', COOR', C(O)R', halo, and C 1-6 alkyl; R 4 is H, C 1-6 alkyl, halo, CN, NO2, or OR'; R 5 is H or C 1-6 Alkyl alkyl (C 1-6 alkyl alkyl); or R 4 and R 5 together with the pyrrolidine ring to which they are attached, form C 1-6 forming an alkylene linker; R 6 is H, C 1-6 Alkyl, C optionally substituted with 1 to 3 fluorine atoms 1-3 alkoxy, halo, CN, NO2, OR', COOR', or C(O)R'; R 7 is OR', OC(O)R', OC(O)OR', COR', CON(R')2, SON(R')2, SOR', OSOR', or OSON(R')2; Each R' is independently H, C 1-6 Alkyl or C 3-6 is cycloalkyl; Each R" is H, C 1-6 alkyl, halo, or OR'; n and m are each, independently of one another, 0, 1, 2, or 3; Each occurrence of alkyl, alkkylene, and cycloalkyl may optionally, and independently of one another, be selected from the group consisting of up to three of OH', SH, CN, NO2, COOH, halo, or COOC. 1-4 is alkyl substituted; Heterocycloalkyl, aryl, and heteroaryl each optionally, and independently of one another, may be selected from up to three of OR', SR', CN, NO2, COOR', halo, C 1-4 substituted with alkyl or oxo; Provided are compounds of Formula I, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or optical isomer thereof:

[0030] In some embodiments, the compound is a compound of formula I: [ka] or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or optical isomer thereof; A is OR', C(O)R', CO2R', C(O)N(R')2, C(O)N(R')S(O)2R', S(O)2R', S(O)2OR', SO2N(R')2, C 1-8 alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; Ring B is aryl or heteroaryl; X and Y are each, independently of each other, CR″ or N, and at least one of X and Y is CH; R 1 and R 2 are, independently of each other, H, C 1-6 Alkyl, C 1-6 Alkoxy or R 1 and R 2 together with the carbon atoms to which they are attached, form C 3-6 forming a cycloalkane-1,1-diyl; Each R 3 are, independently of each other, H, OR', COOR', C(O)R', halo, and C 1-6 alkyl; R 4 is C 1-6 alkyl, halo, CN, NO2, or OR'; R 5 is H or C 1-6 Alkyl alkyl (C 1-6 alkyl alkyl); or R 4 and R 5 together with the pyrrolidine ring to which they are attached, form C 1-6forming an alkylene linker; R 6 is H, C 1-6 alkyl, halo, CN, NO2, OR', COOR', or C(O)R'; R 7 is OR', OC(O)R', OC(O)OR', COR', CON(R')2, SON(R')2, SOR', OSOR', or OSON(R')2; Each R' is independently H, C 1-6 Alkyl or C 3-6 is cycloalkyl; Each R" is H, C 1-6 alkyl, halo, or OR'; n and m are each, independently of one another, 0, 1, 2, or 3; Each occurrence of alkyl, alkkylene, and cycloalkyl may optionally, and independently of one another, be selected from the group consisting of up to three of OH', SH, CN, NO2, COOH, halo, or COOC. 1-4 is substituted with alkyl; Heterocycloalkyl, aryl, and heteroaryl each optionally, and independently of one another, may be selected from up to three of OR', SR', CN, NO2, COOR', halo, C 1-4 substituted with alkyl or oxo; A compound of Formula I, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or optical isomer thereof:

[0031] In some embodiments, the compound is a compound of formula I, a compound of formula IIa, a compound of formula IIb, a compound of formula IIc, a compound of formula IId, a compound of formula IIe, a compound of formula (1), a compound of formula (1a), a compound of formula (1b), a compound of formula (2), a compound of formula (2a), a compound of formula (2b), a compound of formula 3, a compound of formula (3a), a compound of formula (3b), a compound of formula (4), a compound of formula (4a), a compound of formula (4b), a compound of formula (5), , a compound of formula (5a), a compound of formula (5b), a compound of formula (6), a compound of formula (6a), a compound of formula (6b), a compound of formula (7), a compound of formula (7a), a compound of formula (7b), a compound of formula (8), a compound of formula (8a), a compound of formula (8b), a compound of formula (9), a compound of formula (9a), a compound of formula (9b), a compound of formula (10), a compound of formula (10a), a compound of formula (10b), or a pharmaceutically acceptable salt or tautomer thereof.

[0032] In some embodiments, the compound is a compound of formula I, a compound of formula IIa, a compound of formula IIb, a compound of formula IIc, a compound of formula IId, a compound of formula IIe, a compound of formula (1), a compound of formula (1a), a compound of formula (1b), a compound of formula (2), a compound of formula (2a), a compound of formula (2b), a compound of formula 3, a compound of formula (3a), a compound of formula (3b), a compound of formula (4), a compound of formula (4a), a compound of formula (4b), a compound of formula (5) a compound of formula (5a), a compound of formula (5b), a compound of formula (6), a compound of formula (6a), a compound of formula (6b), a compound of formula (7), a compound of formula (7a), a compound of formula (7b), a compound of formula (8), a compound of formula (8a), a compound of formula (8b), a compound of formula (9), a compound of formula (9a), a compound of formula (9b), a compound of formula (10), a compound of formula (10a), a compound of formula (10b), or a pharmaceutically acceptable salt thereof.

[0033] In some embodiments, A is CO2R', C(O)N(R')S(O)2R', S(O)2R', or heteroaryl.

[0034] In some embodiments, A is COOH or a 5-membered heteroaryl optionally substituted with OR' or SR'.

[0035] In some embodiments, each B ring optionally, and independently of each other, contains up to three OR', SR', CN, NO2, CO2R', halo, or C 1-4 It is a 5- to 6-membered aryl or 5- to 6-membered heteroaryl substituted with alkyl.

[0036] In some embodiments, Ring B is a 5-6 membered aryl or a 5-6 membered heteroaryl.

[0037] In some embodiments, Ring B is phenyl optionally substituted with up to 3 OH.

[0038] In some embodiments, Ring B is a 6-membered heteroaryl containing 1 or 2 nitrogen atoms, each of which is optionally substituted with oxo.

[0039] In some embodiments, Ring B is pyridine-N-oxide.

[0040] In some embodiments, each R 3 are, independently of each other, OR', halo, or C 1-6 alkyl.

[0041] In some embodiments, each R 3 are each independently selected from OR′ or alkyl; and n is 0 or 1. In some embodiments, n is 0.

[0042] In some embodiments, n is 1.

[0043] In some embodiments, n is 0 or 1.

[0044] In some embodiments, R4 are each independently selected from OR' or halo; and m is 0 or 1. In some embodiments, m is 0.

[0045] In some embodiments, m is 1.

[0046] In some embodiments, m is 0 or 1.

[0047] In some embodiments, R 5 is H.

[0048] In some embodiments, R 4 and R 5 together with the pyrrolidine ring to which they are attached form a CH2 linker.

[0049] In some embodiments, R 4 is R 5 By bonding to the carbon atom to which R is bonded, 4 together with the pyrrolidine ring to which it is attached form a C5 bridged bicyclic ring.

[0050] In some embodiments, R 4 and R 5 together with the pyrrolidine ring to which they are attached form a C5 bridged bicyclic ring.

[0051] In some embodiments, R 6 is H, C 1-6 It is alkyl, halo, or OR'.

[0052] In some embodiments, R 6 is H, methyl, or OH.

[0053] In some embodiments, R 7 is OR', OC(O)R', CO2R', CON(R')2, SO2N(R')2, SO2R', or OSO2N(R')2.

[0054] In some embodiments, R 7 is OR', CO2R', CON(R')2, SO2N(R')2, or OSO2N(R')2. In some embodiments, R' is H.

[0055] In some embodiments, R 7 is OH, CO2H, CONH2, SO2NH2, or OSO2NH2. In some embodiments, R 7 is CO2H, CONH2, SO2NH2, or OSO2NH2.

[0056] In some embodiments, R 7 is CONH2.

[0057] In some embodiments, R 7 is OH, then U, V, and Z are CH and W is COH.

[0058] In some embodiments, the compound of formula IIa, the compound of formula IIb, the compound of formula IIc, the compound of formula IId, and the compound of formula IIe: [ka] or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or optical isomer thereof, A, X, Y, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 is as defined above, Provided herein are compounds of Formula IIa, IIb, IIc, IId, and IIe, or pharmaceutically acceptable salts, solvates, hydrates, tautomers, or optical isomers thereof.

[0059] In one embodiment, the compound of formula (1): [ka] or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or optical isomer thereof, U, V, W, and Z are each independently CH, COH, N, or N + -O - is selected from the group consisting of at least three of U, V, W, and Z are CH; Provided herein are compounds of formula (1), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or optical isomer thereof:

[0060] In some embodiments, R 4 is H, OH, F, or R 5 It forms a CH2 bridge by binding to

[0061] In some embodiments, R 5 is H or R 4 It forms a CH2 bridge by binding to

[0062] In some embodiments, A is [ka] selected from the group consisting of: R 9 is C 1-3 Alkyl or C 3-6 It is a cycloalkyl ring.

[0063] In one embodiment, the compound of formula (1): [ka] or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or optical isomer thereof; A is, [ka] selected from the group consisting of: U, V, W, and Z are each independently CH, COH, N, or N + -O - wherein at least three of U, V, W, and Z are CH; X and Y are each, independently of one another, selected from the group consisting of CH, CF, COH, or N; R 1 is H, C optionally substituted with 1 to 3 fluorine atoms 1-3 alkyl or R 2 C optionally substituted with 1 to 3 fluorine atoms by bonding to 3-6 forming a cycloalkyl ring; R 2 is H, C optionally substituted with 1 to 3 fluorine atoms 1-3 alkyl or R 1 C optionally substituted with 1 to 3 fluorine atoms by bonding to 3-6 forming a cycloalkyl ring; R 3 is H, OH, or F; R 4 is H, OH, F, or R 5 to form a CH2 linker; R 5 is H or R 4 It forms a CH2 bridge by binding to R 6 is H, OH, CN, halo, C optionally substituted with 1 to 3 fluorine atoms 1-3 Alkoxy or C optionally substituted with 1 to 3 fluorine atoms 1-3 is alkyl; R 7 is OH, CO2H, CONH2, SO2NH2, or OSO2NH2; R 9 is C 1-3 Alkyl or C 3-6 is a cycloalkyl ring, Provided herein are compounds of formula (1), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or optical isomer thereof:

[0064] In some embodiments, the compound of Formula (1a) or Formula (1b): [ka] or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or optical isomer thereof, U, V, W, X, Y, Z, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 is as defined above, Provided herein are compounds of formula (1b), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or optical isomer thereof:

[0065] In some embodiments, a compound of Formula (2), Formula (2a), or Formula (2b): [ka] or a pharmaceutical salt, solvate, hydrate, or tautomer thereof, A, U, V, W, X, Y, Z, R 1 , R 2 , R 3 , R 4 , R 6 , and R 7 is as defined above, Provided herein are compounds of Formula (2), Formula (2a), or Formula (2b), or pharmaceutical salts, solvates, hydrates, or tautomers thereof.

[0066] In some embodiments, the compound is a compound of formula (2a): [ka] or a pharmaceutically acceptable salt, solvate, hydrate, or tautomer thereof, U, V, W, X, Y, Z, R 1 , R 2 , R 3 , R 4 , R 6 , and R 7 is as defined herein, A compound of formula (2a) or a pharmaceutically acceptable salt, solvate, hydrate, or tautomer thereof:

[0067] In some embodiments, the compound is a compound of formula (2a): [ka] or a pharmaceutically acceptable salt, solvate, hydrate, or tautomer thereof; U, V, W, and Z are each independently CH, COH, N, or N + -O - wherein at least three of U, V, W, and Z are CH; X and Y are each, independently of one another, selected from the group consisting of CH, CF, COH, or N; R 1 is H, C optionally substituted with 1 to 3 fluorine atoms 1-3 alkyl or R 2 C optionally substituted with 1 to 3 fluorine atoms by bonding to 3-6 forming a cycloalkyl ring; R 2 is H, C optionally substituted with 1 to 3 fluorine atoms 1-3 alkyl or R 1 C optionally substituted with 1 to 3 fluorine atoms by bonding to 3-6 forming a cycloalkyl ring; R 3 is H, OH, or F; R 4 is H, OH, F, or R 5to form a CH2 linker; R 6 is H, OH, CN, halo, C optionally substituted with 1 to 3 fluorine atoms 1-3 Alkoxy or C optionally substituted with 1 to 3 fluorine atoms 1-3 is alkyl; R 7 is OH, CO2H, CONH2, SO2NH2, or OSO2NH2, A compound of formula (2a) or a pharmaceutically acceptable salt, solvate, hydrate, or tautomer thereof:

[0068] In some embodiments, R 1 and R 2 are each independently H, C optionally substituted with 1 to 3 fluorine atoms, 1-3 alkyl or R 1 is R 2 C optionally substituted with 1 to 3 fluorine atoms by bonding to 3-6 It forms a cycloalkyl ring.

[0069] In some embodiments, R 1 is H or methyl, or R 2 It is bonded to form a cyclopropane-1,1-diyl ring.

[0070] In some embodiments, a compound of Formula (3), Formula (3a), or Formula (3b): [ka] or a pharmaceutically acceptable salt, solvate, hydrate, or tautomer thereof, A, U, V, W, X, Y, Z, R 3 , R 4 , R 6 , and R 7 is as defined above, Provided herein are compounds of Formula (3), Formula (3a), or Formula (3b), or a pharmaceutically acceptable salt, solvate, hydrate, or tautomer thereof:

[0071] In some embodiments, the compound is a compound of formula (3a): [ka] or a pharmaceutically acceptable salt, solvate, hydrate, or tautomer thereof, U, V, W, X, Y, Z, R 3 , R 4 , R 6 , and R 7 is as defined herein, A compound of formula (3a) or a pharmaceutically acceptable salt, solvate, hydrate, or tautomer thereof:

[0072] In some embodiments, the compound is a compound of formula (3a): [ka] or a pharmaceutically acceptable salt, solvate, hydrate, or tautomer thereof; U, V, W, and Z are each independently CH, COH, N, or N + -O - wherein at least three of U, V, W, and Z are CH; X and Y are each, independently of one another, selected from the group consisting of CH, CF, COH, or N; R 3 is H, OH, or F; R 4 is H, OH, F, or R 5 to form a CH2 linker; R 6 is H, OH, CN, halo, C optionally substituted with 1 to 3 fluorine atoms 1-3 Alkoxy or C optionally substituted with 1 to 3 fluorine atoms 1-3is alkyl; R 7 is OH, CO2H, CONH2, SO2NH2, or OSO2NH2, A compound of formula (3a) or a pharmaceutically acceptable salt, solvate, hydrate, or tautomer thereof:

[0073] In some embodiments, R 3 is H, OH, or F.

[0074] In some embodiments, R 3 is H or OH.

[0075] In some embodiments, R 4 is H, OH, or F.

[0076] In some embodiments, R 6 is H, OH, CN, halo, C optionally substituted with 1 to 3 fluorine atoms 1-3 Alkoxy or C optionally substituted with 1 to 3 fluorine atoms 1-3 It is alkyl.

[0077] In some embodiments, R 6 is H, OH, CN, or methyl.

[0078] In some embodiments, R 6 is OH, CN, or methyl.

[0079] In some embodiments, R 6 is methyl.

[0080] In some embodiments, R 7 is OH, CO2H, CONH2, SO2NH2, or OSO2NH2.

[0081] In some embodiments, R 7 is CO2H, CONH2, SO2NH2, or OSO2NH2.

[0082] In some embodiments, R 7 is CONH2 or SO2NH2.

[0083] In some embodiments, X and Y are each, independently of each other, selected from the group consisting of CH, CF, COH, or N.

[0084] In some embodiments, a compound of Formula (4), Formula (4a), or Formula (4b): [ka] or a pharmaceutically acceptable salt, solvate, hydrate, or tautomer thereof; A, U, V, W, Z, R 3 , R 4 , R 6 , and R 7 is as defined above, Provided herein are compounds of Formula (4), Formula (4a), or Formula (4b), or a pharmaceutically acceptable salt, solvate, hydrate, or tautomer thereof:

[0085] In some embodiments, a compound of Formula (5), Formula (5a), or Formula (5b): [ka] or a pharmaceutically acceptable salt, solvate, hydrate, or tautomer thereof, A, R 8 is H or OH, and R 3 , R 4 , R 6 , and R 7 is as defined above, Provided herein are compounds of Formula (5), Formula (5a), or Formula (5b), or a pharmaceutically acceptable salt, solvate, hydrate, or tautomer thereof.

[0086] In some embodiments, a compound of Formula (6), Formula (6a), or Formula (6b): [ka] or a pharmaceutically acceptable salt, solvate, hydrate, or tautomer thereof; A, R 3 , R 6 , R 7 , and R 8 is as defined above, Provided herein are compounds of Formula (6), Formula (6a), or Formula (6b), or a pharmaceutically acceptable salt, solvate, hydrate, or tautomer thereof.

[0087] In some embodiments, a compound of Formula (7), Formula (7a), or Formula (7b): [ka] or a pharmaceutically acceptable salt, solvate, hydrate, or tautomer thereof, A, U, V, W, X, Y, Z, R 3 , R 6 , and R 7 is as defined above, Provided herein are compounds of Formula (7), Formula (7a), or Formula (7b), or a pharmaceutically acceptable salt, solvate, hydrate, or tautomer thereof.

[0088] In some embodiments, a compound of Formula (8), Formula (8a), or Formula (8b): [ka] or a pharmaceutically acceptable salt, solvate, hydrate, or tautomer thereof, A, U, V, W, X, Y, Z, R 3 , R 4 , R 6 , and R 7 is as defined above, Provided herein are compounds of Formula (8), Formula (8a), or Formula (8b), or a pharmaceutically acceptable salt, solvate, hydrate, or tautomer thereof:

[0089] In some embodiments, a compound of Formula (9), Formula (9a), or Formula (9b): [ka] or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or optical isomer thereof, A, U, V, W, X, Y, Z, R 1 , R 2 , R 3 , R 6 , and R 7 is as defined herein, Provided herein are compounds of Formula (9), Formula (9a), or Formula (9b), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or optical isomer thereof:

[0090] In some embodiments, a compound of Formula (10), Formula (10a), or Formula (10b): [ka] or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or optical isomer thereof; A, U, V, W, X, Y, Z, R 3 , R 6 , and R 7 is as defined herein, Provided herein are compounds of Formula (10), Formula (10a), or Formula (10b), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or optical isomer thereof.

[0091] In some embodiments, the compound is a compound of Formula (1) or Formula (9), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or optical isomer thereof; A is OR', C(O)R', CO2R', C(O)N(R')2, C(O)N(R')S(O)2R', S(O)2R', S(O)2OR', SO2N(R')2, C 1-8 alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; U, V, W, and Z are each independently CH, COH, N, or N + -O - wherein at least three of U, V, W, and Z are CH; X and Y are each, independently of one another, CR″ or N, and at least one of X and Y is CH; R 1 and R 2 are, independently of each other, H, C 1-6 Alkyl, C 1-6 Alkoxy or R 1 and R 2 together with the carbon atoms to which they are attached, form C 3-6 forming a cycloalkane-1,1-diyl ring; Each R 3 are, independently of each other, H, OR', COOR', C(O)R', halo, and C 1-6 alkyl; R 4 is C 1-6 alkyl, halo, CN, NO2, or OR'; R 5 is H or C 1-6 is alkyl; R 6 is H, C 1-6 alkyl, halo, CN, NO2, OR', CO2R', or C(O)R'; R 7 is OR', OC(O)R', OC(O)OR', COR', CON(R')2, SON(R')2, SOR', OSOR', or OSON(R')2; Each R' is independently H, C 1-6 Alkyl or C 3-6 is cycloalkyl; Each R" is H, C 1-6 alkyl, halo, or OR'; n and m are each, independently of one another, 0, 1, 2, or 3; Each occurrence of alkyl, alkylene, and cycloalkyl may optionally, and independently of one another, be selected from the group consisting of up to three OH, SH, CN, NO, COOH, halo, or COOC. 1-4 is substituted with alkyl; Each occurrence of heterocycloalkyl, aryl, and heteroaryl may optionally, and independently of one another, be selected from the group consisting of up to three of OR', SR', CN, NO2, CO2R', halo, C 1-4 substituted with alkyl or oxo; A compound of formula (1) or formula (9), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or optical isomer thereof:

[0092] In some embodiments, the compound is a compound of Formula (1), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or optical isomer thereof; A is COOH; U is CH; V is CH; W is CH, COH, N, or N + -O - and; Z is CH or COH; X is CH; Y is CH or COH; R 1 is H or methyl, and R 2 is H or R 1 is R 2 is bonded to form a cyclopropane-1,1-diyl ring; R 3 is H or OH; R 4 is H or OH, and R 5 is H or R 4 is R 5It forms a CH2 bridge by binding to R 6 is H, OH, CN, or methyl; R 7 is OH, CO2H, CONH2, SO2NH2, or OSO2NH2, A compound of formula (1) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or optical isomer thereof:

[0093] In some embodiments, the compound is a compound of Formula (1) or Formula (9), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or optical isomer thereof; A is COOH; U is CH; V is CH; W is CH, COH, N, or N + -O - and; Z is CH or COH; X is CH; Y is CH or COH; R 1 is H or methyl, and R 2 is H, or R 1 is R 2 is bonded to form a cyclopropane-1,1-diyl ring; R 3 is H or OH; R 4 is H or OH; R 5 is H; R 6 is H, OH, CN, or methyl; R 7 is OH, CO2H, CONH2, SO2NH2, or OSO2NH2, A compound of formula (1) or formula (9), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or optical isomer thereof:

[0094] In some embodiments, A is COH, tetrazole, 1,2,4-oxadiazol-5(2H)-one, 1,3,4-oxadiazol-2(3H)-one, CONHSOR 6 , CONHSO2Me, SO3H, 1,3,4-oxadiazole-2(3H)-thione, 1,2,4-oxadiazole-5(2H)-thione, 1,2,4-thiadiazol-5(2H)-one, 1,2,5-thiadiazolidin-3-one 1,1-dioxide, and 2,4-oxazolidinedione.

[0095] In some embodiments, A is [ka] is selected from.

[0096] In some embodiments, A is selected from CO2H and a tetrazole ring. A can be CO2H. A can be a tetrazole ring.

[0097] In some embodiments, U can be CH. U can be COH. U can be N. U can be N + -O - It could be.

[0098] In some embodiments, U is CH.

[0099] In some embodiments, V can be CH. V can be COH. V can be N. V can be N + -O - It could be.

[0100] In some embodiments, V is CH.

[0101] In some embodiments, W can be CH. W can be COH. W can be N. W can be N + -O - It could be.

[0102] In some embodiments, W is CH, COH, N, or N + -O - is.

[0103] In some embodiments, W is CH or COH.

[0104] In some embodiments, Z can be CH. Z can be COH. Z can be N. Z can be N + -O - It could be.

[0105] In some embodiments, Z is CH or COH.

[0106] In some embodiments, at least three of U, V, W, and Z are CH. U, V, and W can be CH. U, V, and Z can be CH. U, W, and Z can be CH. V, W, and Z can be CH. U, V, W, and Z can be CH. U, V, and Z can be CH and W can be COH.

[0107] In some embodiments, X can be CH. X can be CF. X can be COH. X can be N.

[0108] In some embodiments, Y can be CH. Y can be CF. Y can be COH. Y can be N.

[0109] In some embodiments, Y can be CH or COH.

[0110] In the compounds described herein above, at least one of X and Y is CH. Both X and Y may be CH.

[0111] In some embodiments, X can be CH and Y can be CH or COH.

[0112] In some embodiments, R 1is H or C optionally substituted with 1 to 3 fluorine atoms 1-3 R can be alkyl. 1 can be H. R 1 is C optionally substituted with 1 to 3 fluorine atoms 1-3 R can be alkyl. 1 is C 1-3 R can be alkyl. 1 is R 2 C optionally substituted with 1 to 3 fluorine atoms linked to 3-6 It can form a cycloalkyl ring. R 1 is R 2 Connected to C 3-6 It can form a cycloalkyl ring. R 1 can be H or methyl, or R 2 may be linked to form a cyclopropane ring. 1 R can be methyl optionally substituted with 1 to 3 fluorine atoms. 1 R can be methyl. 1 is R 2 may be linked to form a cyclopropane ring optionally substituted with 1 to 3 fluorine atoms. 1 is R 2 may be linked to form a cyclopropane ring.

[0113] In some embodiments, R 2 can be H. R 2 is C optionally substituted with 1 to 3 fluorine atoms 1-3 R can be alkyl. 2 is C 1-3 R can be alkyl. 2 is R 1 C optionally substituted with 1 to 3 fluorine atoms linked to 3-6 It can form a cycloalkyl ring. R 2 is R 1 Connected to C 3-6 It can form a cycloalkyl ring. R 2 is R 1 may be linked to form a cyclopropane ring optionally substituted with 1 to 3 fluorine atoms.2 is R 1 may be linked to form a cyclopropane ring.

[0114] In some embodiments, R 3 can be H. R 3 can be OH. 3 can be F.

[0115] In some embodiments, R 4 can be H. R 4 can be OH. R 4 can be F. R 4 is R 5 to form a CH2 bridge.

[0116] In some embodiments, R 5 can be H. R 5 is R 4 to form a CH2 bridge.

[0117] In some embodiments, R 6 and R 7 together with the ring to which they are attached can be a group consisting of: [ka]

[0118] In some embodiments, R 6 R can be H, OH, CN, or methyl. 6 can be H. R 6 can be OH. 6 can be CN. R 6 can be a halo. R 6 can be F. R 6 R can be Cl. 6 can be Br. 6 is C optionally substituted with 1 to 3 fluorine atoms 1-3 R can be alkoxy. 6 is C 1-3 R can be alkoxy.6 R can be methoxy optionally substituted with 1 to 3 fluorine atoms. 6 R can be methoxy. 6 is C optionally substituted with 1 to 3 fluorine atoms 1-3 R can be alkyl. 6 is C 1-3 R can be alkyl. 6 can be H or methyl. R 6 R can be methyl optionally substituted with 1 to 3 fluorine atoms. 6 can be methyl.

[0119] In some embodiments, R 7 can be OH. 7 can be CO2H. R 7 can be CONH2. R 7 can be SO2NH2. R 7 can be OSO2NH2.

[0120] In some embodiments, R 8 can be H. R 8 can be OH.

[0121] In some embodiments, R 9 is C 1-3 R can be alkyl. 9 is C 3-6 R may be a cycloalkyl ring. 9 can be methyl.

[0122] In some embodiments, A can be COH; U, V, and Z can be CH; W can be COH; R 1 can be methyl; R 2 can be H; R 6 can be methyl.

[0123] In some embodiments, the compounds or pharmaceutically acceptable salts disclosed herein have EP4 receptor agonist activity.

[0124] In some embodiments, the present invention includes a pharmaceutical composition comprising a compound described herein, a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or optical isomer, and a pharmaceutically acceptable excipient.

[0125] In some embodiments, the pharmaceutical composition further comprises at least one additional therapeutic agent selected from the group consisting of an aminosalicylates, corticosteroids, immunomodulators, and combinations thereof.

[0126] In some embodiments, disclosed herein are methods for treating an EP4 receptor-mediated disease, comprising administering to a patient in need of treatment for an EP4 receptor-mediated disease a compound or pharmaceutically acceptable salt disclosed herein.

[0127] In some embodiments, the method of treating an EP4 receptor-mediated disease is a gastrointestinal disorder.

[0128] In some embodiments, the gastrointestinal disorder is selected from the group consisting of constipation, constipation-predominant irritable bowel syndrome, mixed irritable bowel syndrome, chronic idiopathic constipation, gastrointestinal symptoms associated with Parkinson's disease, gastrointestinal symptoms associated with cystic fibrosis, intestinal motility dysfunction, postoperative ileus, food allergy or intolerance, celiac disease, gastrointestinal motility disorders, functional gastrointestinal disorders, drug-induced enteropathy, NSAID-induced gastrointestinal injury, chemotherapy-induced mucositis, gastroesophageal reflux disease (GERD), duodenogastric reflux, diarrhea, immune-mediated gastrointestinal disorders, Crohn's disease, ulcerative colitis, inflammatory bowel disease and ischemic colitis, or a pulmonary disease or condition such as chronic obstructive pulmonary disease, asthma, chronic bronchitis, cystic fibrosis, emphysema, chronic idiopathic cough, reactive airways disease, and idiopathic pulmonary fibrosis.

[0129] In some embodiments, the compound of Formula I or Formula (1) is a compound listed in Table 1, or a pharmaceutically acceptable salt, solvate, hydrate, or tautomer thereof.

[0130] In some embodiments, the compound of Formula I or Formula (1) is a compound listed in Table 1, or a pharmaceutically acceptable salt thereof. [Table 1-1] [Table 1-2] [Table 1-3] Abbreviation aq aqueous solution Bn Benzyl DCM dichloromethane DMA Dimethylacetamide DMF Dimethylformamide dppf 1,1'-bis(diphenylphosphino)ferrocene EDCI 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide FA formic acid EtOAc ethyl acetate HATU 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate HOBt Hydroxybenzotriazole HPLC High-Performance Liquid Chromatography hr time hrs time LC / MS Liquid Chromatography Mass Spectrometry M molar concentration MeCN acetonitrile MeOH Methanol N specified concentration Prep HPLC Preparative High Performance Liquid Chromatography RT room temperature sat saturation THF tetrahydrofuran UPLC Ultra High Performance Liquid Chromatography

[0131] definition For the purposes of this application, the following definitions apply unless otherwise indicated.

