EA046234B1 - N-BENZYL-2-PHENOXYBENZAMIDE DERIVATIVES AS PROSTAGLANDIN E2 (PGE2) RECEPTOR MODULATORS - Google Patents

Description

Field of technology to which the invention relates

The present invention relates to novel, optionally substituted H-benzyl-2phenoxybenzamide derivatives as prostaglandin E2 (PGE2) EP4 and/or EP2 receptor modulators.

Other objects of the present invention are to provide a process for preparing these compounds; pharmaceutical compositions comprising an effective amount of these compounds and these compounds, for use in the treatment of pathological conditions or diseases that can be improved by modulators of the EP4 and/or EP2 receptors, such as cancer, pain and inflammatory conditions, such as acute and chronic pain, osteoarthritis , diseases of rheumatoid arthritis, endometriosis and kidney diseases.

State of the art

Prostaglandin E2 (PGE2) is involved in several biological processes such as pain, fever, regulation of vascular tone, renal function, mucosal integrity, inflammation, angiogenesis and tumor growth. PGE2 often causes complex and varied effects that can be explained by the activation of four so-called E-type prostanoid receptors (EP1 - EP4). The physiological activity of PGE2 is mediated by 4 plasma membrane G protein-coupled receptors identified as group E prostanoid receptors 1-4 (EP1, EP2, EP3 and EP4), each of which can activate different downstream signaling pathways. (SUGIMOTO, Yukihiko; NARUMIYA, Shuh. Prostaglandin E receptors. Journal of Biological Chemistry, 2007, vol. 282, no 16, p. 1161311617).

PGE2 is the predominant eicosanoid found in inflammatory conditions and, in addition, it is also involved in various physiological and/or pathological conditions such as hyperalgesia, uterine contraction, digestive motility, wakefulness, suppression of gastric acid secretion, blood pressure, platelet function, bone metabolism, angiogenesis, cancer metastasis and the like. Eicosanoids: (From Biotechnology to Therapeutic Applications, Folco, Samuelsson, Maclouf and Velo eds, Plenum Press, New York, 1996, chapter 14, p. 137-154); (Journal of Lipid Mediators and Cell Signaling, 14: 83-87 (1996)), (Prostaglandins and Other Lipid Mediators, 69: 557-573 (2002)).

On the other hand, PGE2 is reported to be highly expressed in cancer tissue in various types of cancer, and it is also explained that PGE2 is related to cancer development and disease state. PGE2 is known to be associated with the activation of cell proliferation and inhibition of cell death (apoptosis) and plays an important role in the process of cancer progression and metastasis.

Each EP receptor subtype is specifically distributed in the human body; EP1: myometrium, pulmonary veins, colon, skin, mast cells; EP2: leukocytes, smooth muscles, central nervous system (CNS), reproductive system, bones; EP3: CNS, cardiovascular system, reproductive system, kidneys, bladder; EP4: leukocytes, smooth muscle, cardiovascular system and bone (SUGIMOTO, Yukihiko; NARUMIYA, Shuh. Journal of Biological Chemistry, 2007, vol. 282, no 16, p. 11613-11617), and (Woodward, D.F. et al (2011) International Union of Basic and Clinical Pharmacology. LXXXIII: Pharmacol. Rev. 63, 471-538 5).

EP2 receptor.

Studies using EP2 receptor knockout mice have demonstrated a role for the EP2 receptor in malignancies, with EP2 receptor-deficient mice developing significantly fewer lung, skin, and mammary tumors after exposure to carcinogenic promoters. Genetic ablation of the EP2 receptor also reduced both the size and number of intestinal polyps in adenomatous polyposis coli (APC) 1309 mice, which are genetically susceptible to intestinal polyp development. Moreover, the EP2 receptor has been shown to be expressed by tumor cells in several types of cancer, including colon, prostate and breast cancer (GUSTAFSSON, Annika, et al. International journal of cancer, 2007, vol. 121, no 2, p. 232240) and (Chang SH, et al. (2004). Proc Natl Acad Sci USA 101: 591-596).

It is known that androgen deprivation therapy (ADT) is the main treatment for prostate cancer, but the disease often recurs and becomes castration-resistant in almost all patients. Mechanistically, after androgen deprivation, increased PGE2-EP2 signaling was found to inhibit CD4 expression in thymocytes. Therapeutically, inactivation of PGE2 signaling with celecoxib dramatically suppressed the onset of castration-resistant prostate cancer (CRPC). These results indicate a new therapeutic pathway of combining ADT with PGE2 inhibition for the treatment of prostate cancer (WANG, C., et al. Cell research, 2018).

PGE2-EP2 signaling functions as a chronic inflammatory hub that shapes the tumor microenvironment and is thus a strong candidate target for colorectal cancer chemoprevention (AOKI, Tomohiro; NARUMIYA, Shuh. Inflammation and regeneration, 2017, vol. 37, no 1 , p. 4.)

In addition, a recent study showed that activation of the EP2 receptor by PGE2 markedly increases the ability of hepatocellular carcinoma cells to invade and migrate by increasing the expression level of Snail, a key inducer of EMT (CHENG, Shan-Yu, et al. Oncology reports,

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2014, vol. 31, no 5, p. 2099-2106.) and (ZANG, Shengbing, et al. Human pathology, 2017, vol. 63, p. 120-127). The EP2 receptor has also been linked to metastasis in breast cancer, in part due to its ability to alter the response of cells to TGF-β (Tian M, Schiemann WP (2010). FASEB J 24: 1105-1116).

EP2 antagonism in neurodegenerative diseases.

Chronic inflammatory neurodegenerative diseases such as epilepsy, Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS) contribute to mortality and morbidity in a large proportion of the population. AD and PD are particularly associated with symptoms of dementia in older adults. However, all of these diseases share the common feature of overactivated inflammatory pathways. Interestingly, PGE2 is the main prostaglandin produced during the progression of these diseases and has been shown to mediate proinflammatory functions through EP2 (and to a lesser extent, EP4) receptors. Studies have shown that administration of a potent and selective EP2 antagonist, TG4-15585, significantly blocks neuronal damage in the hippocampus (>60% in the hilus, 80% in the CA3 region and >90% in the CA1 region) in a pilocarpine model of status epilepticus. (JIANG, Jianxiong, et al. Proceedings of the National Academy of Sciences, 2012, vol. 109, no 8, p. 3149-3154).

Another potent EP2 antagonist, TG6-10-186, suppresses neurodegeneration, upregulation of inflammatory cytokines and chemokines, and glial activation in mice following status epilepticus, suggesting the potential therapeutic benefit of an EP2 antagonist in blocking epileptogenesis. (JIANG, Jianxiong, et al. Proceedings of the National Academy of Sciences, 2013, vol. 110, no 9, p. 3591-3596).

Based on the beneficial effects observed in EP2 knockout mouse models of AD, PD, and ALS (see above), an EP2 receptor antagonist may be useful as an adjuvant therapeutic agent in chronic inflammatory neurodegenerative diseases, including epilepsy, Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. (LIANG, Xibin, et al. Annals of Neurology: Official Journal of the American Neurological Association and the Child Neurology Society, 2008, vol. 64, no 3, p. 304-314). (Liang X., et al. J. Neurosci. 2005; 25:10180-10187); (Jin J, et al. Journal of Neuroinflammation. 2007).

EP4 receptor.

The EP4 receptor, unlike the EP2 receptor, is expressed in a variety of tissues and cells, including the immune, musculoskeletal, cardiovascular, gastrointestinal and respiratory systems, and cancer cells. Recent findings have shown that regulation of EP4 signaling may be involved in therapeutic strategies for colon cancer (MUTOH, Michihiro, et al. Cancer research, 2002, vol. 62, no 1, p. 28-32.), aortic aneurysm (YOKOYAMA, Utako, et al. PloS one, 2012, vol. 7, no 5, p. e36724.), rheumatoid arthritis (CHEN, Q., et al. British journal of pharmacology, 2010, vol. 160, no 2 , p. 292-310.), osteoporosis and autoimmune disease (YAO, Chengcan, et al. Nature medicine, 2009, vol. 15, no 6, p. 633.).

Accordingly, regulation of EP4 signaling has received even more attention as a potential therapeutic target.

Recent reports suggest that the EP4 receptor, which is expressed in certain types of cancer, promotes tumor cell proliferation and metastasis (YOKOYAMA, et al. Pharmacological reviews, 2013, vol. 65, no 3, p. 1010-1052).

In breast cancer, studies have shown that tumor progression and metastasis due to multiple cellular events, including inactivation of host antitumor immune cells such as natural killer (NK) cells and T cells, increase the immunosuppressive function of tumor-associated macrophages, promoting tumor cell migration , invasiveness and tumor-associated angiogenesis, due to the activation of multiple angiogenic factors, including vascular endothelial growth factor (VEGF)-A, increased lymphangiogenesis (due to activation of VEGF-C/D) and stimulation of stem-like cells (SLC) in cancer cells are primarily mediated by activation of the prostaglandin (PG) E receptor EP4 on tumor cells or host cells, and that selective EP4 antagonists can mitigate all of these events, tested with cells in vitro as well as in vivo in syngeneic mice bearing breast cancer glands expressing COX-2, or immunodeficient mice bearing human breast cancer xenografts overexpressing COX-2. (MAJUMDER, Mousumi, et al. International journal of molecular sciences, 2018, vol. 19, no 4, p. 1019).

EP4 expression levels also correlated with prostate cancer cell invasiveness, and the specific EP4 antagonist ONO-AE3-208 suppressed cell invasion, migration, and bone metastasis (XU, Song, et al. Cell biochemistry and biophysics, 2014, vol. 70, no 1, pp. 521-527).

Another study demonstrated that EP4 inhibition attenuated renal cell carcinoma (RCC) intravasation and metastasis by reducing CD24 levels and that P-selectin was involved in tumor intravasation, implying the possibility of using these molecules as therapeutic targets for the promising treatment of RCC. (ZHANG, Yushan, et al. Cancer letters, 2017, vol. 391, p. 50-58).

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The EP4 antagonist, L-161,982, induces apoptosis, cell cycle arrest, and inhibits prostaglandin E2-induced proliferation in Tca8113 oral squamous cell carcinoma cells. (LI, Xiaohui, et al. The Journal of Oral Pathology & Medicine, 2017, vol. 46, no 10, p. 991-997).

Another study demonstrated that EP4 antagonism, a more selective inhibition of PGE2 signaling, reduced the number of cancer stem cells (CSCs) in tumors and increased tumor chemosensitivity. EP4 antagonism converts CSCs into chemotherapy-sensitive non-stem cells by triggering the release of extracellular vesicles/exosomes and enhances tumor response to conventional chemotherapy. (LIN, MengDChieh, et al. International journal of cancer, 2018).

In addition, selective EP4 receptor antagonists are expected to provide an effective therapeutic approach for the treatment of autoimmune diseases such as inflammatory bowel disease (IBD), rheumatoid arthritis (RA) and multiple sclerosis (MS)16–18 by inhibiting the production of interleukin-23 ( IL-23) and suppression of T helper 1 (Th1) and T helper 17 (Th17) cells.

The role of the EP4 receptor in liver cancer has recently been published in the non-patent literature. PGE2/EP4 receptor signaling through PKA/CREB activation increased cMyc expression and resulted in promotion of cell growth in HCC cells in vitro (XIA, Shukai, et al. Oncology reports, 2014, vol. 32, no 4, p. 1521-1530 ).

PGE2-activated EP4 receptor signaling may be associated with various pathological conditions such as pain (particularly inflammatory, neuropathic and visceral), inflammation, neuroprotection, dermatitis, bone disease, immune system dysfunction, sleep stimulation, renal regulation, secretion gastric or intestinal mucus and secretion of bicarbonates from the duodenal mucosa. Studies show that PGE2 inhibits proteoglycan synthesis and stimulates matrix degradation in osteoarthritis-associated chondrocytes through the EP4 receptor. Targeting EP4 rather than cyclooxygenase 2 could represent a future disease modification strategy for osteoarthritis. (ATTUR, Mukundan, et al. The Journal of Immunology, 2008, vol. 181, no 7, p. 50825088). Another study suggests that pharmacological blockade of the prostanoid receptor EP4 may represent a new therapeutic strategy for alleviating the signs and symptoms of osteoarthritis and/or rheumatoid arthritis. (MURASE, Akio, et al. European journal of pharmacology, 2008, vol. 580, no 1-2, p. 116-121).

On the other hand, some studies have shown the role of the EP4 receptor in the development of kidney diseases.

In this sense, a recent study demonstrated the renoprotective properties of the selective EP4 PGE2 receptor antagonist ASP7657 in a 5/6 nephrectomized rat model of chronic kidney disease (CKD). This study suggests that ASP7657 suppresses the progression of chronic renal failure by modulating renin release and improving renal hemodynamics (ELBERG, Dorit, et al. Prostaglandins & other lipid mediators, 2012, vol. 98, no 1-2, p. 11-16) .

Another study shows that EP4 antagonism improves the NTS phenotype of nephrotoxic serum nephritis, probably by reducing mainly Cxcl-5 production in tubular cells, thereby reducing neutrophil infiltration in the kidney (ARINGER, Ida, et al. American Journal of Physiology-Renal Physiology, 2018).

In rodent models of diabetic and nondiabetic chronic kidney disease (CKD), EP4 inhibition attenuated kidney damage through mechanisms distinct from broad-spectrum COX inhibition or standard treatment blockade of the renin-angiotensin system. (THIEME, Karina, et al. Scientific Reports, 2017, vol. 7, no 1, p. 3442.)

Finally, another study mentioned that EP4 plays a key role in anti-inflammatory and anti-apoptotic effects through Akt and NF-κΒ signaling after paricalcitol pretreatment in lipopolysaccharide (LPS)-induced renal proximal tubular cell injury. (HONG, Yu Ah, et al. Kidney research and clinical practice, 2017, vol. 36, no 2, p. 145).

Prostaglandin E2 (PGE2) is known to promote cystogenesis in genetically non-orthologous models of autosomal dominant polycystic kidney disease (ADPKD). PGE2 activates aberrant signaling pathways in polycystin-1 (PC-1)-deficient renal epithelial cells that contribute to the proliferative and secretory phenotype characteristic of ADPKD. Antagonism of EP4 receptors abolishes the growth of polycystin-1-deficient renal epithelial cells (PC-1-deficient cells), implying a central role for the EP4 receptor in proliferation. (LIU, Yu, et al. American Journal of Physiology-Renal Physiology, 2012, vol. 303, no 10, p. F1425-F1434).