[0132] Formula I, Formula IIa, Formula IIb, Formula IIc, Formula IId, Formula IIe, Formula (1), Formula (1a), Formula (1b), Formula (2), Formula (2a), Formula (2b), Formula (3), Formula (3a), Formula (3b), Formula (4) , Equation (4a), Equation (4b), Equation (5), Equation (5a), Equation (5b), Equation (6), Equation (6a), Equation (6b), Equation (7), Equation (7a), Equation (7b), Equation (8), Equation (8a), Equation (8b), Equation ( The term "treatment" in connection with the use of any of the compounds described herein, including compounds of Formula 9, Formula 9a, Formula 9b, Formula 10, Formula 10a, and Formula 10b, is used to describe any form of intervention in which a compound is administered to a subject suffering from, at risk of, or potentially at risk of suffering from the disease or disorder in question. That is, the term "treatment" encompasses both prophylactic treatment and treatment when measurable or detectable symptoms of the disease or condition are present.

[0133] The term "therapeutically effective amount" (e.g., in connection with a method of treating a disease or condition) refers to an amount of a compound effective to produce a desired therapeutic effect. For example, if the condition is pain, a therapeutically effective amount is an amount sufficient to provide a desired level of analgesia. The desired level of analgesia can be, for example, complete elimination of pain or a reduction in the severity of pain.

[0134] As used herein, the term "hydroxyl" or "hydroxy" refers to an --OH moiety.

[0135] As used herein, 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. The alkyl group can be straight-chained 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. Alkyl groups include halo, phospho, cycloaliphatic [e.g., cycloalkyl or cycloalkenyl], heterocycloaliphatic [e.g., heterocycloalkyl or heterocycloalkenyl], aryl, heteroaryl, alkoxy, aroyl, heteroaroyl, acyl [e.g., (aliphatic)carbonyl, (cycloaliphatic)carbonyl, or (heterocycloaliphatic)carbonyl], nitro, cyano, amido [e.g., (cycloalkylalkyl)carbonylamino, arylcarbonylamino, aralkylcarbonylamino, (heterocycloalkyl)carbonylamino, (heterocycloalkylalkyl)carbonylamino, heteroarylcarbonylamino, heteroaralkylcarbonylamino], and the like. It may be substituted (i.e., optionally substituted) with one or more substituents such as alkylaminocarbonyl, cycloalkylaminocarbonyl, heterocycloalkylaminocarbonyl, arylaminocarbonyl, or heteroarylaminocarbonyl], amino [e.g., aliphatic amino, cycloaliphatic amino, or heterocycloaliphatic amino], sulfonyl [e.g., aliphatic -SO2-], sulfinyl, sulfanyl, sulfoxy, urea, thiourea, sulfamoyl, sulfamido, oxo, carboxy, carbamoyl, cycloaliphaticoxy, heterocycloaliphaticoxy, aryloxy, heteroaryloxy, aralkyloxy, heteroarylalkoxy, alkoxycarbonyl, alkylcarbonyloxy, or hydroxy.Some examples of substituted alkyl include, but are not limited to, carboxyalkyl (such as HOOC-alkyl, alkoxycarbonylalkyl, and alkylcarbonyloxyalkyl), cyanoalkyl, hydroxyalkyl, alkoxyalkyl, acylalkyl, aralkyl, (alkoxyaryl)alkyl, (sulfonylamino)alkyl (such as (alkyl-SO2-amino)alkyl), aminoalkyl, amidoalkyl, (cycloaliphatic)alkyl, or haloalkyl.

[0136] As used herein, an "alkylene" group refers to a divalent branched or straight-chain alkyl group containing 2 to 12 (e.g., 2 to 8, 2 to 6, or 2 to 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). Alkylene groups can be substituted (i.e., optionally substituted) with one or more substituents as defined for alkyl groups.

[0137] As used herein, "amide" encompasses both "aminocarbonyl" and "carbonylamino." These terms, when used alone or in conjunction with another group, include -N(R X )-C(O)-R Y or -C(O)-N(R X )2, and -C(O)-N(R when used internally X )- or -N(R X )-C(O)-, and R X and R Ycan be aliphatic, cycloaliphatic, aryl, araliphatic, heterocycloaliphatic, heteroaryl, or heteroaraliphatic. Examples of amido groups include alkylamido (such as alkylcarbonylamino or alkylaminocarbonyl), (heterocycloaliphatic)amido, (heteroaralkyl)amido, (heteroaryl)amido, (heterocycloalkyl)alkylamido, arylamido, aralkylamido, (cycloalkyl)alkylamido, or cycloalkylamido.

[0138] As used herein, an "amino" group is -NR X R Y In the formula, R X and R Y and each independently represent hydrogen, aliphatic, cycloaliphatic, (cycloaliphatic)aliphatic, aryl, araliphatic, heterocycloaliphatic, (heterocycloaliphatic)aliphatic, heteroaryl, carboxy, sulfanyl, sulfinyl, sulfonyl, (aliphatic)carbonyl, (cycloaliphatic)carbonyl, ((cycloaliphatic)aliphatic)carbonyl, arylcarbonyl, (araliphatic)carbonyl, (heterocycloaliphatic)carbonyl, ((heterocycloaliphatic)aliphatic)carbonyl, (heteroaryl)carbonyl, or (heteroaraliphatic)carbonyl, each of which is defined herein and optionally substituted. Examples of amino groups include alkylamino, dialkylamino, or arylamino. The term "amino" when not a terminal group (e.g., alkylcarbonylamino) does not include -NR X -, where R X has the same meaning as defined above.

[0139] As used herein, the term "aryl," 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, where the monocyclic ring system is aromatic or at least one ring in a bicyclic or tricyclic ring system is aromatic. Bicyclic and tricyclic groups encompass benzo-fused 2- to 3-membered carbocyclic rings. For example, benzo-fused groups include groups having two or more C 4-8 and phenyl fused to a carbocyclic moiety. Aryl is optionally aliphatic (e.g., alkyl, alkenyl, or alkynyl); cycloaliphatic; (cycloaliphatic)aliphatic; heterocycloaliphatic; (heterocycloaliphatic)aliphatic; aryl; heteroaryl; alkoxy; (cycloaliphatic)oxy; (heterocycloaliphatic)oxy; aryloxy; heteroaryloxy; (araliphatic)oxy; (heteroaraliphatic)oxy; aroyl; heteroaroyl; amino; oxo (on the non-aromatic carbocyclic ring of a benzo-fused bicyclic or tricyclic aryl); nitro; carboxy; amido; acyl (e.g., (aliphatic)carbonyl; (cycloaliphatic)oxy; The aryl may be substituted with one or more substituents, including (aliphatic)carbonyl; ((cycloaliphatic)aliphatic)carbonyl; (araliphatic)carbonyl; (heterocycloaliphatic)carbonyl; ((heterocycloaliphatic)aliphatic)carbonyl; or (heteroaraliphatic)carbonyl]; sulfonyl [e.g., aliphatic -SO2- or amino-SO2-]; sulfinyl [e.g., aliphatic -S(O)- or cycloaliphatic -S(O)-]; sulfanyl [e.g., aliphatic -S-]; cyano; halo; hydroxy; mercapto; sulfoxy; urea; thiourea; sulfamoyl; sulfamido; or carbamoyl. Alternatively, the aryl may be unsubstituted.

[0140] Non-limiting examples of substituted aryls include haloaryls [e.g., mono-, di-(p,m-dihaloaryls, etc.), and (trihalo)aryls]; (carboxy)aryls [e.g., (alkoxycarbonyl)aryls, ((aralkyl)carbonyloxy)aryls, and (alkoxycarbonyl)aryls]; (amido)aryls [e.g., (aminocarbonyl)aryls, (((alkylamino)alkyl)aminocarbonyl)aryls, (alkylcarbonyl)aminoaryls, (arylaminocarbonyl)aryls, and (((heteroaryl)amino)carbonyl)aryls]; aminoaryls [e.g., ((alkylsulfonyl)amino)aryls, or ((dialkyl)amino)aryls]; (cyanoalkyl)aryls; (alkoxy)aryls; (sulfamoyl)aryls [e.g., (aminosulfonyl)amino (m-(heterocycloaliphatic)-o-(alkyl)aryl; (((m-(m-alkoxy)aryl); (hydroxy)aryl, ((carboxy)alkyl)aryl; (((dialkyl)amino)alkyl)aryl; (nitroalkyl)aryl; (((alkylsulfonyl)amino)alkyl)aryl; ((heterocycloaliphatic)carbonyl)aryl; ((alkylsulfonyl)alkyl)aryl; (cyanoalkyl)aryl; (hydroxyalkyl)aryl; (alkylcarbonyl)aryl; alkylaryl; (trihaloalkyl)aryl; p-amino-m-alkoxycarbonylaryl; p-amino-m-cyanoaryl; p-halo-m-aminoaryl; or (m-(heterocycloaliphatic)-o-(alkyl))aryl.

[0141] As used herein, a "cycloalkyl" group refers to a saturated carbocyclic monocyclic or bicyclic (fused or bridged) 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, octahydro-indenyl, decahydro-naphthyl, 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.

[0142] Cycloalkyl groups are optionally selected from the group consisting of phospho, aliphatic [e.g., alkyl, alkenyl, or alkynyl], cycloaliphatic, (cycloaliphatic)aliphatic, heterocycloaliphatic, (heterocycloaliphatic)aliphatic, aryl, heteroaryl, alkoxy, (cycloaliphatic)oxy, (heterocycloaliphatic)oxy, aryloxy, heteroaryloxy, (araliphatic)oxy, (heteroaraliphatic)oxy, aroyl, heteroaroyl, amino, amido [e.g., (aliphatic)carbonylamino, (cycloaliphatic)carbonylamino, ((cycloaliphatic)aliphatic)carbonylamino, (aryl)carbonylamino, (araliphatic)carbonylamino, (heterocycloaliphatic)carbonylamino, ((heterocycloaliphatic)aliphatic)carbonylamino, (heteroaryl)carbonylamino, and (heteroaraliphatic)carbonylamino, or (heteroaraliphatic)carbonylamino], nitro, carboxy [e.g., HOOC-, alkoxycarbonyl, or alkylcarbonyloxy], acyl [e.g., (cycloaliphatic)carbonyl, ((cycloaliphatic)aliphatic)carbonyl, (araliphatic)carbonyl, (heterocycloaliphatic)carbonyl, ((heterocycloaliphatic)aliphatic)carbonyl, or (heteroaraliphatic)carbonyl], cyano, halo, hydroxy, mercapto, sulfonyl [e.g., alkyl-SO2- and aryl-SO2-], sulfinyl [e.g., alkyl-S(O)-], sulfanyl [e.g., alkyl-S-], sulfoxy, urea, thiourea, sulfamoyl, sulfamido, oxo, or carbamoyl.

[0143] As used herein, a "heterocycloalkyl" group refers to a 3- to 10-membered monocyclic or bicyclic (fused or bridged) (e.g., 5- to 10-membered monocyclic or bicyclic) saturated ring structure in which one or more of the ring atoms is a heteroatom (e.g., N, O, S, or combinations thereof). Examples of heterocycloalkyl groups include piperidyl, piperazyl, tetrahydropyranyl, tetrahydrofuryl, 1,4-dioxolanyl, 1,4-dithianyl, 1,3-dioxolanyl, oxazolidyl, isoxazolidyl, morpholinyl, thiomorpholyl, octahydrobenzofuryl, octahydrochromenyl, octahydrothiochromenyl, octahydroindolyl, octahydropyrindinyl, decahydroquinolinyl, octahydrobenzo[b]thiophenyl, 2-oxa-bicyclo[2.2.2]octyl, 1-aza-bicyclo[2.2.2]octyl, 3-aza-bicyclo[3.2.1]octyl, and 2,6-dioxa-tricyclo[3.3.1.0]octyl. 3,7 Monocyclic heterocycloalkyl groups can be fused with a phenyl moiety to form structures such as tetrahydroisoquinoline, which would be classified as heteroaryl.

[0144] Heterocycloalkyl groups are optionally selected from the group consisting of phospho, aliphatic [e.g., alkyl, alkenyl, or alkynyl], cycloaliphatic, (cycloaliphatic)aliphatic, heterocycloaliphatic, (heterocycloaliphatic)aliphatic, aryl, heteroaryl, alkoxy, (cycloaliphatic)oxy, (heterocycloaliphatic)oxy, aryloxy, heteroaryloxy, (araliphatic)oxy, (heteroaraliphatic)oxy, aroyl, heteroaroyl, amino, amido [e.g., (aliphatic)carbonylamino, (cycloaliphatic)carbonylamino, ((cycloaliphatic)aliphatic)carbonylamino, (aryl)carbonylamino, (araliphatic)carbonylamino, (heterocycloaliphatic)carbonylamino, ((heterocycloaliphatic)aliphatic)carbonylamino, (heteroaryl)carbonyl], and the like. and (heteroaraliphatic)amino, or (heteroaraliphatic)carbonylamino], nitro, carboxy [e.g., HOOC-, alkoxycarbonyl, or alkylcarbonyloxy], acyl [e.g., (cycloaliphatic)carbonyl, ((cycloaliphatic)aliphatic)carbonyl, (araliphatic)carbonyl, (heterocycloaliphatic)carbonyl, ((heterocycloaliphatic)aliphatic)carbonyl, or (heteroaraliphatic)carbonyl], nitro, cyano, halo, hydroxy, mercapto, sulfonyl [e.g., alkylsulfonyl or arylsulfonyl], sulfinyl [e.g., alkylsulfinyl], sulfanyl [e.g., alkylsulfanyl], sulfoxy, urea, thiourea, sulfamoyl, sulfamido, oxo, or carbamoyl.

[0145] A "heteroaryl" group, as used herein, refers to a monocyclic, bicyclic, or tricyclic ring system having 4 to 15 ring atoms, wherein one or more of the ring atoms is a heteroatom (e.g., N, O, S, or a combination thereof), and wherein the monocyclic ring system is aromatic, or at least one of the rings in the bicyclic or tricyclic ring system is aromatic.

[0146] Heteroaryl groups include benzo-fused ring systems having 2 to 3 rings. For example, a benzo-fused group includes benzo fused to one or two 4- to 8-membered heterocycloaliphatic moieties (e.g., indolyl, indolyl, isoindolyl, 3H-indolyl, indolinyl, benzo[b]furyl, benzo[b]thiophen-yl, quinolinyl, or isoquinolinyl). Some examples of heteroaryl are azetidinyl, pyridyl, 1H-indazolyl, furyl, pyrrolyl, thienyl, thiazolyl, oxazolyl, imidazolyl, tetrazolyl, benzofuryl, isoquinolinyl, benzthiazolyl, xanthene, thioxanthene, phenothiazine, dihydroindole, benzo[1,3]dioxole, benzo[b]furyl, benzo[b]thiophenyl, indazolyl, benzimidazolyl, benzthiazolyl, puryl, cinnolyl, quinolyl, quinazolyl, cinnolyl, phthalazyl, quinazolyl, quinoxalyl, isoquinolyl, 4H-quinolidyl, benzo-1,2,5-thiadiazolyl, or 1,8-naphthyridyl.

[0147] Heteroaryl groups include N-oxide heteroaryl compounds, such as pyridine, pyrimidine, pyrazine, pyrrole, imidazole, thiazole, quinoline, or isoquinoline, in which oxidation occurs at the nitrogen atom. Examples of N-oxide heteroaryls include those of the formula C5H5N - →O + There are pyridine-N-oxides having the formula:

[0148] Monocyclic heteroaryls include, but are not limited to, furyl, thiophen-yl, 2H-pyrrolyl, pyrrolyl, oxazolyl, thazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, 1,3,4-thiadiazolyl, 2H-pyranyl, 4H-pranyl, pyridyl, pyridazyl, pyrimidyl, pyrazolyl, pyrazyl, or 1,3,5-triazyl. Monocyclic heteroaryls are numbered according to standard compound nomenclature.

[0149] Bicyclic heteroaryls include, but are not limited to, indolyl, indolyl, isoindolyl, 3H-indolyl, indolinyl, benzo[b]furyl, benzo[b]thiophenyl, quinolinyl, isoquinolinyl, indolyl, isoindolyl, indolyl, benzo[b]furyl, benzo[b]thiophenyl, indazolyl, benzimidazyl, benzthiazolyl, purinyl, 4H-quinolizyl, quinolyl, isoquinolyl, cinnolyl, phthalazyl, quinazolyl, quinoxalyl, 1,8-naphthyridyl, or pteridyl. Bicyclic heteroaryls are numbered according to standard compound nomenclature.

[0150] Heteroaryl is optionally aliphatic [e.g., alkyl, alkenyl, or alkynyl]; cycloaliphatic; (cycloaliphatic)aliphatic; heterocycloaliphatic; (heterocycloaliphatic)aliphatic; aryl; heteroaryl; alkoxy; (cycloaliphatic)oxy; (heterocycloaliphatic)oxy; aryloxy; heteroaryloxy; (araliphatic)oxy; (heteroaraliphatic)oxy; aroyl; heteroaroyl; amino; oxo (on a non-aromatic carbocyclic or heterocyclic ring of a bicyclic or tricyclic heteroaryl); carboxy; amido; acyl [e.g., aliphatic carbonyl; Heteroaryl may be substituted with one or more substituents such as (cycloaliphatic)carbonyl; ((cycloaliphatic)aliphatic)carbonyl; (araliphatic)carbonyl; (heterocycloaliphatic)carbonyl; ((heterocycloaliphatic)aliphatic)carbonyl; or (heteroaraliphatic)carbonyl]; sulfonyl [e.g., aliphatic sulfonyl or aminosulfonyl]; sulfinyl [e.g., aliphatic sulfinyl]; sulfanyl [e.g., aliphatic sulfanyl]; nitro; cyano; halo; hydroxy; mercapto; sulfoxy; urea; thiourea; sulfamoyl; sulfamido; or carbamoyl. Alternatively, the heteroaryl may be unsubstituted.

[0151] Non-limiting examples of substituted heteroaryls include (halo)heteroaryls [e.g., mono- and di-(halo)heteroaryls]; (carboxy)heteroaryls [e.g., (alkoxycarbonyl)heteroaryls]; cyanoheteroaryls; aminoheteroaryls [e.g., ((alkylsulfonyl)amino)heteroaryls and ((dialkyl)amino)heteroaryls]; (amido)heteroaryls [e.g., aminocarbonylheteroaryls, ((alkylcarbonyl)amino)heteroaryls, ((((alkyl)amino)alkyl)aminocarbonyl)heteroaryls, (((heteroaryl)amino)carbonyl)heteroaryls, ((heterocycloaliphatic)carbonyl)heteroaryls, and ((alkylcarbonyl)amino)heteroaryls]; (cyanoalkyl)heteroaryls; (alkoxy)heteroaryls; (sulfamoyl)heteroaryls. (aminosulfonyl)heteroaryl; (sulfonyl)heteroaryl [e.g., (alkylsulfonyl)heteroaryl]; (hydroxyalkyl)heteroaryl; (alkoxyalkyl)heteroaryl; (hydroxy)heteroaryl; ((carboxy)alkyl)heteroaryl; (((dialkyl)amino)alkyl]heteroaryl; (heterocycloaliphatic)heteroaryl; (cycloaliphatic)heteroaryl; (nitroalkyl)heteroaryl; (((alkylsulfonyl)amino)alkyl)heteroaryl; ((alkylsulfonyl)alkyl)heteroaryl; (cyanoalkyl)heteroaryl; (acyl)heteroaryl [e.g., (alkylcarbonyl)heteroaryl]; (alkyl)heteroaryl; or (haloalkyl)heteroaryl [e.g., trihaloalkylheteroaryl].

[0152] As used herein, an "alkoxy" group refers to an alkyl-O- group, where "alkyl" is defined above.

[0153] As used herein, a "carboxy" group refers to a -COOH, -COOR group when used as a terminal group. X , -OC(O)H, -OC(O)R Xor, when used as an internal group, refers to -OC(O)- or -C(O)O-.

[0154] As used herein, a "mercapto" group refers to -SH.

[0155] As used herein, a "sulfo" group refers to -SO3H or -SO3R when used terminally. X , or -S(O)3- when used internally.

[0156] As used herein, a "sulfamido" group refers to a group having the structure -NR when used terminally. X -S(O)2-NR Y R Z , and -NR when used internally X -S(O)2-NR Y - refers to R X , R Y , and R Z is defined above.

[0157] As used herein, a "sulfamoyl" group refers to a group having the structure -OS(O)2-NR Y R Z refers to R Y and R Z is defined above.

[0158] As used herein, a "sulfonamide" group refers to a group having the structure -S(O)-NR when used terminally. x R y or -NR x -S(O)2-R z or -S(O)2-NR when used internally x -or-NR x -S(O)2-, R x , R y , and R Z is defined above.

[0159] As used herein, a "sulfanyl" group refers to a group such as -SR when used terminally. X , and when used internally refers to -S-, R X is defined above. Examples of sulfanyl include aliphatic-S-, cycloaliphatic-S-, aryl-S-, or the like.

[0160] As used herein, a "halogen" or "halo" group refers to fluorine, chlorine, bromine, or iodine.

[0161] As used herein, "oxo" refers to =O.

[0162] As used herein, the term "vicinal" generally refers to the positioning of substituents on a group that includes two or more carbon atoms, the substituents being attached to adjacent carbon atoms.

[0163] As used herein, the term "geminal" generally refers to the placement on a group that includes two or more carbon atoms of substituents that are attached to the same carbon atom.

[0164] The terms "terminally" and "internally" refer to the location of a group within a substituent. A group is terminal if it is at the end of the substituent and is not further attached to the rest of the chemical structure. Carboxyalkyl, i.e., R X O(O)C-alkyl is an example of a carboxy group used terminally. When a group is present in the middle of a substituent in a chemical structure, the group is internal. Alkylcarboxy (e.g., alkyl-C(O)O- or alkyl-OC(O)-) and alkylcarboxyaryl (e.g., alkyl-C(O)O-aryl- or alkyl-O(CO)-aryl-) are examples of carboxy groups used internally.

[0165] As used herein, "aliphatic chain" refers to a branched or straight-chain aliphatic group (e.g., an alkyl group, an alkenyl group, or an alkynyl group). A straight-chain aliphatic chain is a group having a structure similar to -[CH2]v -structure, and v is 1 to 12. A branched aliphatic chain is a linear aliphatic chain substituted with one or more aliphatic groups. A branched aliphatic chain has a -[CQQ] v - structure, and each Q is, independently, hydrogen or an aliphatic group, provided that at least one Q is an aliphatic group. The term aliphatic chain encompasses alkyl chains, alkenyl chains, and alkynyl chains, where alkyl, alkenyl, and alkynyl are defined above.

[0166] The phrase "optionally substituted" is used interchangeably herein with the phrase "substituted or unsubstituted." As described herein, the compounds of the invention can be optionally substituted with one or more substituents, as exemplified by the general formulas above or by the specific classes, subclasses, and species of the invention. Unless otherwise specified, each of the specific groups of variables described herein can be optionally substituted with one or more substituents described herein. Each substituent of a specific group can be optionally further substituted with one to three of halo, cyano, oxo, alkoxy, hydroxy, amino, nitro, aryl, cycloaliphatic, heterocycloaliphatic, heteroaryl, haloalkyl, and alkyl. For example, an alkyl group can be substituted with alkylsulfanyl, which can be optionally substituted with one to three of halo, cyano, oxo, alkoxy, hydroxy, amino, nitro, aryl, haloalkyl, and alkyl. As an additional example, the cycloalkyl portion of a (cycloalkyl)carbonylamino can be optionally substituted with one to three of halo, cyano, alkoxy, hydroxy, nitro, haloalkyl, and alkyl. When two alkoxy groups are bound to the same atom or adjacent atoms, the two alkoxy groups can be combined with the atoms to which they are bound to form a ring.

[0167] As used herein, the term "substituted," whether preceded by the term "optionally," generally refers to the replacement of a hydrogen atom in a given structure with the radical of a specified substituent. Specific substituents are described above in the definitions and in the description of compounds and examples below. Unless otherwise specified, an optionally substituted group may have a substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, those substituents may be the same or different at each position. A ring substituent, such as a heterocycloalkyl, can be attached to another ring, such as a cycloalkyl, to form a spiro-bicyclic ring system (e.g., both rings share one common atom). As one of skill in the art will recognize, combinations of substituents envisioned by this invention are those that result in the formation of stable or chemically feasible compounds.

[0168] As used herein, the phrase "stable or chemically feasible" refers to a compound that does not change substantially when subjected to conditions that allow for its production, detection, and preferably recovery, purification, and use for one or more purposes disclosed herein. In some embodiments, a stable compound or a chemically feasible compound is one that does not change substantially when kept at a temperature of 40° C. or below, in the absence of moisture, or other chemically reactive conditions, for at least one week.

[0169] If any of the compounds described have a chiral center, the present invention extends to all optical isomers of such compounds, whether in the form of a racemate or separated enantiomers. The invention described herein relates to all crystalline forms, solvates, and hydrates of any of the disclosed compounds, however prepared. If any of the compounds disclosed herein have an acid or basic center, such as a carboxylic acid or amino group, all salt forms of said compounds are included in the present invention. For pharmaceutical use, the salts should be considered to be pharmaceutically acceptable salts.

[0170] The salts or pharmaceutically acceptable salts that may be mentioned include acid addition salts and base addition salts.Such salts can be formed by conventional means, for example, by reacting the free acid or free base form of the compound with one or more equivalents of a suitable acid or base, optionally in a solvent or in a medium in which the salt is insoluble, followed by removing the solvent or medium using standard techniques (for example, in vacuo, lyophilization, or filtration).Salts can also be prepared by exchanging the counterion of the compound in the form of a salt with another counterion, for example, using a suitable ion exchange resin.

[0171] Examples of pharmaceutically acceptable salts include acid addition salts derived from mineral and organic acids, as well as salts derived from metals such as sodium, magnesium, potassium, and calcium.

[0172] Examples of acid addition salts include acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, arylsulfonic acids (e.g., benzenesulfonic acid, naphthalene-2-sulfonic acid, naphthalene-1,5-disulfonic acid, and p-toluenesulfonic acid), ascorbic acid (e.g., L-ascorbic acid), L-aspartic acid, benzoic acid, 4-acetamidobenzoic acid, butanoic acid, (+) camphoric acid, camphorsulfonic acid, (+)-(1S)-camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, gluconic acid (e.g., D-gluconic acid), glucuronic acid (e.g., D-glucuronic acid), glutamic acid (e.g., L-glutamic acid), α-oxoglutaric acid, glycolic acid, hippuric acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, isethionic acid, lactic acid (e.g., (+)-L-lactic acid and (±)-DL-lactic acid), lactobionic acid, maleic acid, malic acid (e.g., (-)-L-malic acid), malonic acid, (±)-DL-mandelic acid, metaphosphoric acid, methanesulfonic acid, 1- Included are acid addition salts formed with hydroxy-2-naphthoic acid, nicotinic acid, nitric acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid, propionic acid, L-pyroglutamic acid, salicylic acid, 4-amino-salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, tannic acid, tartaric acid (e.g., (+)-L-tartaric acid), thiocyanic acid, undecylenic acid, and valeric acid.

[0173] Also included are any solvates of the compounds and their salts. Preferred solvates are those formed by incorporating molecules of a non-toxic, pharmaceutically acceptable solvent (hereinafter referred to as the solvating solvent) into the solid structure (e.g., crystalline structure) of the compounds of the present 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 present invention with a solvent or a mixture of solvents containing the solvating solvent. Whether a solvate has formed in any given case can be determined by analyzing the crystals of the compound using well-known standard techniques, such as thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), and X-ray crystallography.

[0174] Solvate can be stoichiometric or non-stoichiometric solvate.Particular solvate can be hydrate, and examples of hydrate include hemihydrate, monohydrate and dihydrate.For more detailed discussion of solvate and the methods used to prepare and characterize solvate, see Bryn et al., Solid-State Chemistry of Drugs, Second Edition, Publisher SSCI, Inc. (West Lafayette, Indiana, USA), 1999, ISBN0-967-06710-3.

[0175] In the context of the present invention, the term "pharmaceutical composition" refers to a composition containing an active agent and further containing one or more pharmaceutically acceptable carriers or excipients. Depending on the mode of administration and the nature of the dosage form, the composition may further contain components selected from, for example, diluents, adjuvants, excipients, vehicles, preservatives, fillers, disintegrants, wetting agents, emulsifiers, suspending agents, sweeteners, flavorings, fragrances, antibacterial agents, antifungal agents, lubricants, and dispersing agents. The composition may take the form of, for example, tablets, dragees, powders, elixirs, syrups, liquid preparations including suspensions, sprays, inhalants, tablets, confectionery tablets, emulsions, solutions, cachets, granules, capsules, and suppositories, as well as injectable liquid preparations including liposomal preparations.