Prostaglandin E2 (PGE2) stimulates cAMP production and cyst formation in human ADPKD cells. Studies performed on isolated human ADPKD renal epithelial cells have shown that the effects of PGE2 appear to be mediated by EP2 receptors, suggesting the therapeutic potential of EP2 receptor antagonists in the treatment of cystogenesis in ADPKD. Selective prostanoid-E receptor antagonists that inhibit EP2 or EP4 receptor activity may be used as a pharmacological strategy to limit cyst formation and progression of ADPKD. (ELBERG, Dorit, et

- 3 046234 al. Prostaglandins & other lipid mediators, 2012, vol. 98, no. 1-2, p. 11-16).

Modulation of EP2 and EP4 receptors has also been implicated in several diseases.

Activation of PGE2/EP2 and PGE2/EP4 signaling pathways positively regulates PD'1 levels in infiltrating CD8+ T cells in lung cancer patients, leading to immune tolerance in the lung cancer microenvironment. (WANG, Jinhong, et al. Oncology letters, 2018, vol. 15, no 1, p. 552558).

Activation of EP2/EP4 correlates with the induction of urothelial cancer initiation and growth, as well as chemoresistance, presumably through suppression of phosphatase and tensin homolog (PTEN) expression. In BC cell lines, EP2/EP4 antagonists and celecoxib effectively inhibited cell viability and migration, and also increased PTEN expression (KASHIWAGI, Eiji, et al. British journal of cancer, 2018, vol. 118, no 2, p. 213.)

Activation of the S1P3 receptor in metastatic breast cancer cells is known to increase migration and invasion by inducing PGE2 and EP2/EP4 activation. (FILIPENKO, Iuliia, et al. Biochimica et biophysica acta (BBA)-molecular and cell biology of lipids, 2016, vol. 1861, no 11, p. 1840-1851).

It is also known that human prostate cancer is associated with overexpression of EP4 and EP2 and decreased expression of EP3 (HUANG, Hosea FS, et al. Significance of divergent expression of prostaglandin EP4 and EP3 receptors in human prostate cancer. Molecular Cancer Research, 2013, p. molcanres 0464.2012). Similarly, another study showed that prostaglandin E2 regulates tumor angiogenesis in prostate cancer through E prostanoid 2 (EP2)-mediated and EP4-mediated pathways. (JAIN, Shalini, et al. Cancer Research, 2008, vol. 68, no 19, p. 7750-7759).

Other studies mention that PGE2 increases the invasion of SN12C cells through a signaling pathway that involves EP2 and EP4, promoting the invasion of renal carcinoma cells. (LI, Zhenyu, et al. PGE2 promotes renal carcinoma cell invasion through activated RalA. Oncogene, 2013, vol. 32, no 11, p. 1408) and (LI, Zhenyu, et al. Oncogene, 2013, vol. 32, no. 11, p. 1408).

PGE2 receptor agonists (EP2 and EP4) promote the migration of melanoma cells, while PGE2 receptor antagonists inhibit the migratory ability of melanoma cells, a very aggressive form of skin cancer. (VAID, Mudit, et al. American journal of cancer research, 2015, vol. 5, no 11, p. 3325).

In addition, inhibition of EP2 and EP4 was proven to show that PGE2 induces COX-2 protein expression through EP2 and EP4 receptors in LoVo colon cancer cells. (HSU, HsiHsien, et al. International journal of molecular sciences, 2017, vol. 18, no 6, p. 1132).

Other studies have shown that inhibition of EP2/EP4 reduces the growth and duration of endometriosis lesions; reduces angiogenesis and innervation of endometriosis foci; suppresses the pro-inflammatory state of dorsal root ganglion neurons, reducing pelvic pain; reduces the pro-inflammatory, estrogen-dominant and progesterone-resistant molecular environment of the endometrium and endometriosis lesions; and restores the functional receptivity of the endometrium through several mechanisms (AROSH, Joe A., et al. Proceedings of the National Academy of Sciences, 2015, vol. 112, no 31, p. 9716-9721) (Banu, S.K.; Lee, J .; Speights, V.O., Jr.; Starzinski-Powitz, A.; Arosh, J.A. Molecular Endocrinology 2009, 23, 1291-1305) and new selective EP4 antagonists for the treatment of endometriosis have been identified (BAURLE, Stefan, et al. Identification of a Benzimidazolecarboxylic Acid Derivative (BAY 1316957) as a Potent and Selective Human Prostaglandin E2 Receptor Subtype 4 (hEP4-R) Antagonist for the Treatment of Endometriosis. Journal of Medicinal Chemistry, 2019).

EP2 and EP4 in the immune response.

In tumors of various types, all four receptors are important, but the expression of EP2 and EP4 receptors is much more dominant on immune cells than on tissue resident cells.

PGE2-induced EP2 receptor signaling also plays an important role in suppressing the antitumor immune response. Indeed, most of the immunomodulatory effects of PGE2 on immune cells occur as a result of signal transduction through the EP2 and EP4 receptors (KALINSKI, Pawel. The Journal of Immunology, 2012, vol. 188, no 1, p. 21-28.). This is likely due to the fact that the signal through both of these receptors is transmitted by the same stimulatory protein Gas, and when activated leads to an increase in the intracellular concentration of cAMP. This increase in cAMP has been shown to be responsible for the inhibition of T helper (TH)1 cells and the associated decrease in IL-2 and IFNy, which is important given that CD4+ TH cells are a key effector of the adaptive immune system required for fight against cancer. (O'CALLAGHAN, G.; HOUSTON, A. British journal of pharmacology, 2015, vol. 172, no 22, p. 52).

PGE2 also inhibits, in an EP2 and EP4 receptor-mediated manner, the activity of NK cells and cytotoxic T cells (CTL) (HOLT, Dawn, et al. Journal of immunotherapy, 2012, vol. 35, no 2, p. 179.) two cell types that may also form part of the antitumor immune response. In addition, by directly inhibiting the activity of immune cells, signaling through the EP2 and EP4 receptors promotes the development of Treg cells. Treg cells are potent inhibitors of the immune system, suppressing the activity of a variety of immune cells, including dendritic cells (DC) (NARENDRA, Bodduluru Lakshmi, et al. Inflammation Research, 2013, vol. 62, no 9, p. 823-834.). DCs play a central role in initiating tumor-specific immune responses, and the presence of DCs in tumors correlates with improved prognosis. Signaling through the EP2 (and EP4) receptors not only blocked DC activity through the induction of Treg cells, but also blocked their generation from monocytes, which instead led to the development of immunosuppressive MDSCs from monocytes (DE KEIJZER, Sandra, et al. International journal of molecular sciences, 2013, vol. 14, no 4, pp. 6542-6555.).

Activation of PGE2/EP2 and PGE2/EP4 signaling pathways positively regulates PD1 levels in infiltrating CD8+ T cells in lung cancer patients. (WANG, Jinhong, et al. Oncology letters, 2018, vol. 15, no 1, p. 552-558).

Another study demonstrated that PGE2 produced by thyroid cancer cells suppresses the cytolytic activity of NK cells by inhibiting the expression of NK-activating receptors through the EP2 and EP4 receptors on NK cells. (PARK, Arum, et al. Frontiers in immunology, 2018, vol. 9).

On the other hand, it was shown that specific blockade of EP4 with E7046, an EP4 antagonist, reversed PGE2-induced myeloid-mediated immunosuppression, and that E7046 in combination with E7777, an IL-2-diphtheria toxin fusion protein that preferentially kills Tregs, synergistically attenuates both myeloid- and Treg-derived immunosuppression in the TME to promote robust antitumor immune responses, providing a combination therapy that may benefit cancer patients with tumors enriched for myeloid and Treg cells synergistically attenuated both myeloid- and Treg-derived immunosuppression in the TME to promote robust antitumor immune responses, providing combination therapies that may benefit cancer patients with tumors enriched for myeloid and Treg cells (ALBU, Diana I., et al. Oncoimmunology, 2017, vol. 6, no 8, p. e1338239).

Therefore, the problem to be solved by the present invention is to provide compounds as prostaglandin E2 (PGE2) EP4 and/or EP2 receptor modulators.

The present inventors have discovered new N-benzyl-2-phenoxybenzamide derivatives suitable for use as potent modulators of the EP4 and/or EP2 PGE2 receptors. Therefore, the compounds may be useful for the treatment of diseases or conditions mediated by modulation of EP4 and/or EP2 receptors, such as cancer, pain such as acute and chronic pain, inflammation such as osteoarthritis, rheumatoid arthritis, neurodegenerative diseases, endometriosis and kidney diseases .

The essence of the invention

In a first aspect (aspect 1), the present invention relates to new N-benzyl-2phenoxybenzamide derivatives of formula (I)

F where A represents a group selected from phenyl and a five- or six-membered heteroaryl with one, two or three heteroatoms selected from N, S and O;

R ¹ and R ² independently represent a group selected from a hydrogen atom, a halogen atom and a C13 alkyl, or R ¹ and R ² together with the carbon atom to which they are attached form a C34 cycloalkyl group;

R ³ , R ⁴ , R ⁵ and each R 6 independently represent a group selected from a hydrogen atom, a halogen atom, a cyano group, a linear or branched C _1-3 haloalkyl group, a linear or branched C _1-3 alkyl group, a C _3-4 cycloalkyl group , linear or branched C _1-3 alkoxy and pyridyl group;

m is an integer from 1 to 5;

and pharmaceutically acceptable salts thereof.

Other aspects of the present invention are as follows.

Aspect 2). Methods for preparing compounds of aspect 1.

Aspect 3). Pharmaceutical compositions comprising a therapeutically effective amount of a compound of aspect 1.

Aspect 4). The pharmaceutical compositions of aspect 3, further comprising a therapeutically effective amount of chemotherapeutic agents, anti-inflammatory agents, steroids, immunotherapeutic agents and other agents such as therapeutic antibodies.

Aspect 5). Compounds of aspect 1 for use in the treatment of diseases that may be

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Diseases that can be alleviated by modulating EP4 and/or EP2 receptors can be selected from the group consisting of cancer, pain, inflammation, neurodegenerative diseases and kidney diseases. The cancer is preferably selected from colon cancer, gastric cancer, prostate cancer, lung cancer, hepatocellular carcinoma, kidney cancer and breast cancer.

Aspect 6). Use of the compounds of aspect 1 or the pharmaceutical compositions of aspect 3 or 4 in the preparation of a medicament for the treatment of diseases that can be alleviated by modulation of EP4 and/or EP2 receptors.

Aspect 7). Methods for treating or preventing diseases that can be alleviated by modulating EP4 and/or EP2 receptors by administering compounds of aspect 1 or pharmaceutical compositions of aspect 3 or 4 to a subject in need of said treatment.

Aspect 8). combination products comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and one or more therapeutic agents selected from the group consisting of chemotherapeutic agents, anti-inflammatory agents, steroids, immunosuppressants, therapeutic antibodies, which may be used in combination with the compounds of this application for the treatment of diseases, disorders or conditions associated with the modulation of prostaglandin E2 receptors EP4 and/or EP2. One or more additional pharmaceutical agents can be administered to the patient simultaneously or sequentially.

Examples of chemotherapeutic agents include proteasome inhibitors (eg, bortezomib), CNS cancer chemotherapeutic agents including temozolomide, carboplatin, carmustine (BCNU), cisplatin, cyclophosphamide, etoposide, irinotecan, lomustine (CCNU), methotrexate, procarbazine, vincristine, and other chemotherapeutic agents. agents such as thalidomide, revlimid, and DNA damaging agents such as melphalan, doxorubicin, cyclophosphamide, vincristine, etoposide, carmustine and the like.

Examples of anti-inflammatory compounds include aspirin, choline salicylates, celecoxib, diclofenac potassium, diclofenac sodium, diclofenac sodium with misoprostol, diflunisal, etodolac, fenoprofen, flurbiprofen, ibuprofen, ketoprofen, meclofenamate sodium, mefenamic acid, nabumetone, naproxen, naproxen sodium, oxapro zine, piroxican , rofecoxib, salsalate, sodium salicylate, sulindac, tolmetin sodium, valdecoxib and the like.

Examples of steroids include corticosteroids such as cortisone, dexamethasone, hydrocortisone, methylprednisolone, prednisolone, prednisone and the like.

Examples of immunosuppressants include azathioprine, chlorambucil, cyclophosphamide, cyclosporine, daclizumab, infliximab, methotrexate, tacrolimus and the like.

Examples of therapeutic antibodies for use in combination therapy include, but are not limited to, trastuzumab (eg, anti-HER2), ranibizumab (eg, anti-VEGF-A), bevacizumab (eg, anti-VEGF), panitumumab (eg, anti-VEGF-A). EGFR), cetuximab. (eg, anti-EGFR), Rituxan (anti-CD20), and antibodies targeting c-MET.

In yet another aspect, the present invention provides a combination product comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and one or more immunotherapies useful for the treatment of cancer selected from colon cancer, gastric cancer, prostate cancer, lung cancer, and breast cancer.

In a preferred embodiment, the combination product comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof and one or more immunotherapies selected from the group consisting of anti-CTLA4 antibodies selected from ipilimumab and tremelimumab, anti-PD1 antibodies such as nivolumab, pembrolizumab , cemiplimab, pidilizumab, spartalizumab, MEDI0680, REGN2810 and AMP-224, anti-PDL1 antibodies such as atezolizumab, avelumab, durvalumab and MDX-1105, and a monoclonal antibody targeting the GD2 glycolipid such as dinutuximab. The components of the combination product are in one dosage form or in separate dosage forms.

Accordingly, the derivatives of the present invention and pharmaceutically acceptable salts and pharmaceutical compositions comprising such compounds and/or salts thereof can be used in a method of treating pathological conditions or diseases of the human body, which includes administering to a subject in need of said treatment an effective amount of Nbenzyl derivatives. 2-phenoxybenzamide according to the invention or pharmaceutically acceptable salts thereof.

As stated previously, the N-benzyl-2-phenoxybenzamide derivatives of the present invention are useful in the treatment or prevention of diseases that are known to be ameliorated by treatment with prostaglandin E2 receptor EP4 and/or EP2 modulators. Such diseases are selected from the group consisting of cancer, such as gastric cancer, colorectal cancer, prostate cancer, lung cancer, hepatocellular carcinoma, kidney cancer and breast cancer, pain, inflammation, neurodegenerative diseases and kidney diseases.

As used herein, the term halogen atom includes a chlorine, fluorine, bromine or iodine atom, preferably a fluorine, chlorine or bromine atom, more preferably a fluorine or chlorine atom.

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The term halogen, when used as a prefix, has the same meaning.

As used herein, the term C _1-3 haloalkyl is used to refer to C ₁₃ alkyl substituted with one or more halogen atoms, preferably one, two or three halogen atoms. Preferably, the halogen atoms are selected from the group consisting of fluorine or chlorine atoms, more preferably fluorine atoms. In a preferred embodiment, the haloalkyl groups are C1-alkyl substituted with three fluorine atoms (trifluoromethyl group).