[0176] 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: 1 H, 2 H(D), and 3 Similarly, references to carbon and oxygen include within their scope: 12 C. 13 C, and 14 C and 16 O and 18 and O, respectively. Similarly, reference to a particular functional group also includes within its scope isotopic variations unless the context indicates otherwise. For example, reference to an alkyl group such as an ethyl group or an alkoxy group such as a methoxy group also includes variations in which one or more of the group's hydrogen atoms are in the form of a deuterium or tritium isotope, such as, for example, an ethyl group in which all five hydrogen atoms are in the deuterium isotope form (a perdeuteroethyl group), or a methoxy group in which all three hydrogen atoms are in the deuterium isotope form (a trideuteromethoxy group). Isotopes may be radioactive or non-radioactive.

[0177] Therapeutic dosage can vary depending on the patient's requirements, the severity of the condition being treated, and the compound being used.Determining the dosage that is appropriate for a particular situation is within the skill of a person skilled in the art.Generally, treatment is initiated with a smaller dosage that is less than the appropriate amount of the compound.Then, the dosage is gradually increased until the optimal effect under the situation is reached.For convenience, optionally, the total daily dosage can be divided and administered in portions throughout the day.

[0178] The magnitude of an effective amount of a compound will, of course, vary depending on the nature and severity of the condition being treated, as well as the particular compound and its route of administration. Selecting an appropriate dose is within the ability of one skilled in the art and does not pose an undue burden. Typically, the daily dose ranges from about 10 μg to about 30 mg per kg of body weight for humans and non-human animals, preferably about 50 μg to about 30 mg per kg of body weight for humans and non-human animals, for example, about 50 μg to about 10 mg per kg of body weight for humans and non-human animals, for example, about 100 μg to about 30 mg per kg of body weight for humans and non-human animals, for example, about 100 μg to about 10 mg per kg of body weight for humans and non-human animals, and most preferably, about 100 μg to about 1 mg per kg of body weight for humans and non-human animals.

[0179] Combination therapy An effective amount can be achieved in a method or pharmaceutical composition of the invention using a compound of the invention (including a pharmaceutically acceptable salt or solvate (e.g., hydrate)) alone or in combination with an additional appropriate therapeutic agent, such as an antiviral agent or a vaccine. When "combination therapy" is used, an effective amount can be achieved using a first amount of a compound of the invention and a second amount of an additional appropriate therapeutic agent.

[0180] In another embodiment of the invention, the 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, the compound of the invention and the additional therapeutic agent are each administered in an amount that would not provide a therapeutic effect alone (a subtherapeutic dose). In yet another embodiment, the 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, the compound of the invention can be administered in a subtherapeutic dose while the additional therapeutic agent, e.g., a suitable cancer therapeutic agent, is administered in an effective amount.

[0181] As used herein, the terms "in combination" or "co-administration" can be used interchangeably to refer to the use of two or more therapies (e.g., one or more prophylactic and / or therapeutic agents). The use of these terms does not restrict the order in which therapies (e.g., prophylactic and / or therapeutic agents) are administered to a subject.

[0182] Simultaneous administration includes essentially simultaneous administration of a first and second amount of the compound, for example, in the form of a single pharmaceutical composition, such as a capsule or tablet, having a fixed ratio of the first and second amounts, or in the form of multiple separate capsules or tablets for each. In addition, such simultaneous administration also includes use of each compound sequentially, in any order.

[0183] In one embodiment, a compound of the invention and an additional therapeutic agent are administered separately, sequentially, or simultaneously to a subject.

[0184] When simultaneous administration involves separate administration of a first amount of a compound of the present invention and a second amount of an additional therapeutic agent, these compounds are administered close enough in time to produce the desired therapeutic effect. For example, the period between each administration that can produce the desired therapeutic effect can range from several minutes to several hours and can be determined by taking into account the properties of each compound, such as potency, solubility, bioavailability, plasma half-life, and kinetic profile. For example, the compound of the present invention and the second therapeutic agent can be administered in any order within 24 hours of each other, within 16 hours of each other, within 8 hours of each other, within 4 hours of each other, within 1 hour of each other, or within 30 minutes of each other.

[0185] More specifically, a first therapy (e.g., a prophylactic or therapeutic agent such as a compound of the invention) can be administered to a subject prior to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks before), concomitantly with, or subsequent to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks after) the administration of a second therapy (e.g., a prophylactic or therapeutic agent such as an anti-cancer agent).

[0186] It is understood that the simultaneous administration of a first amount of a compound of the invention and a second amount of an additional therapeutic agent can result in an enhanced or synergistic therapeutic effect, which combined effect is greater than the additive effect that would result from separate administration of a first amount of a compound of the invention and a second amount of an additional therapeutic agent.

[0187] 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 prophylactic or therapeutic agent) may allow a subject to use lower dosages of one or more of the therapies and / or less frequent administration of the therapies. The availability of lower dosages of a therapy (e.g., a prophylactic or therapeutic agent) and / or less frequent administration of the therapy may reduce the toxicity associated with administering the therapy to a subject without reducing the efficacy of the therapy in preventing, managing, or treating a disorder. In addition, a synergistic effect may improve the efficacy of each agent in preventing, managing, or treating a disorder. And, a synergistic effect of a combination of therapies (e.g., a prophylactic or therapeutic agent) may avoid or reduce adverse or unwanted side effects associated with the use of either therapy alone.

[0188] The presence or absence of synergy can be determined using a suitable method for assessing drug interactions. Suitable methods include, for example, the sigmoid-E 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)). By applying these equations to experimental data, corresponding graphs can be generated to aid in assessing the effectiveness of drug combinations. The corresponding graphs associated with the above equations are the concentration-effect curve, the isobologram curve, and the combination index curve, respectively.

[0189] In one aspect, the present invention provides a pharmaceutical composition comprising a compound of the present invention, a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or optical isomer, a pharmaceutically acceptable excipient, and at least one additional therapeutic agent. In some embodiments, the compound of the present invention, a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or optical isomer, and at least one additional therapeutic agent are formulated together. In some embodiments, the compound of the present invention, a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or optical isomer, and at least one additional therapeutic agent are formulated separately.

[0190] In another aspect, the invention provides a kit comprising a compound of the invention, a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or optical isomer, and at least one additional therapeutic agent. The kit may include instructions for administering the compound of the invention, a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or optical isomer, and at least one additional therapeutic agent to a subject in need thereof.

[0191] In another aspect, the present invention provides a combination therapy for use as a pharmaceutical, comprising administering a compound of the present invention, a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or optical isomer to a subject in need thereof, and administering an additional therapeutic agent to a subject in need thereof.

[0192] The compound of the invention, a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or optical isomer, and the additional therapeutic agent may be administered to a subject separately, sequentially, or simultaneously.

[0193] The pharmaceutical composition, kit, and / or combination therapy may be for use in treating a gastrointestinal disorder or a pulmonary disease or condition. The gastrointestinal disorder may be selected from the group consisting of constipation, constipation-predominant irritable bowel syndrome, mixed irritable bowel syndrome, chronic idiopathic constipation, gastrointestinal symptoms associated with Parkinson's disease, gastrointestinal symptoms associated with cystic fibrosis, intestinal motility dysfunction, postoperative ileus, food allergy or food intolerance, celiac disease, gastrointestinal motility disorder, functional gastrointestinal disorder, drug-induced bowel disease, NSAID-induced gastrointestinal injury, chemotherapy-induced mucositis, gastroesophageal reflux disease (GERD), duodenogastric reflux, diarrhea, immune-mediated gastrointestinal disease, 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 disease, asthma, chronic bronchitis, cystic fibrosis, emphysema, chronic idiopathic cough, reactive airway disease, and idiopathic pulmonary fibrosis.

[0194] The at least one additional therapeutic agent may be selected from the group consisting of an aminosalicylate, a corticosteroid, an immunomodulator, and combinations thereof. An aminosalicylates is also known as 5-aminosalicylate (5-ASA). The at least one additional therapeutic agent may be an aminosalicylate. The aminosalicylate may be mesalamine. The aminosalicylate may be sulfasalazine. The at least one additional therapeutic agent may be a corticosteroid. The corticosteroid may be budesonide. The at least one additional therapeutic agent may be an immunomodulator. The immunomodulator may be a thiopurine. The immunomodulator may be methotrexate.

[0195] Pharmaceutical Composition While it is possible for the active compound to be administered alone, it is preferable to present it as a pharmaceutical composition (eg, a formulation).

[0196] Therefore, in another embodiment of the present invention, there is provided a pharmaceutical composition comprising at least one compound of formula (1) as defined above, together with at least one pharmaceutically acceptable excipient.

[0197] When the pharmaceutical composition includes at least one additional therapeutic agent, the compound of the invention and the at least one additional therapeutic agent can be formulated together, or the compound of the invention and the at least one additional therapeutic agent can be formulated separately.

[0198] The composition may be a tablet composition.

[0199] The composition may be a capsule composition.

[0200] Pharmaceutically acceptable excipients may be selected from, for example, carriers (e.g., solid, liquid, or semi-solid carriers), adjuvants, diluents (e.g., solid diluents such as fillers or bulking agents; and liquid diluents such as solvents and co-solvents), granulating agents, binders, flow aids, coating agents, release-controlling agents (e.g., polymers or waxes that retard or delay release), binding agents, disintegrants, buffers, lubricants, preservatives, antifungal and antibacterial agents, antioxidants, buffers, isotonicity agents, thickeners, flavors, sweeteners, pigments, plasticizers, taste-masking agents, stabilizers, or any other excipient conventionally used in pharmaceutical compositions.

[0201] The term "pharmaceutically acceptable," as used herein, means that the compound, substance, composition, and / or dosage form is, within the scope of sound medical judgment, suitable for use in contact with the tissues of a subject (e.g., a human subject) without excessive toxicity, irritation, allergic response, or other problem or complication commensurate with a reasonable risk / benefit ratio. Each excipient must also be "acceptable" in the sense of being compatible with the other ingredients of the formulation.

[0202] Pharmaceutical compositions containing compounds of formula (1) can be formulated according to known techniques, see, for example, Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pennsylvania, USA.

[0203] The pharmaceutical composition can be in any form suitable for oral, parenteral, topical, intranasal, intrabronchial, sublingual, ophthalmic, otic, rectal, vaginal, or transdermal administration.

[0204] Pharmaceutical dosage forms suitable for oral administration include tablets (coated or uncoated), capsules (hard or soft), caplets, pills, lozenges, syrups, solutions, powders, granules, elixirs and suspensions, sublingual tablets, wafers, or patches such as buccal patches.

[0205] The tablet composition may contain a unit dose of 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 (sodium carbonate, calcium phosphate, calcium carbonate, or cellulose or its derivatives (e.g., microcrystalline cellulose (MCC), methylcellulose, ethylcellulose, hydroxypropylmethylcellulose), and starch (e.g., corn starch). Tablets may also contain standard ingredients such as binders and granulating agents (e.g., polyvinylpyrrolidone), disintegrants (e.g., swellable cross-linked polymers such as cross-linked carboxymethylcellulose), lubricants (e.g., stearates), preservatives (e.g., parabens), antioxidants (e.g., BHT), buffers (e.g., phosphate buffer or citrate buffer), and effervescent agents (e.g., citrate / bicarbonate mixtures). Such excipients are well known and need not be discussed at length herein.

[0206] Tablets may be designed to release the drug upon contact with gastric fluids (immediate-release tablets) or may be designed to release in a controlled manner over an extended period of time or in specific areas of the gastrointestinal tract (controlled-release tablets).

[0207] Pharmaceutical compositions typically contain about 1% (w / w) to about 95% (w / w), preferably 1% (w / w), of the active ingredient and 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 composition contains about 20% (w / w) to about 90% (w / w) of the active ingredient and 80% (w / w) to 10% (w / w) of a pharmaceutically acceptable excipient or combination of excipients. Pharmaceutical compositions contain about 1% to about 95%, preferably about 20% to about 90%, of the active ingredient. Pharmaceutical compositions of the present invention may be, for example, in unit dose form, such as in the form of an ampule, vial, suppository, prefilled syringe, dragee, powder, tablet, or capsule.

[0208] Tablets and capsules may contain, for example, 0-20% disintegrant, 0-5% lubricant, 0-5% flow aid, and / or 0-99% (w / w) filler or bulking agent (depending on drug dose). Tablets and capsules may also contain 0-10% (w / w) polymeric binder, 0-5% (w / w) antioxidant, and 0-5% (w / w) pigment. Sustained-release tablets will also typically contain 0-99% (w / w) release-controlling (e.g., retarding) polymer (depending on dose). Tablet or capsule film coatings typically contain 0-10% (w / w) polymer, 0-3% (w / w) pigment, and / or 0-2% (w / w) plasticizer.

[0209] Parenteral formulations typically contain 0-20% (w / w) buffer, 0-50% (w / w) cosolvent, and / or 0-99% (w / w) water for injection (WFI) (depending on the dose and whether it is lyophilized). Depot intramuscular formulations may also contain 0-99% (w / w) oil.

[0210] Pharmaceutical formulations are sometimes provided to patients in "patient packs", containing the entire course of treatment in one package, usually a blister pack.

[0211] The compounds of Formula (1) will generally be provided in unit dose form and, as such, will typically contain sufficient compound to provide a desired level of biological activity. For example, a formulation may contain 1 nanogram to 2 grams of active ingredient, e.g., 1 nanogram to 2 milligrams of active ingredient. Within these ranges, particular subranges of compound are 0.1 milligram to 2 grams of active ingredient (more usually 10 milligrams to 1 gram, e.g., 50 milligrams to 500 milligrams), or 1 microgram to 20 milligrams (e.g., 1 microgram to 10 milligrams, e.g., 0.1 milligram to 2 milligrams of active ingredient).

[0212] For oral compositions, a unit dose form may contain from 1 milligram to 2 grams, more typically from 10 milligrams to 1 gram, for example, 50 milligrams to 1 gram, for example, 100 milligrams to 1 gram, of active compound.

[0213] The active compound will be administered to a patient (e.g., a human or animal patient) in need thereof in an amount sufficient to achieve the desired therapeutic effect (an effective amount). The exact amount of the compound to be administered can be determined by a supervising physician according to standard procedures.

[0214] Process for preparing compounds of formula (I) General synthetic scheme Scheme 1 [ka] Referring to Scheme 1, compounds of general formula G-5 can be synthesized from proline derivatives of formula G-1a, where PG is a protecting group such as BOC. Coupling of an amine compound of general formula G-2 with G-1a, followed by deprotection of the amine protecting group PG, affords amides of general formula G-3. Common coupling reagents for achieving this transformation are well known to those skilled in the art, such as EDC, DCC, and BOP. Compounds of formula G-3 can be reacted with benzyl compounds of general formula G-4a via SN-2 reaction conditions, where bromide is the leaving group, to yield compounds of general formula G-5, or with aldehyde compounds of general formula G-4b via reductive amination conditions to yield compounds of general formula G-5. Scheme 2 [ka] Referring to Scheme 2, compounds of general formula G-5 can also be prepared from proline derivatives of general formula G-1b, where the carboxylic acid of G-1b is protected by a simple ester such as a methyl ester. Compounds of general formula G-8 can be synthesized by reacting G-1b with benzyl compounds of general formula G-4a via SN-2 conditions, where bromide is the leaving group, or with aldehyde compounds of general formula G-4b via reductive amination conditions. Compounds of general formula G-8 can then be coupled with amine compounds of general formula G-2 using the coupling conditions described above to provide compounds of general formula G-5. Scheme 3 [ka] Referring to Scheme 3, compounds of formula (1) can be synthesized from organoboronic acid compounds of general formula G-6 via palladium-catalyzed coupling conditions using a palladium catalyst selected from those known to those skilled in the art, such as PdCl(dppf)DCM. Compounds of general formula G-6 can be coupled with aryl bromide compounds of general formula G-4a or benzaldehyde compounds of general formula G-4b to produce compounds of general formula G-7a or G-7b, respectively. Benzyl compounds of general formula G-7a, in which the bromide is a leaving group, can be reacted with amine compounds of general formula G-3 via SN-2 reaction conditions to produce compounds of formula (1). Benzaldehyde compounds of general formula G-7b can be reacted with amine compounds of general formula G-3 via reductive amination conditions to produce compounds of formula (1).

[0215] Scheme 4 [ka] Referring to Scheme 4, compounds of general formula G-5 can be coupled with organoboronic acid compounds of general formula G-6 using the palladium-catalyzed coupling chemistry described above to generate compounds of formula (1). It is also well known to those skilled in the art that some compounds of formula (1) are capable of undergoing further derivatization. For example, R 7 Compounds of formula (1) where is OH can be further derivatized by reaction with a suitable electrophile, for example, reaction with sulfamic acid chloride to produce a sulfamoyloxy derivative, reaction with carbamic acid chloride to produce a carbamate derivative, etc.

[0216] Chromatography LC / MS Method A

[0217] Instrument: ACQUITY UPLC equipped with a photodiode array detector and a QDa mass detector; Column: ACQUITY C-18, 1.6 micron, 50x1.6 mm; Gradient [time (min) / % B in solvent 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.

[0218] LC / MS Methods B and C

[0219] Apparatus: HP 1100 with G1315A DAD, Waters Micromass ZQ; Column: Phenomenex Gemini-NX C-18, 3 micron, 2.0 x 30 mm; Gradient for Method B [time (min) / % B in solvent A]: 0.00 / 2, 0.10 / 2, 2.50 / 95, 3.50 / 95; Gradient for Method C [time (min) / % B in solvent A]: 0.00 / 2, 0.01 / 2, 8.40 / 95, 10.00 / 95; Solvents: Solvent A = 2.5 L HO + 2.5 mL 28% ammonia in HO; Solvent B = 2.5 L MeCN + 135 mL HO + 2.5 mL 28% ammonia in HO. Injection volume 1 μL; UV detection 230–400 nm; mass detection 130–800 amu; column temperature 45°C; flow rate 1.5 mL / min.

[0220] LC / MS method D

[0221] Instrumentation: Agilent 1260 Infinity LC with diode array detector, Agilent 6120B Single Quadrupole MS with API-ES source; Column: Restek Penta Fluoro Phenyl Propyl, 3 micron, 2.1 x 30 mm. Gradient [time (min) / % B in Solvent A]: 0.00 / 2, 0.1 / 2, 8.4 / 95, 10 / 95, 10.1 / 2, 12 / 2; Solvents: Solvent A = water (2.5 L) + 2.5 mL formic acid; Solvent B = MeCN (2.5 L) + 125 mL water and 2.5 mL formic acid. Injection volume: 0.5 μL; UV detection: 190-400 nm; Mass detection: 130-800 amu; Column temperature: 40 °C; Flow rate: 1.5 mL / min.

[0222] LC / MS method E

[0223] Instrument: Agilent Technologies 1290 Series equipped with a binary pump, diode array detector, and quadrupole MS G6120A. Column: Agilent Poroshell 120 EC-C18, 2.7 μm, 4.6 × 50 mm. Gradient [time (min) / % B in Solvent A]: 0.00 / 10, 0.50 / 10, 4.00 / 90, 4.50 / 100, 4.51 / 10, 5.00 / 10. Solvents: Solvent A = 0.05% formic acid in water; Solvent B = 0.05% formic acid in acetonitrile. Column temperature: 35 °C. Flow rate: 1.0 mL / min.

[0224] LC / MS method F

[0225] Apparatus: Water 2690 equipped with a photodiode array detector and a QDa mass detector; Column: X-Bridge C-18, 5 micron, 100x1.6 mm; Gradient [time (min) / % B in solvent 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.

[0226] LC / MS method G

[0227] Apparatus: Water 2690 equipped with a 996 photodiode array detector and a Micromass ZQ mass detector; Column: C-18, 3.5 micron, 50x4.6 mm; Gradient [time (min) / % B in solvent A]: 0.00 / 10, 1.00 / 10, 4.00 / 100, 6.00 / 100, 6.50 / 10, 7.00 / 10; Solvents: Solvent A = 10 mM ammonium bicarbonate in water; Solvent B = methanol; Flow rate 1.2 mL / min.

[0228] LC / MS method H

[0229] Apparatus: Agilent 1290 RRLC equipped with Agilent 6120 Mass Detector; Column: X-Bridge C18 50*4.6mm, 3.5μm; Gradient: 95:5 at 0.01 min, 15:85 at 2.8 min, 5:95 at 3.5 min to 5.0 min, 95:5 at 5.01 min to 6.0 min; Solvent: Solvent A = 5mM ammonium bicarbonate in water; Solvent B = acetonitrile; Flow rate 1mL / min.

[0230] LC / MS Method I

[0231] Apparatus: Agilent 1290 RRLC equipped with Agilent 6120 Mass Detector; Column: BEH C18 2.1X50mm, 1.7μm; Gradient: 98:2 from 0.01 to 0.5 min, 30:70 at 3.0 min (flow rate: 0.45ml / min), 5:95 from 4.0 to 5.5 min (flow rate: 0.50ml / min), 98:2 from 5.51 to 6.0 min (flow rate: 0.45ml / min); Solvents: Solvent A = 5mM ammonium acetate + 0.1% FA in water; Solvent B = 0.1% FA in acetonitrile; Flow rate 0.45mL / min.

[0232] LC / MS method J

[0233] Instrument: Waters ACQUITY H-Class LCMS, Mass Lynx software, PDA detector, and QDa mass detector; Column: Gemini-NX C18, 3 μm, 30 x 2 mm; Gradient: [time (min) / %A:%B] 3 min run: [0.00 / 100:0], [1.30 / 0:100], [1.55 / 0:100], [1.60 / 100:0], [3.00 / 100:0]; Solvent: (A): 50 mM ammonium acetate solution at pH 7.40 (B): acetonitrile; Column temperature: 40 °C; Flow rate: 0.5 mL / min; Mass Spectrometric Solvent: 90 v / v% methanol: 0.1% formic acid solution in water; Injection: 1.0 μL; λ range: 200 nm–500 nm.

[0234] LC / MS method K

[0235] Apparatus: Waters ACQUITY H Class with SQ Mass Detector; Column: BEH C18 2.1 x 50 mm, 1.7 μm; Gradient: 95:5 from 0.01 to 0.6 min (flow rate: 0.55 ml / min), 30:70 at 0.6 min (flow rate: 0.60 ml / min), 10:90 at 0.80 min (flow rate: 0.65 ml / min), 0:100 from 1.1 to 1.70 min (flow rate: 0.65 ml / min), 95:5 from 1.71 to 2.0 min (flow rate: 0.55 ml / min); Solvents: Solvent A = 2 mM ammonium acetate + 0.1% FA in water; Solvent B = 0.1% FA in acetonitrile; Flow rate 0.55 ml / min.

[0236] LC / MS method L

[0237] Apparatus: Waters ACQUITY H Class with SQ Mass Detector; Column: BEH C18 2.1X50mm, 1.7μm; Gradient: 98:2 from 0.01 to 0.5 min, 30:70 at 3.0 min (flow rate: 0.45ml / min), 5:95 at 4.0 to 5.5 min (flow rate: 0.50ml / min), 98:2 at 5.51 to 6.0 min (flow rate: 0.45ml / min); Solvents: Solvent A = 5mM ammonium acetate + 0.1% FA in water; Solvent B = 0.1% FA in acetonitrile; Flow rate 0.45mL / min.

[0238] Preparative HPLC purification

[0239] Where stated, intermediates or final compounds were purified by reverse phase preparative HPLC conditions using the equipment and methods shown below:

[0240] HPLC Method A

[0241] Gilson semi-preparative HPLC system equipped with a 321 pump, a 171 diode array detector, and a GX-271 liquid handler, with Gilson Trilution software. Column: Phenomenex Kinetix C18, 100 x 30 mm, 5 μm. Flow rate: 30 mL / min. Gradient of solvent B in solvent A: 5% → 35% solvent B over 10 min, 100% solvent B over 2 min; Solvent A: water containing 0.1% TFA. Solvent B: MeCN].

[0242] HPLC method B

[0243] Gilson semi-preparative HPLC system equipped with a 321 pump, a 171 diode array detector, and a GX-271 liquid handler, with Gilson Trilution software. Column: Gemini-NX C18, 100 × 30 mm, 5 μm. Flow rate: 30 mL / min. Gradient of solvent B in solvent A: 5% → 35% solvent B (over 10 min), 100% solvent B (2 min); Solvent A: water containing 0.2% 28% aqueous ammonia; Solvent B: MeCN.

[0244] HPLC method C

[0245] Gilson semi-preparative HPLC system equipped with dual piston pumps 331 and 332, a 171 diode array detector, and a GX-271 liquid handler, and Gilson Trilution software. Column: Gemini-NX C18, 100 × 30 mm, 5 μm. Flow rate: 30 mL / min. Gradient of solvent B in solvent A: 5% → 35% solvent B (over 10 min), 100% solvent B (2 min); solvent A: water containing 0.2% 28% aqueous ammonia; solvent B: MeCN.

[0246] HPLC method D

[0247] Agilent Preparative 1200 infinity series

[0248] Column: SunFire C18 250x19mm 5µm. Flow rate: 17mL / min. Gradient of solvent B in solvent A: 0.00 / 10, 17.00 / 16, 17.01 / 98, 19.00 / 98, 19.01 / 10, 21 / 10. Solvent A: water containing 0.1% FA, solvent B: MeCN.

[0249] HPLC method E

[0250] Shimadzu preparative HPLC system equipped with an LC-20AP pump, an SPD-20A detector, and Labsolutions (version 5.90) software. Column: Agilent 10, Prep-C18, 250 x 21.2 mm. Solvent / gradient: 10 → 80% acetonitrile / water with 0.1% TFA. Flow rate: 20 mL / min.

[0251] HPLC method F

[0252] The equipment used was a Shimadzu LC-20AP and an ultraviolet absorption detector. The column used was a Sunfire C18 (250 x 19) mm, 5 μm. The column flow rate was 12.0 mL / min. The mobile phases used were (A) 0.1% formic acid / water and (B) 100% acetonitrile. The gradient of solvent B was 0 to 20% over 30 minutes, 100% over 2 minutes, and then 100 to 0% over 5 minutes.

[0253] HPLC method G

[0254] Waters Xbridge C 18 150*50mm*10um; Mobile phase: [Water (10mM NH4HCO3)-ACN]; B%: 33%→63%, min.

[0255] HPLC method H

[0256] Luna C manufactured by Phenomenex 18 150*25mm*10um; Mobile phase: [Water (0.225% FA)-ACN]; B%: 3% → 33%, 10 minutes.

[0257] HPLC Method I

[0258] The Shimadzu LC-20AP and UV detector were used. The column used was a SunFire c18 (250 x 19) mm, 5 micron, with a column flow rate of 14.0 ml / min. The mobile phases were (A) 0.1% formic acid / water and (B) 100% acetonitrile. The gradient of solvent B was 0 to 20% over 23 minutes, followed by 20 to 20% over 2 minutes, 100% over 2 minutes, and then 100 to 0% over 6 minutes. [Example]

[0259] Compounds of formula (1) can be prepared according to synthetic methods known to those skilled in the art. The following examples are provided to facilitate a better understanding of the present invention and are not intended to limit the invention in any way.

[0260] Where preparative routes are not included, relevant intermediates are commercially available. Commercially available reagents were used without further purification. Final compounds and intermediates are named using ChemDraw Professional (version 17.0.0.206(121)). Room temperature (RT) refers to approximately 20-27 °C. 1H NMR spectra were recorded at 400 MHz or 500 MHz on Bruker, Varian, or JEOL instruments. Chemical shift values are expressed in parts per million (ppm), or δ, relative to a deuterated solvent such as chloroform-d (7.26 ppm), DMSO-d (2.50 ppm), or methanol-d (3.31 ppm). The following abbreviations are used for NMR signal multiplicity: s = singlet, br = broad, d = doublet, t = triplet, q = quartet, and m = multiplet. Coupling constants are listed as J values and are measured in Hz. NMR and mass spectrometry results were corrected for background peaks. Chromatography refers to column chromatography performed using 60-120 mesh or 40-633 μm, 60 Å silica gel under nitrogen pressure (flash chromatography) conditions, or automated flash chromatography using a Biotage Isolera instrument. Microwave-mediated reactions were carried out in a Biotage Initiator or CEM Discover microwave reactor.

[0261] Preparation of synthetic intermediates

[0262] Intermediate 1: 4-((S)-1-((R)-pyrrolidine-2-carboxamido)ethyl)benzoate methyl hydrochloride (Intermediate 1-HCl) [ka]

[0263] Step (i): To a mixture of N-Boc-D-proline (2.0 g, 9.29 mmol) in DMF (43.85 mL) was added diisopropylethylamine (4.82 mL, 27.87 mmol), HATU (4.25 g, 11.15 mmol), and methyl 4-[(1S)-1-aminoethyl]benzoate (2.0 g, 11.15 mmol). After stirring at room temperature overnight, the mixture was diluted with EtOAc and water (1:1) and the organic layer was separated. The organic phase was washed with brine (2 x 50 mL), dried (frit), and concentrated under reduced pressure. The residue was purified by flash column chromatography (normal phase, 25 g Biotage® SNAP KP-Sil, 70 mL / min, gradient 0% to 100% ethyl acetate / isohexane) to give tert-butyl (2R)-2-[[(1S)-1-(4-methoxycarbonylphenyl)ethyl]carbamoyl]pyrrolidine-1-carboxylate (3.383 g, 9.0 mmol, 97% yield) as a pale yellow solid. LC / MS (Method B) 2.05 min [M+H] + 377

[0264] Step (ii): To a solution of tert-butyl (2R)-2-[[(1S)-1-(4-methoxycarbonylphenyl)ethyl]carbamoyl]pyrrolidine-1-carboxylate (4.03 g, 10.71 mmol) in 1,4-dioxane (20.2 mL) was added 4 M HCl in 1,4-dioxane (20.2 mL, 10.71 mmol) and allowed to stir at room temperature for 3 hours. After completion, monitored by LC / MS, 1,4-dioxane (20.2 mL) was added to the reaction mixture. The reaction mixture was then concentrated under reduced pressure to give intermediate 1-HCl (3.39 g, 101%) as a white solid. LC / MS (Method B) 1.73 min [M+H] + 277.