As used herein, the term C^alkyl is used to designate linear or branched hydrocarbon radicals ( _{CnH2n +1} ) having from 1 to 3 carbon atoms. Examples include methyl, ethyl, n-propyl, isopropyl radicals.

As used herein, the term Cn-Cm-cycloalkyl embraces hydrocarbon monocyclic groups having n to m carbon atoms, for example 3 to 6 or 3 to 4 carbon atoms. Such cycloalkyl groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

As used herein, the term C _1-3 alkoxy is used to refer to radicals that contain a linear or branched C _1-3 alkyl group bonded to an oxygen atom (C _n H _2n+1 -O-). A preferred alkoxy radical is methoxy.

As used herein, the term C _3-4 cycloalkoxy is used to refer to radicals containing C _3-4 cycloalkyl groups bonded to an oxygen atom.

As used herein, the terms five- to six-membered heteroaryl are used to denote a heteroaromatic ring containing carbon, hydrogen and one or more, preferably one, two or three heteroatoms selected from N, O and S, as part of the ring, such as furan, pyridine, pyrimidine, pyrazine, pyrrole, imidazole, pyrazole, oxazole, thiazole and thiophene, preferably furan, pyridine, pyrazine, pyrrole, imidazole, pyrazole, oxazole, thiazole and thiophene. Said groups may optionally be replaced by one or more substituents as determined in each case. Preferred radicals are optionally substituted pyridinyl, pyrimidinyl. When a heteroaryl radical bears two or more substituents, the substituents may be the same or different.

As used herein, some of the atoms, radicals, chains or rings present in the general structures of the invention are optionally substituted. This means that these atoms, radicals, chains or rings may be unsubstituted or substituted at any position with one or more, for example 1, 2, 3 or 4 substituents, such that the hydrogen atoms associated with the unsubstituted atoms, radicals, chains or rings , are replaced by chemically acceptable atoms, radicals, chains or rings. When two or more substituents are present, each substituent may be the same or different.

As used herein, the term pharmaceutically acceptable salt is used to refer to salts with a pharmaceutically acceptable base. Pharmaceutically acceptable bases include hydroxides of alkali metals (eg sodium or potassium), alkaline earth metals (eg calcium or magnesium) and organic bases such as alkylamines, arylalkylamines and heterocyclic amines.

The term modulator refers to a molecule that blocks or otherwise interferes with a particular biological activity of a receptor.

The term Ki as used herein refers to the concentration causing half-maximal inhibition of control specific binding. Ki values can be estimated from the IC50, the concentration of the radioligand in the assay, and the affinity of the radioligand for the receptor. IC50 values can be estimated from the corresponding dose-response curve, more precisely, IC50 values can be determined using nonlinear regression analysis.

According to one embodiment of the present invention, in the compounds of formula (I), R ¹ and R ² are independently selected from hydrogen and a C1-3 alkyl atom, or R ¹ and R ² together with the carbon atom to which they are attached form a C3-4 cycloalkyl group ; R ³ is selected from a hydrogen atom and a halogen atom; and R ⁴ and R ⁵ represent hydrogen atoms.

According to one embodiment of the present invention, in the compounds of formula (I), R ¹ , R ² , R ³ , R ⁴ and R ⁵ represent hydrogen atoms.

According to one embodiment of the present invention, in the compounds of formula (I), A is selected from the group consisting of phenyl, pyridinyl, pyrazolyl, pyrimidinyl, thiophenyl and furanyl, preferably selected from the group consisting of phenyl, pyridinyl, pyrazolyl, pyrimidinyl and thiophenyl; more preferably selected from the group consisting of phenyl, pyridinyl, pyrimidinyl and thiophenyl; even more preferably selected from the group consisting of phenyl, pyridinyl and thiophenyl.

According to one embodiment of the present invention, A is a phenyl group.

In a preferred embodiment, each R ⁶ independently represents a group

- 7 046234 selected from:

a) a hydrogen atom,

b) a halogen atom, c) a cyano group, d) a carbamoyl (-CONH2) group and d) a linear or branched C _1-3 haloalkyl group.

In a specific embodiment, each R ⁶ independently represents a group selected from:

a) hydrogen atom,

b) a fluorine atom, c) a chlorine atom, c) a cyano group, d) a carbamoyl (-CONH2) group and d) a trifluoromethyl group.

In a more preferred embodiment, A is a phenyl group and each ^R6 is independently a group selected from fluoro, trifluoromethyl and cyano and m is an integer from 1 to 4.

According to another embodiment of the present invention, A is a five- or six-membered heteroaryl ring with one or two N atoms in the ring. In a preferred embodiment, A represents a group selected from a pyridyl or thiophene group, each R ⁶ independently represents a group selected from fluorine, trifluoromethyl and cyano, and m is an integer from one to four.

According to another embodiment of the present invention, R ¹ , R ² , R ³ , R ⁴ and R ⁵ represent hydrogen atoms, A represents a phenyl group and each R ⁶ independently represents a group selected from fluorine or trifluoromethyl groups, and m represents an integer from one to five.

In another embodiment, m is an integer from 1 to 4, preferably m is an integer from 1 to 2.

In another embodiment, A is a group selected from phenyl, pyridinyl, pyrimidinyl, thiophenyl, R ¹ , R ² , R ³ , R ⁴ , R ⁵ are hydrogen atoms, each R ⁶ independently represents a group selected from hydrogen, fluorine, chlorine, cyano group, trifluoromethyl and pyridyl group, and m is an integer from 1 to 2.

Specific individual compounds of the present invention include 4-((2-(4-fluorophenoxy)-5-(pyridin-4-yl)benzamido)methyl)benzoic acid, 4-((4-(4-fluorophenoxy)-[1, 1'-biphenyl]-3-carboxamido)methyl)benzoic acid, 4-((4'-chloro-4-(4-fluorophenoxy)-[1,1'-biphenyl]-3-carboxamido)methyl)benzoic acid, 4-((4'-fluoro-4-(4-fluorophenoxy)-[1,1'-biphenyl]-3-carboxamido)methyl)benzoic acid, 4-((3'-fluoro-4-(4-fluorophenoxy )-[1,1'-biphenyl]-3-carboxamido)methyl)benzoic acid, 4-((2'-fluoro-4-(4-fluorophenoxy)-[1,1'-biphenyl]-3-carboxamido) methyl)benzoic acid, 4-((4'-cyano-4-(4-fluorophenoxy)-[1,1'-biphenyl]-3-carboxamido)methyl)benzoic acid, 4-((3'-cyano-4 -(4-fluorophenoxy)-[1,1'-biphenyl]-3-carboxamido)methyl)benzoic acid, 4-((2-(4-fluorophenoxy)-5 -(3-fluoropyridin-4-yl))benzamido )methyl)benzoic acid, 4-((2-(4-fluorophenoxy)-5 -(pyridin-3 -yl)benzamido)methyl)benzoic acid, 4-((2-(4-fluorophenoxy)-5-(3 -chloropyridin-4-yl)benzamido)methyl)benzoic acid, 4-((2-(4-fluorophenoxy)-5-(pyrimidin-5-yl)benzamido)methyl)benzoic acid, 4-((3',4 '-difluoro-4-(4-fluorophenoxy)-[1,1'-biphenyl]-3-carboxamido)methyl)benzoic acid, 4-((4-(4-fluorophenoxy)-4'-(trifluoromethyl)-[ 1,1'-biphenyl]-3-carboxamido)methyl)benzoic acid, 4-((4-(4-fluorophenoxy)-3'-(trifluoromethyl)-[1,1'-biphenyl]-3-carboxamido)methyl )benzoic acid, 4-((2-(4-fluorophenoxy)-5-(pyridin-2-yl)benzamido)methyl)benzoic acid, 4-((2-(4-fluorophenoxy)-5-(pyrimidin-4 -yl)benzamido)methyl)benzoic acid, 4-((2-(4-fluorophenoxy)-5-(thiophen-2-yl)benzamido)methyl)benzoic acid, 4-((3',5'-difluoro- 4-(4-fluorophenoxy)-[1,1'-biphenyl]-3-carboxamido)methyl)benzoic acid, 4-((3'-chloro-4-(4-fluorophenoxy)-[1,1'-biphenyl ]-3-carboxamido)methyl)benzoic acid, 4-((3'-fluoro-4-(4-fluorophenoxy)-5'-(trifluoromethyl)-[1,1'-biphenyl]-3-carboxamido)methyl) benzoic acid,

4-((3'-carbamoyl-5'-chloro-4-(4-fluorophenoxy)-[1,1'-biphenyl]-3 -ylcarboxamido)methyl)benzoic acid,

4-((2-(4-fluorophenoxy)-5-(III-pyrazol-4-yl)benzamido)methyl)benzoic acid, 4-((2-(4-fluorophenoxy)-5 -(1 -methyl-III -pyrazol-4-yl))benzamido)methyl)benzoic acid, 4-((2-(4-fluorophenoxy)-5 -(1 -methyl-III-pyrazol-5 -yl))benzamido)methyl)benzoic acid, 4-((4-(4-fluorophenoxy)-3 '-(pyridin-4-yl))-[1,1 '-biphenyl]-3 -ylcarboxamido)methyl)benzoic acid, 4-((5-(5 -carbamoylfuran-2-yl))-2-(4-fluorophenoxy)benzamido)methyl)benzoic acid,

- 8 046234

-fluoro-4-((4-(4-fluorophenoxy)-3 '-(trifluoromethyl)-[1,1 '-biphenyl]-3 -ylcarboxamido)methyl)benzoic acid, (R)-4-( 1 -( 4-(4-fluorophenoxy)-3'-(trifluoromethyl)-[1,1'-biphenyl]-3-carboxamido)ethyl)benzoic acid,

4-(1 -(4-(4-fluorophenoxy)-3'-(trifluoromethyl)-[1,1'-biphenyl]-3-carboxamido)cyclopropyl)benzoic acid,

4-((3'-fluoro-5'-cyano-4-(4-fluorophenoxy)-[1,1'-biphenyl]-3-carboxamido)methyl)benzoic acid, 4-((3'-chloro-5 '-cyano-4-(4-fluorophenoxy)-[1,1'-biphenyl]-3-carboxamido)methyl)benzoic acid.

The compounds of the present invention can be prepared using the procedures described below. Specific examples have been used to facilitate the description of procedures, but they do not limit the scope of the present invention in any way.

Scheme 1

Reagents and conditions: (a) MeOH, H ₂ SO ₄ , 70°C; b) NaH, DMF, 120°C, overnight; c) NaOH, MeOH/H ₂ O, room temperature, 3h; d) HATU, DIPEA, DCM, room temperature, overnight; e) [1,1'-bis-(diphenylphosphino)ferrocene] dichloropalladium(II), Cs ₂ CO ₃ , dio^an^O, 100°C, overnight, f) NaOH, MeOH/H ₂ O, room temperature, overnight.

The compounds of formula (I) can be prepared by the synthesis described in Scheme 1.

Starting with the 5-bromo-2-fluorobenzoic acid derivative of formula (II), reaction with methanol results in the formation of ester (III), which in turn is reacted with phenol derivatives of formula (IV) to produce compounds of formula (V).

Hydrolysis under basic aqueous conditions of compounds of formula (V) produces intermediates of formula (VI), which are reacted with an amine of formula (VII) in the presence of a coupling agent such as HATU, resulting in a compound of formula (VIII). Aryl bromides of formula (VIII) can be converted to compounds of formula (I) by reaction with boronic acids or boronate esters under palladium-catalyzed conditions, followed by hydrolysis under basic aqueous conditions.

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Scheme 2

Reagents and conditions: g) [1,1'-bis-(diphenylphosphino)ferrocene]dichloropalladium(H), Cs ₂ CO ₃ , dioxane/H ₂ O, 100°C, overnight; h) NaH, DMF, 120°C, overnight; i) NaOH, MeOH/H ₂ O, room temperature, overnight; j) HATU, DIPEA, DCM, room temperature, overnight; k) NaOH, MeOH/H ₂ O, room temperature, overnight.

An alternative route to the compounds of formula (I) is shown in Scheme 2. Aryl bromides of formula (III) react with boronic acids, boronate esters, zinc reagent or tributyl stannane reagents in the presence of a palladium catalyst to produce intermediates of formula (X).

Using reactions similar to those described in Scheme 1, compounds of formula (X) react with phenol (IV) to form, after hydrolysis under basic aqueous conditions, intermediates of formula (XI), which react with amines of formula (VII) in the presence of a coupling agent such as HATU, yielding, after hydrolysis under basic aqueous conditions, the corresponding compounds of formula (I).

The synthesis of the compounds of the invention is illustrated by the following examples, including the preparation of intermediate compounds, which in no way limit the scope of the invention.

Abbreviations.

In this application the following abbreviations with corresponding definitions are used:

room temp.: room temperature,

HATU: N-[(dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridin-1-yl)methylene]-N-methylmethanaminium hexafluorophosphate N-oxide,

DIPEA: N,N-diisopropylethylamine,

DMF: dimethylformamide,

DCM: dichloromethane,

THF: tetrahydrofuran,

DMSO: dimethyl sulfoxide.

Pharmacological activity.

Results.

The compounds of the present invention were analyzed for binding to the human EP1, EP2, EP3 and EP4 receptors and were tested at several concentrations to determine the IC ₅₀ .

Competitive binding in the human EP1 receptor.

Competitive prostaglandin EP1 receptor binding experiments were performed in a polypropylene 96-well microplate with binding buffer (Mes 10 mM, EDTA 1 mM, MgCl ₂ 1 mM, pH 6.0). In each well, 10 μg of membranes from the HEK-EP1 cell line were incubated and obtained in the laboratory of the authors of the invention (Lot: A003/19-10-2011, protein concentration = 1756 μg/ml), 3 nM [3H]Prostaglandin E2 (169.8 Ci/mmol, 0.1 mCi/ml, Perkin Elmer NET428250UC) and test compounds and standard. Nonspecific binding was determined in the presence of 10 μM PGE2 (Cayman 14010). The reaction mixture (total volume: 250 μl/well) was incubated at 25°C for 60 min, 200 μl was transferred to a GF/C 96-well plate (Millipore, Madrid, Spain), then filtered and washed four times with 250 μl wash buffer (Mes 10 mM, EDTA 1 mM, MgCl2 1 mM, pH 6.0), before

- 10 046234 by measurement in a microplate beta scintillation counter (Microbeta Trilux, PerkinElmer, Madrid, Spain) (Abramovitz et al., Biochim Biophys Acta 2000; 1483:285-293).

Competitive binding in the human EP2 receptor.