[0265] Intermediate 2: 4-((S)-1-((R)-1-(3-bromobenzyl)pyrrolidine-2-carboxamido)ethyl)benzoate methyl ester (Intermediate 2) [ka]

[0266] To a solution of intermediate 1-HCl (1.0 g, 3.2 mmol) in MeCN (96 mL) was added potassium carbonate (1.1 g, 7.99 mmol) and 3-bromobenzyl bromide (1.6 g, 6.39 mmol). The resulting mixture was heated to 70 °C overnight, then filtered through a phase separator, washed with EtOAc, and concentrated under reduced pressure. The residue was dissolved in EtOAc, and the organic phase was washed with water and brine, dried through a hydrophobic frit, and concentrated under reduced pressure. The residue was purified by flash column chromatography (10 g Biotage® SNAP KP-Sil, 30 mL / min, gradient 30% to 100% ethyl acetate / isohexane) to give intermediate 2 (1.18 g, 83%) as a white solid. LC / MS (Method B) 1.73 min [M+H] + 445

[0267] Intermediate 3: 4-((S)-1-((2R,4R)-4-hydroxypyrrolidine-2-carboxamido)ethyl)benzoate methyl hydrochloride (Intermediate 3) [ka]

[0268] Intermediate 3-HCl was synthesized by a process similar to that of intermediate 1 using (2R,4R)-1-tert-butoxycarbonyl-4-hydroxy-pyrrolidine-2-carboxylic acid. LC / MS (Method B) 1.47 min [M+H] + 293

[0269] Intermediate 4: 4-((S)-1-((2R,4R)-1-(3-bromobenzyl)-4-hydroxypyrrolidine-2-carboxamido)ethyl)methyl benzoate (Intermediate 4) [ka]

[0270] Intermediate 4 was synthesized in a similar process to Intermediate 2 using Intermediate 3-HCl. LC / MS (Method B) 2.17 min [M+H] + 463

[0271] Intermediate 5: 4-((S)-1-((R)-1-(3-bromo-4-methoxybenzyl)pyrrolidine-2-carboxamido)ethyl)methyl benzoate (Intermediate 5) [ka]

[0272] To a mixture of intermediate 1-HCl (300 mg, 0.96 mmol) and 3-bromo-4-methoxybenzaldehyde (412.49 mg, 1.92 mmol) in DCM (5 mL) was added sodium triacetoxyborohydride (426.87 mg, 2.01 mmol). The mixture was stirred at room temperature for 16 hours and then diluted with saturated NaHCO. The organic layer was separated, washed with brine, dried (by passing through a hydrophobic frit), and concentrated. The residue was purified by flash column chromatography (normal phase, 10 g Biotage® SNAP KP-Sil, 30 mL / min, gradient 30% to 100% ethyl acetate / isohexane) to afford intermediate 5 (380 mg, 0.80 mmol, 83% yield) as a clear gum, which was sonicated in EtO to give a fluffy white solid. LC / MS (Method B) 2.36 min [M+H] + 475.

[0273] Intermediate 6: 4-((S)-1-((R)-1-(3-bromo-5-methoxybenzyl)pyrrolidine-2-carboxamido)ethyl)methyl benzoate (Intermediate 6) [ka]

[0274] To a solution of intermediate 1-HCl (300 mg, 0.96 mmol) in MeCN (10.8 mL) was added 1-bromo-3-(bromomethyl)-5-methoxybenzene (0.15 mL, 1.92 mmol) and potassium carbonate (331.4 mg, 2.4 mmol). The resulting mixture was heated at reflux for 16 h and then partitioned between EtOAc and water. The organic layer was separated, washed with brine, dried (frit), and concentrated. The residue was purified by flash column chromatography (25 g Biotage® SNAP KP-Sil 60 mL / min, gradient 0% to 90% EtOAc / isohexane) to give intermediate 6 (300 mg, 0.63 mmol, 66% yield) as a white solid. LC / MS (Method B) 2.44 min [M+H] + 475

[0275] Intermediate 7: (3-Bromobenzyl)-D-proline (Intermediate 7) [ka]

[0276] Step (i): Methyl D-proline hydrochloride (10.00 g, 60.38 mmol) was dissolved in ACN (120 mL), Na2CO3 (12.80 g, 120.77 mmol) was added, and the reaction mixture was stirred at room temperature for 15 min. Next, 1-bromo-3-(bromomethyl)benzene (18.11 g, 72.46 mmol) was added, and the reaction mixture was stirred at 800 °C for 16 h. The reaction mixture was then partitioned between water (300 mL) and EtOAc (200 mL), and the aqueous layer was extracted again with EtOAc (2 × 100 mL). The organic layers were combined, dried (Na2SO4), the solvent was removed under reduced pressure, and the crude product was purified by gradient column chromatography. The product was eluted with 0% to 20% EtOAc / hexane to give pure methyl (3-bromobenzyl)-D-prophosphate (11.00 g, 61.34%) as a yellow sticky material. LC / MS: (Method A): m / z 298 [M+H] + , 1.35 minutes.

[0277] Step (ii): Methyl (3-bromobenzyl)-D-proline (10.60 g, 35.68 mmol) was dissolved in dioxane (50 mL) and water (30 mL). LiOH monohydrate (7.48 g, 178.42 mmol) was added at room temperature, and the reaction mixture was stirred at room temperature for 6 hours. Glacial acetic acid (20 mL) was then added to adjust the solution to approximately pH 6. The reaction mixture was then concentrated under reduced pressure to give the crude product, which was purified by reverse-phase gradient flash column chromatography (reverse-phase, C18 silica). The product was eluted with 0% to 13% MeCN / water (0.1% FA as a modifier) to give pure (3-bromobenzyl)-D-proline (7.8 g, 77%) as a white solid. LC / MS: (Method A): m / z 284 [M+H] + , 1.28 minutes.

[0278] Intermediate 8: (R)-4-((1-(3-bromobenzyl)pyrrolidine-2-carboxamido)methyl)-2-hydroxybenzoate methyl ester (Intermediate 8) [ka]

[0279] Step (i): Intermediate 7 (2.50 g, 8.83 mmol) was dissolved in MeCN (15 mL), and methyl 4-(aminomethyl)-2-methoxybenzoate (1.90 g, 9.71 mmol) was added to the mixture at room temperature. Next, propylphosphonic anhydride (50% solution in EtOAc) (11.42 mL, 17.66 mmol) was added, and the reaction mixture was stirred at room temperature for 30 minutes. Next, TEA (3.88 mL, 26.54 mmol) was added at 0° C., and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was partitioned between saturated aqueous NaHCO3 (100 mL) and EtOAc (100 mL). The aqueous layer was further extracted with EtOAc (2×70 mL). The organic layers were combined, dried over Na2SO4, the solvent removed under reduced pressure, and the crude product purified by gradient flash column chromatography (normal phase, silica), eluting the product with 0% to 64% EtOAc / hexanes to give pure (R)-methyl 4-((1-(3-bromobenzyl)pyrrolidine-2-carboxamido)methyl)-2-methoxybenzoate (2.50 g, 60%) as a yellow sticky material. LC / MS: (Method A): m / z 461 [M+H] + , 1.56 minutes.

[0280] Step (ii): (R)-4-((1-(3-bromobenzyl)pyrrolidine-2-carboxamido)methyl)-2-methoxybenzoate (0.30 g, 0.65 mmol) was dissolved in DCM (30 mL) and the reaction mixture was cooled to −78 °C. BBr was added as a 1 M solution in DCM (3.3 mL, 3.26 mmol) and the reaction mixture was stirred at −78 °C for 1 h. The reaction mixture was then partitioned between saturated aqueous NaHCO (70 mL) and DCM (70 mL) and the aqueous layer was extracted again with DCM (2 × 40 mL). The organic layers were combined, dried (NaSO), and the solvent removed under reduced pressure to give pure intermediate 8 (0.25 g, 86%) as an off-white solid. LC / MS: (Method A): m / z 447 [M+H] + , 1.67 minutes.

[0281] Intermediate 9: (S)-4-(1-aminoethyl)-2-methoxybenzoate methyl (Intermediate 9) [ka]

[0282] (S)-4-(1-aminoethyl)-2-methoxybenzoic acid (2.00 g, 10.25 mmol) was dissolved in methanol (20 mL) at room temperature. HCl was added as a 4N solution in dioxane (10 mL, 40 mmol), and the reaction mixture was stirred at 70° C. for 8 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by trituration with diethyl ether to give Intermediate 9 (2.1 g, quantitative) as a white solid. LC / MS: (Method A) 0.93 min, no mass ion.

[0283] Intermediate 10: 4-((S)-1-((R)-1-(3-bromobenzyl)pyrrolidine-2-carboxamido)ethyl)-2-hydroxybenzoate methyl ester (Intermediate 10) [ka]

[0284] Step (i): Intermediate 9 (1.5 g, 7.71 mmol) was dissolved in MeCN (15 mL), and Intermediate 7 (2.23 g, 7.89 mmol) was added to the reaction mixture at room temperature. HATU (4.09 g, 10.75 mmol) was then added and stirred for 30 min. N,N-Diisopropylethylamine (2.50 mL, 14.34 mmol) was then added at 0 °C and stirred at room temperature for 2 h. The reaction mixture was then partitioned between saturated aqueous NaHCO (250 mL) and EtOAc (250 mL). The aqueous layer was further extracted with EtOAc (2 × 150 mL). The organic layers were combined, dried over NaSO, and the solvent was removed under reduced pressure. The crude product was purified by gradient flash column chromatography (reverse-phase, then normal-phase). The first product from reverse-phase flash column chromatography was eluted using MeCN in water from 0% to 68% as the mobile phase. The second, normal phase chromatography product was eluted using a gradient of 0% to 78% EtOAc in hexanes to give methyl 4-((S)-1-((R)-1-(3-bromobenzyl)pyrrolidine-2-carboxamido)ethyl)-2-methoxybenzoate (1.50 g, 44.11%) as a white solid. LC / MS (Method G): Product was observed at m / z 475.1 (ES+, M+2) at 1.438 min.

[0285] Step (ii): Methyl 4-((S)-1-((R)-1-(3-bromobenzyl)pyrrolidine-2-carboxamido)ethyl)-2-methoxybenzoate (1.50 g, 3.16 mmol) was dissolved in DCM (30 mL) and the mixture was cooled to −78 °C. BBr was added as a 1 M solution in DCM (3.79 mL, 3.79 mmol) and the reaction mixture was stirred at −78 °C for 1 h. The reaction mixture was then partitioned between saturated aqueous NaHCO (200 mL) and DCM (250 mL). The aqueous layer was extracted again with DCM (2 × 150 mL) and the organic layers were combined and dried (NaSO). The solvent was removed under reduced pressure and the crude product was purified by reverse-phase gradient flash column chromatography (reverse phase, C18 silica) eluting the product with 0% to 65% MeCN / water to give pure Intermediate 10 (0.99 g, 68%) as a white solid. LC / MS: (Method G): m / z 461 [M+H]+ , 5.43 minutes.

[0286] Intermediate 11: 3'-(bromomethyl)-5'-hydroxy-2-methyl-[1,1'-biphenyl]-4-carboxamide (Intermediate 11) [ka]

[0287] Step (i): 3-Bromo-5-hydroxybenzaldehyde (4.00 g, 20.00 mmol), 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (5.74 g, 22.00 mmol), and K2CO3 (3.20 g, 60.01 mmol) were dissolved in 1,4-dioxane (15 mL) and water (15 mL). The mixture was then purged with nitrogen gas at room temperature for 20 minutes, after which PdCl2(dppf)DCM (1.63 g, 2.00 mmol) was added. The reaction mixture was then stirred at 80 °C for 2 hours. The reaction mixture was then partitioned between water (400 mL) and EtOAc (250 mL), and the aqueous layer was further extracted with EtOAc (2 x 100 mL). The organic layers were combined, dried (NaSO), the solvent removed under reduced pressure, and the crude product purified by reverse-phase gradient flash column chromatography (reverse-phase, C18 silica), eluting the product with 0% to 35% MeCN / water to give 3'-formyl-5'-hydroxy-2-methyl-[1,1'-biphenyl]-4-carboxamide (3.60 g, 71%) as a brown solid. LC / MS: (Method A): m / z 256 [M+H] + , 1.09 minutes.

[0288] Step (ii): 3'-Formyl-5'-hydroxy-2-methyl-[1,1'-biphenyl]-4-carboxamide (1.50 g, 5.88 mmol) was dissolved in methanol (15 mL) at room temperature. The reaction mixture was cooled to 0 °C, and sodium borohydride (0.44 g, 11.76 mmol) was added at 0 °C, followed by stirring at room temperature for 2 h. The reaction mixture was partitioned between saturated aqueous NaHCO (100 mL) and EtOAc (80 mL), and the aqueous layer was further extracted with EtOAc (3 × 50 mL). The organic layers were combined, dried (NaSO), and the solvent was removed under reduced pressure to give 3'-hydroxy-5'-(hydroxymethyl)-2-methyl-[1,1'-biphenyl]-4-carboxamide (1.36 g, 90%) as an off-white solid. LC / MS: (Method A): m / z 258 [M+H] + , 0.94 minutes.

[0289] Step (iii): 3'-Hydroxy-5'-(hydroxymethyl)-2-methyl-[1,1'-biphenyl]-4-carboxamide (1.36 g, 5.29 mmol) was dissolved in 33% HBr / CH3COOH (12 mL) at room temperature, and the resulting reaction mixture was stirred at room temperature for 16 h. The reaction mixture was then partitioned between saturated aqueous NaHCO3 (200 mL) and EtOAc (150 mL), and the aqueous layer was further extracted with EtOAc (2 x 50 mL). The organic layers were combined, dried (Na2SO4), and the solvent removed under reduced pressure to give 3'-(bromomethyl)-5'-hydroxy-2-methyl-[1,1'-biphenyl]-4-carboxamide (1.59 g, 94%) as a red-brown solid. LC / MS: (Method A): m / z 320 [M+H] + , 1.23 minutes.

[0290] Intermediate 12: 3'-(bromomethyl)-2-methyl-[1,1'-biphenyl]-4-sulfonamide (Intermediate 12) [ka] Step (i): 4-bromo-3-methyl-benzenesulphonamide (1.00 g, 3.99 mmol), bis(pincaolato)diborone (2.02 g, 7.98 mmol), and KOAc (1.17 g, 11.97 mmol) were dissolved in dioxane (10 mL) at room temperature. This was purged with nitrogen gas at room temperature for 30 minutes. After this time, PdCl(dppf)DCM (0.325 g, 0.399 mmol) was added, and the reaction mixture was stirred at 80 °C for 2 hours. The reaction mixture was then partitioned between water (100 mL) and EtOAc (100 mL), and the aqueous layer was further extracted with EtOAc (2 × 100 mL). The organic layers were combined and dried (NaSO). The solvent was removed under reduced pressure and the crude product was purified by gradient flash column chromatography (normal phase, silica) eluting the product with 0% to 30% EtOAc / hexanes to give pure 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide (1.0 g, 85%) as a yellow solid. LC / MS: (Method F): No product m / z was observed in the major peak at 0.46 min (ES+). Step (ii): 3-Bromobenzaldehyde (4.50 g, 24.46 mmole), 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide (8.72 g, 29.35 mmole), and K2CO3 (10.20 g, 73.38 mmole) were dissolved in 1,4-dioxane (18 mL) and water (12 mL). A nitrogen gas purge was performed at room temperature for 30 minutes. Next, PdCl2(dppf)DCM (1.99 g, 2.44 mmole) was added, and the reaction mixture was stirred at 80 °C for 2 hours. The reaction mixture was partitioned between water (500 mL) and EtOAc (150 mL). The aqueous layer was further extracted with EtOAc (2 × 150 mL). The organic layers were combined and dried (Na2SO4).The solvent was removed under reduced pressure, and the crude product was purified by gradient column chromatography (normal phase, silica) eluting with 0% to 40% EtOAc / hexane to give pure 3'-formyl-2-methyl-[1,1'-biphenyl]-4-sulfonamide (4.5 g, 67%) as an off-white solid. LC / MS: (Method A): No major peak of the desired mass was observed at 1.74 min. Step (iii): 3'-formyl-2-methyl-[1,1'-biphenyl]-4-sulfonamide (4.00 g, 14.54 mmole) was dissolved in methanol (30 mL) at room temperature. The reaction mixture was cooled to 0 °C, and sodium borohydride (1.65 g, 43.62 mmole) was added in portions. The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with cold water (50 mL). A solid precipitated, which was collected by filtration and dried in vacuo to give 3'-(hydroxymethyl)-2-methyl-[1,1'-biphenyl]-4-sulfonamide (3.6 g, 79%) as an off-white solid. LC / MS: (Method A): 260 [M+H-HO]. + , 1.51 min. Step (iv): 3'-(hydroxymethyl)-2-methyl-[1,1'-biphenyl]-4-sulfonamide (3.60 g, 12.99 mmole) was dissolved in HBr (64% in water) (35 mL) and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with cold water (50 mL). A solid precipitated, which was collected by filtration and dried in vacuo to give 3'-(bromomethyl)-2-methyl-[1,1'-biphenyl]-4-sulfonamide (3.7 g, 84%) as a yellow solid. LC / MS: (Method A): No mass was observed at 1.51 min.

[0291] Intermediate 13: 3'-(bromomethyl)-2-methyl-[1,1'-biphenyl]-4-carboxamide (Intermediate 13) Intermediate 13 was synthesized in a similar process to Intermediate 12 using 4-bromo-3-methylbenzamide to give Intermediate 13. LC / MS: (Method A): m / z 305 [M+H] + , 2.02 minutes.

[0292] Intermediate 14 [ka]

[0293] Step (i): To a solution of compound a1 (2.4 g, 11.16 mmol, 1 equiv.) and compound a2 (1.62 g, 13.39 mmol, 1.2 equiv.) in THF (50 mL) was added Ti(OEt) (5.09 g, 22.32 mmol, 4.63 mL, 2 equiv.). The mixture was stirred at 30 °C for 5 h. TLC (PE:EA = 5:1) showed that compound a1 was completely consumed and one new spot was formed. The reaction mixture was diluted with HO (50 mL) and extracted with EA (100 mL × 2). The combined organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® silica flash column, 0–30% ethyl acetate / petroleum ether gradient elution, 50 mL / min) to give compound a3 (3.5 g, 11.00 mmol, 98.55% yield) as a yellow oil, which was confirmed by H NMR.

[0294] 1 H NMR (CDCl3,400MHz)δ8.54(s,1H),7.67(d,J=8.0Hz,1H),7.40(d,J=1.6Hz,1H),7.30(dd,J=1.6,8.0Hz,1H),3.98(s,3H),1.28(s,9H).

[0295] Step (ii): Dimethyl zinc (1 M, 13.36 mL, 1.7 equiv) was dissolved in THF (50 mL), and MeMgBr (3 M, 3.93 mL, 1.5 equiv) was added dropwise at 10 °C. The mixture was then stirred at 10 °C for 30 minutes. The reaction mixture was then cooled to 0 °C, and a solution of compound a3 (2.50 g, 7.86 mmol, 1 equiv) in THF (12.5 mL) was added dropwise. The reaction mixture was then stirred at 10 °C for 1 hour. TLC (PE:EA = 1:1) showed that compound a3 was completely consumed. The reaction mixture was diluted with HO (30 mL) and extracted with EA (50 mL × 2). The combined organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® silica flash column, elution with a 30–60% ethyl acetate / petroleum ether gradient at 50 mL / min) to give compound a4 (1.2 g, 3.52 mmol, 44.83% yield, 98.1% purity) as a white solid, which was confirmed by H NMR.

[0296] SFC: retention time = 1.220 min, enantiomeric excess (ee): 97.1%

[0297] 1 H NMR(CDCl3,400MHz)δ7.49(d,J=8.4Hz,1H),6.90(s,1H),6.82(d,J=8.0Hz,1H),4.55 (dd,J=2.0,6.4Hz,1H),3.90(s,3H),3.32(s,1H),1.52(d,J=6.8Hz,3H),1.22(s,9H).

[0298] Step (iii): To a solution of compound a4 (1.4 g, 4.19 mmol, 1 equiv.) in EtOH (40 mL), TEA (1.27 g, 12.56 mmol, 1.75 mL, 3 equiv.) and Pd(dppf)Cl2.CHCl2 (342.03 mg, 418.82 µmol, 0.1 equiv.) were added. The mixture was stirred at 80 °C under CO2 (50 PSI) for 16 h. LC-MS showed that compound a4 was completely consumed and one major peak with the desired mass was detected. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 3 / 1 to 1 / 1) to give compound a5 (1.35 g, 4.09 mmol, 97.65% yield, 99.2% purity) as a yellow oil, which was confirmed by HNMR.

[0299] LCMS:[M+1] + =328.4.

[0300] SFC: retention time = 0.901 min, ee = 97.9%.

[0301] 1 H NMR(CDCl3,400MHz)δ7.77(d,J=7.6Hz,1H),7.02-6.90(m,2H),4.63-4.57(m,1H),4.36(q,J=7.2Hz ,2H),3.91(s,3H),3.33(d,J=1.6Hz,1H),1.54(d,J=6.8Hz,3H),1.38(t,J=7.2Hz,3H),1.23(s,9H).

[0302] Step (iv): To a solution of compound a5 (1.35 g, 4.12 mmol, 1 equiv.) in DCM (15 mL) was added HCl / dioxane (4 M, 20 mL) at 0° C. The mixture was stirred at 15° C. for 12 h. LC-MS showed that compound a5 was completely consumed. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was triturated with PE:EA=5:1 (10 mL) at 15° C. for 10 min to give compound a6 (920 mg, 3.54 mmol, 85.91% yield, HCl) as a yellow solid, which was confirmed by HNMR.

[0303] 1 H NMR(DMSO-d6,400MHz)δ8.67(s,3H),7.64(d,J=8.0Hz,1H),7.44(s,1H),7.13(d,J=8.0Hz,1H),4. 50-4.36(m,1H),4.24(q,J=6.8Hz,2H),3.85(s,3H),1.52(d,J=6.4Hz,3H),1.27(t,J=7.2Hz,3H).

[0304] Step (v): To a solution of compound a7 (795.58 mg, 3.70 mmol, 1.5 equiv) in DMF (8 mL), HATU (1.87 g, 4.93 mmol, 2 equiv) and DIEA (1.59 g, 12.32 mmol, 2.15 mL, 5 equiv) were added, and the mixture was stirred at 25 °C for 0.5 h. Compound a6 (640 mg, 2.46 mmol, 1 equiv, HCl) was added, and the resulting mixture was stirred at 25 °C for 1 h. LC-MS showed that compound a6 was completely consumed and one major peak with the desired mass was detected. The reaction mixture was diluted with HO (30 mL) and extracted with EA (50 mL × 2). The combined organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® silica flash column, 0–50% ethyl acetate / petroleum ether gradient elution, 40 mL / min) to give compound a8 (1.26 g, crude) as a yellow oil, which was confirmed by HNMR.

[0305] LCMS: [M-Boc] + =321.5

[0306] SFC: Retention time = 0.926 min, ee: 100%

[0307] 1H NMR (DMSO-d6,400MHz)δ8.39-8.23(m,1H),7.56(d,J=7.6Hz,1H),7.12(s,1H),6.97(d,J=7.6Hz,1H),5.04-4.81(m,1H),4.23(q,J=7.2Hz,2H),4.18 -4.05(m,1H),3.88-3.78(m,3H),3.49-3.35(m,1H),3.29-3.22(m,1H),2. 22-2.03(m,1H),1.95-1.71(m,3H),1.47-1.29(m,8H),1.24-1.11(m,7H).

[0308] Step (vi): To a solution of compound a8 (1.2 g, 2.85 mmol, 1 equiv.) in DCM (10 mL) was added HCl / dioxane (4 M, 10 mL). The mixture was stirred at 15° C. for 1 h. LC-MS showed that compound a8 was completely consumed and one major peak with the desired mass was detected. The reaction mixture was concentrated under reduced pressure to give intermediate 14 (830 mg, crude, HCl) as a yellow oil.

[0309] LCMS:[M+1] + =321.2

[0310] Intermediate 15 [ka]

[0311] Step (i): A mixture of compound b1 (1 g, 4.65 mmol, 1 equiv.), NH4Cl (373.12 mg, 6.98 mmol, 1.5 equiv.), HATU (2.65 g, 6.98 mmol, 1.5 equiv.), and DIEA (1.20 g, 9.30 mmol, 1.62 mL, 2 equiv.) in DMF (25 mL) was degassed and purged with N2 three times, and then the mixture was stirred under a N2 atmosphere at 30 °C for 12 h. LCMS showed that compound b1 was completely consumed. The mixture was slowly added dropwise to water (35 mL). The precipitate was filtered, and the filter cake was concentrated to give compound b2 (600 mg, 2.80 mmol, 60.28% yield) as a brown solid, which was confirmed by HNMR.

[0312] LCMS: m / z=213.7 [M+1].

[0313] 1 H NMR (DMSO-d6,400MHz)δ8.00(s,1H),7.85(d,J=1.6Hz,1H),7.67-7.65(m,1H),7.62-7.59(m,1H),7.42(s,1H),2.38(s,3H).

[0314] Step (ii): A mixture of compound b2 (450 mg, 2.10 mmol, 1 equiv.), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (640.60 mg, 2.52 mmol, 1.2 equiv.), AcOK (412.63 mg, 4.20 mmol, 2 equiv.), and Pd(dppf)Cl (153.82 mg, 210.22 µmol, 0.1 equiv.) in dioxane (12 mL) was degassed and purged with N three times, after which the mixture was stirred under N at 85 °C for 12 h. LCMS showed that compound b2 was completely consumed and one major peak with the desired mass was detected. TLC (petroleum ether:ethyl acetate = 1:1) showed that compound b2 was completely consumed. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® silica flash column, elution with a gradient of 0 to 65% ethyl acetate / petroleum ether at 45 mL / min) to give compound b3 (440 mg, 1.69 mmol, 80.15% yield) as a white solid, which was confirmed by HNMR.

[0315] LCMS: m / z=261.9 [M+1].

[0316] 1 H NMR (CDCl3,400MHz) δ7.82(d,J=7.6Hz,1H),7.65-7.54(m,2H),6.22-5.84(m,2H),2.58(s,3H),1.36(s,12H).

[0317] Step (iii): To a solution of compound b3 (1 g, 3.83 mmol, 1 equiv.) and compound b4 (1.07 g, 4.98 mmol, 1.3 equiv.) in dioxane (30 mL) and HO (3 mL), KCO (1.06 g, 7.66 mmol, 2 equiv.) and Pd(dppf)Cl (280.21 mg, 382.96 μmol, 0.1 equiv.) were added. The mixture was stirred at 80 °C under N for 12 h. TLC (PE:EA = 1:1) showed that compound b3 was completely consumed and one new spot was formed. The reaction mixture was diluted with HO (30 mL) and extracted with EA (50 mL × 2). The combined organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 3 / 1 to 1 / 2) to give intermediate 15 (550 mg, 2.04 mmol, yield 53.33%) as a yellow solid, which was confirmed by HNMR.

[0318] 1 H NMR(CDCl3,400MHz)δ10.03(s,1H),7.80(s,1H),7.69(d,J=4.4Hz,1H),7.42(s,2H) ),7.33(d,J=4.8Hz,1H),7.13(s,1H),6.55-5.32(m,2H),3.92(s,3H),2.34(s,3H).

[0319] Intermediate 16: (S)-1-(4-bromo-3-methoxyphenyl)ethan-1-amine (Intermediate 16) [ka]

[0320] Step (i): A solution of 4-bromo-3-methoxybenzaldehyde (31.16 g, 0.14 mol, 1 equiv.) was dissolved in THF (240 mL) at room temperature. Then, Ti(OEt)4 (66.10 g, 0.28 mol, 61.20 mL, 2 equiv.) was added to the reaction mixture at room temperature, and the reaction mixture was stirred at room temperature for 15 min. (R)-2-methylpropane-2-sulfinamide (28.09 g, 0.23 mol, 1.6 equiv.) predissolved in THF (60 mL) was added to the reaction mixture, and the mixture was stirred at 30 °C overnight. TLC (EA:hexane = 2:8) showed that 4-bromo-3-methoxybenzaldehyde was completely consumed and one new spot was formed. The reaction mixture was diluted with HO (300 mL), followed by salts, filtered through a vacuum pump, and the filtrate was extracted with EA (3 × 500 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (normal phase silica, 0–15.0% EA / hexanes) to give (R,E)-N-(4-bromo-3-methoxybenzylidene)-2-methylpropane-2-sulfinamide (35.9 g, 77.85% yield) as a white solid.

[0321] TLC: (2.0:8.0, EtOAc / hexane, RF: 0.40).

[0322] Mass (ESI+ve): 318.0[M].

[0323] LCMS: 100.0% (LCMS method H), retention time: 3.545 minutes, 280.0 nm.

[0324] 1 H NMR (400MHz, CDCl3) δ: 8.57 (s, 1H), 7.69-7.71 (d, 1H), 7.44 (d, 1H), 7.30-7.33 (dd, 1H), 4.01 (s, 3H), 1.31 (s, 9H).

[0325] Step (ii): Dimethylzinc (1.5 M in toluene, 269.66 mL, 3.7 equiv.) was dissolved in THF (150 mL) and MeMgBr (3.0 M in diethyl ether, 116.6 mL, 3.2 equiv.) was added dropwise at 15-20°C. The mixture was then stirred at 15-20°C for 45 min. The reaction mixture was then cooled to 0°C, and a solution of (R,E)-N-(4-bromo-3-methoxybenzylidene)-2-methylpropane-2-sulfinamide (34.79 g, 0.034 mol, 1 equiv.) predissolved in THF (150 mL) was added dropwise. The reaction mixture was then stirred at 0°C for 30 min. TLC (EA:hexane = 5:5) showed that (R,E)-N-(4-bromo-3-methoxybenzylidene)-2-methylpropane-2-sulfinamide was completely consumed. The reaction mixture was diluted with cold HO (1000 mL), and the solid was followed by acidification with 1N HCl (pH = 2-3) and extraction with EA (800 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (normal phase silica, 0-45.0% EA / hexane) to give (R)-N-((S)-1-(4-bromo-3-methoxyphenyl)ethyl)-2-methylpropane-2-sulfinamide (25.57 g, 69.97% yield, 97.20% purity) as an off-white solid.

[0326] TLC: (5.0:5.0, EtOAc / hexane, RF: 0.25).

[0327] Mass (ESI+ve): 335.8[M+1].

[0328] LCMS: 100.0% (LCMS method H), retention time: 3.067 min, 254.0 nm.

[0329] 1H NMR(400MHz,CDCl3)δ:7.50-7.52(s,1H),7.01(s,1H),6.82-6.84(dd,1H),4 .77-4.78(s,1H),4.42(s,1H),3.93(s,3H),1.58-1.62(t,6H),1.29(s,9H).

[0330] Step (iii): To a solution of (R)-N-((S)-1-(4-bromo-3-methoxyphenyl)ethyl)-2-methylpropane-2-sulfinamide (25.57 g, 0.07 mol, 1 equiv.) in dioxane (20 mL) was added HCl / dioxane (4.0 M, 125 mL) at 0° C. The mixture was stirred at room temperature for 3 h. TLC (EA:hexane=5:5) showed that (R)-N-((S)-1-(4-bromo-3-methoxyphenyl)ethyl)-2-methylpropane-2-sulfinamide was completely consumed. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was washed with dioxane (40 mL) and concentrated under reduced pressure to give (S)-1-(4-bromo-3-methoxyphenyl)ethan-1-amine (Intermediate 16) (18.73 g, HCl salt) as a white solid.

[0331] TLC: (5.0:5.0, EtOAc / hexane, RF: 0.25).

[0332] LCMS: 100.0% (LCMS method H), retention time: 2.371 minutes, 230.0 nm.

[0333] 1 H NMR(400MHz,DMSO-D2O)δ:8.75(s,3H),7.59-7.68(d,1H),7.49(s,1H),7.02 -7.04(d,1H),4.36-4.39(s,1H),3.88(s,3H),3.56(s,1H),1.51-152(t,3H).

[0334] Intermediate 17: 4'-Hydroxy-5-methoxy-2'-methyl-[1,1'-biphenyl]-3-carbaldehyde (Intermediate 17) [ka]

[0335] To a solution of (4-hydroxy-2-methylphenyl)boronic acid (3.5 g, 0.02 mol, 1 equiv.) and 3-bromo-5-methoxybenzaldehyde (4.95 g, 0.020 mol, 1.0 equiv.) in dioxane (35 mL) and HO (11 mL), KCO (6.35 g, 0.046 mol, 2 equiv.) was added, and the mixture was degassed for 10 min. After degassing, Pd(dppf)Cl (1.6 g, 0.002 mol, 0.1 equiv.) was added to the reaction mixture. The reaction mixture was then stirred at 80 °C overnight. TLC (EA:hexane = 5:5) showed that (4-hydroxy-2-methylphenyl)boronic acid was completely consumed and one new spot had formed. The reaction mixture was diluted with HO (300 mL) and extracted with EA (3 × 150 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue, which was purified by column chromatography (normal phase silica, 0-46.0% EA / hexane) to give 4'-hydroxy-5-methoxy-2'-methyl-[1,1'-biphenyl]-3-carbaldehyde (Intermediate 17) (4.0 g, 71.68% yield) as a brown solid.

[0336] TLC: (5.0:5.0, EtOAc / hexane, RF: 0.25).

[0337] Mass (ESI+ve): 243.0[M+1].

[0338] LCMS: 95.66% (LCMS method H), retention time: 3.029 minutes, 254.0 nm.

[0339] 1 H NMR(400MHz,DMSO-D2O)δ:10.01(s,1H),9.48(s,1H),7.43-7.36(d,2H),7. 16(s,1H),7.08-7.06(d,1H),6.67-6.71(m,2H),3.86(s,3H),2.18(s,3H).

[0340] Preparation of Compounds of Formula I by Synthesis

[0341] Example 1: 4-((1S)-1-((2R)-1-((4'-hydroxy-2'-methyl-1',2',3',4',5',6'-hexahydro-[1,1'-biphenyl]-3-yl)methyl)pyrrolidine-2-carboxamido)ethyl)benzoic acid (Compound 1) [ka]

[0342] Step (i): A mixture of Intermediate 2 (150 mg, 0.3400 mmol), (4-hydroxy-2-methylphenyl)boronic acid (56.3 mg, 0.3700 mmol), potassium carbonate (0.09 g, 0.67 mmol), and tetrakis(triphenylphosphine)palladium(0) (11.68 mg, 0.01 mmol) in 1,4-dioxane (1.4 mL) and water (0.3 mL) was heated to 100 °C in a microwave reactor and maintained for 1 h. After further addition of (4-hydroxy-2-methylphenyl)boronic acid (56.3 mg, 0.3700 mmol), the mixture was placed in the microwave reactor for an additional 1 h. The crude product was diluted with water and EtOAc, and the organic layer was separated, washed with water, brine, dried by passing through a hydrophobic frit, and then concentrated under reduced pressure. The residue was purified by flash column chromatography (normal phase, 10 g, Biotage® SNAP KP-Sil, 30 mL / min, 30% to 100% ethyl acetate / isohexane gradient) to give methyl 4-[(1S)-1-[[(2R)-1-[[3-(4-hydroxy-2-methyl-phenyl)phenyl]methyl]pyrrolidine-2-carbonyl]amino]ethyl]benzoate (148 mg, 93%) as a pale yellow gum. LC / MS (Method B) 2.36 min [M+H] + 473.

[0343] Step (ii): To a solution of methyl 4-[(1S)-1-[[(2R)-1-[[3-(4-hydroxy-2-methyl-phenyl)phenyl]methyl]pyrrolidine-2-carbonyl]amino]ethyl]benzoate (148 mg, 0.31 mmol) in 1,4-dioxane (2.62 mL) and water (2.62 mL) was added lithium hydroxide monohydrate (59.13 mg, 1.41 mmol). The reaction was left stirring at room temperature for 3 hours, after which time it was determined complete by LC / MS and concentrated under reduced pressure. The crude residue was purified by reverse-phase HPLC (HPLC Method A) to give compound 1 (52.5 mg, 36%) as a white solid. LC / MS (Method C): m / z 459 [M+H] + 2.30 minutes. 1 H NMR(400MHz,DMSO-d6)δ7.91(m,1H),7.74(m,2H),7.33(dd,J=7.5Hz,1H),7.27-7.21(m ,2H),7.18-7.08(m,3H),6.98(m,1H),6.68-6.61(m,2H),4.85-4.76(m,1H),3.80(d,J=1 2.9 Hz, 1H), 3.52 (d, J = 12.9 Hz, 1H), 3.08 (dd, J = 9.5, 4.1 Hz, 1H), 2.99-2.93 (m, 1H), 2.39-2.29 (m, 1H), 2.13 (s, 3H), 2.09-1.97 (m, 2H), 1.72-1.61 (m, 3H), 1.24 (d, J = 7.0 Hz, 3H). No exchangeable acid protons were observed in the spectrum.

[0344] Example 2: 4-((S)-1-((R)-1-((2'-methyl-4'-sulfamoyl-[1,1'-biphenyl]-3-yl)methyl)pyrrolidine-2-carboxamido)ethyl)benzoic acid (Compound 2)

[0345] Compound 2 was synthesized using intermediate 2 and (2-methyl-4-sulfamoylphenyl)boronic acid in a process similar to Example 1, in which only one addition of boronic acid is required in step (i) of the process. The crude product was purified by preparative HPLC (HPLC Method A) to give compound 2 (48.5 mg, 0.09 mmol, 34%) as a white foam. LC / MS (Method C): m / z 522 [M+H] + 2.28 minutes. 1 H NMR(400MHz,DMSO-d6)δ7.94(d,J=8.0Hz,1H),7.71(s,1H),7.67(m,3H),7.47(brs,2H),7 .39(dd,J=7.6Hz,1H),7.36-7.27(m,3H),7.23(m,1H),7.17(m,2H),4.83-4.74(m,1H),3.8 4 (d, J = 13.2 Hz, 1H), 3.52 (d, J = 13.1 Hz, 1H), 3.08 (dd, J = 7.8 Hz, 1H), 2.95-2.88 (m, 1H), 2.35-2.26 (m, 1H), 2.23 (s, 3H), 2.07-1.96 (m, 1H), 1.71-1.57 (m, 3H), 1.24 (d, J = 6.9 Hz, 3H). No exchangeable acid protons were observed in the spectrum.

[0346] Example 3: 4-((S)-1-((R)-1-((4'-carbamoyl-2'-methyl-[1,1'-biphenyl]-3-yl)methyl)pyrrolidine-2-carboxamido)ethyl)benzoic acid (Compound 3)

[0347] Compound 3 was synthesized using intermediate 2 and 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide in a process similar to that described in Example 1, in which only a single addition of the boronic ester was required in step (i) of the process. The crude product was purified by HPLC (HPLC Method C) to give compound 3 (71 mg, 0.15 mmol, 43%) as a white foam. LC / MS (Method C): m / z 486 [M+H] + 2.36 minutes. 1H NMR(400MHz,DMSO-d6)δ8.06-7.96(m,2H),7.80-7.74(m,3H),7.72(m,1H),7.3 8(m,1H),7.33-7.18(m,7H),4.85-4.76(m,1H),3.82(d,J=13.0Hz,1H),3.52(d ,J=13.0Hz,1H),3.07(dd,J=9.8,4.1Hz,1H),2.98-2.90(m,1H),2.35-2.27(m, 1H),2.21(s,3H),2.06-1.96(m,1H),1.73-1.59(m,3H),1.25(d,J=7.0Hz,3H). No exchangeable acid protons were observed in the spectrum.

[0348] Example 4: 4-((S)-1-((2R,4R)-4-hydroxy-1-((2'-methyl-4'-sulfamoyl-[1,1'-biphenyl]-3-yl)methyl)pyrrolidine-2-carboxamido)ethyl)benzoic acid (Compound 4)

[0349] Compound 4 was synthesized using intermediate 4 and (2-methyl-4-sulfamoylphenyl)boronic acid in a process similar to Example 1, in which only one addition of the boronic ester was required in step (i) of the process. The crude residue was purified by HPLC (HPLC Method C) to give compound 4 (73.1 mg, 0.14 mmol, 60%) as a white foam. LC / MS (Method C): m / z 538 [M+H] + 2.12 minutes. 1H NMR(400MHz,DMSO-d6)δ7.86(d,J=8.0Hz,2H),7.81(s,1H),7.75(m,1H),7.46-7.34(m,4H) ),7.32(d,J=8.0Hz,2H),7.25(m,1H),4.75-5.00(m,1H),4.32-4.25(m,1H),3.87(d,J=12. 9Hz, 1H), 3.69 (d, J = 12.9Hz, 1H), 3.23 (dd, J = 10.6, 4.6Hz, 1H), 3.10 (d, J = 10.3Hz, 1H), 2.65-2.58 (m, 1H), 2.53-2.43 (m, 1H), 2.31 (s, 3H), 1.82-1.74 (m, 1H), 1.31 (d, J = 7.0Hz, 3H). No exchangeable protons were observed in the spectrum.

[0350] Example 5: 4-((S)-1-((2R,4R)-4-hydroxy-1-((4'-hydroxy-2'-methyl-[1,1'-biphenyl]-3-yl)methyl)pyrrolidine-2-carboxamido)ethyl)benzoic acid (Compound 5)

[0351] Compound 5 was synthesized using intermediate 4 and (4-hydroxy-2-methylphenyl)boronic acid in a process similar to that described in Example 1, in which only a single addition of the boronic ester was required in step (i) of the process. The crude residue was purified by HPLC (HPLC Method B) to give compound 5 (63.6 mg, 0.13 mmol, 65%) as a white solid. LC / MS (Method C): m / z 475 [M+H] + 2.11 minutes. 1H NMR(400MHz,DMSO-d6)δ9.72(brs,1H),8.73(brs,1H),7.78(m,2H),7.43(s,1H),7.38-7.28(m,2H),7. 21-7.16(m,1H),7.14-7.02(m,2H),6.84(d,J=8.3Hz,1H),6.65-6.62(m,1H),6.58(dd,J=8.2,2.5Hz,1H ),5.36(brs,1H),4.83-4.74(m,1H),4.51-4.37(m,2H),4.32-4.15(m,2H),3.63-3.52(m,1H),3.50-3.1 6(m,2H,underwaterpeak),),2.75-2.63(m,1H),2.02(s,3H),1.96-1.85(m,1H),1.30(d,J=7.0Hz,3H).

[0352] Example 6: 4-((S)-1-((2R,4R)-1-((4'-carbamoyl-2'-methyl-[1,1'-biphenyl]-3-yl)methyl)-4-hydroxypyrrolidine-2-carboxamido)ethyl)benzoic acid (Compound 6)

[0353] Compound 6 was synthesized using intermediate 4 and 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide in a process similar to that described in Example 1, in which only a single addition of the boronic ester was required in step (i) of the process. The crude residue was purified by HPLC (HPLC Method B) to give compound 6 (106.5 mg, 0.21 mmol, 86%) as a white foam. LC / MS (Method C): m / z 502 [M+H] + 2.12 minutes. 1H NMR(400MHz,DMSO-d6)δ9.74(brs,1H),8.74(d,J=7.7Hz,1H),7.92(s,1H),7.79-7.74(m,3H),7.68(dd,J= 7.8,1.8Hz,1H),7.52(s,1H),7.47-7.43(m,1H),7.38(m,1H),7.33(s,1H),7.25(dt,J=7.6,1.5Hz,1H),7.0 7(m,3H),5.36(brs,1H),4.82-4.74(m,1H),4.52-4.41(m,2H),4.33-4.25(m,1H),4.25-4.18(m,1H),3.65 -3.54(m,1H),3.43-3.30(m,1H),2.76-2.64(m,1H),2.11(s,3H),1.97-1.89(m,1H),1.30(d,J=7.0Hz,3H).

[0354] Example 7: 4-((S)-1-((R)-1-((4'-hydroxy-[1,1'-biphenyl]-3-yl)methyl)pyrrolidine-2-carboxamido)ethyl)benzoic acid (Compound 7)

[0355] Intermediate 7 was synthesized using Intermediate 2 and 4-hydroxybenzeneboronic acid in a process similar to that of Intermediate 1. The crude residue was purified by HPLC (HPLC Method C) to give compound 7 (49.2 mg, 0.11 mmol, 56%) as a white foam. LC / MS (Method D): m / z 445 [M+H] + 1.82 minutes. 1H NMR(400MHz,DMSO-d6)δ8.07(d,J=8.2Hz,1H),7.84-7.79(m,2H),7.51-7.49(m,1H),7.48 -7.42(m,3H),7.36-7.29(m,3H),7.25-7.20(m,1H),6.84-6.79(m,2H),4.87-4.79(m,1H), 3.79 (d, J = 12.8 Hz, 1H), 3.54 (d, J = 12.8 Hz, 1H), 3.09 (dd, J = 9.7, 4.4 Hz, 1H), 3.01-2.95 (m, 1H), 2.36 (dd, J = 8.2 Hz, 1H), 2.08-1.98 (m, 1H), 1.74-1.62 (m, 3H), 1.27 (d, J = 7.0 Hz, 3H). No exchangeable acid protons or hydroxyl protons were observed in the spectrum.

[0356] Example 8: 4-((S)-1-((R)-1-((2'-cyano-4'-hydroxy-[1,1'-biphenyl]-3-yl)methyl)pyrrolidine-2-carboxamido)ethyl)benzoic acid (Compound 8)

[0357] Compound 8 was synthesized using intermediate 2 and 5-hydroxy-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile in a process similar to that described in Example 1, in which only a single addition of the boronic ester was required in step (i) of the process. The crude residue was purified by HPLC (HPLC Method C) to give compound 8 (22 mg, 0.05 mmol, 32%) as a white foam. LC / MS (Method C): m / z 470 [M+H] + 1.60 minutes. 1H NMR(400MHz,DMSO-d6)δ8.04(d,J=8.2Hz,1H),7.82-7.76(m,2H),7.48(brs,1H),7.45-7.3 3(m,4H),7.28-7.23(m,2H),7.22(d,J=2.6Hz,1H),7.17(dd,J=8.6,2.6Hz,1H),4.89-4.80( m, 1H), 3.85 (d, J = 13.0 Hz, 1H), 3.53 (d, J = 13.0 Hz, 1H), 3.10 (dd, J = 9.7, 4.3 Hz, 1H), 3.02-2.94 (m, 1H), 2.37-2.29 (m, 1H), 2.09-1.98 (m, 1H), 1.72-1.61 (m, 3H), 1.28 (d, J = 6.9 Hz, 3H). Exchangeable acid protons and hydroxyl protons were not observed in the spectrum.

[0358] Example 9: 3'-(((R)-2-(((S)-1-(4-carboxyphenyl)ethyl)carbamoyl)pyrrolidin-1-yl)methyl)-2-methyl-[1,1'-biphenyl]-4-carboxylic acid (Compound 9)

[0359] Compound 9 was synthesized using intermediate 2 and 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid in a process similar to Example 1, in which only one addition of the boronic ester is required in step (i) of the process. The crude residue was purified by HPLC (HPLC Method B) to give compound 9 (34.7 mg, 0.07 mmol, 34%) as a white foam. LC / MS (Method C): m / z 487 [M+H] + , 1.29 minutes. 1H NMR(400MHz,DMSO-d6)δ12.88(brs,1H),9.67(brs,1H),8.93(d,J=7.7Hz,1H),7.84-7.82(m,1H) ),7.81-7.77(m,2H),7.77-7.73(m,1H),7.48-7.41(m,3H),7.36-7.30(m,1H),7.17-7.10(m,3H ),4.88-4.79(m,1H),4.45-4.31(m,2H),4.21-4.13(m,1H),3.64-3.56(m,1H),3.35-3.23(m,1H) ),2.55-2.51(m,1H),2.16(s,3H),2.13-2.04(m,1H),1.96-1.81(m,2H),1.31(d,J=6.9Hz,3H).

[0360] Example 10: 4-((S)-1-((R)-1-((2'-methyl-4'-(sulfamoyloxy)-1',2',3',4',5',6'-hexahydro-[1,1'-biphenyl]-3-yl)methyl)pyrrolidine-2-carboxamido)ethyl)benzoic acid (Compound 10) [ka]

[0361] To a solution of compound 1 (74.0 mg, 0.16 mmol) in DMA (1.4 mL) was added sulfamic acid chloride (46.61 mg, 0.40 mmol), and the mixture was allowed to stir at room temperature for 18 hours, after which completion was confirmed by LC / MS. An additional addition of sulfamic acid chloride (46.61 mg, 0.40 mmol) was made, and the reaction mixture was allowed to stir for an additional 18 hours, after which the reaction was quenched by the addition of 0.5 mL of water. The mixture was purified by reverse-phase HPLC (HPLC Method B) to give compound 10 (68.4 mg, 0.127 mmol, 79% yield) as a colorless glass. LC / MS (Method C): m / z 538 [M+H] + , 1.88 minutes. 1H NMR(400MHz,MeOD-d4)δ7.87-7.83(m,2H),7.42-7.37(m,3H),7.30-7.26(m,1H),7.20-7.17 (m,1H),7.17-7.09(m,3H),7.00-6.96(m,1H),4.91(q,J=7.0Hz,1H),4.50(d,J=12.8Hz,1H) , 4.29 (d, J = 12.8 Hz, 1H), 4.22 (dd, J = 9.4, 6.1 Hz, 1H), 3.82-3.74 (m, 1H), 3.41-3.35 (m, 1H), 2.69-2.57 (m, 1H), 2.28-2.18 (m, 1H), 2.14 (s, 3H), 2.12-1.99 (m, 2H), 1.40 (d, J = 7.0 Hz, 3H). No exchangeable protons were observed.

[0362] Example 11: 4-((S)-1-((R)-1-((4'-carbamoyl-2'-hydroxy-[1,1'-biphenyl]-3-yl)methyl)pyrrolidine-2-carboxamido)ethyl)benzoic acid (Compound 11) [ka]

[0363] Step (i): A mixture of 4-bromo-3-hydroxybenzamide (204.79 mg, 0.95 mmol), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (200.00 mg, 0.86 mmol), potassium carbonate (238.21 mg, 1.72 mmol), and tetrakis(triphenylphosphine)palladium(0) (99.58 mg, 0.09 mmol) in 1,4-dioxane (4.5 mL) and water (1 mL) was heated to 100 °C in a microwave reactor for 40 min. The mixture was diluted with EtOAc and 1 M HCl (aq). The organic layer was separated, dried over MgSO, filtered, and concentrated. The gummy residue was suspended in EtO and sonicated. The liquid was removed by pipetting to give 4-(3-formylphenyl)-3-hydroxy-benzamide (150 mg, 0.6218 mmol, 72% yield) as a yellow solid which was used without further purification.

[0364] Step (ii): A mixture of Intermediate 1 (150.0 mg, 0.480 mmol) and 4-(3-formylphenyl)-3-hydroxybenzamide (138.83 mg, 0.58 mmol) in DMF (3 mL) was stirred at room temperature for 30 minutes, after which sodium triacetoxyborohydride (203.27 mg, 0.96 mmol) was added. The mixture was stirred overnight at room temperature and then directly purified by HPLC (HPLC Method A) to give methyl 4-[(1S)-1-[[(2R)-1-[[3-(4-carbamoyl-2-hydroxyphenyl)phenyl]methyl]pyrrolidine-2-carbonyl]amino]ethyl]benzoate (56.8 mg, 0.11 mmol, 23% yield) as a clear gum. LC / MS (Method C): m / z 502 [M+H] + 3.69 minutes.

[0365] Step (iii): Carried out in the same manner as step (ii) of Example 1 to give compound 11 (40.2 mg 73%) as a white foam. LC / MS (Method C): m / z 488 [M+H] + 1.72 minutes 1H NMR(400MHz,DMSO-d6)δ12.88br(s,1H),9.87(s,1H),9.73(brs,1H),8.94(d,J=7.8Hz,1H),7.88(s,1 H),7.84(d,J=8.0Hz,2H),7.68(s,1H),7.65-7.59(m,1H),7.46(s,1H),7.40-7.35(m,3H),7.31(brs, 1H),7.25(d,J=7.9Hz,1H),7.18(d,J=8.0Hz,2H),4.87(q,J=7.1Hz,1H),4.43-4.32(m,2H),4.22-4.1 4(m,1H),3.36-3.26(m,1H),3.16(s,1H),2.16-2.05(m,1H),1.96-1.82(m,2H),1.34(d,J=6.9Hz,3H). LC / MS (Method C): m / z488[M+H] + 1.72 minutes

[0366] Example 12: 4-((S)-1-((R)-1-((4'-carbamoyl-6-hydroxy-[1,1'-biphenyl]-3-yl)methyl)pyrrolidine-2-carboxamido)ethyl)benzoic acid (Compound 12) [ka]

[0367] Step (i): A mixture of intermediate 5 (100.0 mg, 0.21 mmol), (4-carbamoylphenyl)boronic acid (38.0 mg, 0.23 mmol), potassium carbonate (58.15 mg, 0.42 mmol), and tetrakis(triphenylphosphine)palladium(0) (24.31 mg, 0.02 mmol) in 1,4-dioxane (1.6 mL) and water (0.50 mL) was heated to 100° C. in a microwave reactor for 40 minutes, after which the mixture was diluted with EtOAc and water. The organic layer was separated, and the aqueous layer was washed with brine, dried over MgSO, filtered, and concentrated. The residue was purified by flash column chromatography (normal phase, 10 g Biotage® SNAPKP-Sil, 30 mL / min, 0% to 8% MeOH / DCM gradient) to give methyl 4-[(1S)-1-[[(2R)-1-[[3-(4-carbamoylphenyl)-4-methoxy-phenyl]methyl]pyrrolidine-2-carbonyl]amino]ethyl]benzoate (48 mg, 0.093 mmol, 44% yield) as a clear glass. LC / MS (Method B): m / z 516 [M+H] + 2.11 minutes.

[0368] Step (ii): To a solution of methyl 4-[(1S)-1-[[(2R)-1-[[3-(4-carbamoylphenyl)-4-methoxy-phenyl]methyl]pyrrolidine-2-carbonyl]amino]ethyl]benzoate (45.0 mg, 0.09 mmol) in DCM (1.5 mL) at −78° C., 1 M boron tribromide solution in DCM (0.44 mL, 0.44 mmol) was added dropwise. The mixture was gradually warmed to room temperature and stirred overnight at room temperature. The mixture was cooled to 0° C., and MeOH / HO 1:1 (2 mL) was added dropwise. After stirring for 1 h, the mixture was concentrated, and the crude product was purified by reverse-phase HPLC (HPLC Method C) to give compound 12 (25 mg, 0.05 mmol, 59% yield) as a white foam. LC / MS (Method C): m / z 488 [M+H] + 1.64 minutes. 1 H NMR (400MHz, methanol-d4) δ7.97-7.87(m,2H),7.87-7.79(m,2H),7.62-7.49(m,2H),7.41(d,J=2 .3Hz,1H),7.26(dd,J=8.5,2.3Hz,1H),7.13(d,J=8.2Hz,2H),6.91(d,J=8.3Hz,1H),4.90(q,J = 8.5, 7.1 Hz, 1H), 4.43 (d, J = 12.9 Hz, 1H), 4.23-4.11 (m, 2H), 3.76 (dt, J = 11.6, 6.0 Hz, 1H), 3.41-3.33 (m, 1H), 2.64-2.50 (m, 1H), 2.31-2.14 (m, 1H), 2.12-1.94 (m, 2H), 1.40 (d, J = 7.0 Hz, 3H). There are no exchangeable protons.

[0369] Example 13: 4-((S)-1-((R)-1-((4'-carbamoyl-5-hydroxy-2'-methyl-1,2,3,4,5,6-hexahydro-[1,1'-biphenyl]-3-yl)methyl)pyrrolidine-2-carboxamido)ethyl)benzoic acid (Compound 13) [ka]

[0370] Step (i): A mixture of methyl 4-[(1S)-1-[[(2R)-1-[(3-bromo-5-methoxy-phenyl)methyl]pyrrolidine-2-carbonyl]amino]ethyl]benzoate intermediate 6 (250 mg, 0.53 mmol), 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (151 mg, 0.58 mmol), potassium carbonate (145.4 mg, 1.05 mmol), and tetrakis(triphenylphosphine)palladium(0) (60.8 mg, 0.050 mmol) in 1,4-dioxane (3.5 mL) and water (0.8 mL) was heated to 100° C. in a Biotage microwave reactor for 1 h, after which the mixture was diluted with EtOAc and water. The organic layer was separated, and the aqueous layer was washed with brine, dried over MgSO, filtered, and concentrated. The residue was purified by flash column chromatography (normal phase, 10 g, Biotage® SNAPKP-Sil-50 μm irregular silica, 30 mL / min, [0% to 8% MeOH / DCM gradient] to give an impure gum, which was sonicated in ether and the solid collected by filtration to give methyl 4-[(1S)-1-[[(2R)-1-[[3-(4-carbamoyl-2-methyl-phenyl)-5-methoxy-phenyl]methyl]pyrrolidine-2-carbonyl]amino]ethyl]benzoate (174 mg, 0.33 mmol, 62% yield) as a cream-colored solid. LC / MS (Method B): m / z 530 [M+H] + 2.16 minutes.