Competitive prostaglandin EP2 receptor binding experiments were performed in a polypropylene 96-well microplate with binding buffer (Hepes 50 mM, CaCl ₂ 1 mM, MgCl ₂ 5 mM, pH 7.4). Each well was incubated with 10 μg of membranes from the EP2 cell line (Millipore HTS185M, protein concentration = 2000 μg/ml), 7.5 nM Ig-prostaglandin E2 (169.8 Ci/mmol, 0.1 mCi/ml, Perkin Elmer NET428250UC) and test compounds and standard. Nonspecific binding was determined in the presence of 200 μM PGE2 (Cayman 14010). The reaction mixture (total volume: 250 μl/well) was incubated at 25°C for 90 min, 200 μl was transferred to a GF/C 96-well plate (Millipore, Madrid, Spain), then filtered and washed four times with 250 μl wash buffer (Hepes 50 mM, NaCl 500 mM, pH 7.4), before measurement in a microplate beta scintillation counter (Microbeta Trilux, PerkinElmer, Madrid, Spain). (Wilson et al., Br J Pharmacol 2006; 148:326-339 ).

Competitive binding in the human EP3 receptor.

Competitive prostaglandin EP3 receptor binding experiments were performed in a 96-well GF/C multiscreen plate (Millipore, Madrid, Spain) pretreated with binding buffer (Tris-HCl 50 mM, MgCl2 10 mM, EDTA 1 mM, pH 7.4). Each well was incubated with 5 μg of cell line membranes (Millipore; HTS092M, protein concentration = 2000 μg/ml), 1.5 nM [3H]Prostaglandin E2 (169.8 Ci/mmol, 0.1 mCi/ml, Perkin Elmer NET428250UC) and test compounds and standard. Nonspecific binding was determined in the presence of 200 μM PGE2 (Cayman 14010). The reaction mixture (total volume: 250 μl/well) was incubated at 25°C for 90 min, 200 μl was transferred to a GF/C 96-well plate (Millipore, Madrid, Spain), then filtered and washed four times with 250 μl wash buffer (Tris-HCl 50 mM, pH 7.4), before measurement in a betascintillation microplate counter (Microbeta Trilux, PerkinElmer, Madrid, Spain) (Audoly et al., Mol Pharmacol 1997; 51:61-68).

Competitive binding in the human EP4 receptor.

Competitive prostaglandin EP4 receptor binding experiments were performed in a 96-well GF/B multiscreen plate (Millipore, Madrid, Spain) pretreated with binding buffer (Mes 25 mM, EDTA 1 mM, MgCl ₂ 10 mM, pH 6.0). In each well, 35 μg of membranes from the HEK-EP4 cell line were incubated and obtained in the laboratory of the authors of the invention (Lot: A003/27-042011, protein concentration = 2803 μg/ml), 1 nM Ig-prostaglandin E2 (169.8 Ci/ mmol, 0.1 mCi/ml, Perkin Elmer NET428250UC) and test compounds and standard. Nonspecific binding was determined in the presence of 10 μM PGE2 (Cayman 14010). The reaction mixture (total volume: 250 μl/well) was incubated at 25°C for 120 min, 200 μl was transferred to a GF/B 96-well plate (Millipore, Madrid, Spain), then filtered and washed six times with 250 μl wash buffer (Mes 25 mM, BSA 0.01%, pH 6.0), before measurement in a microplate beta scintillation counter (Microbeta Trilux, PerkinElmer, Madrid, Spain). (Abramovitz et al., Biochim Biophys Acta 2000; 1483:285 -293).

Inhibition constants (Ki) were calculated using the Cheng Prusoff equation

Kg— (I+L/K _d ),

where L is the concentration of the radioligand in the assay and KD is the affinity of the radioligand for the receptor.

The Scatchard plot is used to determine KD.

The compounds of the present invention do not exhibit any significant binding affinity for the EP1 and EP3 receptors.

In table 1 shows the Ki values of some compounds of the present invention for the EP2 and EP4 receptors.

Ki ranges: A<0.1 µM; 0.1 µM<= B <1 µM; 1 µM<= C <10 µM, D >=10 µM.

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Table 1

Example Ki values EP2 EP4 1 D A 2 D A 3 D A 4 A A 5 A A 6 WITH A 7 WITH A 8 A A 9 WITH A 10 WITH A

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eleven D IN 12 D IN 13 A IN 14 IN WITH 15 A A 18 WITH A 19 A A 20 WITH A 21 A A 26 D A 27 WITH WITH 28 WITH A 29 WITH A thirty WITH A 31 WITH A 32 WITH A

As can be seen from the results described in table. 1, the compounds of the present invention bind effectively to the prostaglandin E2 receptors EP4 and/or EP2.

The compounds of the invention are useful for the treatment or prevention of diseases that are known to be susceptible to improvement by modulation of the EP4 and/or EP2 receptors. Such diseases are selected from cancer, pain, inflammation, neurodegenerative diseases and kidney diseases.

Thus, the compounds of the invention and their salts are used in the preparation of a medicament for the treatment or prevention of diseases that are known to be susceptible to improvement by modulation of the EP4 and/or EP2 receptors.

Accordingly, derivatives of the invention and pharmaceutically acceptable salts thereof and pharmaceutical compositions containing such compounds and/or salts thereof can be used in a method of treating or preventing diseases of the human body that are known to be susceptible to improvement by modulation of EP4 and/or EP2 receptors wherein said method comprises administering to a subject in need of such treatment or prophylaxis an effective amount of the Nbenzyl-2-phenoxybenzamide derivatives of the invention or pharmaceutically acceptable salts thereof.

By an effective amount or a therapeutically effective amount of a compound, drug or pharmacologically active agent is meant a non-toxic but dosage

- 13 046234 the exact amount of a compound, drug or agent to provide the desired effect. The amount that is effective will vary from subject to subject, depending on the age and general condition of the individual, the particular active agent or agents, and the like. Therefore, it is not always possible to specify an exact effective amount. However, the appropriate effective amount in each individual case can be determined by one skilled in the art using routine experimentation.

One therapeutic use of the compounds of the present invention is the treatment of proliferative diseases or disorders such as cancer. The cancer is selected from colon cancer, gastric cancer, prostate cancer, lung cancer, hepatocellular carcinoma, kidney cancer and breast cancer.

The present invention also relates to pharmaceutical compositions which contain as an active ingredient at least N-benzyl-2-phenoxybenzamide derivatives of formula (I) or a pharmaceutically acceptable salt thereof in combination with other therapeutic agents and a pharmaceutically acceptable excipient such as a carrier or diluent. The active ingredient may constitute from 0.001 to 99% by weight, preferably from 0.01 to 90% by weight of the composition, depending on the nature of the drug and whether further dilution is required before use. Preferably, the compositions are prepared in a form suitable for oral, topical, nasal, rectal, transdermal or injectable administration.

Pharmaceutically acceptable excipients that are mixed with the active compound or salts of such a compound to form the compositions of the present invention are themselves well known, and the actual excipients used depend, among other things, on the intended route of administration of the compositions.

The compositions of the present invention are preferably adapted for injection and oral administration. In this case, the compositions for oral administration may take the form of tablets, retard tablets, sublingual tablets, capsules, inhalation aerosols, inhalation solutions, dry powder inhalations or liquid preparations such as mixtures, elixirs, syrups or suspensions, all containing a compound of the invention ; such preparations can be prepared by methods well known in the art.

Diluents that can be used in preparing the compositions include those liquid and solid diluents that are compatible with the active ingredient, together with colors or flavors, if desired. Tablets or capsules may generally contain from 2 to 500 mg of the active ingredient or an equivalent amount of a salt thereof.

The liquid composition adapted for oral administration may be in the form of solutions or suspensions. The solutions may be aqueous solutions of a soluble salt or other derivative of the active compound combined, for example, with sucrose to form a syrup. Suspensions may comprise the insoluble active compound of the invention or a pharmaceutically acceptable salt thereof in combination with water, together with a suspending agent or flavoring agent.

Compositions for parenteral injection can be prepared from soluble salts, which may or may not be lyophilized, and which can be dissolved in a pyrogen-free aqueous medium or other suitable liquid for parenteral injection.

Effective doses are usually in the range of 2-2000 mg of active ingredient per day. The daily dose may be administered in one or more courses of treatment, preferably 1 to 4 times daily.

The present invention will be further illustrated by the following examples. The following data is provided for illustration purposes and is not intended to limit the scope of the invention in any way.

Examples

General. Reagents, solvents, and starting materials were purchased from commercial sources. The term concentration refers to vacuum evaporation using a Buchi rotary evaporator. When indicated, reaction products were purified by flash chromatography on silica gel (40-63 μm) with the indicated solvent system. Spectroscopic data were measured on a Varian Mercury 400 spectrometer. Melting points were measured on a Buchi 535. HPLC-MS was performed on a Gilson instrument equipped with a Gilson 321 piston pump, Gilson 864 vacuum degasser, Gilson 189 injection module, 1/1000 Gilson divider, Gilson 307 pump , Gilson 170 detector and Thermoquest Fennigan aQa detector.

Intermediate connection. Methyl 4-(azidomethyl)-3-fluorobenzoate

F F

Oh Oh

A solution of methyl 4-(bromomethyl)-3-fluorobenzoate (100 mg, 1.0 eq.) and sodium azide (29 mg, 1.2 eq.) in

- 14 046234

DMF (1.0 ml) was stirred at 80°C for 90 minutes. After cooling, the reaction mixture was diluted with brine (3 ml) and extracted with ethyl acetate (3x10 ml). The combined organic solution was washed with water (25 ml) and brine (25 ml), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The desired azide was obtained as a pale yellow liquid (quantitative), which was used in the next step without further purification.

¹ H-NMR (400 MHz, DMSO-d ⁶ ): δ=7.82 (dd, 1H), 7.74 (dd, 1H), 7.64 (t, 1H), 4.62 (s, 2H ), 3.87 (s, 3H). HPLC-MS: Rt 2.65 m/z 182.0 (MH ⁺ ).

Intermediate 2: Methyl 4-(aminomethyl)-3-fluorobenzoate

A solution of methyl 4-(azidomethyl)-3-fluorobenzoate (110 mg, 1.0 eq.), triphenylphosphine (189 mg, 1.2 eq.) and water (0.9 ml) in THF (2 ml) was stirred at room temperature temperature for 20 hours. The solvent was removed under reduced pressure and purified by flash column chromatography (dichloromethane:methanol, 30:1) to give methyl 4-(aminomethyl)-3-fluorobenzoate as a yellow wax (70 mg, 63.7% yield).

¹ H-NMR (400 MHz, DMSO-d ⁶ ): δ=7.78 (dd, 1H), 7.67 (t, 1H), 7.61 (dd, 1H), 3.85 (s, 3H ), 3.80 (s, 2H), 1.96 (s, 2H).

HPLC-MS: Rt 1.63 m/z 184.1 (MH ⁺ ).

Intermediate 3: Methyl 4-fluoro-[1,1'-biphenyl]-3-carboxylate

A catalytic amount of H ₂ SO ₄ was added to a solution of 4-fluoro-[1,1'-biphenyl]-3-carboxylic acid (200.0 mg, 0.93 mmol) in methanol (1 ml) and the reaction mixture was stirred at 70° C overnight. The solution was partitioned between water and ethyl acetate and the organic layer was washed with sat. NaHCO ₃ and saturated saline solution. It was dried over anhydrous sodium sulfate, filtered and concentrated to give intermediate 1 as an oil (167.0 mg, 76.0%).

¹ H-NMR (400 MHz, DMSO-d ⁶ ): δ=8.09 (dd, 1H), 7.96 (dd, 1H), 7.68 (d, 2H), 7.46 (m, 2H ), 3.89 (s, 3H).

HPLC-MS: Rt 5.337 m/z 231.0 (MH ⁺ )

The following intermediate was synthesized using the procedure described for intermediate 3.

Intermediate 4: Methyl 5-bromo-2-fluorobenzoate.

¹ H-NMR (400 MHz, DMSO-d ⁶ ): δ=7.98 (dd, 1H), 7.87 (m, 1H), 7.37 (dd, 1H), 3.86 (s, 3H ).

Intermediate 5. Methyl 5-bromo-2-(4-fluorophenoxy)benzoate

A solution of methyl 5-bromo-2-fluorobenzoate (1000 mg, 4 .29 mmol) in N,N-dimethylformamide. The solution was heated to 120°C and stirred for 16 hours. After cooling to room temperature, the mixture was diluted with water (20 ml) and extracted with ethyl acetate (3x20 ml). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound as a light yellow oil (1028.3 mg, 73.7%).

¹ H-NMR (400 MHz, DMSO-d ⁶ ): δ=7.95 (d, 1H), 7.75 (dd, 1H), 7.22 (m, 2H), 7.04 (m, 2H ), 6.95 (d, 1H), 3.75 (s, 3H).

HPLC-MS: Rt 5.602 m/z 326.9 (MH ⁺ ).

The following intermediate was synthesized using the procedure described for intermediate 5 and the corresponding methyl esters and 4-fluorophenol.

Intermediate 6: Methyl 4-(4-fluorophenoxy)-[1,1'-biphenyl]-3-carboxylate.

¹ H-NMR (400 MHz, DMSO-d ⁶ ): δ=8.07 (d, 1H), 7.88 (dd, 1H), 7.68 (d, 2H), 7.49 (t, 2H ), 7.39 (t, 1H), 7.23 (t, 2H), 7.10 (s, 1H), 7.06 (m, 2H), 3.77 (s, 3H).

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HPLC-MS: Rt 5.948 m/z 323.0 (MH ⁺ ).

Intermediate 7. 5-Bromo-2-(4-fluorophenoxy)benzoic acid

To a solution of methyl 5-bromo-2-(4-fluorophenoxy)benzoate (1101.3 mg, 3.39 mmol) in methanol (8 ml) and THF (8 ml) was added NaOH 2M (8.5 ml, 16.94 mmol) and the mixture was stirred for 3 hours at room temperature. The solution was diluted with water (15 ml) and the pH was adjusted to 4.0 by adding HCl 1M. The mixture was extracted with ethyl acetate (3x50 ml) and the combined organic layer was dried with sodium sulfate and concentrated to give a white solid, which was washed with pentane (823.5 mg, 78.1%).

¹ H-NMR (400 MHz, DMSO-d ⁶ ): δ=13.24 (s, 1H), 7.92 (s, 1H), 7.72 (d, 1H), 7.21 (t, 2H ), 7.01 (s, 2H), 6.94 (d, 1H).

HPLC-MS: Rt 3.087 m/z 312.9 (MH ⁺ ).

The following intermediate was synthesized using the procedure described for intermediate 7 and the corresponding methyl esters.