[0371] Step (ii): To a solution of methyl 4-[(1S)-1-[[(2R)-1-[[3-(4-carbamoyl-2-methyl-phenyl)-5-methoxy-phenyl]methyl]pyrrolidine-2-carbonyl]amino]ethyl]benzoate (170 mg, 0.32 mmol) in DCM (5 mL) at −78° C., 1 M boron tribromide solution in DCM (1.6 mL, 1.6 mmol) was added dropwise. The mixture was gradually warmed to room temperature and stirred overnight at room temperature. The mixture was cooled to 0° C., and MeOH / HO 1:1 (2 mL) was added dropwise. The mixture was stirred for 1 h and then concentrated. The crude product was purified by reverse-phase HPLC (HPLC Method C) to give compound 13 (89 mg, 0.18 mmol, 55% yield) as a white foam. LC / MS (Method C): m / z 502 [M+H] + 1.66 minutes. 1 H NMR (400MHz, methanol-d4) δ8.00-7.85(m,2H),7.73(s,1H),7.63(d,J=8.0Hz,1H),7.19 (d,J=8.1Hz,2H),7.00(d,J=7.9Hz,1H),6.95-6.69(m,3H),4.96(q,J=6.7Hz,1H),4.4 3 (d, J = 12.8 Hz, 1H), 4.28-4.12 (m, 2H), 3.88-3.71 (m, 1H), 3.40-3.35 (m, 1H), 2.67-2.55 (m, 1H), 2.31-2.18 (m, 1H), 2.16 (s, 3H), 2.13-1.97 (m, 2H), 1.42 (d, J = 7.0 Hz, 3H). No exchangeable protons present.

[0372] Example 14: 4-((1S)-1-((2R)-1-((4'-carbamoyl-6-hydroxy-2'-methyl-1,2,3,4,5,6-hexahydro-[1,1'-biphenyl]-3-yl)methyl)pyrrolidine-2-carboxamido)ethyl)benzoic acid (Compound 14)

[0373] Compound 14 was synthesized in a similar process to Example 12 using intermediate 5 and 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide to give compound 14. LC / MS (Method C): m / z 502 [M+H]+ 3.69 minutes. 1 H NMR (400MHz, methanol-d4) δ7.94(d,J=8.2Hz,2H),7.73(d,J=1.8Hz,1H),7.68-7.54(m,1H),7.35-7.2 6(m,1H),7.21(d,J=8.1Hz,2H),7.16(d,J=2.3Hz,1H),7.09-6.96(m,1H),6.90(d,J=8.3Hz,1H),4. 96 (q, J = 7.0, 6.5 Hz, 1H), 4.38 (d, J = 12.8 Hz, 1H), 4.23-4.11 (m, 2H), 3.78-3.66 (m, 1H), 3.34-3.31 (m, 1H), 2.64-2.52 (m, 1H), 2.29-2.15 (m, 1H), 2.11 (s, 3H), 2.09-1.98 (m, 2H), 1.44 (d, J = 7.0 Hz, 3H). No exchangeable protons present.

[0374] Example 15: (R)-4-((1-((4'-carbamoyl-2'-methyl-[1,1'-biphenyl]-3-yl)methyl)pyrrolidine-2-carboxamido)methyl)-2-hydroxybenzoic acid (Compound 15) [ka]

[0375] Step (i): Intermediate 8 (0.20 g, 0.45 mmol), 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (0.15 g, 0.58 mmol), and K2CO3 (0.123 g, 0.89 mmol) were dissolved in 6 mL of a 3:3 dioxane:water mixture, and nitrogen gas was purged through the mixture at room temperature for 30 minutes. PdCl2(dppf)DCM (0.036 g, 0.045 mmol) was then added, and the reaction mixture was stirred at 80 °C for 4 hours. The reaction mixture was then partitioned between water (70 mL) and EtOAc (70 mL). The aqueous layer was further extracted with EtOAc (2 × 50 mL), and the organic layers were combined and dried (Na2SO4). The solvent was removed under reduced pressure, and the crude product was purified by reverse-phase gradient flash column chromatography (reverse-phase, C18 silica). The product was eluted with 0% → 55% MeCN / water to give pure (R)-methyl 4-((1-((4'-carbamoyl-2'-methyl-[1,1'-biphenyl]-3-yl)methyl)pyrrolidine-2-carboxamido)methyl)-2-hydroxybenzoate (0.147 g, 65%) as a light brown solid. LC / MS: (Method A): m / z 502 [M+H] + , 1.46 minutes.

[0376] Step (ii): Methyl 4-((S)-1-((3R,6R)-6-methyl-4-(4-(trifluoromethyl)benzyl)morpholine-3-carboxamido)ethyl)benzoate (0.147 g, 0.29 mmol) was dissolved in dioxane (2 mL) and water (1 mL). LiOH monohydrate (0.036 g, 0.88 mmol) was added at room temperature and stirred at room temperature for 16 hours. The reaction mixture was then acidified with 4N aqueous HCl (2 mL) to adjust the pH to ∼1 and extracted with EtOAc (40 mL). The aqueous layer was further extracted with EtOAc (3 × 30 mL), and the organic layers were combined and dried (NaSO). The solvent was removed under reduced pressure and the crude product was purified by reverse-phase gradient flash column chromatography (reverse phase, C18 silica) eluting the product with 0% to 26% MeCN / water to give compound 15 (0.10 g, 70%) as an off-white solid. LC / MS: (Method A): m / z 488 [M+H] +, 1.34 minutes. 1 H NMR:(400MHz,DMSO)1.79(s,3H),2.24(s,3H),3.17(s,3H),3.81(s,1H),4 .08(s,1H),4.26-4.14(m,2H),6.62-6.60(d,1H,J=8.0Hz),6.66(s,1H),7. 34-7.24(m,3H),7.44-7.401(m,3H),7.64-7.62((d,1H,J=8.0Hz),7.75-7 .73(d,1H,J=7.6Hz),7.80(s,1H),7.97(s,1H),8.53(s,1H),12.97(s,2H).

[0377] Example 16: (R)-2-hydroxy-4-((1-((2'-methyl-4'-sulfamoyl-[1,1'-biphenyl]-3-yl)methyl)pyrrolidine-2-carboxamido)methyl)benzoic acid (Compound 16)

[0378] Compound 16 was synthesized in a similar process to Example 15 using intermediate 8 and 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide to give compound 16. LC / MS: (Method A) m / z 524 [M+H] + , 1.40 minutes. 1 H NMR:(400MHz,DMSO):1.77-1.74(t,3H,J=6.6Hz),2.17(s,1H),2.26(s,3H),3.05(s,1H),3.42-3.40 (m,1H),3.50-3.47(m,1H),3.68(s,1H),4.00-3.97(d,1H,J=12.4Hz),4.25-4.13(m,2H),6.57-6.56 (d,1H,J=8.0Hz),6.61(s,1H),7.28-7.268(d,1H,J=6.8Hz),7.44-7.35(m,6H),7.60-7.58(d,1H,J= 8.0Hz), 7.70-7.67(dd,1H,J=1.6Hz&J=4.0Hz),7.74-7.74(d,1H,1.2Hz),8.39(s,1H),13.62(s,2H).

[0379] Example 17: 4-((S)-1-((R)-1-((4'-carbamoyl-2'-methyl-[1,1'-biphenyl]-3-yl)methyl)pyrrolidine-2-carboxamido)ethyl)-2-hydroxybenzoic acid (Compound 17)

[0380] Compound 17 was synthesized in a similar process to Example 15 using intermediate 10 and 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide to give compound 17. LC / MS: (Method A): Product mass confirmed m / z 502 [M+H] + , 1.16 minutes. 1 H NMR:(400MHz,DMSO)1.28-1.26(d,3H,J=7.2Hz),1.85-1.75(m,3H),2.24(s,4H),3.1 6(s,2H),3.84(s,1H),4.01(s,1H),4.79-4.72(m,1H),6.66-6.64(d,1H,J=7.2Hz),6. 72(s,1H),7.30-7.23(dd,2H,J=7.6Hz),7.45-7.35.(m,4H),7.64-7.62(d,1H,J=8.0H z),7.75-7.73(d,1H,J=8.0Hz),7.80(s,1H),7.98(s,1H),8.32(s,1H),12.97(s,1H).

[0381] Example 18: 2-hydroxy-4-((S)-1-((R)-1-((2'-methyl-4'-sulfamoyl-[1,1'-biphenyl]-3-yl)methyl)pyrrolidine-2-carboxamido)ethyl)benzoic acid (Compound 18)

[0382] Compound 18 was synthesized in a similar process to Example 15 using intermediate 10 and 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide to give compound 18. LC / MS: (Method A) m / z 538 [M+H] + , 1.22 minutes. 1H NMR:(400MHz,DMSO)1.27-1.26(d,3H,J=6.8Hz),1.84-1.75(m,3H),2.26(s,4H),3 .20(s,1H),3.87-3.80(bs,1H),4.02-3.80(bs,1H),4.77-4.73(t,1H,J=7.2Hz),6 .65-6.64 (d, 1H, J = 6.4 Hz), 6.72 (s, 1H), 7.46-7.29 (m, 7H), 7.62-7.60 (d, 1H, J = 8.0 Hz), 7.69-7.670 (d, 1H, J = 8.0 Hz), 7.74 (s, 1H), 8.32-8.31 (m, 1H), 13.08 (s, 1H). (Some aliphatic protons overlap with the peaks of DMSO-d6 water.)

[0383] Example 19: 4-((S)-1-((R)-1-((6-hydroxy-4'-sulfamoyl-[1,1'-biphenyl]-3-yl)methyl)pyrrolidine-2-carboxamido)ethyl)cyclohex-3-ene-1-carboxylic acid (Compound 19)

[0384] Compound 19 was synthesized in a similar process to Example 12 using intermediate 5 and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide to give compound 19. LC / MS (Method D): m / z 524 [M+H] + 1.56 minutes. 1 H NMR (400MHz, methanol-d4) δ7.86(d,J=8.0Hz,2H),7.82-7.77(m,2H),7.59-7.54(m,2H),7.39 (d,J=2.3Hz,1H),7.29-7.23(m,1H),7.08(d,J=8.0Hz,2H),6.89(d,J=8.3Hz,1H),4.91-4. 85 (m, 1H), 4.43 (d, J = 12.9 Hz, 1H), 4.22-4.07 (m, 2H), 3.75 (dt, J = 11.6, 6.0 Hz, 1H), 3.39-3.32 (m, 1H), 2.65-2.47 (m, 1H), 2.27-2.13 (m, 1H), 2.11-1.92 (m, 2H), 1.36 (d, J = 7.0 Hz, 3H). No exchangeable protons present.

[0385] Example 20: 4-((S)-1-((R)-1-((5-hydroxy-2'-methyl-4'-sulfamoyl-[1,1'-biphenyl]-3-yl)methyl)pyrrolidine-2-carboxamido)ethyl)benzoic acid (Compound 20)

[0386] Compound 20 was synthesized in a similar process to Example 12 using intermediate 6 and 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide to give compound 20. LC / MS (Method D): m / z 538 [M+H] + 1.69 minutes. 1 H NMR (400 MHz, methanol-d4) δ 7.92-7.83 (m, 2H), 7.76-7.71 (m, 1H), 7.65-7.59 (m, 1H), 7.21-7.13 (m, 2H), 7.03 (d, J = 8.1 Hz, 1H), 6.93 (dd, J = 2.3, 1.6 Hz, 1H), 6.85 (t, J = 1.5 Hz, 1H), 6.76 (dd, J = 2.4, 1.4 Hz, 1H). 1H), 4.94 (q, J = 7.0 Hz, 1H), 4.45 (d, J = 12.7 Hz, 1H), 4.27-4.15 (m, 2H), 3.86-3.72 (m, 1H), 3.43-3.35 (m, 1H), 2.69-2.55 (m, 1H), 2.31-2.17 (m, 1H), 2.17 (s, 3H), 2.15-1.98 (m, 2H), 1.41 (d, J = 7.0 Hz, 3H). No exchangeable protons present.

[0387] Example 21: 4-((S)-1-((2R,4R)-1-((4'-carbamoyl-5-hydroxy-2'-methyl-[1,1'-biphenyl]-3-yl)methyl)-4-hydroxypyrrolidine-2-carboxamido)ethyl)benzoic acid (Compound 21)

[0388] Compound 21 was synthesized in a similar process to Example 12 using intermediate 6 and 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide to give compound 21. LC / MS (Method D): m / z 518 [M+H] + 1.46 minutes.1 H NMR (400MHz, methanol-d4) δ7.91-7.84(m,2H),7.71(dt,J=2.0,0.6Hz,1H),7.64-7.59(m,1H),7.19-7.12(m,2H),6.97 (d,J=8.0Hz,1H),6.92(dd,J=2.3,1.5Hz,1H),6.89(t,J=1.5Hz,1H),6.75(dd,J=2.3,1.5Hz,1H),4.93(q,J=7.0Hz,1 1H), 4.59-4.55 (m, 1H), 4.52 (d, J = 12.6 Hz, 1H), 4.31 (dd, J = 10.8, 4.2 Hz, 1H), 4.17 (d, J = 12.7 Hz, 1H), 3.79 (d, J = 11.8 Hz, 1H), 3.43 (dd, J = 11.8, 3.8 Hz, 1H), 2.83 (ddd, J = 14.0, 10.8, 4.7 Hz, 1H), 2.19-2.08 (m, 4H), 1.42 (d, J = 7.0 Hz, 3H). No exchangeable protons present.

[0389] Example 22: 4-((1S)-1-((2R)-1-((2'-hydroxy-4'-sulfamoyl-1',2',3',4',5',6'-hexahydro-[1,1'-biphenyl]-3-yl)methyl)pyrrolidine-2-carboxamido)ethyl)benzoic acid (Compound 22) [ka]

[0390] Step (i): Intermediate 1-HCl (0.35 g, 1.12 mmol) and 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (0.31 g, 1.34 mmol) were dissolved in DCM (4 mL) under a nitrogen atmosphere. 4 Å molecular sieves (300 mg) were also added to maintain anhydrous conditions. Potassium acetate (0.11 g, 1.68 mmol) was then added at room temperature, and the reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was then cooled to 0° C., and sodium triacetoxyborohydride (0.28 g, 1.34 mmol) was added in portions, and the reaction mixture was stirred at room temperature for 16 hours. The solvent was removed under reduced pressure to give the crude product, which was purified by reverse-phase gradient flash column chromatography (reverse phase, C18 silica) eluting the product with 0% to 22% MeCN to give methyl 4-((S)-1-((R)-1-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)pyrrolidine-2-carboxamido)ethyl)benzoate (0.26 g, 47.18%) as a yellow solid. LC / MS: (Method A): m / z 411 [M+H] + , (boronic acid), 1.22 min, and m / z 493 [M+H] + , 1.81 minutes.

[0391] Step (ii): Methyl 4-((S)-1-((R)-1-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)pyrrolidine-2-carboxamido)ethyl)benzoate (0.16 g, 0.32 mmol), 4-bromo-3-hydroxybenzenesulfonamide (0.10 g, 0.39 mmol), and KCO (0.13 g, 0.97 mmol) were dissolved in toluene (1 mL), ethanol (0.5 mL), and water (0.5 mL). After purging with nitrogen gas at room temperature for 20 minutes, PdCl(dppf)DCM (0.014 g, 0.016 mmol) was added, and the reaction mixture was stirred at 90 °C for 1.5 hours. The reaction mixture was partitioned between water (70 mL) and EtOAc (70 mL), and the aqueous layer was further extracted with EtOAc (2×40 mL). The organic layers were combined, dried (NaSO), the solvent removed under reduced pressure, and the crude product purified by reverse-phase gradient flash column chromatography (reverse-phase, C18 silica). The product was eluted with 0% to 24% MeCN / water to afford methyl 4-((S)-1-((R)-1-((2′-hydroxy-4′-sulfamoyl-[1,1′-biphenyl]-3-yl)methyl)pyrrolidine-2-carboxamido)ethyl)benzoate (0.08 g, 46.96%) as a yellow solid, which was used in the next step without further purification. LC / MS: (Method A): m / z 538 [M+H] + , 1.33 minutes.

[0392] Step (iii): Methyl 4-((S)-1-((R)-1-((2'-hydroxy-4'-sulfamoyl-[1,1'-biphenyl]-3-yl)methyl)pyrrolidine-2-carboxamido)ethyl)benzoate (0.08 g, 0.15 mmol) was dissolved in dioxane (0.5 mL) and water (0.5 mL). LiOH (0.03 g, 0.76 mmol) was added at room temperature, and the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure to give the crude product, which was purified using preparative HPLC (HPLC Method D).

[0393] LC / MS: (Method A): m / z524[M+H] + , 1.18 minutes. 1H NMR:(400MHz,CD3OD):δ1.34-1.35(d,3HJ=6.8Hz),2.05-1.89(m,3H),2.34 (s,1H),2.82-2.81(d,1H,J=4.8Hz),3.38-3.37(d,1H,J=3.2Hz),3.55-3.5 3(d,1H,J=6.0Hz),4.00(s,2H),7.26-7.25(d,2H,J=7.2Hz),7.45-7.34(m, 5H), 7.58-7.56(d,1H,J=7.6Hz),7.64(s,1H),7.91--7.89(d,2H,J=7.2Hz).

[0394] Example 23: (S)-4-(1-(2-((4'-carbamoyl-5-hydroxy-2'-methyl-[1,1'-biphenyl]-3-yl)methyl)-2-azabicyclo[2.1.1]hexane-1-carboxamido)ethyl)benzoic acid (Compound 23) [ka]

[0395] Step (i): 2-(tert-Butoxycarbonyl)-2-azabicyclo[2.1.1]hexane-1-carboxylic acid (0.25 g, 1.10 mmol) was dissolved in MeCN (3 mL), and (S)-methyl 4-(1-aminoethyl)benzoate (0.23 g, 1.32 mmol) was added to the reaction mixture at room temperature. HATU (0.63 g, 1.65 mmol) was then added, and the reaction mixture was stirred at room temperature for 30 minutes. N,N-Diisopropylethylamine (0.6 mL, 3.30 mmol) was then added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was partitioned between water (60 mL) and EtOAc (50 mL), and the aqueous layer was further extracted with EtOAc (2 x 30 mL). The organic layers were then combined, dried (NaSO), the solvent removed under reduced pressure, and the crude product purified by reverse-phase gradient flash column chromatography (C silica) eluting the product with 100% MeCN to give (S)-tert-butyl 1-((1-(4-(methoxycarbonyl)phenyl)ethyl)carbamoyl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (0.42 g, 98%) as a yellow solid. LC / MS: (Method A): m / z 289 [M+H-Boc] + , 2.23 minutes.

[0396] Step (ii): (S)-tert-butyl 1-((1-(4-(methoxycarbonyl)phenyl)ethyl)carbamoyl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (0.42 g, 1.08 mmol) was dissolved in dioxane (2 mL) under a nitrogen atmosphere. Then, 4 N HCl / dioxane (4 mL) was added at room temperature and stirred at room temperature for 3 hours. The solvent was removed under reduced pressure, and the crude product was purified by trituration with diethyl ether (5 mL) to give (S)-methyl 4-(1-(2-azabicyclo[2.1.1]hexane-1-carboxamido)ethyl)benzoate hydrochloride (0.34 g, quantitative) as a pale yellow solid. LC / MS: (Method A): m / z 289 (ES+), 1.00 min.

[0397] Step (iii): (S)-methyl 4-(1-(2-azabicyclo[2.1.1]hexane-1-carboxamido)ethyl)benzoate hydrochloride (0.26 g, 0.80 mmol) and DIPEA (0.4 mL, 2.40 mmol) were dissolved in MeCN (3 mL) at room temperature. After this time, 3'-(bromomethyl)-5'-hydroxy-2-methyl-[1,1'-biphenyl]-4-carboxamide (0.30 g, 0.96 mmol) was added, and the reaction mixture was stirred at 80 °C for 16 h. The reaction mixture was partitioned between water (80 mL) and EtOAc (80 mL), and the aqueous layer was further extracted with EtOAc (2 × 25 mL). The organic layers were combined, dried (NaSO), the solvent was removed under reduced pressure, and the crude product was purified by reverse-phase gradient flash column chromatography (C18 silica). The product was eluted with 0% to 59% MeCN / water to give (S)-4-(1-(2-((4'-carbamoyl-5-hydroxy-2'-methyl-[1,1'-biphenyl]-3-yl)methyl)-2-azabicyclo[2.1.1]hexane-1-carboxamido)ethyl)methyl benzoate (0.20 g, 48%) as a yellow solid. LC / MS (Method A): m / z 528.17 (ES+), 1.65 min.

[0398] Step (iv): (S)-4-(1-(2-((4'-carbamoyl-5-hydroxy-2'-methyl-[1,1'-biphenyl]-3-yl)methyl)-2-azabicyclo[2.1.1]hexane-1-carboxamido)ethyl)methyl benzoate (0.20 g, 0.39 mmol) was dissolved in dioxane (1 mL) and water (1 mL). LiOH monohydrate (0.084 g, 1.99 mmol) was then added at room temperature and stirred for 3 hours. The reaction mixture was acidified with glacial acetic acid (2 mL) to adjust the pH to approximately 4 and then concentrated under reduced pressure. The crude product was purified by reverse-phase gradient flash column chromatography (reverse-phase, C18 silica). The product was eluted with 0% to 36% ACN / water to give compound 23 (0.17 g, 85.19%) as an off-white solid. LC / MS (Method A): m / z 514.2 (ES+), 1.456 min. 1H NMR:(400MHz,DMSO)δ1.373-1.355(d,3H,J=7.2Hz),1.791-1.768(d,4H,J=9.2Hz),2.267(s,3H),2.619-2.59 5(d,2H,J=9.6Hz),2.686-2.666(d,1H,J=8.0Hz),3.475(s,2H),5.041-4.986(m,1H),6.594(s,1H),6.848-6.8 22(d,2H,J=10.4Hz),7.251-7.231(d,1H,J=8.0Hz),7.341(s,1H),7.403-7.383(d,2H,J=8.0Hz),7.735-7.71 6(d,1H,J=7.6Hz),7.800-7.780(t,3H,J=4.0Hz),7.968(s,1H),8.228-8.208(d,1H,J=8.0Hz),12.979(s,1H).

[0399] Example 24: 4-((S)-1-((R)-1-((5-(2-methyl-4-sulfamoylphenyl)pyridin-3-yl)methyl)pyrrolidine-2-carboxamido)ethyl)benzoic acid (Compound 24) [ka]

[0400] Step (i): A mixture of 5-bromonicotinaldehyde (356.81 mg, 1.92 mmol) and Intermediate 1 (300.0 mg, 0.96 mmol) in DCM (4.5 mL) was stirred at room temperature for 1 h, then sodium triacetoxyborohydride (426.87 mg, 2.01 mmol) was added and the mixture was stirred at room temperature for 16 h, then diluted with saturated NaHCO. The organic layer was separated, washed with water and brine, dried (frit), and concentrated. The residue was then purified by flash column chromatography (25 g Biotage® SNAPKP-Sil, 30 mL / min, 30% to 100% ethyl acetate / isohexane gradient) to afford methyl 4-[(1S)-1-[[(2R)-1-[(5-bromo-3-pyridyl)methyl]pyrrolidine-2-carbonyl]amino]ethyl]benzoate (398.1 mg, 0.89 mmol, 93% yield) as a white solid. LC / MS (Method B): m / z 446 [M+H] + , 2.12 minutes.

[0401] Step (ii): A mixture of methyl 4-[(1S)-1-[[(2R)-1-[(5-bromo-3-pyridyl)methyl]pyrrolidine-2-carbonyl]amino]ethyl]benzoate (200.0 mg, 0.45 mmol), 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide (173.11 mg, 0.58 mmol), potassium carbonate (123.86 mg, 0.90 mmol), and tetrakis(triphenylphosphine)palladium(0) (77.67 mg, 0.07 mmol) in 1,4-dioxane (1.8 mL) and water (0.45 mL) was heated to 100° C. in a microwave reactor for 30 minutes. The crude product was diluted with water and EtOAc, and the organic layer was separated, washed with water, brine, dried (fritted), and then concentrated under reduced pressure. The residue was purified by flash column chromatography (50 g Biotage® SNAPKP-Sil 80 mL / min, 30% to 100% ethyl acetate / isohexane gradient) to afford methyl 4-[(1S)-1-[[(2R)-1-[[5-(2-methyl-4-sulfamoyl-phenyl)-3-pyridyl]methyl]pyrrolidine-2-carbonyl]amino]ethyl]benzoate (231 mg, 96.065%) as an off-white solid. LC / MS (Method B): m / z 537 [M+H] + , 1.93 minutes.

[0402] Step (iii): To a solution of lithium hydroxide monohydrate (63.22 mg, 1.51 mmol) in water (3.2 mL) and 1,4-dioxane (3.2 mL), methyl 4-[(1S)-1-[[(2R)-1-[[5-(2-methyl-4-sulfamoyl-phenyl)-3-pyridyl]methyl]pyrrolidine-2-carbonyl]amino]ethyl]benzoate (231.0 mg, 0.43 mmol) was added, and the resulting mixture was allowed to stir for 3 h, after which LC / MS confirmed completion. The mixture was then concentrated under reduced pressure, and the residue was purified by reverse-phase HPLC (5-35%, low pH) to give compound 24 (136.1 mg, 0.26 mmol, 60.5% yield) as a colorless glass. LC / MS (Method D): m / z 523 [M+H] + , 1.51 minutes. 1H NMR(400MHz,DMSO-d6)δ9.83(br,s,1H),δ9.01(d,J=7.7Hz,1H),8.66(d,J=2.0Hz,1H),8.53(d,J=2.1Hz,1H) ,7.92(t,J=2.1Hz,1H),7.83-7.78(m,2H),7.77-7.73(m,1H),7.71-7.64(m,1H),7.36(s,2H),7.22(d,J=8.0H z, 1H), 7.15 (d, J = 8.1 Hz, 2H), 4.84 (p, J = 7.0 Hz, 1H), 4.51-4.42 (m, 2H), 4.27-4.22 (m, 1H), 3.69-3.55 (m, 1H), 3.44-3.25 (m, 1H), 2.17 (s, 3H), 2.15-2.06 (m, 1H), 1.91 (tq, J = 15.8, 8.7, 8.2 Hz, 2H), 1.31 (d, J = 7.0 Hz, 3H). No exchangeable protons.

[0403] Example 25: 4-((S)-1-((2R,4R)-1-((5-(4-carbamoyl-2-methylphenyl)pyridin-3-yl)methyl)-4-hydroxypyrrolidine-2-carboxamido)ethyl)benzoic acid (Compound 25)

[0404] Compound 25 was synthesized in a similar process to Example 24 using Intermediate 3 and 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide to give Compound 25. LC / MS (Method D): m / z 503 [M+H] + , 1.21 minutes. 1H NMR(400MHz,DMSO-d6)δ8.80(d,J=7.8Hz,1H),8.64(d,J=2.0Hz,1H),8.43(d,J=2.1Hz, 1H),8.00(t,J=2.1Hz,1H),7.95(s,1H),7.87-7.56(m,4H),7.37(s,1H),7.11-6.92(m,3 H), 4.75 (p, J = 7.1 Hz, 1H), 4.66-4.33 (m, 4H), 4.26 (s, 1H), 3.68-3.51 (m, 1H), 3.49-3.25 (m, 1H), 2.84-2.60 (m, 1H), 2.09 (s, 3H), 1.95 (d, J = 13.9 Hz, 1H), 1.28 (d, J = 7.0 Hz, 3H). No exchangeable protons.

[0405] Example 26: 3-(4-carbamoyl-2-methylphenyl)-5-(((R)-2-(((S)-1-(4-carboxyphenyl)ethyl)carbamoyl)pyrrolidin-1-yl)methyl)pyridine 1-oxide (Compound 26) [ka]

[0406] Step (i): To a suspension of (4-carbamoyl-2-methylphenyl)boronic acid pinacol ester (4.00 g, 15.3 mmol, 1.0 equiv.), 5-bromo-3-pyridinemethanol (2.88 g, 15.3 mmol, 1 equiv.), and CHCOOK (4.50 g, 45.9 mmol, 3 equiv.) in dioxane / HO (64 mL / 16 mL) was added Pd(dppf)Cl (1.12 g, 1.53 mmol, 0.1 equiv.) under N. The reaction mixture was stirred at 85 °C for 16 h, after which the mixture was filtered and concentrated. The residue was purified by silica gel column chromatography (eluent—DCM:MeOH=20:1→10:1) to give 4-(5-(hydroxymethyl)pyridin-3-yl)-3-methylbenzamide (2.5 g, 68%) as a yellow solid. LC / MS: (Method E): m / z 243 [M+H] + , 0.80 minutes.

[0407] Step (ii): To a solution of 4-(5-(hydroxymethyl)pyridin-3-yl)-3-methylbenzamide (1.20 g, 4.9 mmol, 1.0 equiv.) in DCM (30.00 mL) was added SOCl (5.83 g, 49.0 mmol, 10.0 equiv.). The mixture was stirred at room temperature for 1 hour, filtered, concentrated, and the residue was purified by silica gel column chromatography (eluent—DCM:MeOH=20:1→10:1) to give 4-(5-(chloromethyl)pyridin-3-yl)-3-methylbenzamide (1.0 g, 78.7%) as a yellow solid. LC / MS: (Method E): m / z 261 [M+H] + , 2.73 minutes.

[0408] Step (iii): To a suspension of 4-(5-(chloromethyl)pyridin-3-yl)-3-methylbenzamide (500.0 mg, 1.92 mmol, 1.0 equiv.) in DCM (15 mL) was added m-CPBA (663.5 mg, 3.84 mmol, 2.0 equiv.). The reaction mixture was stirred at room temperature for 1 hour, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent—DCM:MeOH=20:1→15:1) to give 3-(4-carbamoyl-2-methylphenyl)-5-(chloromethyl)pyridine 1-oxide (500 mg, 94%) as a pale yellow solid. LC / MS: (Method E): m / z 277 [M+H] + , 2.30 minutes.

[0409] Step (iv): To a solution of 3-(4-carbamoyl-2-methylphenyl)-5-(chloromethyl)pyridine 1-oxide (200 mg, 0.72 mmol, 1.0 equiv.) in MeCN (12 mL) and DMF (2 mL) was added Intermediate 1 (226 mg, 0.72 mmol, 1.0 equiv.), NaHCO (182 mg, 2.17 mmol, 3.0 equiv.), and NaI (108 mg, 0.72 mmol, 1.0 equiv.). The resulting mixture was stirred at 70 °C for 4 h, then filtered and concentrated. The residue was purified by silica gel column chromatography (eluent—DCM:MeOH=30:1→15:1) to give 3-(4-carbamoyl-2-methylphenyl)-5-(chloromethyl)pyridine 1-oxide (311 mg, yield: 89%) as a white solid. LC / MS: (Method E): m / z517[M+H] + , 2.50 minutes.

[0410] Step (v): To a solution of compound 3-(4-carbamoyl-2-methylphenyl)-5-(chloromethyl)pyridine 1-oxide (330 mg, 0.60 mmol, 1.0 equiv.) in methanol (10 mL) was added LiOH (1.8 mL, 1.80 mmol, 3.0 equiv.). The mixture was stirred at room temperature for 2 days, then diluted with water (5 mL), acidified to about pH 5 with 1N HCl, and the solvent was removed under reduced pressure. The residue was purified by preparative HPLC (Method E) to give compound 26 (120 mg, yield: 40.0%) as a white solid. LC / MS: (Method E): m / z 503 [M+H] + , 1.20 minutes. 1H NMR (400MHz, methanol-d4): δ8.51-8.48(m,1H),8.18(s,1H),7.87(dd,J=8.0,2.0Hz,2H),7 .80(s,1H),7.73(d,J=8.0Hz,1H),7.63-7.60(m,1H),7.23(d,J=8.0Hz,2H),6.98(d,J=7. 6Hz,1H),4.65-4.59(m,1H),4.42-4.28(m,2H),3.90(s,1H),3.48-3.43(m,1H),2.76-2.6 9(m,1H),2.34-2.27(m,1H),2.21-2.14(m,4H),2.13-2.07(m,1H),1.44(d,J=7.2Hz,3H).

[0411] Example 27: 4-(1-(2-((2'-methyl-4'-sulfamoyl-[1,1'-biphenyl]-3-yl)methyl)-2-azabicyclo[2.1.1]hexane-1-carboxamido)cyclopropyl)benzoic acid (Compound 27) Compound 27 was synthesized in a similar manner to Example 23 using methyl 4-(1-aminocyclopropyl)benzoate and intermediate 12 to give compound 27. LC / MS: (Method A): 546 [M+H] + , 1.40 min. Chiral HPLC: Product purity confirmed at 11.73 min. 1H NMR: (400 MHz, DMSO) 1.13 (m, 2H), 1.23 (m, 2H), 1.85-1.78 (m, 4H), 2.32 (s, 3H), 2.67 (s, 3H), 3.63 (s, 2H), 7.17-7.15 (d, 2H, J = 8 Hz), 7.26-7.25 (d, 1H, J = 6.4 Hz), 7.50-7.37 (m, 6H), 7.76-7.69 (m, 4H), 8.61 (s, 1H), 12.83 (bs, 1H).

[0412] Example 28: (S)-4-(1-(2-((4'-carbamoyl-2'-methyl-[1,1'-biphenyl]-3-yl)methyl)-2-azabicyclo[2.1.1]hexane-1-carboxamido)ethyl)benzoic acid (Compound 28) Compound 28 was synthesized using intermediate 13 in a process similar to that of Example 23 to give compound 28. LC / MS: (Method A): m / z 498 (ES+), 1.27 min. Chiral HPLC: Product purity confirmed at 8.83 min. 1H NMR:(400MHz,DMSO):1.39-1.37(d,3H,J=7.2Hz),1.79(m,4H),2.28(s,3H),2.70-2.61(m,3H),3.57(s,2H),5.06-5. 02(t,1H,J=7.4Hz),7.29-7.24(m,2H),7.46-7.36(m,6H),7.82-7.75(m,4H),7.97(s,1H),8.30(s,1H),12.80(s,1H).

[0413] Example 29: 4-(1-(2-((4'-carbamoyl-2'-methyl-[1,1'-biphenyl]-3-yl)methyl)-2-azabicyclo[2.1.1]hexane-1-carboxamido)cyclopropyl)benzoic acid (Compound 29) Compound 29 was synthesized using methyl 4-(1-aminocyclopropyl)benzoate and intermediate 13 in a similar process to Example 23 to give compound 29. LC / MS: (Method A): m / z 510 [M+H] + , 1.23 minutes. 1H NMR:(400MHz,DMSO):1.14(s,2H),1.24(s,2H),1.78(d,2H,J=3.6Hz),1.85(s,2H),2.29(s,3H),2.61(s,1H),2.67(s,2H),3. 62(s,2H),7.18-7.30(m,4H),7.36-7.48(m,4H),7.74(d,3H,J=8.0Hz),7.82(s,1H),7.98(s,1H),8.65(s,1H),12.82(s,1H).

[0414] Example 30: (R)-4-(1-(1-((2'-methyl-4'-sulfamoyl-[1,1'-biphenyl]-3-yl)methyl)pyrrolidine-2-carboxamido)cyclopropyl)benzoic acid (Compound 30) Compound 30 was synthesized in a similar process to Example 23 using (tert-butoxycarbonyl)-D-proline, methyl 4-(1-aminocyclopropyl)benzoate, and Intermediate 12 to give Compound 30. LC / MS: (Method A): m / z 534 [M+H] + , 1.18 minutes. Chiral HPLC: Product purity confirmed at 11.23 min. 1H NMR:(400MHz,DMSO):1.06-1.04(d,2H,J=4.8Hz),1.19-1.18(m,2H),1.78-1.77(d,3H,J=2. 8Hz),2.14-2.12(m,1H),2.29(s,3H),2.38-2.36(m,1H),3.12-3.11(m,2H),3.62-3.59(d,1H ,J=12.8Hz),3.85-3.82(d,1H,J=13.2Hz),7.11-7.09(d,2H,J=8.4Hz),7.28-7.27(d,1H,J= 6.8Hz),7.44-7.35(m,6H),7.7o-7.67(m,1H),7.78-7.75(q,3H),8.48(s,1H),12.77(s,1H).

[0415] Example 31: (R)-4-(1-(1-((4'-carbamoyl-2'-methyl-[1,1'-biphenyl]-3-yl)methyl)pyrrolidine-2-carboxamido)cyclopropyl)benzoic acid (Compound 31) Compound 31 was synthesized in a similar process to Example 23 using (tert-butoxycarbonyl)-D-proline, methyl 4-(1-aminocyclopropyl)benzoate, and Intermediate 12 to give Compound 31. LC / MS: (Method A): m / z 498 [M+H] + , 1.12 min. Chiral HPLC: Product purity confirmed at 8.98 min. 1H NMR:(400MHz,DMSO)1.20(m,1H),1.23(m,1H),1.77(s,3H),2.08-2.10(m,1H) ,2.27(s,3H),2.67(s,2H),3.04-3.34(m,3H),3.60(d,1H,J=13.2Hz),3.82(d ,1H,J=12.8Hz),7.06(d,2H,J=8.4Hz),7.26(d,2H,J=7.6Hz),7.35-7.42(m,4 H),7.74(d,3H,J=8Hz),7.80(s,1H),7.99(s,1H),8.45(s,1H),12.78(s,1H).

[0416] Example 32: (S)-4-(1-(2-((2'-methyl-4'-sulfamoyl-[1,1'-biphenyl]-3-yl)methyl)-2-azabicyclo[2.1.1]hexane-1-carboxamido)ethyl)benzoic acid (Compound 32) Compound 32 was synthesized in a similar process to Example 23 using intermediate 12 to give compound 32. LC / MS: (Method A): Product m / z 534 (ES+), 1.27 min. Chiral HPLC: Product purity confirmed at 12.16 min. 1H NMR:(400MHz,DMSO)1.39-1.37(d,3H,J=7.2Hz),1.82-1.79(m,4H),2.31(s,3H),2.18-2.61(m,3H),3.61-3.53(m,2H), 7.26-7.24(m,1H),7.47-7.37(m,8H),7.72-7.70(m,1H),7.80-7.76(m,3H),8.28-8.26(d,1H,J=8.4Hz),12.86(s,1H).

[0417] Example 33: 4-((S)-1-((R)-1-((4',5-dihydroxy-2'-methyl-[1,1'-biphenyl]-3-yl)methyl)pyrrolidine-2-carboxamido)ethyl)benzoic acid (Compound 33) [ka]

[0418] Step (i): To a solution of (tert-butoxycarbonyl)-D-proline (5.0 g, 27.90 mmol) in DMF (50 mL) was added HATU (21.22 g, 55.8 mmol, 2 equiv.) and DIPEA (24.15 ml, 139.5 mmol, 5 equiv.), and the mixture was stirred at 25° C. for 0.5 h. (S)-4-(1-aminoethyl)methyl benzoate (6.01 g, 27.90 mmol, 1 equiv.) was added, and the resulting mixture was stirred at 25° C. for 1 h. After completion, the reaction mixture was diluted with HO (500 mL) and extracted with EA (2×150 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography eluting with a 0-50% ethyl acetate / hexane gradient to give tert-butyl (R)-2-(((S)-1-(4-(methoxycarbonyl)phenyl)ethyl)carbamoyl)pyrrolidine-1-carboxylate (8.5 g, 79.31%) as a yellow oil.

[0419] TLC:(5.0:5.0, EA / Hexene, RF:0.7).

[0420] Mass (ESI+ve): 277.0[M-100].

[0421] LCMS: 98.91% (LCMS method H), retention time: 2.949 minutes, 254 nm.

[0422] 1H NMR:(400MHz,DMSO):1.20-1.25(m,9H),1.34-1.47(m,3H),1.78-2.13(m,4H),3.27-3.35(m,2H),3.83(m, 3H),4.06-4.15(m,1H),4.93-5.00(m,1H),7.4-7.52(m,2H),7.8-7.90(m,2H),8.36-8.38(d,J=6.8Hz,1H).

[0423] Step (ii): To a solution of tert-butyl (R)-2-(((S)-1-(4-(methoxycarbonyl)phenyl)ethyl)carbamoyl)pyrrolidine-1-carboxylate (8.5 g, 2.85 mmol, 1 equiv) in DCM (100 mL) was added HCl / dioxane (4.0 M, 85 mL). The mixture was stirred at 15° C. for 1 h. After complete consumption of the starting material, the reaction mixture was concentrated under reduced pressure to remove the HCl / dioxane. Further dioxane (30 ml) was added to the residue and concentrated under reduced pressure to give methyl 4-((S)-1-((R)-pyrrolidine-2-carboxamido)ethyl)benzoate (7.5 g, crude, HCl salt) as a brown solid.

[0424] TLC:(5.0:5.0, EA / Hexene, RF:0.8).

[0425] Mass (ESI+ve): 277.0[M+1].

[0426] LCMS: 89.10% (LCMS method H), retention time: 2.184 minutes, 230 nm.

[0427] 1H NMR:(400MHz,DMSO):1.26-1.41(m,6H),1.89(s,3H),2.33-2.35(m,2H),3.63-3.90(m,9H),3.18(m,3H),4.47-3.84(m,6H),4.21 (m,1H)4.97-5.0(m,1H),7.50-7.52(d,J=4.4Hz,2H),7.90-7.94(dJ=16.0Hz,2H),8.51(s,1H),9.29-9.30(d,1H).10.03(s,1H).

[0428] HPLC analysis: 99.41%5.81 retention time, 240.0nm, 4.0nm

[0429] Step (iii): To a solution of methyl 4-((S)-1-((R)-pyrrolidine-2-carboxamido)ethyl)benzoate (7.5 g, 27.14 mmol, 1 equiv., HCl), 3-bromo-5-methoxybenzaldehyde (7.01 g, 32.57 mmol, 1.2 equiv.) in DCE (40 mL) and DMF (40 mL), TEA (3.76 mL, 27.14 mmol, 1 equiv.) was added, and the mixture was stirred at 30° C. for 1 h. AcOH (1.63 mL, 27.14 mmol, 1 equiv.) and NaBHCN (3.41 g, 54.28 mmol, 2 equiv.) were added, and the resulting mixture was stirred at 30° C. for 12 h. The starting material was completely consumed, and one major peak with the desired mass was detected. The mixture was then diluted with HO (500 mL), the pH was adjusted to 9 with solid NaHCO, and extracted with EA (2 × 200 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography eluting with a 0–10% MEOH / DCM gradient to give the pure compound 4-((S)-1-((R)-1-(3-bromo-5-methoxybenzyl)pyrrolidine-2-carboxamido)ethyl)methyl benzoate (5.40 g, 39.76%) as a white solid.

[0430] TLC: (1.0:9.0, MeOH / DCM, RF:0.2).

[0431] Mass (ESI+ve): 475.2[M+1].

[0432] LCMS: 95.77% (LCMS method H), retention time: 3.656 minutes, 202 nm.

[0433] 1H NMR: (400MHz, DMSO):6.92(s,1H),7.038(s,1H),7.14(s,1H),7.42-7.44(d,J=8.0 Hz,2H),7.89-7.91(d,J=8.0Hz,2H),8.18-8.20(d,J=8.0Hz,1H),1.10-1.14(m,4H) ,1.34-1.36(d,3H),1.65-1.73(m,3H),2.020-2.068(m,1H),2.33-2.36(m,1H),2.7 2-3.10(m,6H),3.47-3.50(d,J=12.0Hz,1H),2.70-3.85(m,6H),4.86-4.90(m,1H).

[0434] 1H NMR: (400MHz, CDCl3):6.79(s,1H),7.017(s,1H),7.092(s,1H),7.36-7.39(d,J=8 .0Hz,2H),7.68(s,1H),8.037-8.058(d,J=8.0Hz,2H),1.16-1.35(m,6H),1.36-1.4 6(s,3H),1.70-1.84(m,3H),2.24(m,1H),2.44-2.46(s,1H),2.64(s,1H),2.84-3. 14(m,5H),3.26(m,1H),3.54-3.57(m,1H),3.72-4.002(m,7H),5.056-5.10(m,1H).

[0435] HPLC analysis: 99.59%, retention time, 6.57 minutes, 239.0 nm.

[0436] Step (iv): To a solution of methyl 4-((S)-1-((R)-1-(3-bromo-5-methoxybenzyl)pyrrolidine-2-carboxamido)ethyl)benzoate (5.3 g, 11.15 mmol, 1 equiv.), (4-hydroxy-2-methylphenyl)boronic acid (2.55 g, 16.72 mmol, 1.5 equiv.) in dioxane (70 mL) and HO (15 mL) was added KCO (3.078 g, 11.15 mmol, 2 equiv.) and Pd(dppf)Cl (0.816 g, 1.11 mmol, 0.1 equiv.). The mixture was stirred at 90 °C under N for 12 h. The starting material was completely consumed and one new spot was formed. The reaction mixture was diluted with HO (100 mL) and extracted with EA (2 × 100 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue that was purified by flash silica gel chromatography eluting with a gradient of 0-0.5% MeOH / DCM to give methyl 4-((S)-1-((R)-1-((4'-hydroxy-5-methoxy-2'-methyl-[1,1'-biphenyl]-3-yl)methyl)pyrrolidine-2-carboxamido)ethyl)benzoate (3.5 g, 66%) as a white solid.

[0437] TLC: (5.0:5.0, EA / Hexene, RF: 0.2).

[0438] Mass (ESI+ve): 503.2[M+1].

[0439] LCMS: 92.39% (LCMS method H), retention time: 3.296 minutes, 230 nm.

[0440] 1H NMR: (400MHz, DMSO):6.62-6.70(m,3H),6.82-6.85(d,J=11.2Hz,2H),7.00-7.02(d, J=8.0Hz,1H),7.40-7.42(d,J=8.0Hz,2H),7.86-7.88(d,J=8.0Hz,2H),8.14-8.16(d, J=8.0Hz,1H),1.23-1.33(m,4H),1.72(m,3H),2.05(m,1H),2.16(s,3H),2.33-2.39( m,1H),3.087-3.097(m,2H),3.49-3.52(m,1H),3.76-3.94(m,7H),4.85-4.90(m,1H).

[0441] 1H NMR: (400MHz, CDCl3): 6.75-6.85(m,5H),7.08-7.10(d,1H),7.30-7.39(m,2H),7.87-8.06(m,3H),1.30-1.48(m,3H),1.72-1. 89(m,4H),2.24(s,4H),2.48(m,1H),3.18(m,1H),3.34-3.35(m,2H),3.49-3.52(m,1H),3.62-3.66(m,1H),3.85-3.95(m,6H).

[0442] HPLC analysis: 89.40% retention time 7.31 minutes, 239.0 nm.

[0443] Step (v): To a solution of methyl 4-((S)-1-((R)-1-((4'-hydroxy-5-methoxy-2'-methyl-[1,1'-biphenyl]-3-yl)methyl)pyrrolidine-2-carboxamido)ethyl)benzoate (3.7 g, 7.36 mmol, 1 equiv.) in DCM (100 mL) was added BBr3 (1.0 M solution in DCM) (40.52 ml, 5.5 equiv.) dropwise at -60 °C. After the addition, the mixture was stirred at this temperature for 30 min, and then the resulting mixture was stirred at 15 °C for 2 h. The starting material was completely converted. The reaction mixture was then quenched at -60 °C by the addition of MeOH (200 mL), and then the mixture was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography eluting with a 0-20% MeOH / DCM gradient to give methyl 4-((S)-1-((R)-1-((4',5-dihydroxy-2'-methyl-[1,1'-biphenyl]-3-yl)methyl)pyrrolidine-2-carboxamido)ethyl)benzoate (2.80 g, 77.85%) as a white solid.

[0444] TLC: (4.0:1.0:5.0 EA / MEOH / DCM, RF: 0.4).

[0445] Mass (ESI+ve): 489.2[M+1].

[0446] LCMS: 84.75% (LCMS method H), retention time: 2.921 minutes, 254.0 nm.

[0447] 1H NMR:(400MHz,DMSO):6.57-6.58(m,2H),6.64(d,1H),6.80-6.84(m,3H),7.17 -7.23(d,J=8.0Hz,2H),7.81-7.89(d,J=8.0Hz,2H),9.01-9.028(d,J=7.2Hz,1 H),1.35-1.37(m,3H),1.90-1.93(m,2H),2.05-2.15(m,4H),2.70(m,1H),3.18 (s,4H),3.32(m,1H),3.60-3.62(s,1H),4.23-4.31(m,3H),4.88-4.31(m,1H).

[0448] Chiral HPLC: 85.25%, retention time 8.23 min, 234.0 nm.

[0449] Step (vi): To a solution of methyl 4-((S)-1-((R)-1-((4',5-dihydroxy-2'-methyl-[1,1'-biphenyl]-3-yl)methyl)pyrrolidine-2-carboxamido)ethyl)benzoate (2.80 g, 5.73 mmol) in EtOH (10 mL) and THF (30 mL) was added LiOH·HO (2.40 g, 57.31 mmol) in HO (30 mL). The mixture was stirred at room temperature for 15 h. RMLCMS showed that starting material remained. Then, LiOH·HO (2.65 g, 63.04 mmol) was added again, and the mixture was stirred at room temperature for 24 h. After complete consumption of the starting material, the reaction mixture was concentrated under reduced pressure to remove EtOH and THF. The mixture was then diluted with HO (20 mL), adjusted to pH 5 with HCl solution (2.0 M), and the mixture was concentrated under reduced pressure to give the crude product, which was purified by preparative HPLC (Method F) to give 4-((S)-1-((R)-1-((4',5-dihydroxy-2'-methyl-[1,1'-biphenyl]-3-yl)methyl)pyrrolidine-2-carboxamido)ethyl)benzoic acid (Compound 33) (500 mg, 18.38%) as a white solid.

[0450] TLC: (1.0:9.0, methanol / DCM, RF:0.1).

[0451] Mass (ESI+ve):475.0[M+H].

[0452] LCMS: 100.0% (LCMS method I), retention time: 2.747 minutes, 304.0 nm.

[0453] LCMS: 100.0% (LCMS method H), retention time: 2.080 minutes, 304.0 nm.

[0454] HPLC analysis: 100.0% [retention time 2.85 min, 220.0 nm].

[0455] 1H NMR:(400MHz,MeOD):6.63-6.70(m,5H),6.95-6.98(d,J=8.0Hz,1H),7.288-7.307(d,J=7.6Hz,2H),7.94-7.97(d,J=8.0Hz,2H),1.3 5-1.39(m,3H),1.87-1.97(m,3H),2.17(m,3H),2.34(m,1H),2.79-2.813(m,1H),3.40(m,1H),3.53-3.55(m,1H),3.86-3.95(m,1H).

[0456] 1H NMR:(400MHz,DMSO):6.57-6.71(m,5H),6.976-6.996(d,J=8.0Hz,1H),7.368- 7.388(d,J=8.0Hz,2H),7.865-7.885(d,J=8.0Hz,2H),8.052-8.072(d,J=8.0H z,1H),9.40(s,1H),1.25-1.33(m,3H),1.70-1.73(m,3H),2.066(m,2H),2.166 (s,3H),3.028(s,1H),3.08-3.12(m,1H),3.70-3.77(m,2H),3.86-4.90(m,1H).

[0457] Example 34: 4-((S)-1-((R)-1-((4'-carbamoyl-5-hydroxy-2'-methyl-[1,1'-biphenyl]-3-yl)methyl)pyrrolidine-2-carboxamido)ethyl)-2-hydroxybenzoic acid (Compound 34) [ka]

[0458] Step (i): To a solution of intermediate 14 (160 mg, 448.38 μmol, 1 equiv., HCl) and intermediate 15 (144.89 mg, 538.05 μmol, 1.2 equiv.) in DCE (2.5 mL) and DMF (2.5 mL), TEA (45.37 mg, 448.38 μmol, 62.41 μL, 1 equiv.) was added, and the mixture was stirred at 30° C. for 1 h. After adding AcOH (26.93 mg, 448.38 μmol, 25.64 μL, 1 equiv.) and NaBHCN (56.35 mg, 896.75 μmol, 2 equiv.), the resulting mixture was stirred at 30° C. for 12 h. LC-MS showed that intermediate 14 was completely consumed, and one major peak with the desired mass was detected. The combined mixture was then diluted with HO (20 mL), the pH was adjusted to 9 with solid NaHCO, and extracted with EtOAc (30 mL*2). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (HPLC Method G) to give compound c1 (102 mg, 174.07 μmol, 38.82% yield, 97.9% purity) as a yellow solid, which was confirmed by HNMR.

[0459] LCMS:[M+1] + =574.2.

[0460] SFC: retention time = 1.404 min, ee = 100%

[0461] 1 HNMR:(MeOD,400MHz)δ7.80(s,1H),7.75-7.71(m,1H),7.67(d,J=8.0Hz,1H),7. 29(d,J=7.6Hz,1H),6.98(d,J=11.2Hz,2H),6.91-6.85(m,2H),6.79(s,1H),4.85 -4.81(m,1H),4.30(q,J=6.8,2H),3.86-3.71(m,8H),3.27-3.17(m,2H),2.61-2. 49(m,1H),2.30(s,3H),2.27-2.13(m,1H),1.88-1.74(m,3H),1.39-1.29(m,6H).

[0462] Step (ii): To a solution of compound c1 (230 mg, 400.92 μmol, 1 equiv) in DCM (8 mL) was added BBr3 (502.20 mg, 2.00 mmol, 193.15 μL, 5 equiv) in DCM (2 mL) at −60° C. dropwise. After the addition, the mixture was stirred at this temperature for 30 minutes, and then the resulting mixture was stirred at 15° C. for 2 hours. LC-MS showed that compound c1 was completely consumed. The reaction mixture was quenched by the addition of MeOH (5 mL) at −60° C., and then the mixture was allowed to warm to room temperature and concentrated under reduced pressure to give compound c2 (220 mg, crude) as a yellow solid.

[0463] LCMS:[M+1] + =546.2.

[0464] Step (iii): To a solution of compound c2 (220 mg, 403.21 μmol, 1 equiv.) in EtOH (1 mL) and THF (5 mL) was added LiOH·HO (50.76 mg, 1.21 mmol, 3 equiv.) in HO (1 mL). The mixture was stirred at 30 °C for 15 h. LC-MS showed that compound c2 remained. LiOH·HO (50.76 mg, 1.21 mmol, 3 equiv.) was added, and the mixture was stirred at 30 °C for 15 h. LC-MS showed that 9.1% of compound c2 remained and one major peak with the desired mass was detected. The reaction mixture was concentrated under reduced pressure to remove EtOH and THF. The mixture was then diluted with HO (3 mL), adjusted to pH 5 with HCl (2 M), and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (HPLC method H) to give 4-((S)-1-((R)-1-((4'-carbamoyl-5-hydroxy-2'-methyl-[1,1'-biphenyl]-3-yl)methyl)pyrrolidine-2-carboxamido)ethyl)-2-hydroxybenzoic acid (compound 34) (111.7 mg, 214.09 μmol, 53.10% yield, 99.2% purity) as a white solid, which was characterized by HNMR.

[0465] LCMS (LCMS method J): 1.25 min, m / z518.34[MH+]

[0466] SFC: retention time = 1.499 min, ee = 100%

[0467] 1 HNMR(MeOD,400MHz)δ7.79-7.71(m,2H),7.66(dd,J=1.6,8.0Hz,1H),7.09(d,J=8.0Hz,1H),6.91- 6.86(m,1H),6.82(s,1H),6.77-6.74(m,1H),6.69(d,J=1.2Hz,1H),6.58(dd,J=1.6,8.0Hz,1H),4 .84-4.80(m,1H),4.28-4.17(m,1H),4.14-4.06(m,1H),3.92(dd,J=4.8,8.4Hz,1H),3.67-3.56(m ,1H),3.20-3.06(m,1H),2.57-2.42(m,1H),2.22(s,3H),2.16-1.91(m,3H),1.36(d,J=7.2Hz,3H).

[0468] Example 35: 4-((S)-1-((R)-1-((4',5-dihydroxy-2'-methyl-[1,1'-biphenyl]-3-yl)methyl)pyrrolidine-2-carboxamido)ethyl)-2-hydroxybenzoic acid (Compound 35) [ka]

[0469] Step (i): To a solution of (tert-butoxycarbonyl)-D-proline (7.250 g, 0.027 mol, 1.0 equiv.) in DMF (72 mL), HATU (15.50 g, 0.04 mol, 1.5 equiv.) was added, and the reaction mixture was stirred at 0° C. for 15 min. DIPEA (13.94 mL, 0.08 mol, 3 equiv.) was added to the reaction mixture at 0° C. The mixture was stirred at room temperature for 30 min. (S)-1-(4-bromo-3-methoxyphenyl)ethan-1-amine HCl salt (Intermediate 16) (5.85 g, 0.027 mol, 1 equiv., HCl) was added, and the resulting mixture was stirred at 25° C. overnight. LC-MS showed that Intermediate 16 was completely consumed and one major peak with the desired mass was detected. The reaction mixture was diluted with cold HO (800 mL) and extracted with EA (3 × 300 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (normal phase silica, 0–40.0% EA / hexanes) to give tert-butyl (R)-2-(((S)-1-(4-bromo-3-methoxyphenyl)ethyl)carbamoyl)pyrrolidine-1-carboxylate (11.4 g, 98.10% yield, 96% purity) as a colorless gum.

[0470] TLC: (5.0:5.0, hexane / EtOAc, RF: 0.4).

[0471] LCMS: 96.31% (LCMS method H), retention time: 3.161 minutes, 254.0 nm.

[0472] Chiral HPLC: 80.05%, 4.23 retention time.

[0473] 1H NMR:(400MHz,CDCl3)δ:7.47-7.39(s,3H),6.91-6.73(m,3H),5.04(s,2H),4.34(s,2H),3.96-3.86(s,5H),3.46-3.3(m,4H),2 .99(s,1H),2.91-2.89(s,1H),2.84-2.83(s,7H),2.40-2.31(m,1H),2.19-2.08(m,2H),1.89-1.63(s,5H),1.58-1.22(m,25H).

[0474] Step (ii): To a solution of (R)-2-(((S)-1-(4-bromo-3-methoxyphenyl)ethyl)carbamoyl)pyrrolidine-1-carboxylate (11.4 g, 0.026 mol, 1 equiv.) in EtOH (120 mL) was added TEA (8.08 g, 0.08 mol, 11.1 mL, 3 equiv.) and Pd(dppf)Cl.CHCl (2.12 g, 0.002 mol, 0.1 equiv.). The mixture was stirred at 100 °C under CO gas (125 PSI) for 16 h. TLC showed complete consumption of (R)-2-(((S)-1-(4-bromo-3-methoxyphenyl)ethyl)carbamoyl)pyrrolidine-1-carboxylate, with one major peak having the desired mass. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue. The reaction mixture was diluted with HO (1200 mL) and extracted with EA (3 × 400 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (normal phase silica, 0–49.0% EA / hexanes) to give tert-butyl (R)-2-(((S)-1-(4-(ethoxycarbonyl)-3-methoxyphenyl)ethyl)carbamoyl)pyrrolidine-1-carboxylate (7.25 g, 59.37% yield) as a colorless gum.