Intermediate 8: 4-(4-fluorophenoxy)-[1,1'-biphenyl]-3-carboxylic acid.

¹ H-NMR (400 MHz, DMSO-d ⁶ ): δ=13.04 (s, 1H), 8.06 (d, 1H), 7.84 (dd, 1H), 7.68 (d, 2H ), 7.48 (t, 2H), 7.39 (t, 1H), 7.22 (t, 2H), 7.04 (m, 3H).

HPLC-MS: Rt 3.435 m/z 309.0 (MH ⁺ ).

Intermediate 9: 4-(4-Fluorophenoxy)-3'-(trifluoromethyl)-[1,1'-biphenyl]-3-carboxylic acid.

¹ H-NMR (400 MHz, DMSO-d ⁶ ): δ=13.09 (s, 1H), 8.13 (d, 1H), 7.95 (m, 4H), 7.72 (m, 2H ), 7.23 (m, 2H), 7.05 (m, 2H).

HPLC-MS: Rt 2.20 m/z 377.0 (MH ⁺ ).

Intermediate 10: Methyl 4-((5-bromo-2-(4-fluorophenoxy)benzamido)methyl)benzoate

To a solution of 5-bromo-2-(4-fluorophenoxy)benzoic acid (600 mg, 1.93 mmol) in DCM eng. (15 ml) HATU (880.0 mg, 2.30 mmol) and DIPEA (1.31 ml, 7.71 mmol) were added. After stirring the reaction mixture at room temperature under N2 for 15 minutes, methyl 4(aminomethyl)benzoate hydrochloride (466.7 mg, 2.30 mmol) was added and the reaction mixture was left stirring overnight at room temperature. After adding 20 ml H2O, the aqueous phase was extracted with DCM 3x20 ml. The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a white solid (728.5 mg, 82.4%).

¹ H-NMR (400 MHz, DMSO-d ⁶ ): δ=8.97 (t, 1H), 7.85 (d, 2H), 7.79 (d, 1H), 7.63 (dd, 1H ), 7.38 (d, 2H), 7.24 (t, 2H), 7.11 (dd, 2H), 6.86 (d, 1H), 4.51 (d, 2H), 3.83 (c, 3H).

HPLC-MS: Rt 5.523 m/z 459.0 (MH ⁺ ).

The following intermediate was synthesized using the procedure described for intermediate 10 and appropriate chemicals or derivatives.

Intermediate 11. Methyl ^)-4-(1-(5-bromo-2-(4-fluorophenoxy)benzamido)ethyl)benzoate.

¹ H-NMR (400 MHz, DMSO-d ⁶ ): δ=8.89 (d, 1H), 7.84 (d, 2H), 7.69 (d, 1H), 7.62 (dd, 1H ), 7.45 (d, 2H), 7.22 (t, 2H), 7.07 (m, 2H), 6.89 (d, 1H), 5.08 (p, 1H), 3.83 (s, 3H), 1.38 (d, 3H).

HPLC-MS: Rt 3.21 m/z 473.9 (MH ⁺ ).

Intermediate 12: Methyl 4-(1-(5-bromo-2-(4-fluorophenoxy)benzamido)cyclopropyl)benzoate.

¹ H-NMR (400 MHz, DMSO-d ⁶ ): δ=9.13 (s, 1H), 7.78 (s, 1H), 7.76 (d, 2H), 7.65 (dd, 1H ), 7.24 (m, 4H), 7.08 (m, 2H), 6.95 (d, 1H), 3.82 (s, 3H), 1.28 (m, 2H), 1.21 (m, 2H).

HPLC-MS: Rt 3.18 m/z 485.9 (MH ⁺ ).

Intermediate 13: Methyl 4-((4-(4-fluorophenoxy)-[1,1'-biphenyl]-3-carboxamido)methyl)benzoate.

¹ H-NMR (400 MHz, DMSO-d ⁶ ): δ=8.96 (t, 1H), 7.93 (d, 1H), 7.86 (d, 2H), 7.76 (dd, 1H ), 7.68 (d, 2H),

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7.48 (t, 2H), 7.39 (m, 3H), 7.25 (t, 2H), 7.13 (m, 2H), 7.00 (d, 1H), 4.54 (d , 2H), 3.84 (s, 3H).

HPLC-MS: Rt 5.843 m/z 456.1 (MH ⁺ ).

Intermediate 14: 4-((5-Bromo-2-(4-fluorophenoxy)benzamido)methyl)benzoic acid.

To a solution of methyl 4-((5-bromo-2-(4-fluorophenoxy)benzamido)methyl)benzoate (200 mg, 1.0 eq.) in THF (2.0 ml) and methanol (2.0 ml) was added NaOH (2 M) (1.1 ml, 5.0 eq.)) and the mixture was stirred for 20 hours at room temperature. After dilution with water (10 ml), the mixture was neutralized with aqueous HCl, filtered and washed with water and pentane to give the acid as a white solid (176 mg, 90.9% yield).

¹ H-NMR (400 MHz, DMSO-d ⁶ ): δ=12.88 (s, 1H), 8.98 (t, 1H), 7.82 (m, 3H), 7.63 (dd, 1H ), 7.32 (m, 2H), 7.24 (m, 2H), 7.12 (m, 2H), 6.86 (d, 1H), 4.49 (d, 2H).

HPLC-MS: Rt 1.26 m/z 444.0 (MH ⁺ ).

Intermediate 15: Methyl 4-((2-(4-fluorophenoxy)-5-(pyridin-4yl)benzamido)methyl)benzoate

F F

To a solution of methyl 4-((5-bromo-2-(4-fluorophenoxy)benzamido)methyl)benzoate (70.0 mg, 0.15 mmol) in dioxane, pyridine-4-boronic acid (37.6 mg, 0 .31 mmol) [1,1'-bis-(diphenylphosphino)ferrocene]dichloropalladium(P) (7.5 mg, 0.009 mmol) was added Cs ₂ CO ₃ 2M (0.23 ml, 0.46 mmol). The mixture was degassed with N2 and stirred at 100°C overnight. The reaction mixture was then filtered through celite and extracted with ethyl acetate. The organic fraction was washed with NaOH 1 M, sat. NaHCO ₃ and brine and dried over anhydrous sodium sulfate. The solvent was removed in vacuo and the residue was purified using flash chromatography (hexane:ethyl acetate 1:1). Removal of the solvent gave the product as a white solid, which was washed with pentane/diethyl ether (44.7 mg, 65.3%).

1H-NMR (400 MHz, DMSO-d ⁶ ): δ=9.00 (t, 1H), 8.65 (d, 2H), 8.08 (d, 1H), 7.89 (m, 3H) , 7.75 (d, 2H), 7.42 (d, 2H), 7.27 (m, 2H), 7.17 (m, 2H), 7.01 (d, 1H), 4.56 ( d, 2H), 3.84 (s, 3H).

HPLC-MS: Rt 4.875 m/z 457.1 (MH ⁺ ).

The following intermediates were synthesized using the procedure described for intermediate 15 using appropriate chemicals or derivatives.

Intermediate 16: Methyl 4-((4'-chloro-4-(4-fluorophenoxy)-[1,1'-biphenyl]-3-carboxamido)methyl)benzoate.

Ή-NMR (400 MHz, DMSO-d ⁶ ): δ=8.99 (t, 1H), 7.92 (d, 1H), 7.85 (d, 2H), 7.74 (m, 3H) , 7.51 (t, 2H), 7.39 (d, 2H), 7.25 (t, 2H), 7.12 (m, 2H), 6.99 (d, 1H), 4.53 ( d, 2H), 3.83 (s, 3H).

HPLC-MS: Rt 6.203 m/z 490.1 (MH ⁺ ).

Intermediate 17. Methyl 4-((4'-fluoro-4-(4-fluorophenoxy)-[1,1'-biphenyl]-3carboxamido)methyl)benzoate.

Ή-NMR (400 MHz, DMSO-d ⁶ ): δ=8.98 (s, 1H), 7.86 (m, 3H), 7.72 (s, 3H), 7.37 (m, 2H) , 7.27 (m, 4H), 7.12 (s, 2H), 6.98 (d, 1H), 4.53 (d, 2H), 3.83 (s, 3H).

HPLC-MS: Rt 5.945 m/z 474.1 (MH ⁺ ).

Intermediate 18. Methyl 4-((3'-fluoro-4-(4-fluorophenoxy)-[1,1'-biphenyl]-3carboxamido)methyl)benzoate.

Ή-NMR (400 MHz, DMSO-d ⁶ ): δ=8.99 (s, 1H), 7.95 (d, 1H), 7.85 (d, 2H), 7.80 (dd, 1H) , 7.53 (t, 3H), 7.40 (d, 2H), 7.24 (dd, 3H), 7.13 (dd, 2H), 6.98 (d, 1H), 4.54 ( d, 2H), 3.83 (s, 3H).

HPLC-MS: Rt 5.963 m/z 474.1 (MH ⁺ ).

Intermediate 19. Methyl 4-((2'-fluoro-4-(4-fluorophenoxy)-[1,1'-biphenyl]-3carboxamido)methyl)benzoate.

Ή-NMR (400 MHz, DMSO-d ⁶ ): δ=8.99 (s, 1H), 7.85 (d, 3H), 7.64 (d, 1H), 7.57 (s, 1H) , 7.40 (d, 3H), 7.30 (m, 4H), 7.17 (s, 2H), 6.98 (d, 1H), 4.54 (d, 2H), 3.83 ( s, 3H).

HPLC-MS: Rt 5.936 m/z 474.1 (MH ⁺ ).

Intermediate 20. Methyl 4-((4'-cyano-4-(4-fluorophenoxy)-[1,1'-biphenyl]-3carboxamido)methyl)benzoate.

Ή-NMR (400 MHz, DMSO-d ⁶ ): δ=9.01 (t, 1H), 8.02 (d, 1H), 7.93 (m, 4H), 7.85 (m, 3H) , 7.41 (d, 2H), 7.27 (t, 2H), 7.16 (m, 2H), 7.00 (d, 1H), 4.55 (d, 2H), 3.83 ( s, 3H).

HPLC-MS: Rt 5.649 m/z 481.1 (MH ⁺ ).

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Intermediate 21: Methyl 4-((3'-cyano-4-(4-fluorophenoxy)-[1,1'-biphenyl]-3carboxamido)methyl)benzoate.

Ή-NMR (400 MHz, DMSO-d ⁶ ): δ=9.00 (t, 1H), 8.20 (s, 1H), 8.04 (dd, 2H), 7.85 (t, 4H) , 7.68 (t, 1H), 7.41 (d, 2H), 7.27 (t, 2H), 7.15 (dd, 2H), 7.00 (d, 1H), 4.55 ( d, 2H), 3.84 (s, 3H).

HPLC-MS: Rt 5.668 m/z 481.1 (MH ⁺ ).

Intermediate 22: Methyl 4-((2-(4-phorophenoxy)-5-(3-fluoropyridin-4-yl))benzamido)methyl)benzoate.

Ή-NMR (400 MHz, DMSO-d ⁶ ): δ=9.03 (t, 1H), 8.67 (d, 1H), 8.51 (d, 1H), 7.97 (s, 1H) , 7.86 (d, 2H), 7.77 (d, 1H), 7.68 (dd, 1H), 7.42 (d, 2H), 7.29 (dd, 2H), 7.20 ( m, 2H), 7.01 (d, 1H), 4.56 (d, 2H), 3.83 (s, 3H).

HPLC-MS: Rt 5.199 m/z 475.1 (MH ⁺ ).

Intermediate 23: Methyl 4-((2-(4-fluorophenoxy)-5-(pyridin-3yl)benzamido)methyl)benzoate.

Ή-NMR (400 MHz, DMSO-d ⁶ ): δ=9.00 (t,1H), 8.92 (d, 1H), 8.58 (dd, 1H), 8.11 (m, 1H) , 7.99 (d, 1H),

7.84 (m, 3H), 7.50 (dd, 1H), 7.41 (d, 2H), 7.26 (t, 2H), 7.14 (m, 2H), 7.02 (d , 1H), 4.54 (d, 2H), 3.83 (s, 3H).

HPLC-MS: Rt 5.015 m/z 457.1 (MH ⁺ ).

Intermediate 24: Methyl 4-((2-(4-fluorophenoxy)-5-(3-chloropyridin-4yl)benzamido)methyl)benzoate.

Ή-NMR (400 MHz, DMSO-d ⁶ ): δ=9.02 (t, 1H), 8.75 (s, 1H), 8.59 (d, 1H), 7.86 (d, 2H) , 7.84 (d, 1H), 7.64 (dd, 1H), 7.53 (d, 1H), 7.42 (d, 2H), 7.30 (t, 2H), 7.21 ( m, 2H), 6.98 (d, 1H), 4.55 (d, 2H), 3.83 (s, 3H).

HPLC-MS: Rt 5.378 m/z 491.1 (MH ⁺ ).

Intermediate 25: Methyl 4-((2-(4-fluorophenoxy)-5-(pyrimidin-5yl)benzamido)methyl)benzoate.

Ή-NMR (400 MHz, DMSO-d ⁶ ): δ=9.18 (m, 3H), 9.02 (t, 1H), 8.08 (d, 1H), 7.88 (m, 3H) , 7.42 (d, 2H), 7.27 (t, 2H), 7.15 (m, 2H), 7.04 (d, 1H), 4.55 (d, 2H), 3.83 ( s, 3H).

HPLC-MS: Rt 4.715 m/z 458.1 (MH ⁺ ).

Intermediate 26: Methyl 4-((3',4'-difluoro-4-(4-fluorophenoxy)-[1,1'-biphenyl]-3carboxamido)methyl)benzoate.

Ή-NMR (400 MHz, DMSO-d ⁶ ): δ=8.98 (t, 1H), 7.95 (d, 1H), 7.81 (m, 4H), 7.53 (m, 2H) , 7.40 (d, 2H), 7.26 (t, 2H), 7.13 (m, 2H), 6.98 (d, 1H), 4.54 (d, 2H), 3.83 ( s, 3H).

HPLC-MS: Rt 5.977 m/z 492.1 (MH ⁺ ).

Intermediate 27. Methyl 4-((4-(4-fluorophenoxy)-4'-(trifluoromethyl)-[1,1'-biphenyl]-3carboxamido)methyl)benzoate.

Ή-NMR (400 MHz, DMSO-d ⁶ ): δ=9.02 (t, 1H), 8.01 (d, 1H), 7.93 (d, 2H), 7.84 (m, 5H) , 7.41 (d, 2H), 7.27 (dd, 2H), 7.16 (m, 2H), 7.01 (d, 1H), 4.55 (d, 2H), 3.83 ( s, 3H).

HPLC-MS: Rt 6.223 m/z 524.1 (MH ⁺ ).

Intermediate 28. Methyl 4-((4-(4-fluorophenoxy)-3'-(trifluoromethyl)-[1,1'-biphenyl]-3carboxamido)methyl)benzoate.

Ή-NMR (400 MHz, DMSO-d ⁶ ): δ=9.00 (t, 1H), 8.01 (m, 3H), 7.85 (d, 3H), 7.71 (m, 2H) , 7.40 (d, 2H), 7.26 (t, 2H), 7.15 (dd, 2H), 7.01 (d, 1H), 4.55 (d, 2H), 3.83 ( s, 3H).

HPLC-MS: Rt 6.199 m/z 524.1 (MH ⁺ ).

Intermediate 29. Methyl 4-((2-(4-fluorophenoxy)-5-(thiophen-2yl)benzamido)methyl)benzoate.

Ή-NMR (400 MHz, DMSO-d ⁶ ): δ=8.99 (t, 1H), 7.90 (d, 1H), 7.85 (d, 2H), 7.74 (dd, 1H) , 7.56 (d, 1H), 7.52 (d, 1H), 7.39 (d, 2H), 7.25 (t, 2H), 7.13 (m, 3H), 6.95 ( d, 1H), 4.52 (d, 2H), 3.83 (s, 3H).

HPLC-MS: Rt 3.21 m/z 462.1 (MH ⁺ ).

Intermediate 30. Methyl 4-((3',5'-difluoro-4-(4-fluorophenoxy)-[1,1'-biphenyl]-3carboxamido)methyl)benzoate.

Ή-NMR (400 MHz, DMSO-d ⁶ ): δ=9.00 (t, 1H), 8.00 (d, 1H), 7.84 (m, 3H), 7.48 (m, 2H) , 7.41 (d, 2H), 7.25 (m, 3H), 7.14 (m, 2H), 6.97 (d, 1H), 4.54 (d, 2H), 3.83 ( s, 3H).

HPLC-MS: Rt 3.31 m/z 492.21 (MH ⁺ ).

Intermediate 31. Methyl 4-((3'-chloro-4-(4-fluorophenoxy)-[1,1'-biphenyl]-3carboxamido)methyl)benzoate.

Ή-NMR (400 MHz, DMSO-d ⁶ ): δ=8.99 (t, 1H), 7.96 (d, 1H), 7.86 (d, 2H), 7.80 (dd, 1H) , 7.76 (m, 1H),

7.66 (d, 1H), 7.50 (t, 1H), 7.43 (m, 3H), 7.25 (m, 2H), 7.14 (m, 2H), 6.87 (d , 1H), 4.54 (d, 2H), 3.83 (s, 3H).

HPLC-MS: Rt 3.41 m/z 490.16 (MH ⁺ ).

Intermediate 32. Methyl 4-((3'-fluoro-4-(4-fluorophenoxy)-5'-(trifluoromethyl)-[1,1'biphenyl]-3-carboxamido)methyl)benzoate.

Ή-NMR (400 MHz, DMSO-d ⁶ ): δ=9.01 (t, 1H), 8.06 (d, 1H), 7.95 (d, 1H), 7.88 (m, 4H) , 7.67 (d, 1H), 7.41 (d, 2H), 7.26 (m, 2H), 7.15 (m, 2H), 7.00 (d, 1H), 4.55 ( d, 2H), 3.83 (s, 3H).

HPLC-MS: Rt 3.48 m/z 542.21 (MH ⁺ ).

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Intermediate 33: Methyl 4-((3'-cyano-5'-fluoro-4-(4-fluorophenoxy)-[1,1'-biphenyl]-3carboxamido)methyl)benzoate.

1H-NMR (400 MHz, DMSO-d ⁶ ): δ=9.00 (t, 1H), 8.12 (s, 1H), 8.07 (d, 1H), 8.00 (m, 1H) , 7.88 (m, 4H), 7.42 (d, 2H), 7.26 (m, 2H), 7.15 (m, 2H), 6.99 (d, 1H), 4.53 ( d, 2H), 3.83 (s, 3H).

HPLC-MS: Rt 3.13 m/z 499.21 (MH ⁺ ).

Intermediate 34. Methyl 4-((3'-chloro-5'-cyano-4-(4-fluorophenoxy)-[1,1'-biphenyl]-3carboxamido)methyl)benzoate.

¹ H-NMR (400 MHz, DMSO-d ⁶ ): δ=9.00 (t, 1H), 8.22 (d, 1H), 8.16 (t, 1H), 8.05 (m, 2H ), 7.87 (m, 3H), 7.42 (d, 2H), 7.27 (m, 2H), 7.15 (m, 2H), 6.98 (d, 1H), 4.55 (d, 2H), 3.84 (s, 3H).

HPLC-MS: Rt 3.26 m/z 515.1 (MH ⁺ ).

Intermediate 35. Methyl 4-((2-(4-fluorophenoxy)-5-(III-pyrazol-4yl)benzamido)methyl)benzoate.

¹ H-NMR (400 MHz, DMSO-d ⁶ ): δ=12.83 (s, 1H), 8.99 (t, 1H), 7.82 (m, 4H), 7.62 (m, 2H ), 7.36 (dd, 2H), 7.24 (m, 2H), 7.12 (m, 2H), 6.86 (d, 1H), 4.50 (d, 2H), 3.83 (c, 3H).

HPLC-MS: Rt 2.03 m/z 446.0 (MH ⁺ ).

Intermediate 36. Methyl 4-((2-(4-fluorophenoxy)-5-(1-methyl-III-pyrazol-4yl))benzamido)methyl)benzoate.

¹ H-NMR (400 MHz, DMSO-d ⁶ ): δ=8.92 (t, 1H), 8.18 (s, 1H), 7.84 (m, 4H), 7.64 (dd, 1H ), 7.37 (d, 2H), 7.21 (m, 2H), 7.06 (m, 2H), 6.93 (d, 1H), 4.51 (d, 2H), 3.86 (s, 3H), 3.83 (s, 3H).

HPLC-MS: Rt 2.70 m/z 460.2 (MH ⁺ ).

Intermediate 37. Methyl 4-((2-(4-fluorophenoxy)-5-(1-methyl-III-pyrazol-5yl))benzamido)methyl)benzoate.

¹ H-NMR (400 MHz, DMSO-d ⁶ ): δ=9.01 (t, 1H), 7.85 (d, 2H), 7.77 (d, 1H), 7.61 (dd, 1H ), 7.48 (d, 1H), 7.40 (d, 2H), 7.26 (m, 2H), 7.17 (m, 2H), 6.98 (d, 1H), 6.43 (d, 1H), 4.54 (d, 2H), 3.86 (s, 3H), 3.83 (s, 3H).

HPLC-MS: Rt 2.73 m/z 460.13 (MH ⁺ ).

Intermediate 38. Methyl 4-((4-(4-fluorophenoxy)-3'-(pyridin-4-yl))-[1,1'-biphenyl]-3ylcarboxamido)methyl)benzoate.

¹ H-NMR (400 MHz, DMSO-d ⁶ ): δ=9.00 (t, 1H), 8.66 (dd, 2H), 8.06 (m, 2H), 7.85 (m, 7H ), 7.63 (t, 1H), 7.40 (d, 2H), 7.25 (m, 2H), 7.14 (m, 2H), 7.02 (d, 1H), 4.55 (d, 2H), 3.83 (s, 3H).

HPLC-MS: Rt 3.06 m/z 533.2 (MH ⁺ ).

Intermediate 39: Methyl 4-((5-(5-cyanofuran-2-yl))-2-(4-fluorophenoxy)benzamido)methyl)benzoate.

¹ H-NMR (400 MHz, DMSO-d ⁶ ): δ=9.02 (t, 1H), 8.10 (s, 1H), 7.87 (m, 3H), 7.42 (m, 3H ), 7.28 (m, 4H), 7.18 (m, 2H), 6.97 (d, 1H), 4.55 (d, 2H), 3.83 (s, 3H).

HPLC-MS: Rt 3.08 m/z 471.1 (MH ⁺ ).

Intermediate 40. Methyl 3-fluoro-4-((4-(4-fluorophenoxy)-3'-(trifluoromethyl)-[1,1'biphenyl]-3-ylcarboxamido)methyl)benzoate ¹ H-NMR (400 MHz , DMSO-d ⁶ ): δ=9.01 (t, 1H), 8.01 (m, 2H), 7.86 (dd, 1H), 7.74 (dd, 2H), 7.67 (m , 2H), 7.44 (t, 1H), 7.25 (m, 2H), 7.15 (m, 2H), 7.01 (d, 1H), 4.55 (d, 2H), 3 .85 (s, 3H).

Intermediate 41. Methyl A)-4-(1-(4-(4-fluorophenoxy)-3'-(trifluoromethyl)-[1,Gbiphenyl]-3-carboxamido)ethyl)benzoate.

1H-NMR (400 MHz, DMSO-d ⁶ ): δ=8.89 (d, 1H), 8.01 (m, 2H), 7.91 (d, 1H), 7.84 (m, 3H) , 7.72 (m, 2H), 7.48 (d, 2H), 7.24 (t, 2H), 7.11 (m, 2H), 7.03 (d, 1H), 5.14 ( n, 1H), 3.83 (s, 3H), 1.41 (d, 3H).

HPLC-MS: Rt 3.51 m/z 538.0 (MH ⁺ ).

Intermediate 42. Methyl 4-(1-(4-(4-fluorophenoxy)-3'-(trifluoromethyl)-[1,1'-biphenyl]-3carboxamido)cyclopropyl)benzoate.

¹ H-NMR (400 MHz, DMSO-d ⁶ ): δ=9.13 (s, 1H), 8.04 (d, 2H), 7.96 (d, 1H), 7.86 (dd, 1H ), 7.75 (m, 4H), 7.27 (m, 4H), 7.13 (dd, 2H), 7.09 (d, 1H), 3.82 (s, 3H), 1.32 (t, 2H), 1.25 (t, 2H).

HPLC-MS: Rt 3.48 m/z 550.0 (MH ⁺ ).

Intermediate 43. Methyl 4-((2-(4-fluorophenoxy)-5-(pyridin-2yl)benzamido)methyl)benzoate.

To a solution of methyl 4-((5-bromo-2-(4-fluorophenoxy)benzamido)methyl)benzoate (100.0 mg, 0.22 mmol) and tetrakis(triphenylphosphine)palladium(0) (15.1 mg, 0.013 mmol) in dry dioxane (1.5 ml), 2(tributylstannyl)pyridine (113.4 mg, 0.26 mmol) was added. The mixture was purged with N2 and stirred for 2 days at room temperature. The reaction mixture was diluted with ethyl acetate and washed with NaOH 2M. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by flash chromatography (hexane:ethyl acetate 1:1) to give a white solid. The product was washed with pentane/diethyl ether (40.3 mg, 40.5%).

1H-NMR (400 MHz, DMSO-d ⁶ ): δ=9.00 (t, 1H), 8.66 (d, 1H), 8.39 (d, 1H), 8.16 (dd, 1H) , 7.98 (d, 1H), 7.90 (dd, 1H), 7.86 (d, 2H), 7.42 (d, 2H), 7.36 (dd, 1H), 7.27 ( t, 2H), 7.17 (dd, 2H), 6.98 (d, 1H), 4.56 (d, 2H), 3.84 (s, 3H).

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HPLC-MS: Rt 5.308 m/z 457.1 (MH ⁺ ).

The following intermediate was synthesized using the procedure described for intermediate 43 and appropriate chemicals or derivatives:

Intermediate 44: Methyl 4-((2-(4-fluorophenoxy)-5-(pyrimidin-4yl)benzamido)methyl)benzoate.

1H-NMR (400 MHz, DMSO-d ⁶ ): δ=9.24 (d, 1H), 9.04 (t, 1H), 8.86 (d, 1H), 8.51 (d, 1H) , 8.29 (dd, 1H), 8.12 (dd, 1H), 7.87 (d, 2H), 7.44 (d, 2H), 7.30 (m, 2H), 7.22 ( m, 2H), 7.00 (d, 1H), 4.57 (d, 2H), 3.83 (s, 3H).

HPLC-MS: Rt 4.890 m/z 458.1 (MH ⁺ ).

Example 1: 4-((2-(4-fluorophenoxy)-5-(pyridin-4-yl)benzamido)methyl)benzoic acid

F F

To a solution of methyl 4-((2-(4-fluorophenoxy)-5-(pyridin-4-yl)benzamido)methyl)benzoate (35.0 mg, 0.077 mmol) in methanol (0.5 ml) and THF (0 .5 ml) NaOH 2M (0.19 ml, 0.38 mmol) was added and the mixture was stirred overnight at room temperature. The solution was diluted with water (15 ml) and the pH was adjusted to 4.0 by adding HCl 1M and the precipitate was filtered and washed with pentane (27.8 mg, 82.0%).

1H-NMR (400 MHz, DMSO-d ⁶ ): δ=12.85 (s, 1H), 9.01 (t, 1H), 8.64 (d, 2H), 8.07 (d, 1H) , 7.90 (dd, 1H), 7.84 (d, 2H), 7.74 (d, 2H), 7.39 (d, 2H), 7.27 (t, 2H), 7.17 ( dd, 2H), 7.01 (d, 1H), 4.55 (d, 2H).

HPLC-MS: Rt 3.362 m/z 443.1 (MH ⁺ ).

The following intermediate was synthesized using the procedure described for Example 1 and appropriate chemicals or derivatives.

Example 2: 4-((4-(4-Fluorophenoxy)-[1,1'-biphenyl]-3-carboxamido)methyl)benzoic acid.

Ή-NMR (400 MHz, DMSO-d ⁶ ): δ=12.84 (s, 1H), 8.95 (s, 1H), 7.93 (d, 1H), 7.83 (d, 2H) , 7.76 (dd, 1H), 7.68 (d, 2H), 7.48 (t, 2H), 7.38 (t, 3H), 7.25 (t, 2H), 7.13 ( m, 2H), 7.00 (d, 1H), 4.53 (d, 2H).

HPLC-MS: Rt 3.867 m/z 442.1 (MH ⁺ ).

Example 3: 4-((4'-chloro-4-(4-fluorophenoxy)-[1,1'-biphenyl]-3-carboxamido)methyl)benzoic acid.

Ή-NMR (400 MHz, DMSO-d ⁶ ): δ=12.88 (s, 1H), 8.97 (t, 1H), 7.93 (d, 1H), 7.83 (d, 2H) , 7.75 (m, 3H), 7.53 (d, 2H), 7.37 (d, 2H), 7.26 (t, 2H), 7.13 (m, 2H), 6.99 ( d, 1H), 4.53 (d, 2H).

HPLC-MS: Rt 4.221 m/z 476.0 (MH ⁺ ).