[0475] TLC: (5.0:5.0, hexane / EtOAc, RF: 0.4).

[0476] Mass (ESI+ve): 321.2[M-100+1].

[0477] LCMS: 89.69% (LCMS method H), retention time: 2.999 minutes, 254.0 nm.

[0478] Chiral HPLC: 98.91%, 6.16 retention time.

[0479] 1 H NMR:(400MHz,DMSO-D2O)δ:8.38-8.29(m,1H),7.57-7.55(s,1H),7.12-6.96(m,2H),4.97-4.88(m,1H),4.25- 4.21(d,2H),4.04-4.02(s,1H),3.85-3.80(d,3H),2.11(m,1H),1.77(s,3H),1.38(s,8H),1.28-1.17(m,11H).

[0480] Step (iii): To a solution of (R)-2-(((S)-1-(4-(ethoxycarbonyl)-3-methoxyphenyl)ethyl)carbamoyl)pyrrolidine-1-carboxylate (7.25 g, 0.017 mol, 1 equiv.) in dioxane (20 ml) was added HCl / dioxane (4.0 M, 120 mL). The mixture was stirred at room temperature for 1.5 hours. TLC showed complete consumption of (R)-2-(((S)-1-(4-(ethoxycarbonyl)-3-methoxyphenyl)ethyl)carbamoyl)pyrrolidine-1-carboxylate and one major peak with the desired mass was detected. The reaction mixture was concentrated under reduced pressure to remove HCl / dioxane, dioxane (40 ml*2) was added and the reaction mixture was concentrated under reduced pressure to remove HCl / dioxane to give ethyl 2-methoxy-4-((S)-1-((R)-pyrrolidine-2-carboxamido)ethyl)benzoate. HCl salt (5.5 g, crude) as a brown gum.

[0481] TLC: (5.0:5.0, hexane / EtOAc, RF: 0.2).

[0482] LCMS: 98.97% (LCMS method K), retention time: 1.057 min, 254.0 nm.

[0483] Kirar HPLC: 97.97%, 6.19 retention time.

[0484] 1 H NMR: (400MHz, DMSO-D2O)δ:9.79(s,1H),9.23-9.21(d,1H),8.54(s,1H), 7.61-7.59(d,1H),7.16(s,1H),7.01-6.99(d,1H),4.99-4.95(m,1H),4. 27-4.21(q,3H),3.85(s,3H),3.58(s,2H),3.22-3.18(m,3H),2.70(s,3H ),2.37-2.35(m,1H),1.91(s,3H),1.42-1.40(d,3H),1.26-1.32(t,4H).

[0485] Step (iv): A mixture of ethyl 2-methoxy-4-((S)-1-((R)-pyrrolidine-2-carboxamido)ethyl)benzoate, HCl salt (5.50 g, 0.015 mol, 1 eq.) in DCE (50 ml) was added at 0° C. to TEA (4.66 g, 6.14 ml, 0.046 mol, 3 eq.). The mixture was stirred at 0° C. for 10 minutes, and then 4′-hydroxy-5-methoxy-2′-methyl-[1,1′-biphenyl]-3-carbaldehyde (Intermediate 17) (3.73 g, 0.015 mol, 1 eq.) was added to the reaction mixture. The mixture was stirred at 60° C. for 3 hours. After 3 hours, NaBHCN (2.86 g, 0.046 mol, 3 eq.) was added, and the resulting mixture was stirred at 30° C. overnight. LC-MS showed that ethyl 2-methoxy-4-((S)-1-((R)-pyrrolidine-2-carboxamido)ethyl)benzoate.HCl salt was completely consumed and one major peak with the desired mass was detected. The mixture was then diluted with HO (600 mL) and extracted with EA (400 mL*3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by normal-phase column chromatography (normal-phase neutral activated alumina, 5.0% to 30.0% methanol / DCM) to give ethyl 4-((S)-1-((R)-1-((4'-hydroxy-5-methoxy-2'-methyl-[1,1'-biphenyl]-3-yl)methyl)pyrrolidine-2-carboxamido)ethyl)-2-methoxybenzoate (3.77 g, 44.72% yield, 81.66% purity) as an off-white solid.

[0486] TLC: (7.0:3.0, hexane / EtOAc, RF: 0.4).

[0487] Mass (ESI+ve): 547.33(M+1).

[0488] LCMS: 81.66% (LCMS method H), retention time: 3.382 minutes, 254 nm.

[0489] Chiral HPLC: 83.20% retention time 8.08 min, 232.0 nm.

[0490] 1 H NMR:(400MHz,DMSO-D2O)δ:1.21-1.1.32(m,6H),1.72-1.75(m,3H),2.01-2.06(m,1H),2.18(s,3H) ),2.35-2.39(m,1H),3.05-3.13(m,2H),3.52-3.56(m,1H),3.79-3.81(m,6H),4.21-4.26(m,2H), 4.83-4.86(m,1H),6.64-6.69(m,2H),6.73(s,1H),6.84-6.87(d,2H,J=10Hz),6.91-6.93(d,1H,J =7.6Hz),7.02-7.07(m,2H),7.55-7.57(d,1H,J=7.6Hz),8.14-8.16(d,1H,J=7.6Hz),9.37(s,1H).

[0491] Step (v): To a solution of ethyl 4-((S)-1-((R)-1-((4'-hydroxy-5-methoxy-2'-methyl-[1,1'-biphenyl]-3-yl)methyl)pyrrolidine-2-carboxamido)ethyl)-2-methoxybenzoate (3.77 g, 0.006 mol, 1 equiv.) in DCM (108 mL) was added BBr3 (1.0 M solution in DCM) (8.63 g, 34.42 ml, 0.034 mol, 5 equiv.) to the reaction mixture at -78°C, and the mixture was stirred at -78°C for 1 hour. The resulting mixture was then stirred at room temperature for 2 hours. TLC showed complete consumption of ethyl 4-((S)-1-((R)-1-((4'-hydroxy-5-methoxy-2'-methyl-[1,1'-biphenyl]-3-yl)methyl)pyrrolidine-2-carboxamido)ethyl)-2-methoxybenzoate and one major peak with the desired mass was detected. The reaction mixture was quenched by the slow dropwise addition of MeOH (197.5 mL) at -78 °C, after which the mixture was allowed to warm to room temperature and concentrated under reduced pressure to give ethyl 4-((S)-1-((R)-1-((4',5-dihydroxy-2'-methyl-[1,1'-biphenyl]-3-yl)methyl)pyrrolidine-2-carboxamido)ethyl)-2-hydroxybenzoate (5.04 g, crude) as a yellow solid.

[0492] TLC: (8.0:2.0, hexane / EtOAc, RF: 0.2).

[0493] Mass (ESI+ve): 519.4[M+1].

[0494] LCMS: 52.0% (LCMS method L), retention time: 2.838 minutes, 254 nm.

[0495] Step (vi): To a solution of ethyl 4-((S)-1-((R)-1-((4',5-dihydroxy-2'-methyl-[1,1'-biphenyl]-3-yl)methyl)pyrrolidine-2-carboxamido)ethyl)-2-hydroxybenzoate (5.04 g, 0.009 mol, 1 equiv.) in EtOH (35 mL) and THF (170 mL) was added LiOH HO (3.05 g, 0.07 mol, 7.5 equiv.) in HO (35 mL). The mixture was stirred at 30 °C for 7 days. LC-MS showed that ethyl 4-((S)-1-((R)-1-((4',5-dihydroxy-2'-methyl-[1,1'-biphenyl]-3-yl)methyl)pyrrolidine-2-carboxamido)ethyl)-2-hydroxybenzoate was completely consumed and one major peak with the desired mass was detected. The reaction mixture was concentrated under reduced pressure to remove EtOH and THF. The mixture was then cooled to 0 °C, diluted with HO (20 mL), and adjusted to pH 5 with HCl (2.0 M) at 0 °C; a solid was followed, followed by filtration through a vacuum pump, and the mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (HPLC method I) to give 4-((S)-1-((R)-1-((4',5-dihydroxy-2'-methyl-[1,1'-biphenyl]-3-yl)methyl)pyrrolidine-2-carboxamido)ethyl)-2-hydroxybenzoic acid (Compound 35) (472.5 mg, 9.91% yield, 100.0% purity) as a white solid.

[0496] TLC: (1.0:9.0, methanol / DCM, RF:0.1).

[0497] Mass (ESI+ve): -491.2 (M+1)

[0498] LCMS: 100.0% (LCMS method L), retention time: 2.415 minutes, 304.0 nm.

[0499] LCMS: 99.60% (LCMS method H), retention time: 2.156 minutes, 304.0 nm.

[0500] Kirar HPLC: 100.0%, 6.75 retention time.

[0501] 1 H NMR: (400MHz, MeOD)δ:7.76-7.78(d,1H),6.86-6.88(d,1H),6.79-6.80(d,2H),6.72(s,2H),6.66(s,1H),6.60(s,2H),4.85-4.87(m,1H) ,4.18-4.21(d,1H),4.08-4.11(d,1H),3.94(s,1H),3.60(s,1H),3.15(s,1H),2.49(s,1H),2.12(s,4H),1.99(s,2H),1.37-1.39(d,3H).

[0502] 1 H NMR: (400MHz, DMSO-D2O)δ:9.52(s,1H),9.35(s,1H),8.14-8.31(m,1H),7.64-7.66(d,1H),6.93-6.95(d,1H),6.72(s,3H),6.11-6.65(m ,4H),4.76-4.79(m,1H),3.90(s,1H),3.72(s,1H),3.2-3.5(m,3H),2 .33-2.36(s,1H),2.12(s,3H),1.75-1.85(m,3H),1.29-1.28(d,4H).

[0503] Biological active ingredients Cloning, baculovirus production, large-scale infection of HEK293 cells, and membrane preparation: Human prostaglandin E2 receptor 4 (EP4) was cloned into the pBacMam expression vector (GenScript, UK). EP4 DNA transfer was performed using the Invitrogen Bac-to-BacBaculovirus Expression Systems. P0 baculovirus was generated by transfecting SF9 cells with bacmid DNA using Cellfectin II transfection reagent (Thermo Fisher Scientific, UK). Following the P0 generation, P1 virus was generated and prepared for large-scale infection and membrane preparation. HEK293 cells were grown in DMEM (Thermo Fisher Scientific, UK) supplemented with 10% heat-inactivated fetal bovine serum (FBS). Cells were cultured at 3.5 × 10 6 Seeding density of cells / mL, 500cm 3 The cells were infected with 5% v / v EP4Bacman in a flask. Expression was carried out for 36 hours at 37°C and 5% CO2. Cells were detached using PBS and a cell scraper. The cell culture was centrifuged at 2500 rpm at 4°C for 10 minutes. The supernatant was then decanted, and the pellet was stored at -80°C. The pellet was thawed and resuspended in 15 mL of homogenization buffer (20 mM HEPES, 10 mM EDTA, pH 7.4). It was then homogenized for 10 seconds using a mechanical homogenizer (VMR). The membranes were centrifuged in a centrifuge tube at 40,000 g for 15 minutes at 4°C. The supernatant was decanted, resuspended in 15 mL of homogenization buffer, and homogenized for 20 seconds. The membranes were then centrifuged at 40,000 g for 45 minutes at 4°C. The membranes were then resuspended in 3 mL of storage buffer (20 mM HEPES, 0.1 mM EDTA, pH 7.4) and mixed thoroughly, after which they were stored at -80°C.

[0504] cAMP functional assay: cAMP production after EP4 receptor activation was measured using the Homogeneous Time-Resolved Fluorescence (HTRF) cAMP Dynamic-2 Assay (Cisbio, France). HEK293 cells were transfected with 0.5% EP4 Bacmam virus for 36 hours, then dissociated and frozen at -150°C.

[0505] On the day of the test, increasing concentrations of test compounds were added to a ProxiPlate-384Plus, White 384-shallowwell Microplate (PerkinElmer, USA) using ECHO dispensing, alongside a positive control (10 μM PGE2 (Tocris, Abingdon, UK)) and a negative control (DMSO (Sigma-Aldrich, UK)).

[0506] Cells were thawed in a water bath, resuspended in DMEM supplemented with 10% FBS, and then pelleted by centrifugation at 1200 rpm for 5 minutes. The pellet was then resuspended in assay buffer (DMEM + 0.5 mM IBMX (Tocris, Abingdon, UK)) at 0.5x10 6 The cells were resuspended at 1000 cells / mL. The cell suspension was added to the pre-dispensed assay plate using a Multidrop™ to a final assay concentration of 5,000 cells / well. The plate was then incubated at 37°C and 5% CO2 for 30 minutes. cAMP production was measured according to the manufacturer's instructions, and the plate was read on a PheraStar fluorescent plate reader (BMG Labtec, Germany).

[0507] As shown in Table 2, pEC 50 Values were calculated from the midpoint of the curve using Dotmatics.

[0508] [Table 2]

[0509] Unidirectional CACO-2 cell permeability assay Caco-2 cells (ECACC) were plated at 2x10 5 Cells were seeded at 1000 x g / well and cultured at 37°C under 5% CO2 for 21 days before use as a confluent monolayer. Each test compound was incubated in duplicate with a final concentration of 10 μM in assay buffer (Hank's Balanced Salt Solution, pH 6.5, supplemented with 25 mM HEPES). The basolateral chamber (serving as a receiver) was supplemented with 25 mM HEPES and adjusted to pH 7.4 (final concentration: 0.2% DMSO).

[0510] Incubations were carried out at 37°C, and samples were removed from both the donor and acceptor chambers at T = 0 and 1 h, and the compounds were analyzed by mass spectrometry (LC-MS / MS), including an analytical internal standard (0.5 μM carbamazepine).

[0511] Apparent transmittance (P app ) values are shown in Table 3 and are determined from the following relationship:

[0512]

number

[0513] where V is the volume of each compartment of the Transwell (125 μL apical, 600 μL basolateral), each concentration is the relative MS response value (normalized to an internal standard) of the compound in the donor chamber before incubation and in the acceptor chamber at the end of incubation, and area = the area of the cell exposed to drug translocation (0.33 cm). 2 ).

[0514] Lucifer Yellow (LY) was added to the apical buffer in all wells to assess cell layer viability. Because LY cannot freely penetrate lipophilic barriers, a high degree of LY transport indicates poor cell layer integrity, and the Papp is 10x10 -6 Wells exceeding cm / sec were excluded.

[0515] The recovery rate of compound from each well was determined from the MS response values (normalized to an internal standard) in the donor and acceptor chambers at the end of incubation, compared with the response value in the donor chamber before incubation.

[0516] [Table 3] Numbered Embodiments 1. Compounds of Formula I: [ka] or a pharmaceutically acceptable salt or tautomer thereof; A is OR', C(O)R', CO2R', C(O)N(R')2, C(O)N(R')S(O)2R', S(O)2R', S(O)2OR', SO2N(R')2, C 1-8 alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; Ring B is aryl or heteroaryl; X and Y are each, independently of each other, CR″ or N, and at least one of X and Y is CH; R 1 and R 2 are, independently of each other, H, C 1-6 Alkyl, C 1-6 Alkoxy or R 1 and R 2 together with the carbon atoms to which they are attached, form C 3-6 forming a cycloalkane-1,1-diyl ring; Each R 3 are, independently of each other, H, OR', COOR', C(O)R', halo, and C 1-6 alkyl; R 4 is C 1-6alkyl, halo, CN, NO2, or OR'; R 5 is H or C 1-6 alkyl; or R 4 and R 5 together with the pyrrolidine ring to which they are attached, form C 1-6 forming an alkylene linker; R 6 is H, C 1-6 alkyl, halo, CN, NO2, OR', CO2R', or C(O)R'; R 7 is OR', OC(O)R', OC(O)OR', COR', CON(R')2, SON(R')2, SOR', OSOR', or OSON(R')2; Each R' is independently H, C 1-6 Alkyl or C 3-6 is cycloalkyl; Each R" is H, C 1-6 alkyl, halo, or OR'; n and m are each, independently of one another, 0, 1, 2, or 3; Each occurrence of alkyl, alkylene, and cycloalkyl may optionally, and independently of one another, be selected from the group consisting of up to three OH, SH, CN, NO, COOH, halo, or COOC. 1-4 is alkyl substituted; Each occurrence of heterocycloalkyl, aryl, and heteroaryl may optionally, and independently of one another, be selected from the group consisting of up to three of OR', SR', CN, NO2, CO2R', halo, C 1-4 substituted with alkyl or oxo; A compound of formula I, or a pharmaceutically acceptable salt or tautomer thereof. 2. Ring B is a 5- to 6-membered aryl or a 5- to 6-membered heteroaryl; each optionally, and independently of each other, contains up to three of OR', SR', CN, NO2, CO2R', halo, or C 1-4 The compound of embodiment 1, which is substituted with alkyl. 3. The compound of embodiment 1, wherein Ring B is phenyl optionally substituted with up to three OH, or a 6-membered heteroaryl containing one or two nitrogen atoms, each of which is optionally oxidized. 4. A compound of formula (1), [ka] or a pharmaceutically acceptable salt thereof; A is, [ka] selected from the group consisting of: U, V, W, and Z are each independently CH, COH, N, or N + -O - wherein at least three of U, V, W, and Z are CH; X and Y are each, independently of one another, selected from the group consisting of CH, CF, COH, or N; R 1 and R 2 are each independently H, C optionally substituted with 1 to 3 fluorine atoms, 1-3 alkyl or R 2 C optionally substituted with 1 to 3 fluorine atoms by bonding to 3-6 forming a cycloalkyl ring; R 3 is H, OH, or F; R 4 is H, OH, F, or R 5 It forms a CH2 bridge by binding to R 5 is H or R 4 It forms a CH2 bridge by binding to R 6 is H, OH, CN, halo, optionally C optionally substituted with 1 to 3 fluorine atoms 1-3 Alkoxy, or C optionally substituted with 1 to 3 fluorine atoms1-3 is alkyl; R 7 is OH, CO2H, CONH2, SO2NH2, or OSO2NH2; R 9 is C 1-3 Alkyl or C 3-6 is a cycloalkyl ring, A compound of formula I. 5. R 5 The compound of any one of embodiments 1 to 4, wherein is H. 6. A, [ka] 6. The compound of any one of embodiments 1 to 5, wherein 7. Compound of formula (2a): [ka] or a pharmaceutically acceptable salt thereof, U, V, W, X, Y, Z, R 1 , R 2 , R 3 , R 4 , R 6 , and R 7 is the same as defined in embodiment 4. The compound of embodiment 4. 8. R 1 is H or methyl, or R 2 to form a cyclopropane-1,1-diyl ring. 9. R 1 is methyl. 10. R 2 The compound of any one of embodiments 1 to 9, wherein is H. 11. Compound of formula (3a): [ka] or a pharmaceutically acceptable salt thereof, U, V, W, X, Y, Z, R 3 , R 4 , R 6 , and R 7 is the same as defined in embodiment 4. The compound of embodiment 4. 12. R 3 The compound of any one of embodiments 1 to 11, wherein is H. 13. R 4 The compound of any one of embodiments 1 to 12, wherein is H. 14. R 6 The compound of any one of embodiments 1 to 13, wherein is H, OH, CN, or methyl. 15. R 6 The compound of embodiment 14, wherein is methyl. 16. R 7 The compound of any one of embodiments 1 to 15, wherein is CONH2 or SO2NH2. 17. The compound of any one of embodiments 1 to 16, wherein X and Y are both CH. 18. The compound of any one of embodiments 4 to 17, wherein U, V, W, and Z are CH, or U, V, and Z are CH and W is COH. 19. The compound of embodiment 1, wherein the compound is selected from the following: [ka] [ka] [ka] or a pharmaceutically acceptable salt thereof. 20. 20. A pharmaceutical composition comprising a compound according to any one of embodiments 1 to 19 and a pharmaceutically acceptable excipient. twenty one. A compound according to any one of embodiments 1 to 19 or a composition according to embodiment 20 for use in the treatment of an EP4 receptor-mediated disease. twenty two. The compound or composition for use according to embodiment 21, wherein the EP4 receptor mediated disorder is a gastrointestinal disorder. twenty three. 23. The compound or composition for use according to embodiment 22, wherein the gastrointestinal disorder is selected from the group consisting of constipation, constipation-predominant irritable bowel syndrome, mixed irritable bowel syndrome, chronic idiopathic constipation, gastrointestinal symptoms associated with Parkinson's disease, gastrointestinal symptoms associated with cystic fibrosis, intestinal motility dysfunction, postoperative ileus, food allergy or food intolerance, celiac disease, gastrointestinal motility disorders, functional gastrointestinal disorders, drug-induced enteropathy, NSAID-induced gastrointestinal injury, chemotherapy-induced mucositis, gastroesophageal reflux disease (GERD), duodenogastric reflux, diarrhea, immune-mediated gastrointestinal disorders, Crohn's disease, ulcerative colitis, inflammatory bowel disease, and ischemic colitis. twenty four. The compound or composition for use according to embodiment 21, wherein said EP4 receptor mediated disease is a pulmonary disease or condition. twenty five. 25. The compound or composition for use according to embodiment 24, wherein the pulmonary disease or condition is selected from chronic obstructive pulmonary disease, asthma, chronic bronchitis, cystic fibrosis, emphysema, chronic idiopathic cough, reactive airways disease, and idiopathic pulmonary fibrosis.

Claims

1. Compounds of Formula I: 【Chemical 1】 or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or optical isomer thereof; A is OR', C(O)R', CO ２ R', C(O)N(R') ２ ,C(O)N(R')S(O) ２ R', S(O) ２ R', S(O) ２ OR', SO ２ N(R') ２ , C １－８ alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; Ring B is aryl or heteroaryl; X and Y are each, independently of one another, CR″ or N, and at least one of X and Y is CH; R １ and R ２ are each independently H, C １－６ Alkyl, C １－６ Alkoxy or R １ and R ２ together with the carbon atoms to which they are attached, form C ３－６ forming a cycloalkane-1,1-diyl ring; Each R ３ are, independently of each other, H, OR', COOR', C(O)R', halo, and C １－６ alkyl; R ４ is H, C １－６ Alkyl, halo, CN, NO ２ or OR'; R ５ is H or C １－６ alkyl; or R ４ and R ５ together with the pyrrolidine ring to which they are attached, form C １－６ forming an alkylene linker; R ６ is H, C １－６ alkyl, C optionally substituted with 1 to 3 fluorine atoms １－３ Alkoxy, halo, CN, NO ２ , OR', CO ２ R′, or C(O)R′; R ７ is OR', OC(O)R', OC(O)OR', CO ２ R', CON(R') ２ , S.O. ２ N(R') ２ , S.O. ２ R', OSO ２ R', or OSO ２ N(R') ２ and Each R' is independently H, C, or １－６ Alkyl, or C ３－６ is cycloalkyl; Each R" is H, C １－６ alkyl, halo, or OR'; n and m are each, independently of one another, 0, 1, 2, or 3; Each occurrence of alkyl, alkylene, and cycloalkyl may optionally, and independently of one another, be selected from the group consisting of up to three OH, SH, CN, NO, ２ , COOH, halo, or COOC １－４ is substituted with alkyl; Each occurrence of heterocycloalkyl, aryl, and heteroaryl may optionally, and independently of one another, be selected from the group consisting of up to three of OR', SR', CN, NO, ２ , CO ２ R', Halo, C １－４ substituted with alkyl or oxo; A compound of Formula I, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or optical isomer thereof.

2. Ring B is a 5- to 6-membered aryl or a 5- to 6-membered heteroaryl; each optionally and independently of each other, contains up to three OR', SR', CN, NO ２ , CO ２ R', halo, or C １－４ The compound of claim 1 , which is substituted with alkyl.

3. 2. The compound of claim 1, wherein Ring B is phenyl optionally substituted with up to three OH, or a 6-membered heteroaryl containing one or two nitrogen atoms, each nitrogen atom being optionally oxidized.

4. A compound of formula (1), 【Chemistry 2】 or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or optical isomer thereof; U, V, W, and Z are each independently CH, COH, N, or N ＋ -O － wherein at least three of U, V, W, and Z are CH; A compound according to any one of claims 1 to 3.

5. R ４ is H, OH, F, or R ５ By bonding to CH ２ bridges; preferably, R ４ is H, OH, or R ５ By bonding to CH ２ 5. The compound according to claim 1, which is bridged.

6. R ５ is H or R ４ By bonding to CH ２ bridges; preferably, R ５ 6. The compound of claim 1, wherein is H.

7. A is, 【Chemistry 3】 selected from the group consisting of: R ９ is C １－３ Alkyl or C ３－６ is a cycloalkyl ring; Preferably, A is 【Chemistry 4】 7. The compound of claim 1, wherein

8. A compound of formula (2a), 【Chemistry 5】 or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or optical isomer thereof; U, V, W, X, Y, Z, R １ , R ２ , R ３ , R ４ , R ６ , and R ７ is the same as defined in claim 4, The compound of claim 4.

9. R １ and R ２ are each independently H, C optionally substituted with 1 to 3 fluorine atoms １－３ alkyl or R １ is R ２ C optionally substituted with 1 to 3 fluorine atoms by bonding to ３－６ 9. A compound according to any one of claims 1 to 8, which forms a cycloalkyl ring.

10. R １ is H or methyl, or R ２ and more preferably, R １ is methyl; and / or R ２ 10. The compound of claim 1, wherein is H.

11. A compound of formula (3a), 【Chemistry 6】 or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or optical isomer thereof; U, V, W, X, Y, Z, R ３ , R ４ , R ６ , and R ７ is the same as defined in claim 4, The compound of claim 4.

12. R ３ is H, OH, or F; preferably, R ３ is H or OH; more preferably, R ３ 12. The compound of claim 1, wherein is H.

13. R ４ is H, OH, or F; preferably, R ４ is H or OH; more preferably, R ４ 13. The compound of claim 1, wherein is H.

14. R ６ is H, OH, CN, halo, optionally substituted with 1 to 3 fluorine atoms １－３ Alkoxy or C optionally substituted with 1 to 3 fluorine atoms １－３ alkyl; preferably, R ６ is H, OH, CN, or methyl; more preferably, R ６ 14. The compound of any one of claims 1 to 13, wherein is methyl.

15. R ７ OH, CO ２ H, CONH ２ , S.O. ２ NH ２ , or OSO ２ NH ２ and preferably, R ７ Gonna be CONH ２ or SO ２ NH ２ 15. The compound of any one of claims 1 to 14, wherein

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

17. 17. The compound of any one of claims 4 to 16, wherein U, V, W, and Z are CH, or U, V, and Z are CH and W is COH. 【Request 18】 【Chemical 7-1】 【Chemistry 7-2】 【Chemistry 7-3】 2. The compound of claim 1 selected from: or a pharmaceutically acceptable salt, solvate, hydrate, or tautomer thereof.

19. 20. A pharmaceutical composition comprising a compound, a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or optical isomer of any one of claims 1 to 18, and a pharmaceutically acceptable excipient.

20. 20. The pharmaceutical composition of claim 19, further comprising at least one additional therapeutic agent selected from the group consisting of an aminosalicylates, corticosteroids, immunomodulators, and combinations thereof.

21. 20. A kit comprising a compound of any one of claims 1 to 18, a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or optical isomer, and at least one additional therapeutic agent selected from the group consisting of aminosalicylates, corticosteroids, immunomodulators, and combinations thereof.

22. 22. A compound according to any one of claims 1 to 18, a composition according to claim 19 or 20, or a kit according to claim 21 for use in medicine.

23. A compound according to any one of claims 1 to 18, a composition according to claim 19 or 20, or a kit according to claim 21 for use in the treatment of an EP4 receptor mediated disease.

24. 24. The compound, composition, or kit for use according to claim 23, wherein the EP4 receptor mediated disease is a gastrointestinal disorder.

25. 25. The compound, composition, or kit for use according to claim 24, wherein the gastrointestinal disorder is selected from the group consisting of constipation, constipation-predominant irritable bowel syndrome, mixed irritable bowel syndrome, chronic idiopathic constipation, gastrointestinal symptoms associated with Parkinson's disease, gastrointestinal symptoms associated with cystic fibrosis, intestinal motility dysfunction, postoperative ileus, food allergy or food intolerance, celiac disease, gastrointestinal motility disorder, functional gastrointestinal disorder, drug-induced bowel disease, NSAID-induced gastrointestinal injury, chemotherapy-induced mucositis, gastroesophageal reflux disease (GERD), duodenogastric reflux, diarrhea, immune-mediated gastrointestinal disease, Crohn's disease, ulcerative colitis, inflammatory bowel disease, and ischemic colitis.

26. 24. The compound, composition, or kit for use according to claim 23, wherein the EP4 receptor mediated disease is a pulmonary disease or condition.

27. 27. The compound, composition, or kit for use according to claim 26, wherein the pulmonary disease or condition is selected from chronic obstructive pulmonary disease, asthma, chronic bronchitis, cystic fibrosis, emphysema, chronic idiopathic cough, reactive airway disease, and idiopathic pulmonary fibrosis.

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