Example 4: 4-((4'-fluoro-4-(4-fluorophenoxy)-[1,1'-biphenyl]-3-carboxamido)methyl)benzoic acid.

Ή-NMR (400 MHz, DMSO-d ⁶ ): δ=12.87 (s, 1H), 8.97 (t, 1H), 7.90 (d, 1H), 7.83 (d, 2H) , 7.73 (m, 3H), 7.36 (d, 2H), 7.29 (m, 4H), 7.12 (m, 2H), 6.99 (d, 1H), 4.53 ( d, 2H).

HPLC-MS: Rt 4.029 m/z 460.1 (MH ⁺ ).

Example 5: 4-((3'-fluoro-4-(4-fluorophenoxy)-[1,1'-biphenyl]-3-carboxamido)methyl)benzoic acid.

Ή-NMR (400 MHz, DMSO-d ⁶ ): δ=12.88 (s, 1H), 8.98 (t, 1H), 7.96 (d, 1H), 7.81 (m, 3H) , 7.53 (m, 3H), 7.37 (d, 2H), 7.22 (m, 3H), 7.14 (m, 2H), 6.99 (d, 1H), 4.53 ( d, 2H).

HPLC-MS: Rt 4.033 m/z 460.1 (MH ⁺ ).

Example 6: 4-((2'-fluoro-4-(4-fluorophenoxy)-[1,1'-biphenyl]-3-carboxamido)methyl)benzoic acid.

Ή-NMR (400 MHz, DMSO-d ⁶ ): δ=12.87 (s, 1H), 8.98 (s, 1H), 7.83 (s, 3H), 7.64 (d, 1H) , 7.57 (s, 1H), 7.34 (m, 7H), 7.18 (s, 2H), 6.99 (d, 1H), 4.53 (d, 2H).

HPLC-MS: Rt 4.001 m/z 460.1 (MH ⁺ ).

Example 7: 4-((4'-cyano-4-(4-fluorophenoxy)-[1,1'-biphenyl]-3-carboxamido)methyl)benzoic acid.

Ή-NMR (400 MHz, DMSO-d ⁶ ): δ=12.88 (s, 1H), 9.00 (t, 1H), 8.02 (s, 1H), 7.91 (m, 4H) , 7.84 (d, 3H), 7.38 (d, 2H), 7.27 (t, 2H), 7.16 (m, 2H), 7.00 (d, 1H), 4.54 ( d, 2H).

HPLC-MS: Rt 3.864 m/z 467.1 (MH ⁺ ).

Example 8: 4-((3'-cyano-4-(4-fluorophenoxy)-[1,1'-biphenyl]-3-carboxamido)methyl)benzoic acid.

Ή-NMR (400 MHz, DMSO-d ⁶ ): δ=12.88 (s, 1H), 8.99 (t, 1H), 8.20 (s, 1H), 8.04 (dd, 2H) , 7.84 (d, 4H), 7.68 (t, 1H), 7.38 (d, 2H), 7.27 (t, 2H), 7.15 (dd, 2H), 7.00 ( d, 1H), 4.54 (d, 2H).

HPLC-MS: Rt 3.860 m/z 467.1 (MH ⁺ ).

Example 9: 4-((2-(4-fluorophenoxy)-5-(3-fluoropyridin-4-yl))benzamido)methyl)benzoic acid.

Ή-NMR (400 MHz, DMSO-d ⁶ ): δ=12.88 (s, 1H), 9.01 (t, 1H), 8.67 (d, 1H), 8.51 (d, 1H) , 7.97 (s, 1H), 7.84 (d, 2H), 7.77 (d, 1H), 7.68 (dd, 1H), 7.39 (d, 2H), 7.29 ( t, 2H), 7.20 (m, 2H), 7.01 (d, 1H), 4.55 (d, 2H).

HPLC-MS: Rt 3.495 m/z 461.1 (MH ⁺ ).

Example 10: 4-((2-(4-fluorophenoxy)-5-(pyridin-3-yl)benzamido)methyl)benzoic acid.

1H-NMR (400 MHz, DMSO-d ⁶ ): δ=12.88 (s, 1H), 8.99 (s, 1H), 8.92 (d, 1H), 8.58 (dd, 1H) , 8.11 (m, 1H), 7.99 (d, 1H), 7.83 (m, 3H), 7.50 (dd, 1H), 7.38 (d, 2H), 7.26 ( t, 2H), 7.15 (m, 2H), 7.02 (d, 1H), 4.54 (d, 2H).

HPLC-MS: Rt 3.390 m/z 443.1 (MH ⁺ ).

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Example 11: 4-((2-(4-fluorophenoxy)-5-(3-chloropyridin-4-yl)benzamido)methyl)benzoic acid.

¹ H-NMR (400 MHz, DMSO-d ⁶ ): δ=12.88 (s, 1H), 9.01 (t, 1H), 8.75 (s, 1H), 8.59 (d, 1H ), 7.83 (dd, 3H), 7.64 (dd, 1H), 7.53 (d, 1H), 7.39 (d, 2H), 7.30 (t, 2H), 7.21 (dd, 2H), 6.98 (d, 1H), 4.54 (d, 2H).

HPLC-MS: Rt 3.624 m/z 477.0 (MH ⁺ ).

Example 12: 4-((2-(4-fluorophenoxy)-5-(pyrimidin-5-yl)benzamido)methyl)benzoic acid.

Ή-NMR (400 MHz, DMSO-d ⁶ ): δ=12.88 (s, 1H), 9.17 (m, 3H), 9.01 (t, 1H), 8.08 (d, 1H) , 7.88 (m, 3H), 7.42 (d, 2H), 7.27 (t, 2H), 7.15 (m, 2H), 7.04 (d, 1H), 4.54 ( d, 2H).

HPLC-MS: Rt 3.147 m/z 444.1 (MH ⁺ ).

Example 13: 4-((3',4'-difluoro-4-(4-fluorophenoxy)-[1,1'-biphenyl]-3-carboxamido)methyl)benzoic acid.

Ή-NMR (400 MHz, DMSO-d ⁶ ): δ=12.89 (s, 1H), 8.97 (t, 1H), 7.95 (d, 1H), 7.79 (m, 4H) , 7.54 (m, 2H), 7.37 (d, 2H), 7.26 (t, 2H), 7.13 (dd, 2H), 6.98 (d, 1H), 4.53 ( d, 2H).

HPLC-MS: Rt 4.084 m/z 478.1 (MH ⁺ ).

Example 14: 4-((4-(4-fluorophenoxy)-4'-(trifluoromethyl)-[1,1'-biphenyl]-3-carboxamido)methyl)benzoic acid.

Ή-NMR (400 MHz, DMSO-d ⁶ ): δ=12.88 (s, 1H), 9.00 (t, 1H), 8.01 (d, 1H), 7.93 (d, 2H) , 7.83 (dd, 5H), 7.38 (d, 2H), 7.27 (t, 2H), 7.16 (m, 2H), 7.02 (d, 1H), 4.54 ( d, 2H).

HPLC-MS: Rt 2.53 m/z 510.57 (MH ⁺ ).

Example 15: 4-((4-(4-fluorophenoxy)-3'-(trifluoromethyl)-[1,1'-biphenyl]-3-carboxamido)methyl)benzoic acid.

Ή-NMR (400 MHz, DMSO-d ⁶ ): δ=12.88 (s, 1H), 9.01 (t, 1H), 8.01 (dd, 3H), 7.84 (dd, 3H) , 7.72 (sq, 2H), 7.37 (d, 2H), 7.60 (m, 2H), 7.15 (m, 2H), 7.01 (d, 1H), 4.54 ( d, 2H).

HPLC-MS: Rt 2.47 m/z 510.51 (MH ⁺ ).

Example 16: 4-((2-(4-fluorophenoxy)-5-(pyridin-2-yl)benzamido)methyl)benzoic acid.

Ή-NMR (400 MHz, DMSO-d ⁶ ): δ=12.88 (s, 1H), 8.99 (t, 1H), 8.67 (d, 1H), 8.39 (d, 1H) , 8.16 (dd, 1H), 7.99 (d, 1H), 7.89 (m, 1H), 7.84 (d, 2H), 7.39 (d, 2H), 7.35 ( m, 1H), 7.27 (t, 2H), 7.17 (dd, 2H), 6.99 (d, 1H), 4.55 (d, 2H).

HPLC-MS: Rt 3.502 m/z 433.1 (MH ⁺ ).

Example 17: 4-((2-(4-fluorophenoxy)-5-(pyrimidin-4-yl)benzamido)methyl)benzoic acid.

Ή-NMR (400 MHz, DMSO-d ⁶ ): δ=12.88 (s, 1H), 9.24 (d, 1H), 9.03 (t, 1H), 8.86 (d, 1H) , 8.51 (d, 1H), 8.28 (dd, 1H), 8.12 (dd, 1H), 7.85 (d, 2H), 7.41 (d, 2H), 7.30 ( m, 2H), 7.22 (dd, 2H), 7.00 (d, 1H), 4.56 (d, 2H).

HPLC-MS: Rt 3.243 m/z 444.1 (MH ⁺ ).

Example 18: 4-((2-(4-fluorophenoxy)-5-(thiophen-2-yl)benzamido)methyl)benzoic acid.

Ή-NMR (400 MHz, DMSO-d ⁶ ): δ=12.88 (s, 1H), 8.98 (t, 1H), 7.90 (d, 1H), 7.82 (dd, 2H) , 7.73 (dd, 1H), 7.56 (d, 1H), 7.53 (dd, 1H), 7.35 (, 2H), 7.24 (t, 2H), 7.12 (m , 3H), 6.96 (d, 1H), 4.52 (d, 2H).

HPLC-MS: Rt 2.18 m/z 448.1 (MH ⁺ ).

Example 19: 4-((3',5'-difluoro-4-(4-fluorophenoxy)-[1,1'-biphenyl]-3-carboxamido)methyl)benzoic acid.

Ή-NMR (400 MHz, DMSO-d ⁶ ): δ=12.87 (s, 1H), 8.99 (t, 1H), 8.00 (d, 1H), 7.83 dd, 3H), 7.49 (m, 2H), 7.38 (d, 2H), 7.25 (m, 3H), 7.14 (m, 2H), 6.98 (d, 1H), 4.54 (d , 2H).

HPLC-MS: Rt 2.30 m/z 478.17 (MH ⁺ ).

Example 20: 4-((3'-chloro-4-(4-fluorophenoxy)-[1,1'-biphenyl]-3-carboxamido)methyl)benzoic acid.

Ή-NMR (400 MHz, DMSO-d ⁶ ): δ=12.88 (s, 1H), 8.99 (t, 1H), 7.97 (d, 1H), 7.80 (m, 4H) , 7.68 (d, 1H), 7.51 (t, 1H), 7.46 (m, 1H), 7.39 (d, 2H), 7.27 (m, 2H), 7.15 ( m, 2H), 7.00 (d, 1H), 4.55 (d, 2H).

HPLC-MS: Rt 2.86 m/z 476.13 (MH ⁺ ).

Example 21: 4-((3'-fluoro-4-(4-fluorophenoxy)-5'-(trifluoromethyl)-[1,1'-biphenyl]-3-carboxamido)methyl)benzoic acid.

Ή-NMR (400 MHz, DMSO-d ⁶ ): δ=12.89 (s, 1H), 9.01 (t, 1H), 8.08 (d, 1H), 7.96 (d, 1H) , 7.90 (m, 2H), 7.84 (d, 2H), 7.70 (d, 1H), 7.39 (d, 2H), 7.28 (m, 2H), 7.17 ( m, 2H), 7.01 (d, 1H), 4.56 (d, 2H).

HPLC-MS: Rt 2.46 m/z 528.19 (MH ⁺ ).

Example 22: 4-((3'-carbamoyl-5'-chloro-4-(4-fluorophenoxy)-[1,1'-biphenyl]-3-ylcarboxamido)methyl)benzoic acid.

Ή-NMR (400 MHz, DMSO-d ⁶ ): δ=12.89 (s, 1H), 9.00 (t, 1H), 8.26 (s, 1H), 8.15 (s, 1H) , 8.05 (d, 1H), 7.94 (m, 1H), 7.88 (m, 1H), 7.84 (m, 2H), 7.63 (s, 1H), 7.38 ( d, 2H), 7.26 (m, 2H), 7.15 (m, 2H), 7.01 (d, 1H), 4.54 (d, 2H).

HPLC-MS: Rt 1.96 m/z 519.07 (MH ⁺ ).

Example 23: 4-((2-(4-fluorophenoxy)-5-(III-pyrazol-4-yl)benzamido)methyl)benzoic acid.

Ή-NMR (400 MHz, DMSO-d ⁶ ): δ=12.96 (s, 1H), 8.90 (t, 1H), 8.09 (s, 2H), 7.85 (d, 1H) , 7.81 (m, 2H), 7.69 (dd, 1H), 7.33 (m, 2H), 7.22 (m, 2H), 7.06 (m, 2H), 6.94 ( d, 1H), 4.49 (d, 2H).

HPLC-MS: Rt 1.06 m/z 432.1 (MH ⁺ ).

- 21 046234

Example 24: 4-((2-(4-fluorophenoxy)-5-(1-methyl-1H-pyrazol-4-yl))benzamido)methyl)benzoic acid.

¹ H-NMR (400 MHz, DMSO-d ⁶ ): δ=12.88 (s, 1H), 8.91 (t, 1H), 8.18 (s, 1H), 7.88 (s, 1H ), 7.81 (m, 3H), 7.64 (dd, 1H), 7.33 (d, 2H), 7.22 (m, 2H), 7.06 (m, 2H), 6.94 (d, 1H), 4.50 (d, 2H), 3.86 (s, 3H).

HPLC-MS: Rt 1.78 m/z 446.10 (MH ⁺ ).

Example 25: 4-((2-(4-fluorophenoxy)-5-(1-methyl-III-pyrazol-5-yl))benzamido)methyl)benzoic acid.

Ή-NMR (400 MHz, DMSO-d ⁶ ): δ=12.88 (s, 1H), 9.00 (t, 1H), 7.83 (d, 2H), 7.77 (d, 1H) , 7.61 (dd, 1H), 7.48 (d, 1H), 7.37 (d, 2H), 7.27 (m, 2H), 7.17 (m, 2H), 6.98 ( d, 1H), 6.43 (t, 1H), 4.53 (d, 2H), 3.86 (s, 3H).

HPLC-MS: Rt 1.82 m/z 446.10 (MH ⁺ ).

Example 26: 4-((4-(4-fluorophenoxy)-3'-(pyridin-4-yl))-[1,1'-biphenyl]-3 -ylcarboxamido)methyl)benzoic acid.

Ή-NMR (400 MHz, DMSO-d ⁶ ): δ=12.88 (s, 1H), 9.02 (t, 1H), 8.92 (d, 1H), 8.38 (d, 2H) , 8.25 (s, 1H), 8.10 (d, 1H), 7.98 (d, 1H), 7.92 (d, 2H), 7.83 (d, 2H), 7.71 ( t, 1H), 7.38 (d, 2H), 7.27 (m, 2H), 7.15 (m, 2H), 7.04 (d, 1H), 4.54 (d, 2H).

HPLC-MS: Rt 2.15 m/z 519.2 (MH ⁺ ).

Example 27: 4-((5-(5-carbamoylfuran-2-yl))-2-(4-fluorophenoxy)benzamido)methyl)benzoic acid

Ή-NMR (400 MHz, DMSO-d ⁶ ): δ=12.89 (s, 1H), 9.00 (t, 1H), 8.17 (t, 1H), 8.02 (s, 1H) , 7.94 (m, 2H), 7.45 (s, 2H), 7.37 (t, 2H), 7.26 (m, 2H), 7.13 (m, 3H), 6.99 ( d, 1H), 4.53 (d, 2H).

HPLC-MS: Rt 1.74 m/z 475.0 (MH ⁺ ).

Example 28: 3-fluoro-4-((4-(4-fluorophenoxy)-3'-(trifluoromethyl)-[1,1'-biphenyl]-3-ylcarboxamido)methyl)benzoic acid.

Ή-NMR (400 MHz, DMSO-d ⁶ ): δ=13.26 (s, 1H), 9.00 (t, 1H), 8.00 (m, 3H), 7.86 (dd, 1H) , 7.73 (m, 2H), 7.63 (m, 2H), 7.41 (t, 1H), 7.26 (m, 2H), 7.15 (m, 2H), 7.00 ( d, 1H), 4.54 (d, 2H).

HPLC-MS: Rt 1.54 m/z 528.0 (MH ⁺ ).

Example 29: (R)-4-(1-(4-(4-fluorophenoxy)-3'-(trifluoromethyl)-[1,1'-biphenyl]-3-carboxamido)ethyl)benzoic acid.

Ή-NMR (400 MHz, DMSO-d ⁶ ): δ=12.86 (s, 1H), 8.88 (d, 1H), 8.06 (m, 2H), 7.90 (t, 1H) , 7.84 (dd, 3H), 7.72 (q, 2H), 7.45 (d, 2H), 7.25 (t, 2H), 7.12 (m, 2H), 7.03 ( d, 1H), 5.13 (p, 1H), 1.40 (t, 3H).

HPLC-MS: Rt 2.45 m/z 524.0 (MH ⁺ ).

Example 30: 4-(1-(4-(4-fluorophenoxy)-3'-(trifluoromethyl)-[1,1'-biphenyl]-3-carboxamido)cyclopropyl)benzoic acid.

Ή-NMR (400 MHz, DMSO-d ⁶ ): δ=9.09 (s, 1H), 8.04 (d, 2H), 7.95 (s, 1H), 7.86 (d, 1H) , 7.73 (d, 4H), 7.27 (t, 2H), 7.18 (d, 2H), 7.13 (dd, 2H), 7.08 (d, 1H), 1.27 ( t, 2H), 1.22 (t, 2H).

HPLC-MS: Rt 2.79 m/z 536.0 (MH ⁺ ).

Example 31: 4-((3'-fluoro-5'-cyano-4-(4-fluorophenoxy)-[1,1'-biphenyl]-3-carboxamido)methyl)benzoic acid

To a solution of 4-((5-bromo-2-(4-fluorophenoxy)benzamido)methyl)benzoic acid (80 mg, 1.0 eq.) and (3cyano-5-fluorophenyl)boronic acid (59 mg, 2.0 eq.) in DMF (1.2 ml) 2M Cs ₂ CO ₃ (0.27 ml, 3.0 eq.) and Pd(dppf)Cl ₂ -DCM (9 mg, 0.06 eq.) under nitrogen atmosphere . After stirring at 110°C for 20 hours, the mixture was filtered through celite, washing with ethyl acetate (20 ml). The organic phase was washed with sat. aq. sodium bicarbonate (20 ml) and brine (20 ml), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude material was purified by flash column chromatography (hexanes:ethyl acetate, 1:1) to give acid IV-484-536 as a white solid (22 mg, 25.2% yield).

Ή-NMR (400 MHz, DMSO-d ⁶ ): δ=12.86 (s, 1H), 8.99 (t, 1H), 8.12 (s, 1H), 8.07 (d, 2H) , 8.01 (dd, 1H), 7.89 (dd, 1H), 7.84 (d, 2H), 7.39 (d, 2H), 7.27 (m, 2H), 7.16 ( m, 2H), 6.99 (d, 1H), 4.54 (d, 2H).

HPLC-MS: Rt 2.23 m/z 485.1 (MH ⁺ ).

- 22 046234

Example 32: 4-((3'-chloro-5'-cyano-4-(4-fluorophenoxy)-[1,1'-biphenyl]-3-carboxamido)methyl)benzoic acid

To a solution of methyl 4-((3'-cyano-5'-fluoro-4-(4-fluorophenoxy)-[1,1'-biphenyl]-3-yl)carboxamido)methyl)benzoate (100 mg, 1.0 eq.) in THF (1.0 ml), HCl (4 M) (3.0 ml) was added and the mixture was stirred for 46 hours at 80°C. After dilution with water (5 ml), the mixture was extracted with ethyl acetate (3x10 ml), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude material was purified by flash column chromatography (hexanes:ethyl acetate, 1:1) to give the acid as a white solid (18 mg, 18.6% yield).

¹ H-NMR (400 MHz, DMSO-d ⁶ ): δ=12.87 (s, 1H), 8.98 (t, 1H), 8.22 (s, 1H), 8.16 (t, 1H ), 8.07 (d, 1H), 8.03 (m, 1H), 7.89 (dd, 1H), 7.84 (d, 2H), 7.39 (d, 2H), 7.27 (m, 2H), 7.16 (m, 2H), 6.99 (d, 1H), 4.54 (d, 2H).

HPLC-MS: Rt 2.34 m/z 501.1 (MH+).

Claims (19)

1. Compound of formula (I) F where A represents a group selected from phenyl and a five- or six-membered heteroaryl containing one, two or three heteroatoms selected from N, S and O; R ¹ and R ² independently represent a group selected from hydrogen atom, halogen atom and C1-3 alkyl, or R ¹ and R ² together with the carbon atom to which they are attached form a C3-4 cycloalkyl group; R ³ , R ⁴ , R ⁵ and each R ⁶ independently represent a group selected from a hydrogen atom, a halogen atom, a cyano group, a carbamoyl group, a linear or branched C _1-3 haloalkyl group, a linear or branched C _1-3 alkyl group, C _3-4 cycloalkyl, linear or branched C _1-3 alkoxy group and pyridyl group; m is an integer from 1 to 5; and pharmaceutically acceptable salts thereof. 2. A compound according to claim 1, where R ¹ , R ² , R ³ , R ⁴ and R ⁵ represent hydrogen atoms. 3. A compound according to any one of claims 1, 2, where A represents a phenyl group. 4. A compound according to claim 3, wherein each R ⁶ independently represents a group selected from: a) hydrogen atom, b) a halogen atom, c) cyano groups, d) carbamoyl group, e) linear or branched C _1-3 haloalkyl group. 5. A compound according to any one of claims 1 to 4, wherein A represents a phenyl group and each R ⁶ independently represents a group selected from fluorine, trifluoromethyl and cyano, and m represents an integer from 1 to 4. 6. A compound according to any one of claims 1, 2, where A represents a five- or six-membered heteroaryl ring. 7. A compound according to claim 6, wherein A represents a group selected from pyridinyl or thiophenyl groups, each R ⁶ independently represents a group selected from trifluoromethyl and cyano, and m represents an integer from 1 to 4. 8. A compound according to claim 1, wherein R ¹ , R ² , R ³ , R ⁴ and R ⁵ represent hydrogen atoms, A represents a phenyl group and each R ⁶ independently represents a group selected from fluorine and trifluoromethyl groups, and m represents an integer from 1 to 5. - 23 046234 9. A compound according to any of the preceding claims, where m is an integer from 1 to 2. 10. A compound according to any one of claims 1, 2, where A represents a group selected from phenyl, pyridinyl, pyrimidinyl, thiophenyl, R ¹ , R ² , R ³ , R ⁴ , R ⁵ represent hydrogen atoms, each R ⁶ independently represents a group selected from hydrogen, fluorine, chlorine, cyano, trifluoromethyl and pyridinyl, and m is an integer from 1 to 2. 11. The compound according to claim 1, which is one of 4-((2-(4-fluorophenoxy)-5-(pyridin-4-yl)benzamido)methyl)benzoic acid, 4-((4-(4-fluorophenoxy)-[1,1 '-biphenyl]-3 -carboxamido)methyl)benzoic acid, 4-((4'-chloro-4-(4-fluorophenoxy)-[1,1'-biphenyl]-3-carboxamido)methyl)benzoic acid, 4-((4'- fluoro-4-(4-fluorophenoxy)-[1,1'-biphenyl]-3-carboxamido)methyl)benzoic acid, 4-((3'-fluoro-4-(4-fluorophenoxy)-[1,1' -biphenyl]-3-carboxamido)methyl)benzoic acid, 4-((2'-fluoro-4-(4-fluorophenoxy)-[1,1'-biphenyl]-3-carboxamido)methyl)benzoic acid, 4- ((4'-cyano-4-(4-fluorophenoxy)-[1,1'-biphenyl]-3-carboxamido)methyl)benzoic acid, 4-((3'-cyano-4-(4-fluorophenoxy)- [1,1'-biphenyl]-3-carboxamido)methyl)benzoic acid, 4-((2-(4-fluorophenoxy)-5-(3-fluoropyridin-4-yl)benzamido)methyl)benzoic acid, 4- ((2-(4-fluorophenoxy)-5-(pyridin-3-yl)benzamido)methyl)benzoic acid, 4-((2-(4-fluorophenoxy)-5-(3-chloropyridin-4-yl)benzamido )methyl)benzoic acid, 4-((2-(4-fluorophenoxy)-5-(pyrimidin-5-yl)benzamido)methyl)benzoic acid, 4-((3',4'-difluoro-4-(4 -fluorophenoxy)-[1,1'-biphenyl]-3-carboxamido)methyl)benzoic acid, 4-((4-(4-fluorophenoxy)-4'-(trifluoromethyl)-[1,1'-biphenyl] - 3-carboxamido)methyl)benzoic acid, 4-((4-(4-fluorophenoxy)-3'-(trifluoromethyl)-[1,1'-biphenyl]-3-carboxamido)methyl)benzoic acid, 4-(( 2-(4-fluorophenoxy)-5-(pyridin-2-yl)benzamido)methyl)benzoic acid, 4-((2-(4-fluorophenoxy)-5-(pyrimidin-4-yl)benzamido)methyl)benzoic acid acid, 4-((2-(4-fluorophenoxy)-5-(thiophen-2-yl)benzamido)methyl)benzoic acid, 4-((3',5'-difluoro-4-(4-fluorophenoxy)- [1,1'-biphenyl]-3-carboxamido)methyl)benzoic acid, 4-((3'-chloro-4-(4-fluorophenoxy)-[1,1'-biphenyl]-3-carboxamido)methyl) benzoic acid, 4-((3'-fluoro-4-(4-fluorophenoxy)-5'-(trifluoromethyl)-[1,1'-biphenyl]-3-carboxamido)methyl)benzoic acid, 4-((3'-carbamoyl-5'-chloro-4-(4-fluorophenoxy)-[1,1'-biphenyl]-3 -ylcarboxamido)methyl)benzoic acid, 4-((2-(4-fluorophenoxy )-5-(III-pyrazol-4-yl)benzamido)methyl)benzoic acid, 4-((2-(4-fluorophenoxy)-5-(1-methyl-III-pyrazol-4-yl))benzamido) methyl)benzoic acid, 4-((2-(4-fluorophenoxy)-5-(1-methyl-III-pyrazol-5-yl))benzamido)methyl)benzoic acid, 4-((4-(4-fluorophenoxy )-3 '-(pyridin-4-yl))-[1,1 '-biphenyl]-3 -ylcarboxamido)methyl)benzoic acid, 4-((5-(5-carbamoylfuran-2-yl))-2-(4-fluorophenoxy)benzamido)methyl)benzoic acid, 3-fluoro-4-((4-(4-fluorophenoxy)-3 '-(trifluoromethyl)-[1,1 '-biphenyl]-3 -ylcarboxamido)methyl)benzoic acid, (R)-4-( 1 - (4-(4-fluorophenoxy)-3'-(trifluoromethyl)-[1,1'-biphenyl]-3-carboxamido)ethyl)benzoic acid, 4-(1 -(4-(4-fluorophenoxy)-3'-(trifluoromethyl)-[1,1'-biphenyl]-3-carboxamido)cyclopropyl)benzoic acid, 4-((3'-fluoro-5'-cyano-4-(4-fluorophenoxy)-[1,1'-biphenyl]-3-carboxamido)methyl)benzoic acid, 4-((3'-chloro-5 '-cyano-4-(4-fluorophenoxy)-[1,1'-biphenyl]-3-carboxamido)methyl)benzoic acid, and pharmaceutically acceptable salts thereof. 12. The use of a compound according to any one of claims 1 to 11 for the treatment or prevention of diseases or pathological conditions that can be improved by modulation of prostaglandin EP4 and/or EP2 receptors (PGE2), where the specified disease or pathological condition is selected from the group consisting of cancer, pain, neurodegenerative diseases, osteoarthritis, rheumatoid arthritis, endometriosis and kidney disease. 13. Use of a compound according to any one of claims 1 to 11 for the treatment or prevention of cancer. 14. Use according to claim 13, wherein the cancer is treatable by immunotherapy. 15. The use of a compound according to any one of claims 1 to 11 in the preparation of a medicament for the treatment or prevention of diseases or pathological conditions that can be improved by modulation of prostaglandin EP4 and/or EP2 receptors (PGE2), where the specified disease or pathological condition is selected from group consisting of cancer, pain, neurodegenerative diseases, osteoarthritis, rheumatoid arthritis, endometriosis and kidney disease. 16. Use of a compound according to any one of claims 1 to 11 in the preparation of a medicinal product for the treatment or prevention of cancer. 17. Use according to claim 16, wherein the cancer is treatable by immunotherapy. - 24 046234 18. A pharmaceutical composition comprising a compound according to any one of claims 1 to 11 and a pharmaceutically acceptable diluent or carrier. 19. The pharmaceutical composition according to claim 18, comprising from 0.001 to 99 wt.% of the compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof.