EA043145B1 - PHENYL DERIVATIVES AS MODULATORS OF PGE2 RECEPTORS - Google Patents

Description

The invention relates to phenyl derivatives of formula (II) and their use for the treatment of malignant neoplasms by modulating the immune response, including the reactivation of the immune system in the tumor. The invention also relates to related aspects, including methods for preparing compounds, pharmaceutical compositions containing one or more compounds of formula (III), and their use as modulators of PGE2 EP2 receptors (also called PTGER2, also called PGE2 subtype EP2 receptors) and/or EP4 ( also called PTGER4, also called EP4R, also called PGE2 EP4 receptor subtype). The compounds of formula (III) can in particular be used alone or in combination with one or more therapeutic agents and/or chemotherapy and/or radiotherapy and/or immunotherapy for the prevention/prevention or treatment of malignant neoplasms; in particular the prevention/prevention or treatment of melanoma; lung cancer; bladder cancer; renal carcinoma; malignant neoplasms of the gastrointestinal tract; endometrial cancer; ovarian cancer; cervical cancer; and neuroblastoma.

Prostaglandin E2 (PGE2) is a bioactive lipid that can induce a wide range of biological actions associated with inflammation and malignancy. PGE2 belongs to the prostanoid lipid family. Cyclooxygenase (COX) is the rate-limiting enzyme in the synthesis of a number of biological mediators called prostanoids, consisting of prostaglandins PGD2, PGE2, PGF2a, prostacyclin PGI2, and thromboxane TXA2. Prostanoids function through the activation of seven transmembrane G-protein coupled receptors (GPCRs), in particular EP1, EP2, EP3 and EP4 are receptors for PGE2. Activation of both EP2 and EP4 by PGE2 causes stimulation of adenylate cyclase, which leads to an increase in cytoplasmic cAMP levels with the initiation of numerous downstream events through its prototypical effector protein kinase A. In addition, PGE2 is also capable of signaling through PI3K/AKT and Ras-MAPK/ ERK alarm.

Malignant neoplasms are among the leading causes of death worldwide. Tumors are composed not only of abnormally proliferating malignant cells, but also of a functionally supportive microenvironment. This tumor microenvironment consists of a complex array of cells, extracellular matrix components, and signaling molecules, and is created by altered communication between stromal and tumor cells. As tumors grow in size, they cause the production of a variety of factors that can help tumor growth, such as angiogenic factors (promoting ingrowth of blood vessels), or that can help avoid attack by the host's immune response. PGE2 is such an immunomodulatory factor produced in tumors.

It is well established that COX2, mainly through PGE2, promotes overall tumor growth and is up-regulated and correlated with clinical outcome in a significant percentage of common malignancies, especially colorectal, gastric, esophageal, pancreatic, breast, and cancers. ovaries. High levels of COX-2 and PGE2 expression are associated with neoplastic transformation, cell growth, angiogenesis, invasiveness, metastasis, and immune evasion.

The discovery that COX2 is overexpressed and plays an important role in carcinogenesis in gastrointestinal (GI) malignancies, including but not limited to esophageal, gastric, and colorectal cancer, has led COX inhibitors (coxibs), including Celecoxib, and other non-steroidal anti-inflammatory drugs (NSAIDs), including aspirin, are among the best studied anticancer chemopreventive agents under development to date (for a review see, for example, Wang R. et al., Curr Pharm Des. 2013 ; 19(1):115-25; Garcia Rodriguez L.A. et al., Recent Results Cancer Res. 2013; 191:67-93, Sahin I.H. et al., Cancer Lett. 2014, Apr 10;345(2):249 -57; Drew D. A. et al., Nat Rev Cancer 2016, 16:173; Brotons C. et al., Am J Cardiovasc Drugs 2015 Apr; 15(2):113).

In addition to COX2 and PGE2, also EP receptors, especially EP2 and EP4, are aberrantly overexpressed in numerous types of cancers, especially in gastrointestinal (GI) and pancreatic cancers. In addition, overexpression of PGE2 and/or EP2 and/or EP4 correlates with disease progression in some types of malignancies such as esophageal squamous cell carcinoma (Kuo K.T. et al., Ann Surg One 2009; 16(2), 352-60) ; squamous cell carcinoma of the lung (Alaa M. et al., Int J Oncol 2009, 34(3); 805-12); prostate cancer (Miyata Y. et al., Urology 2013, 81(1):136-42); Badawi A.F. and Badr M.Z. Int J Cancer. 2003, 103(1):84-90); squamous cell carcinoma of the head and neck (Gallo O. et al., Hum Pathol. 2002, 33(7):708-14).

In accordance with studies performed with coxibs, knockout of COX1, COX2, microsomal prostaglandin E synthase 1 (mPTGES1), EP2, or EP4 in mice resulted in a reduction in the incidence and progression of tumors in various tumor models. In contrast, overexpression of COX2 or mPTGES1 in transgenic mice resulted in an increase in tumor incidence and tumor burden (for a review, see Nakanishi M. and Rosenberg D.W., Seminars in Immunopathology 2013, 35: 123-137; Fischer S.M. and

- 1 043145 dr. Cancer Prev Res (Phila) 2011 November; 4(11):1728-35; Fulton A.M. et al. Cancer Res 2006; 66(20); 979497).

Several pharmacological studies of inhibition of tumor growth and progression using EP receptor antagonists or COX2 inhibitors in various tumor models have been performed in mice. Among other things, EP antagonists and/or COX2 inhibitors reduced tumor growth and metastasis in experimental models of colorectal cancer (e.g., Yang L. et al. Cancer Res 2006, 66(19), 9665-9672; Pozzi A. et al. JBC 279 (28); 29797-29804), lung carcinomas (Sharma S. et al. Cancer Res 2005 65(12), 5211-5220), gastrointestinal malignancy (Oshima H et al. Gastroenterology 2011, 140(2); 596-607; Fu S.L. et al. World J Gastroenterol 2004, 10(13); 1971-1974), breast cancer (Kundu N. et al., Breast Cancer Res Treat 117, 2009; 235-242; Ma X and et al., Oncolmmunology 2013; Xin X. et al. Lab Investigation 2012, 1-14; Markosyan N. et al.; Breast Cancer Res 2013, 15:R75), prostate cancer (Xu S. et al., Cell Biochem Biophys 2014, Terada et al. Cancer Res 70(4) 2010; 1606-1615), pancreatic cancer (Al-Wadei HA et al., PLOS One 2012, 7(8):e43376; Funahashi H. et al., Cancer Res 2007, 67(15):7068-71). COX2 inhibitors were first approved for the treatment of familial adenomatous polyposis (FAP), which is an inherited colorectal cancer predisposition syndrome, but were later abandoned due to cardiovascular side effects.

Mechanistically, PGE2 signaling is mainly involved in cross-talk between tumor and stromal cells, thereby creating a microenvironment that is favorable for tumor growth. In particular, PGE2 signaling through EP2 and EP4 can, for example, (i) suppress natural killer cell cytotoxicity and cytokine production, (ii) distort the polarization of tumor-associated macrophages in favor of tumor-promoting M2 macrophages (see, for example, Nakanishi Y. et al. Carcinogenesis 2011, 32:1333-39), (iii) regulate the activation, expansion, and effector function of both Tregs (regulatory T cells) and MDSCs (myeloid-derived suppressor cells), which are potent immunosuppressive cells that accumulate in tumors in both patients and animal models (see e.g. Sharma S. et al., Cancer Res 2005, 5(12):5211-20; Sinha P. et al. Cancer Res 2007, 67(9), 4507-4513; Obermajer N et al., Blood 2011, 118(20):5498-5505); (iv) down-regulate the expression of IFN-γ, TNF-α IL-12, and IL-2 in immune cells such as natural killer cells, T cells, dendritic cells, and macrophages by interfering with the ability of these immune cells to induce tumor cell apoptosis, and inhibit oncogenesis (see e.g. Bao Y.S. et al., Int Immunopharmacol. 2011; 11(10): 1599-605; Kim J.G. and Hahn Y.S., Immunol Invest. 2000; 29(3):257-69; Demeuere C.E. et al., Eur J Immunol 1997;27(12):3526-31; Mitsuhashi M et al., J Leukoc Biol. 2004;76(2):322-32; Pockaj B.A. et al., Ann Surg Oncol. 2004;11(3):328-39;(v) inhibit T cell activation, IL-2 responsiveness, expansion, and cytotoxicity, thereby promoting local immunosuppression (see, e.g., Specht C. et al., Int J Cancer 200191:705-712); (vi) inhibit the maturation of dendritic cells, their ability to present antigens and produce IL-12, resulting in abortive activation of cytotoxic T cells (see, for example, Ahmadi M. et al., Cancer Res 2008 , 68(18):7250-9; Stolina M. et al., J Immunol 2000, 164:361-70); (vii) regulate tumor angiogenesis (formation of new blood vessels to supply nutrients and oxygen) by increasing endothelial cell motility and survival, and by increasing VEGF (vascular endothelial growth factor) expression (see, for example, Zhang Y. and Daaka Y , Blood 2011; 118(19):5355-64; Jain S. et al., Cancer Res. 2008; 68(19):7750-9; Wang and Klein, Molecular Carcinogenesis 2007, 46:912-923; (viii ) increase tumor cell survival (via PI3K/AKT and MAPK signaling) For a review see, for example, Kalinski P., J Immunol 2012, 188(1), 21-28; Obermajer N. et al., Oncoimmunology 1(5 ), 762-4; Greenhough A. et al., carcinogenesis 2009, 30(3), 377-86; Wang D. and Dubois R. N., Gut 2006, 55, 115-122; Harris S. G. et al., Trends Immunol 2002 , 22, 144-150).

Coxibs have been shown to make tumor cells more responsive to radiotherapy and chemotherapy, and several clinical trials have been performed or are ongoing in combining coxibs with radiotherapy and/or chemotherapy (for a review see, for example, Ghosh N. et al., Pharmacol Rep. 2010 , March-April 62(2):233-44 Davis T.W. et al., Am J Clin Oncol 2003, 26(4):S58-61 See also Higgins J.P. et al., Cancer Biol Ther 2009, 8:1440-49).

In addition, there is some evidence for additive effects and/or synergy between coxibs and epidermal growth factor receptor (EGFR) inhibitors (see, for example, Zhang X. et al., Clin Cancer Res. 2005, 11(17):6261-9 ; Yamaguchi N. H. et al., J Gastrointest Oncol 2014, 5(1):57-66); and aromatase inhibitors (see, for example, Generali D. et al., Br J Cancer. 2014; 111(1):46-54; Lustberg M.B. et al., Clin Breast Cancer. 2011, August; 11(4): 221-7; Falandry C. et al., Breast Cancer Res Treat 2009 Aug; 116(3):501-8); Chow L.W. et al., J Steroid Biochem Mol Biol. 2008, 111(1-2): 13-7).

Moreover, additive/synergistic effects have been seen in various mouse tumor models when aspirin (COX1/2 inhibitor) was combined with an anti-VEGF antibody (Motz G.T. et al.; Nat Med 2014 20(6):607) and this combination in currently undergoing clinical trials (NCT02659384).

Recently, it has been shown that various immunotherapeutic approaches, when combined, can exhibit enhanced antitumor efficacy. Thus, due to the immunomodulatory properties of PGE2, coxibs have also been used in combination with various immunotherapeutic approaches. In particular, additive or even synergistic effects could be observed when combining coxibs with dendritic cell vaccination in a rat model of glioma and in a mouse model of mesothelioma or melanoma (Zhang H. et al., Oncol Res. 2013;20(10):44755; Veltman J. D. et al., BMC Cancer 2010; 10:464; Toomey D et al., Vaccine 2008 Jun 25; 26(27-28):35409); with granulocyte-macrophage colony-stimulating factor (GM-CSF) in brain tumors in mice (Eberstal S. et al., Int J Cancer. 2014, June 1; 134(11):2748-53); with gamma interferon (IFN-γ) in brain tumors (Eberstal S et al., Cancer Immunol Immunother. 2012, 61(8): 1191-9); with vaccination with dendritic cells or with GM-CSF in a mouse model of breast cancer (Hahn T. et al., Int J Cancer. 2006,118(9):2220-31); and with adenovirus therapy with interferon beta (IFN-β) in a mouse model of mesothelioma (DeLong P. et al., Cancer Res. 2003, Nov. 15; 63(22):7845-52). For these reasons, additive or even synergistic effects of coxibs and/or EP2 and/or EP4 antagonists can also be expected with agents acting on cytotoxic T lymphocyte-associated protein 4 (CTLA-4), such as anti-CTLA-4 antibodies; anti-TIM-3 antibodies, anti-Lag-3 antibodies; anti-TIGIT antibodies; or, in particular, with agents acting on programmed cell death protein 1 (PD1), such as anti-PD1 or anti-PDL1 (programmed cell death ligand-1) antibodies (Yongkui Li et al. Oncoimmunology 2016, 5(2) :e1074374; Zelenay S. et al., Cell 2015, 162; 1-14; WO2013/090552, indicating a synergistic effect of dual EP2 and EP4 blockade in combination with agents acting on PD1).

Adenosine is another endogenous factor with anti-inflammatory properties that is generated through the activity of ectonucleotidase, CD39 and CD73, expressed on various cell types, including regulatory T cells (Treg) (Mandapathil M. et al., J Biol Chem. 2010; 285(10 ):7176-86). Immune cells also respond to adenosine because they carry receptors for ADO, which are primarily of the A2a/A2b type (Hoskin D.W., et al., Int J Oncol 2008, 32:527-535). Signaling through adenosine receptors and EP2/EP4 receptors converges on cytoplasmic adenylate cyclase, leading to upregulation of cAMP. Adenosine and PGE2 have been shown to work together to suppress immune responses mediated by regulatory T cells (Mandapathil M. et al., J Biol Chem. 2010; 285(36):27571-80; Caiazzo E. et al., Biochem Pharmacol 2016; 112:72-81).

Thus, the present EP2 and/or EP4 antagonists may be useful, alone or in combination with one or more therapeutic agents and/or chemotherapy and/or radiotherapy and/or immunotherapy; in particular in combination with chemotherapy, radiotherapy, EGFR inhibitors, aromatase inhibitors, anti-angiogenic drugs, adenosine inhibitors, immunotherapy, such as, in particular, blockade of PD1 and/or PDL1, or other types of targeted therapy; for the prevention/prevention or treatment of malignant neoplasms, in particular for the prevention/prevention or treatment of skin cancer, including melanoma, including metastatic melanoma; lung cancer, including non-small cell lung cancer; bladder cancer, including cancer of the bladder itself, urothelial cell carcinoma; renal carcinomas, including renal cell carcinoma, metastatic renal cell carcinoma, metastatic clear cell carcinoma of the kidney; gastrointestinal malignancies, including colorectal cancer, metastatic colorectal cancer, familial adenomatous polyposis (FAP), esophageal cancer, gastric cancer, gallbladder cancer, cholangiocarcinoma, hepatocellular carcinoma, and pancreatic cancer such as pancreatic adenocarcinoma or ductal pancreatic carcinoma glands; endometrial cancer; ovarian cancer; cervical cancer; neuroblastomas; prostate cancer, including castration-resistant prostate cancer; brain tumors, including brain metastases, malignant gliomas, glioblastoma multiforme, medulloblastoma, meningiomas; breast cancer, including triple negative breast carcinoma; tumors of the oral cavity; tumors of the nasopharynx; thoracic cancer; head and neck cancer; leukemias, including acute myeloid leukemia, adult T-cell leukemia; carcinoma; adenocarcinoma; thyroid carcinoma, including papillary thyroid carcinoma; choriocarcinomas; Ewing's sarcomas; osteosarcomas; rhabdomyosarcomas; Kaposi's sarcomas; lymphomas, including Burkitt's lymphoma, Hodgkin's lymphoma, MALT-type lymphoma; multiple myelomas; and virus-induced tumors.

In addition, selective or dual EP2 and/or EP4 antagonists may be useful in some other diseases or disorders responding to, for example, treatment with COX2 inhibitors, with the advantage that EP2 and/or EP4 antagonists should not have potential cardiovascular side effects. observed with COX2 inhibitors, which are mainly due to the effect on the synthesis of PGI2 and TXA2 (see, for example, Boyd M.J. et al., bioorganic and medicinal chemistry letters 21, 484, 2011). For example, blockade of prostaglandin production with COX inhibitors is a popular treatment for pain, including especially inflammatory pain and painful menstruation. Thus, EP2 and/or EP4 and/or dual EP2/EP4 antagonists may be useful in the treatment of pain, especially inflammatory pain. Using EP2 knockout mice as an example, it has been shown that EP2 antagonists can be used to treat inflammatory hyperalgesia (Re

- 3 043145 inold H. et al., J Clin Invest 2005, 115(3):673-9). In addition, EP4 antagonists have a positive effect in vivo in models of inflammatory pain (e.g. Murase A., Eur J Pharmacol 2008; Clark P., J Pharmacol Exp Ther. 2008; Maubach KA Br J Pharmacol. 2009; Colucci J Bioorg Med Chem Lett. 2010, Boyd M. J. et al., Bioorg Med Chem Lett 2011, Chn Q. et al. Br J Phramacol 2010, Nakao K. et al., J Pharmacol Exp Ther. 2007, August;322(2):686- 94). Administration of EP2 in combination with an EP4 antagonist showed significant but partial suppression of joint inflammation in a mouse model of collagen-induced arthritis (Honda T. et al. J Exp Med 2006, 203(2):325-35).

EP2 and/or dual EP2/EP4 antagonists can be used to reduce female fertility, ie. they have been shown to prevent pregnancy when used as a contraceptive in macaques (Peluffo M.C. et al. Hum Reprod 2014). EP2 knockout mice have reduced fertility, smaller litter sizes, and reduced cumulus expansion (Matsumoto et al., Biology of reproduction 2001, 64; 1557-65; Hitzaki et al., PNAS 1999, 96(18), 10501-10506; Tilley SL J Clin Inves 1999, 103(11): 1539-45; Kennedy C.R. et al., Nat Med 1999 5(2):217-20).

There is also evidence that EP2 and/or EP4 antagonists can be used to prevent or treat endometriosis: for example, EP2, EP3 and EP4 and COX2 are overexpressed in endometrioid cell lines and tissues (eg, Santulli P. et al. J Clin Endocrinol Metab 2014 , 99(3):881-90); antagonist treatment has been shown to inhibit endometrial cell adhesion in vitro (Lee J. et al. Biol Reprod 2013, 88(3):77; Lee J. et al. Fertil Steril 201, 93(8):2498-506); in addition, COX2 inhibitors have been shown to reduce endometrial lesions in mice via EP2 (Chuang P.C. et al., Am J Pathol 2010, 176(2):850-60); and antagonist treatment has also been shown to induce endometrial cell apoptosis in vitro (Banu S.K. et al., Mol endocrinol 2009, 23(8) 1291-305).

Dual EP2/EP4 antagonists or a combination of selective EP2 antagonists with selective EP4 antagonists can potentially be used in autoimmune disorders; for example, they have been shown to be effective in a mouse model for multiple sclerosis (MS) (Esaki Y. et al. PNAS 2010, 107(27): 12233-8; Schiffinann S. et al., Biochem Pharmacol. 2014, 87 (4): 625-35, see also Kofler D.M. et al. J Clin Invest 2014, 124(6):2513-22). Activation of EP2/EP4 signaling in cells in vitro (Kojima F. et al. Prostaglandins Other Lipid Mediat 2009, 89:26-33) links dual or selective EP2 and/or EP4 antagonists to the treatment of rheumatoid arthritis. In addition, increased levels of PGE(2) have been reported in the synovial fluid and cartilage of patients with osteoarthritis (OA), and PGE2 has been shown to stimulate matrix degradation in osteoarthritis chondrocytes via the EP4 receptor (Attur M. et al., J Immunol. 2008 ; 181(7):5082-8).

Overexpression of EP4 has been associated with increased inflammatory response in atherosclerotic plaques of patients (Cipollone F. et al., Artherioscler Thromb Vasc Biol 2005, 25(9); 1925-31), so the use of EP4 and/or dual EP2/EP4 antagonists may be indicated for stabilization of plaques and prevention/prevention of acute ischemic syndromes. In addition, EP4 deficiency suppresses early atherosclerosis, compromising macrophage survival (Babaev V.R. et al., Cell Metab. 2008 Dec; 8(6):492-501).

EP2 and/or dual EP2/EP4 antagonists may also be useful in the treatment of pneumonia: intrapulmonary administration of apoptotic cells has demonstrated that PGE(2) via EP2 causes a subsequent impairment of leukocyte recruitment to the lung and clearance of Streptococcus pneumoniae, as well as increased generation of IL-10 in vivo (Medeiros A.I. et al. J Exp Med 2009 206(1):61-8).

In addition, EP2 and/or dual EP2/EP4 antagonists may be useful in the treatment of neurodegenerative diseases (for a review, see Cimino P.J. et al., Curr Med Chem. 2008; 15(19):1863-9). EP2 receptor accelerates inflammation progression in a mouse model of amyotrophic lateral sclerosis (ALS) (Liang X. et al., Ann Neurol 2008, 64(3):304-14); COX2 inhibitors have also been shown to exhibit neuroprotective properties in rodent models of stroke, Parkinson's disease and ALS (for a review, see Liang X. et al. J Mol Neurosci 2007, 33(1):94-9), reduced neurotoxicity was observed in EP2 knockout mice treated with parkinsonian toxicant (Jin J. et al., J Neuroinflammation 2007, 4:2), PGE2 aggravates neurodegeneration via EP2 in cultured rat cells (Takadera T. et al., Life Sci 2006, 78(16) :1878-83); reduced amyloid load has been observed in a mouse model of Alzheimer's disease in combination with EP2 knockout mice (Liang X. et al. J Neurosci 2005, 25(44):10180-7; Keene C.D. et al., Am. J Pathol. 2010, 177( 1):346-54). EP2 null mice are protected from CD14-dependent/innate immunity-mediated neuronal damage in neurodegenerative disease (Shie FS et al. Glia 2005, 52(1):70-7); PGE2 through EP2 enhances the expression of amyloid precursor protein (APP) in cultured rat microglial cells (Pooler A.M. et al. Neurosci. Lett. 2004, 362(2):127-30). An EP2 antagonist limits oxidative damage from innate immune activation (intracranial LPS injection) in the brain and can be used in Alzheimer's dementia or HIV-related dementia (Montine T.J. et al., J Neurochem 2002, 83(2):46370). In a mouse model of Alzheimer's disease, cognitive function can be improved by genetic and pharmacological inhibition of EP4 (Hoshino T. et al., J Neurochem 2012, 120(5):795-805).

EP2 and/or dual EP2/EP4 antagonists may also be useful in the treatment of autosomal dominant polycystic kidney disease (ADPKD): PGE2 through EP2 induces cystogenesis in human renal epithelial cells; and EP2 was found to be overexpressed in patient samples (Elberg G. et al., Am J Physiol Renal Physiol 2007, 293(5):F1622-32).

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EP4 and/or dual EP2/EP4 antagonists may also be useful in the treatment of osteoporosis: PGE2 stimulates bone resorption mainly through EP4 and partly through EP2 (Suzawa T. et al., Endocrinology. 2000, Apr; 141(4):1554- 9), EP4 knockout mice showed reduced bone resorption (Miyaura C et al., J Biol Chem 2000, 275(26):19819-23), and EP4 antagonists showed partial inhibition of PGE(2)-stimulated osteoclastogenesis and osteoclastic bone resorption ( Tomita M. et al., Bone 2002 Jan 30(1):159-63).

WO2008/152093 discloses selective EP2 receptor modulators which contain an indole ring attached to the rest of the molecule at the 3-position and a pyrimidine moiety which, however, is not substituted by a directly attached aromatic substituent. WO2006/044732 discloses pyrimidine compounds which are PGD2 modulators and are claimed to be useful, for example, in the treatment of allergic diseases; however, for example, exemplary compound CAS 1001913-77-4, which was tested, was found to be inactive at both EP2 and EP4 receptors in the in vitro assay set out in the experimental section below. WO2008/006583 discloses pyrimidine derivatives which are inhibitors of ALK5. WO2006/044732 and WO2008/039882 disclose certain pyrimidine derivatives as prostaglandin D2 receptor antagonists. Pyrimidin-2-yl derivatives are disclosed in WO2013/020945, WO2012/127032, WO2011/144742, WO2011/022348, WO2009/105220, Bioorg. Med. Chem 2011, 21(13) 4108-4114 and Bioorg. Med. Chem 2011, 21(1) 66-75. Further compounds claimed to be active as antineoplastic agents are disclosed in WO2006/128129, WO2008/008059 and Bioorg. Med. Chem 2013, 21(2), 540-546. WO2012/149528 discloses 2-methylpyrimidine derivatives as inhibitors of the inducible form of phosphofructokinase, which are believed to be useful in the treatment of malignancy by attenuating tumor growth by reducing the extremely high level of glycolysis in tumor cells. WO2018/013840, WO2013/163190, WO2015/058067 and WO2015/058031 disclose certain DNA-PK inhibitors that interact with DNA repair processes. The disclosed compounds are believed to be useful for sensitizing tumor cells by directly modulating tumor cell proliferation, and for enhancing the efficacy of both antitumor chemotherapy and radiotherapy.

The present invention provides phenyl derivatives of formulas (II) or (III) which are modulators of prostaglandin-2 EP2 and/or EP4 receptors. Certain compounds of the present invention are dual antagonists of both the EP2 receptor and the EP4 receptor. Thus, the compounds of the present invention may be useful in the prevention/prevention or treatment of diseases that respond to blockage of EP2 receptors and/or EP4 receptors, such as, in particular, malignancies, where a particular aspect is the treatment of malignancy by modulating the immune response, including reactivation of the immune system in the tumor; as well as pain, including, in particular, inflammatory pain and painful menstruation; endometriosis; acute ischemic syndromes in patients with atherosclerosis; pneumonia; neurodegenerative diseases including amyotrophic lateral sclerosis, stroke; Parkinson's disease, Alzheimer's disease and HIV-related dementia; autosomal dominant polycystic kidney disease; and to control female fertility.

1) The first aspect of the invention relates to compounds of formula (II)

Formula (II) for use in the treatment of cancer, wherein said cancer is treated by modulating an immune response, including reactivation of the immune system in the tumor;

where the specified malignant neoplasm, in particular, is a malignant neoplasm selected from melanoma, including metastatic melanoma; lung cancer, including non-small cell lung cancer; bladder cancer, including cancer of the bladder itself, urothelial cell carcinoma; renal carcinomas, including renal cell carcinoma, metastatic renal cell carcinoma, metastatic clear cell carcinoma of the kidney; gastrointestinal malignancies, including colorectal cancer, metastatic colorectal cancer, familial adenomatous polyposis (FAP), esophageal cancer, gastric cancer, gallbladder cancer, cholangiocarcinoma, hepatocellular carcinoma, and pancreatic cancer such as pancreatic adenocarcinoma or ductal pancreatic carcinoma glands; endometrial cancer; ovarian cancer; cervical cancer; neuroblastomas; prostate cancer, including castration-resistant prostate cancer;

where said compound is optionally used in combination with one or more chemotherapeutic agents and/or radiotherapy and/or targeted therapy;

- 5 043145 where in the compounds of formula (II) (R1) _n represents zero, one, two or three substituents on the phenyl ring, where these substituents are independently selected from (C ₁ _ ₃ )alkyl, (C ₁ . ₃ )alkoxy, -S-(C _1-3 )alkyl, halogen, (C _1-3 )fluoroalkyl, (C _1-3 )fluoroalkoxy, cyano, hydroxy, nitro, -CO-O-(C _1-3 )alkyl, and - NR ^N7 R ⁿ⁸ where R ^N7 and R ^N8 are independently hydrogen or (C _1-4 )alkyl, or R ^N7 and RN ⁸ together with the nitrogen atom to which they are attached form a 4-6 membered carbocyclic ring;

R ³ is hydrogen or methyl;

Ar ¹ is a phenyl group of structure (Ar-I)

^Rm1

(Ar-I) where R ^p is (C _{4 .6} )cycloalkyl containing a ring oxygen atom, wherein said (C _{4 .6} )cycloalkyl containing a ring oxygen atom is unsubstituted or monosubstituted by hydroxy;

hydroxy;

- X ¹ -CO-R ^O1 , where

X ¹ is a direct bond, (C ₁ _ ₃ )alkylene, -O-(C ₁ _ ₃ )alkylene-*, -NH-(C ₁ _ ₃ )alkylene-*, -CH=CH- or -NH- CO-*; where the asterisks indicate a bond that is attached to the -CO-RO ¹ group; And

RO ¹ is

-OH;

- O-(C ₁ . ₄ )alkyl;

- NH-SO2-RS ³ where RS ³ is (C _{1 .4} )alkyl, (C _{3 .6} )cycloalkyl, where (C _{3 .6} )cycloalkyl contains zero or one ring oxygen atom, (C _{3 .6} )cycloalkyl-(C _{1 .3} )alkylene, where (C _{3 .6} )cycloalkyl contains zero or one ring oxygen atom, (C _{1 .3} )fluoroalkyl or -NH2;

N^° ^H

A ' nh ₂ .

- (CH2) _q -HET ¹ where q is an integer 0, 1 or 2; and where HET ¹ is 5oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl or the tautomeric form of 5-hydroxy-[1,2,4]oxadiazol-3-yl, Zoxo-2, 3-dihydro-[1,2,4]oxadiazol-5-yl or a tautomeric form of 3-hydroxy-[1,2,4]oxadiazol-5-yl, or 5-thioxo-4,5-dihydro-[1, 2,4]oxadiazol-3-yl or the tautomeric form of 5-mercapto-[1,2,4]oxadiazol3-yl;

- (CH ₂ ) _p -HET, where p is an integer 0 or 1; and where HET is a group selected from 1H-tetrazol-5-yl, 3-hydroxyisoxazol-5-yl, 2-hydroxy-[1,3,4]oxadiazol-4-yl, Zaminoisoxazol-5-yl, 2- aminooxazol-5-yl, 5-amino-[1,3,4]thiadiazol-2-yl, 5-methylamino-[1,3,4]thiadiazol-2-yl, 5-methoxy-[1,2,4 ]oxadiazol-3-yl, 5-amino-[1,2,4]oxadiazol-3-yl, 5-[(2hydroxyethyl)]amino)-[1,2,4]oxadiazol-3-yl, 5-hydroxymethyl -[1,2,4]oxadiazol-3-yl and 5-(oxetan-3yl)-[1,2,4]oxadiazol-3-yl;

R ^m1 is hydrogen;

(C ₁ . ₆ )alkyl;

(C ₁ . ₄ )alkoxy;

(C ₁ . ₃ )fluoroalkyl;

(C ₁ . ₃ )fluoroalkoxy;

halogen;

(C ₃ . ₆ )cycloalkyloxy;

hydroxy;

hydroxy-(C ₂ _ ₄ )alkoxy;

- X ² -NR ^N1 R ^N2 where X ² represents a direct connection; or X ² is -O-CH2-CH2-*, where the asterisk indicates a bond that is attached to the -NR ^N1 R ^N2 group; and where R ^N1 and RN ² independently represent hydrogen, (C ₁ . ₄ )alkyl or (C ₃ _ ₆ )cycloalkyl;

- S-RS ² where RS ² represents (C ₁ _ ₄ )alkyl or (C ₃ _ ₆ )cycloalkyl containing zero or one ring oxygen atom;

R ^m2 is hydrogen, methyl, fluorine or chlorine and

RO ¹ is hydrogen; or if R ^m2 is hydrogen, RO ¹ is hydrogen or fluorine;

- 6 043145 or Ar ¹ is a 5-membered heteroaryl group of structure (Ar-II)

^R6

(Ar-II), g de Y represents CR ⁸ where R ⁸ represents hydrogen or halogen; or Y is N;

R ⁷ is a (C4.6)cycloalkyl containing a ring oxygen atom, wherein said (C4-6)cycloalkyl containing a ring oxygen atom is unsubstituted or monosubstituted by hydroxy;

- X ¹ -CO-R ^O1 , where

X ¹ is a direct bond, (C ₁ . ₃ )alkylene, -O-(C _{1 .3} )alkylene-*, -NH-(C _{1 .3} )alkylene-*, -CH=CH-, -NH- CO-* or (C ₃ . ₅ )cycloalkylene; where the asterisks indicate a bond that is attached to the -CO-RO ¹ group; And

RO ¹ is

-OH;

- O-(C _1-4 ) alkyl;

- NH-SO2-RS ³ where RS ³ is (C _1-4 )alkyl, (C _{3 .6} )cycloalkyl, where (C _{3 .6} )cycloalkyl contains zero or one ring oxygen atom, (C _{3 .6} )cycloalkyl-(C _{1 .3} )alkylene, where (C ₃ .6)cycloalkyl contains zero or one ring oxygen atom, (C _{1 .3} )fluoroalkyl or -NH2;

- O-CH2-CO-RO ⁴ where RO ⁴ is hydroxy or (C ₁ . ₄ )alkoxy or -N[(Cl. ₄ )αlkyl] ₂ ;

- O-CH2-O-CO-RO ⁵ , where RO ⁵ is (C _{1 .4} )alkyl or (C _{1 .4} )alkoxy;

- O-CH ₂ -CH ₂ -N[(C ₁ . ₄ )alkyl] ₂ or (5-methyl-2-oxo-[1,3]dioxol-4-yl)methyloxy-;

N'° ^H

Y ' nh ₂ .

hydroxy-(C ₁ . ₄ )alkyl;

hydroxy-(C ₂ . ₄ )alkoxy;

- (CH ₂ ) _r -CO-NR ^N3 R ^N4 where r is an integer 0 or 1; and where R ^N3 and R ^N4 independently represent hydrogen or (C ₁ . ₄ )alkyl;

- NH-CO-NR ^N5 R ⁿ⁶ , where R ^N5 and R ^N6 independently represent hydrogen or (C ₁ . ₄ )alkyl;

- SO2-RS ¹ where R ^S1 is (C1.4) alkyl or -NR ^N7 R ⁿ⁸ where R ^N7 and R ^N8 are independently hydrogen or ( _C1.3 ) alkyl;

- (CH ₂ ) _q -HET ¹ where q is an integer 0, 1 or 2; and where HET ¹ is 5oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl or the tautomeric form of 5-hydroxy-[1,2,4]oxadiazol-3-yl, 3oxo-2, 3-dihydro-[1,2,4]oxadiazol-5-yl or a tautomeric form of 3-hydroxy-[1,2,4]oxadiazol-5-yl, or 5-thioxo-4,5-dihydro-[1, 2,4]oxadiazol-3-yl or the tautomeric form of 5-mercapto-[1,2,4]oxadiazol3-yl;

- (CH ₂ ) _p -HET, where p is an integer 0 or 1; and where HET is a group selected from 1H-tetrazol-5-yl, 3-hydroxyisoxazol-5-yl, 2-hydroxy-[1,3,4]oxadiazol-4-yl, 3aminoisoxazol-5-yl, 2- aminooxazol-5-yl, 5-amino-[1,3,4]thiadiazol-2-yl, 5-methylamino-[1,3,4]thiadiazol-2-yl, 5-methoxy-[1,2,4 ]oxadiazol-3-yl, 5-amino-[1,2,4]oxadiazol-3-yl, 5-[(2-hydroxyethyl)]amino)-[1,2,4]oxadiazol-3-yl, 5 -hydroxymethyl-[1,2,4]oxadiazol-3-yl and 5-(oxetan-3-yl)[1,2,4]oxadiazol-3-yl;

R ⁶ is (C ₁ . ₆ )alkyl;

(C ₁ . ₄ )alkoxy;

(C ₁ . ₃ )fluoroalkyl;

(C ₁ . ₃ )fluoroalkoxy;

halogen;

(C ₃ . ₆ )cycloalkyloxy;

hydroxy-(C ₂ . ₄ )alkoxy;

- X ² -NR ⁿ¹ R ⁿ² where X ² represents a direct connection; or X ² is -O-CH2-CH2-*, where the asterisk indicates a bond that is attached to the -NR ⁿ¹ R ⁿ² group; and where R ^N1 and R ^N2 are independently hydrogen, (C _{1 .4} )alkyl or (C _{3 .6} )cycloalkyl;

- S-RS ² where RS ² represents (C ₁ . ₄ )alkyl or (C _{3 .6} )cycloalkyl containing zero or one ring oxygen atom;

or Ar ¹ is an 8-10 membered bicyclic heteroaryl selected from indazolyl, benzoimidazolyl, indolyl, benzofuranyl, and benzoxazolyl; where the specified 8-10-membered bicyclic heteroaryl is independently monosubstituted -(C0.3)alkylene-COOR ^{O 2} where RO ² represents hydrogen or (C1. ₄ )alkyl;

- 7 043145 or Ar ¹ is a group of structure (Ar-III)

(Ag-III), which is selected from 2-oxo-2,3-dihydrobenzooxazol-6-yl, 3-methyl-2-oxo-2,3-dihydrobenzooxazol-5-yl, 1-methyl-3-oxo-2 ,3-dihydro-1 H-indazol-6-yl, 2-oxo-1,2,3,4-tetrahydroquinazolin-6-yl, 1-methyl-2-oxo-1,2,3,4-tetrahydroquinazolin- 6-yl, 1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl, 1-methyl2-oxo-1,2,3,4-tetrahydroquinazolin-7-yl and 1-oxo-1,2, 3,4-tetrahydroisoquinolin-7-yl.

The compounds of formulas (II) or (III) may contain one or more stereogenic or asymmetric centers, such as one or more asymmetric carbon atoms, which may be present in the (R)-as well as ^-configuration. Compounds of formulas (II) or (III) may further encompass compounds with one or more double bonds, which may be present in the Z-as well as E-configuration, and/or compounds with substituents in the ring system, which may be present relative to each other in cis and trans configurations. Thus, the compounds of formulas (II) or (III) may be present as mixtures of stereoisomers, or preferably as pure stereoisomers. Mixtures of stereoisomers can be separated using a method known to the person skilled in the art.

Where a single compound (or generic structure) is designated as the (R)- or (S) enantiomer, such designation should be understood to refer to the corresponding compound (or generic structure) in enriched, especially substantially pure, enantiomeric form. Similarly, in the case where a particular asymmetric center in a compound is designated as being in the (R)- or R-configuration, or as being in a particular relative configuration, such designation should be understood to refer to a compound that is in an enriched, in particular essentially pure form, with regard to the corresponding configuration of said asymmetric center. By analogy, cis or trans designations are to be understood as referring to the corresponding stereoisomer of the corresponding relative configuration in an enriched, especially substantially pure, form. Similarly, in the case where a single compound (or generic structure) is designated as the Z- or E-stereoisomer (or in the case where a particular double bond in a compound is designated as being in the Z- or E-configuration), such designation should be understood as referring to the corresponding compound (or generic structure) in an enriched, especially substantially pure stereoisomeric form (or to a compound that is in an enriched, in particular substantially pure form, with respect to the corresponding double bond configuration).

The term enriched, when used in relation to stereoisomers, should be understood in the context of the present invention to mean that the corresponding stereoisomer is present in a ratio of at least 70:30, in particular at least 90:10 (i.e., with a purity of at least at least 70 wt.%, in particular at least 90 wt.%), relative to the respective other stereoisomer/set of the respective other stereoisomers.

The term substantially pure, when used in relation to stereoisomers, should be understood in the context of the present invention to mean that the corresponding stereoisomer is present in a purity of at least 95 wt.%, in particular at least 99 wt.%, relative to the corresponding other stereoisomer/set of corresponding other stereoisomers.

The present invention also includes isotopically labeled, especially ² H (deuterium) labeled compounds of formulas (II) or (III) according to embodiments of the invention, such compounds being identical to compounds of formulas (II) or (III) except that that one or each of a greater number of atoms has been replaced by an atom having the same atomic number but an atomic mass different from that normally found in nature. Isotopically labeled, especially H (deuterium) labeled compounds of formulas (II) or (III) and their salts are included within the scope of the present invention. Replacement of hydrogen with the heavier isotope H (deuterium) may result in greater metabolic stability, resulting in, for example, increased in-vivo half-life or reduced dosage required, or may result in reduced inhibition of cytochrome P450 enzymes, resulting in, for example, an improved safety profile. . In one embodiment of the invention, the compounds of formulas (II) or (III) are not isotopically labeled, or they are labeled with only one or more deuterium atoms. In a sub-embodiment, the compounds of formulas (II) or (III) are not isotopically labeled at all. Isotopically labeled compounds of formulas (II) or (III) can be obtained by analogy with the methods described in this application below, but using a suitable isotopic variant of suitable reagents or starting materials.

In this patent application, the link drawn with a dotted line indicates the point of attachment of the drawn radical. For example, the radical below

- 8 043145

is a 2-methyl-1H-indol-1-yl group.

In some cases, the compounds of formulas (II) or (III) may include tautomeric forms. Such tautomeric forms are included within the scope of the present invention. In the case where tautomeric forms exist in a particular residue, and only one form of such residue is disclosed or defined, it is understood that the other(s) tautomeric(s) form(s) is also covered in such a disclosed residue. For example, the 2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl group is to be understood as also encompassing its tautomeric forms 2-hydroxy-1H-benzo[d]imidazol-5-yl and 2- hydroxy-3Hbenzo[d]imidazol-5-yl. Similarly, 5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl (alternatively referred to as 5-oxo-4H-[1,2,4]oxadiazol-3-yl) spans its tautomeric form 5-hydroxy[1,2,4]oxadiazol-3-yl, and 3-oxo-2,3-dihydro-[1,2,4]oxadiazol-5-yl (alternatively referred to as 3-oxo2H-[1, 2,4]oxadiazol-5-yl) encompasses its tautomeric form 3-hydroxy-[1,2,4]oxadiazol-5-yl.

If for compounds, salts, pharmaceutical compositions, diseases, etc. the plural form is used, it also implies one single compound, salt, or the like.

Any reference to compounds of formulas (II) or (III) according to embodiments of the invention should be understood to refer also to salts (and in particular pharmaceutically acceptable salts) of such compounds, as appropriate and appropriate.

The term pharmaceutically acceptable salts refers to salts that retain the desired biological activity of the compound of the invention and exhibit minimal undesirable toxic effects. Such salts include addition salts with inorganic or organic acids and/or bases, depending on the presence of basic and/or acidic groups in the compound of the invention. For reference, see, for example, Handbook of Phramaceutical Salts. Properties, Selection and Use., P. Heinrich Stahl, Camille G. Wermuth (ed.), Wiley-VCH, 2008; and Pharmaceutical Salts and Co-crystals, Johan Wouters and Luc Quere (eds.), RSC Publishing, 2012.

The definitions provided in this application are intended to apply equally to the compounds of formulas (II) or (III) as defined in any of the embodiments of the invention, and, mutatis mutandis, throughout the description and claims, unless otherwise unambiguously stated definition does not provide a broader or narrower definition. It is clear that the definition or preferred definition(s) of a term defines and may replace the corresponding term independently of (and in combination with) any definition(s) or preferred definition(s) of any or all other terms as defined in this application. Where the Ar ¹ group or substituents thereof are further defined, such definitions are intended to apply, mutatis mutandis, also to the groups (Ar-I), (Ar-II) and (Ar-III) and their respective substituents.

In cases where a substituent is indicated as optional, it should be understood that such a substituent may be absent (i.e., the corresponding residue is unsubstituted with respect to such an optional substituent), in which case all positions having a free valence (to which such an optional substituent could be attached; such as, for example, ring carbon atoms and/or ring nitrogen atoms in an aromatic ring, which have a free valency) are replaced by hydrogen when required. Similarly, when the term is optionally used in the context of ring(s) heteroatom(s), the term means that either the corresponding(s) optional(s) heteroatom(s), or the like, is(are) absent ( i.e. a certain fragment does not contain a heteroatom(s)/means a carbocycle/or the like), or the corresponding(e) optional(e) heteroatom(s), or the like, is(are) present according to the given clear definition.

The term halogen means fluorine, chlorine, bromine or iodine; in particular fluorine, chlorine or bromine; preferably fluorine or chlorine.

The term alkyl, alone or in combination, refers to a straight or branched chain saturated hydrocarbon group containing from one to six carbon atoms. The term ( _Cx-y )alkyl (x and y are each an integer) refers to an alkyl group as defined above, containing x to y carbon atoms. For example, a (C _1-6 )alkyl group contains from one to six carbon atoms. Examples of alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, 3-methylbutyl, 2,2-dimethylpropyl and 3,3dimethylbutyl. For the avoidance of doubt, it should be noted that when a group is named, for example, propyl or butyl, it means n-propyl, respectively n-butyl. Preferred are methyl and ethyl. Most preferred is methyl. Preferred substituents on the Ar ¹ radical which is phenyl or 5- or 6-membered heteroaryl are methyl, ethyl, propyl, isobutyl, 1-methylpropan-1-yl, tert-butyl, 3-methylbutyl.

The term -(C _x _ _y )alkylene-, used alone or in combination, refers to a divalently attached alkyl group as defined above, containing from x to y carbon atoms. Preferably, the points of attachment of the -( _{C1_y} )alkylene group correspond to the 1,1-9 043145 diyl, 1,2-diyl or 1,3-diyl scheme. In the event that a (C _0-y ) alkylene group is used in combination with another substituent, the term means that either the said substituent is attached via the (C _1-y ) alkylene group to the rest of the molecule, or it is attached directly to the rest of the molecule ( ie the (C ₀ )alkylene group is a direct bond attaching said substituent to the rest of the molecule). The alkylene group -C2H4- refers to -CH2-CH2- unless explicitly stated otherwise. For linker X ¹ , examples of (C1_3)alkylene groups are CH2-, -CH(CH3)-, -C(CH3)2- and -CH2-CH2-, especially -CH2- and -CH2-CH2-. Examples of (C03)alkylene groups used in the substituents -(C0.3)alkylene-COOR ^O2 and ( _C0.3 )alkylene-COOR ^O3 , respectively, are (C ₀ )alkylene and methylene, respectively.

The term alkoxy, alone or in combination, refers to an alkyl-O- group, where the alkyl group is as defined above. The term (C _x-y )alkoxy (x and y are each an integer) refers to an alkoxy group as defined above, containing x to y carbon atoms. For example, (C _1-4 )alkoxy means a group of the formula ( _{C1_4} )alkyl-O-, where the term ( _{C1_4} )alkyl has the meaning given above. Examples of alkoxy groups are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy and tert-butoxy. Ethoxy and especially methoxy are preferred. Preferred substituents on the Ar ¹ radical which is phenyl or 5- or 6-membered heteroaryl are methoxy, ethoxy, propoxy, butoxy, isobutoxy.

The term fluoroalkyl, used alone or in combination, refers to an alkyl group as defined above, containing from one to three carbon atoms, in which one or more (and possibly all) of the hydrogen atoms has been replaced by fluorine. The term ( _Cx-y )fluoroalkyl (x and y are each an integer) refers to a fluoroalkyl group as defined above, having x to y carbon atoms. For example, a ( _C1-3 )fluoroalkyl group contains one to three carbon atoms and has one to seven hydrogen atoms replaced by fluorine. Representative examples of fluoroalkyl groups include trifluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl, and 2,2,2-trifluoroethyl. Preferred are (C1)fluoroalkyl groups such as trifluoromethyl. An example of ( _{C1_3} )fluoroalkyl wherein said ( _{C1_3} )fluoroalkyl is optionally substituted with hydroxy is 2,2,2-trifluoro-1-hydroxyethyl.

The term fluoroalkoxy, alone or in combination, refers to an alkoxy group as defined above, having one to three carbon atoms, in which one or more (and possibly all) of the hydrogen atoms has been replaced by fluorine. The term (Cx _-y )fluoroalkoxy (x and y are each an integer) refers to a fluoroalkoxy group as defined above, having x to y carbon atoms. For example, a ( _C1-3 )fluoroalkoxy group contains one to three carbon atoms and has one to seven hydrogen atoms replaced by fluorine. Representative examples of fluoroalkoxy groups include trifluoromethoxy, difluoromethoxy, 2fluoroethoxy, 2,2-difluoroethoxy and 2,2,2-trifluoroethoxy. Preferred are (C1)fluoroalkoxy groups such as trifluoromethoxy and difluoromethoxy, as well as 2,2,2-trifluoroethoxy.

The term cycloalkyl, used alone or in combination, refers to a saturated monocyclic hydrocarbon ring containing three to six carbon atoms. The term (C _x - _y )cycloalkyl (x and y are each an integer) refers to a cycloalkyl group as defined above, containing x to y carbon atoms. For example, a (C ₃ _ ₆ )cycloalkyl group contains three to six carbon atoms. Examples of cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. Preferred are cyclopropyl, cyclobutyl and cyclopentyl; especially cyclopropyl. An example of cycloalkyl groups containing one ring oxygen atom is, in particular, oxetanyl. Examples of (C ₃ _ ₆ )cycloalkyl groups wherein said (C ₃ _ ₆ )cycloalkyl is optionally monosubstituted with amino are cyclopropyl, 1-aminocyclopropyl. Examples of (C ₃ . ₆ )cycloalkyl groups wherein said (C ₃ _ ₆ )cycloalkyl is monosubstituted with -COOH are 1-carboxycyclopropyl, 1-carboxycyclopentyl.

The term -(C _x _ _y )cycloalkylene-, used alone or in combination, refers to a divalently attached cycloalkyl group as defined above, containing from x to y carbon atoms. Preferably, the points of attachment of any divalently attached cycloalkyl group correspond to the 1,1-diyl or 1,2-diyl pattern. Examples are cyclopropan-1,1-diyl, cyclopropan-1,2-diyl and cyclopentan-1,1-diyl; cyclopropane-1,1-diyl is preferred.

Examples of (C ₃ _ ₆ )cycloalkyloxy are cyclobutyloxy and cyclopentyloxy.

Alkylated amino groups -N[(C ₁ . ₄ )alkyl] ₂ used in groups -X1-CO-RO ¹ where RO ¹ is -O-CH2-CO-RO ⁴ where RO ⁴ is -N[( C1.4)alkyl]2; or where RO ¹ is -O-CH2-CH ₂ -I[(C1_4)alkyl] ₂ are those fragments in which the two corresponding (C _1-4 )alkyl groups are independently selected. A preferred example of such an amino group N[(C ₁ . ₄ )alkyl] ₂ is -N(CH ₃ ) ₂ .

The term heterocycle, used alone or in combination, and unless explicitly defined more broadly or narrower, refers to a saturated monocyclic hydrocarbon

- 10 043145 a ring containing one or two (especially one) ring heteroatoms independently selected from nitrogen, sulfur and oxygen (especially one nitrogen atom, two nitrogen atoms, one nitrogen atom and one oxygen atom, or one nitrogen atom and one sulfur atom). The term (C _x . _y ) heterocycle refers to such a heterocycle containing from x to y ring atoms. Heterocycles are unsubstituted or substituted, as clearly defined in a particular case.

The group consisting of a non-aromatic 5- or 6-membered ring fused to a phenyl group, where the ring (B) contains one or two heteroatoms independently selected from nitrogen and oxygen, used for (Ar-III), refers to phenyl groups which fused to a (C ₃ . ₆ ) heterocycle according to the above definition. Examples are 2,3-dihydro-benzofuranyl, 2,3-dihydro-III-indolyl, 2,3-dihydro-benzo[1,4]dioxinyl, 2,3-dihydro-Shindazolyl, 2,3-dihydro-1H-benzo[d]imidazolyl, 2,3-dihydrobenzo[d]isoxazolyl, 2,3-dihydroisoindolyl, 3-dihydrobenzooxazol-6-yl, 2,3-dihydrobenzooxazol-5-yl, 1,2,3,4-tetrahydroquinazolin-6yl, 1,2, 3,4-tetrahydroquinazolin-7-yl, 1,2,3,4-tetrahydroisoquinolin-6-yl and 1,2,3,4-tetrahydrophthalazin6-yl. The above groups are unsubstituted, mono- or disubstituted, where the substituents are independently selected from oxo, (C _{1 .6} )alkyl and -(C _{0 .3} )alkylene-COOR ^O3 where RO ³ is hydrogen or (C1.3)alkyl (especially methyl); in particular, the substituents are independently selected from oxo, methyl, ethyl, propyl, butyl, isobutyl or -COOH; wherein the substituents are attached to a fused 5- or 6-membered non-aromatic ring. The oxo substituents are preferably attached to a ring carbon atom which is in alpha position to the ring nitrogen atom. Preferred examples of such groups are 2,3-dihydrobenzofuranyl, 2,3-dihydro-Shindolyl, 2,3-dihydrobenzo[1,4]dioxinyl; as well as oxo-substituted heterocyclyl groups 3-oxo2,3-dihydro-1H-indazolyl, 2-oxo-2,3-dihydro-1H-benzo[d]imidazolyl, 3-oxo-2,3-dihydrobenzo[d]isoxazolyl, 2-oxo-1,3-dihydroindolyl, 1-oxo-2,3-dihydroisoindolyl, 2-oxo-2,3-dihydrobenzooxazolyl, 2-oxo-1,2,3,4-tetrahydroquinazolinyl, 1-oxo-1,2, 3,4-tetrahydroisoquinolinyl, 1,4-dioxo-1,2,3,4-tetrahydrophthalazinyl; where the above groups optionally carry one (additional) substituent independently selected from (C1.6)alkyl and -(C0.3)alkylene-COOR ^O3 , where RO ³ is hydrogen or ( _C1.3 )alkyl (especially methyl ). Some examples are 2oxo-2,3-dihydrobenzooxazol-6-yl, 3-methyl-2-oxo-2,3-dihydrobenzooxazol-5-yl, 1-methyl-3-oxo-2,3-dihydro-1H-indazol- 6-yl, 2-oxo-1,2,3,4-tetrahydroquinazolin-6-yl, 1-methyl-2-oxo-1,2,3,4-tetrahydroquinazolin-6-yl, 1-oxo-1, 2,3,4-tetrahydroisoquinolin-6-yl, 1-methyl-2-oxo-1,2,3,4-tetrahydroquinazolin7-yl and 1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl and in addition, 2-oxo-1,3-dihydroindol-5-yl and 1-methyl2-oxo-1,3-dihydroindol-5-yl.

For the avoidance of doubt, certain groups having tautomeric forms that are considered predominantly non-aromatic, such as, for example, 2-oxo-2,3-dihydro-1H-benzo[d]imidazolyl groups, are defined in this application as 8-10-membered partially aromatic fused bicyclic heterocyclyl groups even though their corresponding tautomeric form (2-hydroxy-1H-benzo[d]imidazolyl) can also be considered as an 8-10 membered bicyclic heteroaryl group.

The term aryl, alone or in combination, means phenyl or naphthyl, in particular phenyl. The above aryl groups are unsubstituted or substituted, as clearly defined in the particular case.

Examples of the substituent Ar ¹ representing phenyl are, in particular, those that are at least monosubstituted in the para position relative to the point of attachment of the rest of the molecule. In addition, such an Ar ¹ group, which is phenyl, may carry one or two additional substituents, especially in one or both meta positions relative to the point of attachment of the rest of the molecule. Appropriate substituents on such phenyl groups are well defined in the particular case.

The term heteroaryl, used alone or in combination, means a 5-10 membered monocyclic or bicyclic aromatic ring containing from one to a maximum of four heteroatoms, each independently selected from oxygen, nitrogen and sulfur. Examples of such heteroaryl groups are 5-membered heteroaryl groups such as furanyl, oxazolyl, isoxazolyl, oxadiazolyl, thiophenyl, thiazolyl, isothiazolyl, thiadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl; 6-membered heteroaryl groups such as pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl; and 8-10 membered bicyclic heteroaryl groups such as indolyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzothiophenyl, indazolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzothiazolyl, benzoxadiazolyl, benzothiadiazolyl, thienopyridinyl, quinoline silt, isoquinolinyl, naphthyridinyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, pyrrolopyridinyl, pyrazolopyridinyl, pyrazolopyrimidinyl, pyrrolopyrazinyl, imidazopyridinyl, imidazopyridazinyl and imidazothiazolyl. The aforementioned heteroaryl groups are unsubstituted or substituted, as clearly defined in the particular case.

In the case of an Ar ¹ substituent which is a 5- or 6-membered heteroaryl, the term means the aforementioned 5- or 6-membered groups, such as, in particular, pyridinyl, pyrimidinyl, pyrro- 11 043145 lyl, pyrazolyl, isoxazolyl, thiazolyl or thiophenyl . In particular, the term refers to 5-membered groups such as, in particular, thiazolyl or thiophenyl; in particular thiophen-2-yl, thiophen-3-yl, thiazol-2yl, thiazol-4-yl, thiazol-5-yl. Preferred is thiophenyl, in particular thiophen-2-yl; or thiazolyl, in particular thiazol-2-yl. The above groups are substituted as clearly defined in the particular case. Thiophen-2-yl or thiazol-2-yl is especially disubstituted with one substituent at the 5-position and a second substituent at the 4-position (and, in the case of thiophen-2-yl, optionally with a halogen substituent at the 3-position).

In the case of the Ar ¹ substituent, which is an 8-10 membered bicyclic heteroaryl, the term means the aforementioned 8-10 membered heteroaryl groups. In particular, the term refers to 9- or 10-membered heteroaryl groups such as, in particular, indazolyl, benzoimidazolyl, indolyl, benzotriazolyl, benzoxazolyl, quinoxalinyl, isoquinolinyl, quinolinyl, pyrrolopyridinyl and imidazopyridinyl, as well as benzofuranyl, benzothiophenyl and benzothiazolyl. The above groups are unsubstituted or substituted, as clearly defined in a particular case. Some examples are 1H-indol-2-yl, 1H-indol-3-yl, 1H-indol-4-yl, 1H-indol-5-yl, 1H-indol-6-yl, 1-methyl-1Hindol-5 -yl, 1H-indazol-5-yl, 1H-indazol-6-yl, 1-methyl-1H-indazol-6-yl, 3-methyl-1H-indazol-6-yl, 3methoxy-1H-indazol-6 -yl, 6-methoxy-N-indazol-5-yl, N-benzoimidazol-5-yl, 2-methyl-N-benzoimidazol-5-yl, 2-trifluoromethyl-N-benzoimidazol-5-yl, N-benzotriazol-5 -yl, 2-methylbenzooxazol-5-yl, 2-methylbenzooxazol-6-yl, quinoxalin-6-yl, isoquinolin-7-yl, quinolin-6-yl, 1Hpyrrolo[2,3-c]pyridin-3-yl , 1H-pyrrolo[2,3-b]pyridin-3-yl, 1H-pyrrolo[2,3-b]pyridin-5-yl, 1-methyl1H-pyrrolo[2,3-b]pyridin-5-yl , imidazo[1,2-a]nurudin-6-yl, 2-carboxy-1H-indol-5-yl, 3-carboxy1H-indol-6-yl, 4-carboxy-1H-indol-2-yl, 5 -carboxy-III-indol-2-yl, 6-carboxy-III-indol-2-yl, 7-carboxy-III-indol-2-yl, 7-carboxy-1 H-indol-4-yl, 7-carboxy- 1-methyl-1 H-indol-4-yl, 5-(methoxycarbonyl)-1H-indol-2-yl, 6-(methoxycarbonyl)-1H-indol-2-yl), 6-carboxybenzofuran-2-yl, 3-carboxybenzofuran-6-yl, 2-carboxybenzofuran-5-yl and 2-carboxybenzofuran-6-yl. Preferred examples are 1H-benzoimidazol-5-yl, 1H-indol-6-yl, 1H-indol-5-yl, 1H-indol-2-yl, 1Hindazol-5-yl and in addition imidazo[1,2 -a]pyridin-6-yl; as well as 8-10-membered bicyclic heteroaryl which is monosubstituted with -(C ₀ . ₃ )alkylene-COOR ^O2 such as 3-carboxy-1H-indol-6-yl, 4-carboxy-1Hindol-2-yl, 5- carboxy-III-indol-2-yl, 6-carboxy-1H-indol-2-yl, 7-carboxy-III-indol-2-yl, 5(methoxycarbonyl)-1H-indol-2-yl, 6-( methoxycarbonyl)-1 H-indol-2-yl), 6-carboxybenzofuran-2-yl, 3-carboxybenzofuran-6-yl, 2-carboxybenzofuran-5-yl and 2-carboxybenzofuran-6-yl.

In the case of the substituent -(CH ₂ ) _p -HET, where p is the integer 0 or 1, and where HET is a 5- or 6-membered heteroaryl, such a 5- or 6-membered heteroaryl corresponds to the above definition; in particular is a nitrogen-containing 5-membered heteroaryl such as, in particular, tetrazolyl or oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, imidazolyl, pyrazolyl or triazolyl. The above groups are unsubstituted or substituted, as clearly defined in a particular case. The -(CH2) _p - group is preferably absent, i.e. p is the integer 0 and the HET group is directly attached to Ar ¹ . Individual examples of -(CH ₂ ) _p -HET are, in particular, -(CH ₂ ) ₀ -HET groups 1H-tetrazol-5-yl, 3hydroxyisoxazol-5-yl, 2-hydroxy-[1,3,4]oxadiazol -4-yl; additional examples are 3aminoisoxazol-5-yl, 2-aminooxazol-5-yl, 5-amino-[1,3,4]thiadiazol-2-yl, 5-methylamino[1,3,4]thiadiazol-2-yl, 5-methoxy-[1,2,4]oxadiazol-3-yl, 5-amino-[1,2,4]oxadiazol-3-yl, 5-[(2hydroxyethyl)]amino)-[1,2,4 ]oxadiazol-3-yl, 5-hydroxymethyl-[1,2,4]oxadiazol-3-yl, 5-(oxetan-3-yl)[1,2,4]oxadiazol-3-yl, III-imidazol- 4-yl, 5-methyl-1H-imidazol-4-yl and 2,5-dimethyl-1H-imidazol-4-yl; and also 1H-pyrazol-1-yl, 1H-pyrazol-3-yl, 3-methylpyrazol-1-yl, 1-methyl-1H-pyrazol-3-yl, 5-methyl-Spyrazol-3-yl, 3, 5-dimethylpyrazol-1-yl, 4-carboxy-1H-pyrazol-3-yl, 1H-imidazol-2-yl, 3-methyl-3Himidazol-4-yl, 2-methyl-1H-imidazol-4-yl , 1,5-dimethyl-1H-imidazol-2-yl, 1,2-dimethyl-1H-imidazol-4yl, 1,5-dimethyl-1H-imidazol-4-yl, 2-cyclopropyl-1H-imidazole -4-yl, 2-cyclopropyl-1-methyl-1Himidazol-4-yl, [1,2,4]oxadiazol-5-yl, 5-methyl-[1,2,4]oxadiazol-3-yl, 3 -methyl-[1,2,4]oxadiazol-5-yl, 5-methyl-[1,3,4]oxadiazol-2-yl, isothiazol-5-yl, thiazol-2-yl, thiazol-4-yl , 4-methylthiazol-2-yl, 2-methylthiazol-4-yl, 2-amino-5-methylthiazol-4-yl, 4,5-dimethylthiazol-2-yl, 4-carboxythiazol-2-yl, 2-carboxythiazole -4-yl, 2-hydroxythiazol-4-yl, 2-amino-2-oxoethyl)thiazol-4-yl, isoxazol-3-yl, isoxazol-5-yl, 3-methylisoxazol-5-yl, 4-methylisoxazole -5-yl, 4-carboxy-3-methylisoxazol-5-yl, oxazol-5yl, 2-methyloxazol-5-yl, 2-(2-carboxyethyl)-oxazol-5-yl, 2-(2-carboxyethyl) -4-methyloxazol-5-yl, 4H[1,2,4]triazol-3-yl, 1H-[1,2,4]triazol-1-yl, 2-methyl-2H-[1,2,4 ]triazol-3-yl, pyridin-2-yl, 4-fluoropyridin-2-yl, pyrimidin-2-yl, 5-fluoropyrimidin-2-yl, 5-methoxypyrimidin-2-yl, 4-methoxypyrimidin-2-yl , 6-methoxypyrimidin-4-yl, 6-dimethylaminopyrimidin-4-yl, pyrazin-2-yl, 6methoxypyrazin-2-yl, 6-methoxypyridazin-3-yl, 3H-imidazol-4-yl, 3H-[1, 2,3]triazol-4-yl, oxazol-2-yl and 4,5-dimethyloxazol-2-yl. In particular, the HET groups are selected from 1H-tetrazol-5-yl, 3-hydroxyisoxazol-5-yl, 2-hydroxy-[1,3,4]oxadiazol-4-yl, 3-aminoisoxazol-5-yl, 2- aminooxazol-5yl, 5-amino-[1,3,4]thiadiazol-2-yl, 5-methylamino-[1,3,4]thiadiazol-2-yl, 5-methoxy-[1,2,4]oxadiazole -3-yl, 5amino-[1,2,4]oxadiazol-3-yl, 5-[(2-hydroxyethyl)]amino)-[1,2,4]oxadiazol-3-yl, 5-hydroxymethyl[1 ,2,4]oxadiazol-3-yl and 5-(oxetan-3-yl)-[1,2,4]oxadiazol-3-yl. For the avoidance of doubt, certain

- 12 043145 groups having tautomeric forms that can be considered predominantly aromatic (such as, for example, 3-hydroxyisoxazolyl or 2-hydroxy-[1,3,4]oxadiazolyl groups) are defined in this application as HET heteroaryl groups even though that their corresponding tautomeric form (3oxo-2,3-dihydro-2H-isoxazolyl, respectively, 2-oxo-2,3-dihydro-3H-[1,3,4]oxadiazolyl) can also be considered as a non-aromatic group. Similarly, certain groups having tautomeric forms that can be considered predominantly non-aromatic (such as 5-oxo-4,5-dihydro[1,2,4]oxadiazol-3-yl or 5-thioxo-4,5-dihydro- [1,2,4]oxadiazol-3-yl) as defined by the HET ¹ substituent are defined herein as not being part of the substituted heteroaryl groups as defined by HET even though their corresponding tautomeric form (5-hydroxy[ 1,2,4]oxadiazolyl, respectively, 5-mercapto-[1,2,4]oxadiazolyl) can also be considered as a heteroaryl group. It should be understood that the corresponding tautomer is included in the appropriate scope of the invention as defined.

The term cyano refers to the -CN group.

The term oxo refers to a ═O group which is preferably attached to a carbon or sulfur atom in the chain or ring, such as, for example, a carbonyl group -(CO)- or a sulfonyl group -(SO2)-.

Examples of -X ² -NR ⁿ¹ R ⁿ² groups used as substituents for Ar ¹ being phenyl or 5- or 6-membered heteroaryl are amino, methylamino, ethylamino, propylamino, aminomethyl, methylaminomethyl, isobutylaminomethyl, cyclopropylaminomethyl, cyclobutylaminomethyl, (2methoxyethyl )aminomethyl, (2,2,2-trifluoroethyl)amino; or -NH-CO-H, -N(C ₂ H ₅ ) -CO-H, -NH-CO-C ₂ H ₅ , -NH-CO-CH2-CH2-OH, -NH-CO-O-CH3 , -N(CH ₃ )-CO-O-CH ₃ ; or pyrrolidin-1-yl, 2-oxopyrrolidin-1-yl, 1,1-dioxoisothiazolidin-2-yl, morpholin-4-yl, azetidin-1-yl or piperidin-1-yl; and 2-(dimethylamino)ethoxy.

Examples of the -NH-CO-NR ^N5 R ⁿ⁶ group used as substituents for the Ar ¹ group are ureido (NH-CO-NH2) and 3-ethylureido (NH-CO-NH-C ₂ H ₅ ).

Examples of the group -(CH ₂ ) _r -CO-NR ^N3 R ^N4 where r is an integer 0 or 1 used as substituents of the Ar ¹ group are preferably groups where r is an integer 0 and at least one of R ^N3 and R ^N4 is hydrogen (or less preferably methyl). Individual examples of such a -CO-NR ⁿ³ R ⁿ⁴ group are -CO-NH2, -CO-NH(CH ₃ ), -CO-N(CH ₃ ) ₂ , -CO-NH(C ₂ H ₅ ), -CO- NH-O-methyl, -CO-NH-O-ethyl, -CO-NH-O-isopropyl, -CO-NH-C2H4OH, -CO-NH-O-C2H4-OH, -CO-NH-C2H4-OCH3 , -CO-NH-C ₂ H ₄ -N(CH ₃ ) ₂ and -CO-NH-O-benzyl. Additional examples are -CO-NH-isopropyl and -CO-NH-OH, as well as -CO-N(CH ₃ ) ₂ .

Examples of the -X1-CO-R ^O1 group used as substituents of the Ar ¹ group are, in particular, the following groups:

a) X ¹ is a direct link; and R ^{O 1} is -OH; (i.e. -X1-CO-R ^O1 is -COOH); or

b) X ¹ is a direct link; and R ^O1 is -O-(C1.4)alkyl (especially ethoxy or methoxy); (i.e. -X1-CO-R ^O1 is -CO-( _C1.4 )alkoxy (especially ethoxycarbonyl, methoxycarbonyl)); or

c) X ¹ is a direct link; and R ^O1 is -NH-SO2-RS ³ , where R ^S3 is (C1.4)alkyl; (C3.6)cycloalkyl, where (C3.6)cycloalkyl optionally contains a ring oxygen atom; (C3.6)cycloalkyl-(C1.3)alkylene, where (C3.6)cycloalkyl optionally contains a ring oxygen atom; (C1.3)fluoroalkyl; phenyl; or -NH2; (i.e. -X1-CO-R ^O1 is -CO-NH-SO2-RS ³ where R ^S3 is the above groups; especially methyl, ethyl, isopropyl, cyclopropyl, trifluoromethyl, amino; especially -X1-CO-RO ¹ is -CO-NH-SO2-CH3, -CO-NH-SO2C(CH3) ₂ , -CO-NH-SO ₂ -cyclopropyl, -CO-NH-SO ₂ -ethyl or - CO-NH-SO2-NH2); or

d) X ¹ is (C1.3)alkylene (especially -CH2-, -CH2-CH2-), -O-(C1.3)alkylene-* (especially -O-CH2-*, - O-CH(CH3)-*, -OC(CH3)2-*, O-CH2-CH2-*), -NH-(C1.3)alkylene-* (in particular, -NH-CH2-*, - NHCH(CH3)-*), -S-CH2-*, -CF2-, -CH=CH- or -CH^CH- [in a sub-embodiment X ¹ is especially -O-CH2-*, - NH-CH2-*, -S-CH2-* or ( _C1.3 )alkylene]; where the asterisks indicate a bond that is attached to the -CO-RO ¹ group; and R ^O1 is -OH (i.e. -X1-CO-R ^O1 is -X1-COOH where X ¹ is the above groups; in particular -X1-CO-R ^O1 is -O-CH2 -COOH or -NH-CH2-COOH; and -CH2-COOH, -CH2-CH2-COOH, -CH=CH-COOH, -CHCH-COOH, -O-CH2-CH2COOH, -O-CH(CH ₃ )-COOH or -NH-CH(CH ₃ )-COOH); or

e) -X1 is -NH-CO-* or -CO-; where the asterisk indicates a bond that is attached to the -CO-RO ¹ group; and R ^O1 is -OH (i.e. -X1-CO-R ^O1 is -X ¹ -COOH, where X ¹ is the aforementioned groups; in particular -X ¹ -CO-R ^O1 is -NH -CO-COOH, -CO-COOH); or

f) X ¹ is (C3.5)cycloalkylene; and R ^{O 1} is -OH; (i.e. -X1-CO-R ^O1 is ( _C3.6 ) cycloalkyl which is monosubstituted with COOH; in particular -X1-CO-R ^O1 is 1-carboxycyclopropan-1-yl or 1-carboxycyclopentan-1 -silt); or

- 13 043145

g) X ¹ is a direct link; and R ⁰¹ is -O-CH2-CO-R ⁰⁴ where R ⁰⁴ is hydroxy or (C _{1 .4} )alkoxy or -N[(C _{1 .4} )alkyl] ₂ ; in particular, -X ¹ -CO-R ^O1 is -CO-O-CH ₂ -COOH; or where each of the groups a), b), c), d), e), f) and g) forms a separate sub-option of the invention.

Compounds of formulas (II) or (III) containing a -X ¹ -CO-R ⁰¹ group, where X ¹ is CH=CH-, may be in the E- or Z-configuration. Preferably, such groups are in the E configuration.

Whenever the Ar ¹ group is substituted with a substituent containing a -COOH carboxylic acid group (such as in the substituents -(C0.3)alkylene-COOR ^O2 , where R ^O2 is hydrogen; -( _C0.3 )alkylene-COOR ^O3 , where R ^O3 represents hydrogen, or in substituents -X ¹ -CO-R ⁰¹ *, where R ^O1 represents -OH, in particular in groups -X ¹ -CO-R ^O1 a), d), e) and f) mentioned above), such a carboxylic acid group may be present in the form of a prodrug group. Such prodrugs are included within the scope of the present invention. In some cases, compounds containing such carboxylic acid prodrug groups may as such exhibit biological activity at EP2 and/or EP4 receptors, while in other cases, such compounds containing such carboxylic acid prodrug groups require (e.g., enzymatic ) cleavage of the prodrug to exhibit biological activity at the EP2 and/or EP4 receptors. Prodrugs of the carboxylic acid functional group are well known in the art (see, for example, J. Rautio (Ed.) Prodrugs and Targeted Delivery: Towards Better ADME Properties, Volume 47, Wiley 2010, ISBN: 978-3-527-32603- 7; H. Maag in Stella, V., Borchardt, R., Hageman, M., Oliyai, R., Maag, H., Tilley, J. (ed.) Prodrugs: Challenges and Rewards, Springer 2007, ISBN 978 -0-387-49785-3).

Specific examples of prodrugs, eg suitable for groups -X ¹ -COOH, are ester groups -X ¹ -CO-OP ¹ where P ¹ means, for example, (C1.4)alkyl; (C3.6)cycloalkyl, where (C3.6)cycloalkyl optionally contains a ring oxygen atom; (C3.6)cycloalkyl-(C1.3)alkyl, where (C3.6)cycloalkyl optionally contains a ring oxygen atom; (C1.3)fluoroalkyl; hydroxy-(C2.4)alkyl; or (C1.4)alkoxy-(C2.4)alkyl (in particular P ¹ means ( _C1.4 )alkyl, in particular methyl or ethyl);

group -X ¹ -CO-NH-SO2-RS ³ where RS ³ represents (C1.4)alkyl, (C3.6)cycloalkyl, where (C3.6)cycloalkyl optionally contains a ring oxygen atom; (C3.6)cycloalkyl-(C1.3)alkyl, where (C3.6)cycloalkyl optionally contains a ring oxygen atom; (C1.3)fluoroalkyl, -NH2; (in particular, RS ³ means ( _C1.4 )alkyl, (C _{3 .6} )cycloalkyl; in particular methyl);

groups -X ¹ -CO-R ^O1 , where R ^O1 is -O-CH2 -CO-R ^O4 , where R ^O4 is hydroxy or ( _C1.4 )alkoxy, or -N[(C _{1 .4} )alkyl ] ₂ (especially -CO-O-CH2-COOH, -CO-O-CH ₂ -CO-N(CH ₃ ) ₂ );

groups -X ¹ -CO-R ^O1 , where R ^O1 is -O-CH2-O-CO-R ⁰⁵ _, where R ⁰⁵ is ( _C1.4 )alkyl or (C _1.4 )alkoxy (especially -CO-O-CH ₂ -O-CO-O-ethyl, -CO-O-CH ₂ -O-CO-propyl);

groups -X ¹ -CO-R ⁰¹ where R ⁰¹ is -O-CH ₂ -CH ₂ -N[(C ₁ . ₄ )alkyl] ₂ (especially -CO-OCH2-CH2-N(CH3) 2); and groups -X-CO-R ⁰¹ where R ⁰¹ represents 5-methyl-2-oxo-[1,3]dioxol-4-yl)methyloxy-.

Examples of hydroxy-(C ₁ . ₄ )alkyl groups used as substituents of the Ar ¹ group are hydroxymethyl and 1-hydroxyethyl.

An example of dihydroxy-(C ₂ . ₄ )alkyl groups used as substituents of the Ar ¹ group is 1,2-dihydroxyethyl.

An example of hydroxy-(C ₂ . ₄ )alkoxy groups used as substituents of the Ar ¹ group is 2-hydroxyethoxy.

An example of (C _{1 .4} )alkoxy-(C _{2 .4} )alkoxy groups used as substituents of the Ar ¹ group is 2-methoxyethoxy.

Examples of the -SO2-RS ¹ group used as substituents for the Ar ¹ group are -SO2CH3, -SO2-NH2, -SO2-NH-CH3.

Examples of the S-RS ² group used as substituents of the Ar ¹ group are methylsulfanyl, ethylsulfanyl, n-propylsulfanyl, isopropylsulfanyl, isobutylsulfanyl), cyclobutylsulfanyl and (oxetan-3-yl)-sulfanyl.

An example of a (C ₁ . ₄ )alkoxy-(C ₂ . ₄ )alkyl group is 2-methoxyethyl.

An example of a hydroxy-(C ₂ . ₄ )alkoxy group is 2-hydroxyethoxy.

An example of a hydroxy-(C ₂ . ₄ )alkyl group is 2-hydroxyethyl.

An example of a -CO-(C ₁ . ₄ )alkoxy group used as substituents of the Ar ¹ group is ethoxycarbonyl. Such groups may also be useful as prodrug groups of the corresponding -COOH substituent.

Whenever the word between is used to describe a range of numerical values, it should be understood to mean that the endpoints of the specified range are explicitly included in that range. For example: if a temperature range is described by values between 40°C and 80°C, then this means that the endpoints of 40°C and 80°C are included in that range; or if the variable is defined as an integer between 1 and 4, it means that the variable is an integer 1, 2, 3, or 4.

- 14 043145

When not used in relation to temperatures, the term approximately before the numerical value of X in this application refers to the range that extends from X minus 10% X to X plus 10% X, and preferably to the range that extends from X minus 5 % X to X plus 5% X. In the particular case of temperatures, the term approximately before temperature Y in this application refers to the range that extends from temperature Y minus 10°C to Y plus 10°C, and preferably to an interval that extends from Y minus 5°C to Y plus 5°C. In addition, the term room temperature, as used in this application, refers to a temperature of approximately 25°C.

Additional embodiments of the invention are presented below.

Another embodiment relates to compounds for use according to embodiment 1), where Ar ¹ is a group selected from

- 15 043145

or, in addition, Ar ¹ is a group selected from

- 16 043145

where each of the groups A) and B) forms a separate sub-option of the invention;

where in a further sub-embodiment Ar ¹ in particular means a phenyl group (in particular, a disubstituted phenyl group) or a thiophenyl group, or a thiazolyl group, as defined in groups A) and/or B) above.

- 17 043145

Another embodiment relates to compounds for use according to embodiment 1), where:

(i) Ar ¹ is a phenyl group selected from

(ii) or Ar ¹ is a thiophenyl group selected from

- 18 043145

(iii) or Ar ¹ is a thiazolyl group selected from

(iv) or Ar ¹ is a 9- or 10-membered bicyclic heteroaryl selected from

(v) or Ar ¹ is a group selected from

where in a sub-embodiment, Ar ¹ especially means a phenyl group (in particular, a disubstituted phenyl group) or a thiophenyl group, or a thiazolyl group, as defined herein above.

Another embodiment relates to compounds for use according to embodiment 1), where:

(i) Ar ¹ is a phenyl group selected from

- 19 043145

(ii) or Ar ¹ is a thiophenyl group selected from

(iii) or Ar ¹ is a thiazolyl group selected from

where in a sub-embodiment, Ar ¹ especially means a phenyl group (in particular, a disubstituted phenyl group) or a thiophenyl group, or a thiazolyl group, as defined herein above.

The second embodiment relates to compounds for use according to embodiment 1), where R ³ is hydrogen.

Another embodiment relates to compounds for use according to embodiment 1), where R ³ is methyl.

The third aspect of the invention relates to new compounds of formula (III) ⁿ

Π T ii I n^n (R ¹ ) _n

Formula (III), where in compounds of formula (III) (R1) _n represents one, two or three optional substituents on the phenyl ring (i.e. n represents the integer 0, 1, 2 or 3), where these substituents independently selected from (C _1-3 )alkyl (especially methyl), (C _1-3 )alkoxy (especially methoxy), -S-(C _1-3 )alkyl (especially methylsulfanyl), halogen ( especially fluorine, chlorine or bromine), (C _1-3 )fluoroalkyl (especially trifluoromethyl), (C _1-3 )fluoroalkoxy (especially trifluoromethoxy), cyano, hydroxy, nitro, -COO-(C _{1 -3} ) alkyl (especially methoxycarbonyl), -NR ^N7 R ^N8 where R ^N7 and R ^N8 are independently

- 20 043145 is hydrogen or (C _1-4 )alkyl, or R ^N7 and R ^N8 together with the nitrogen atom to which they are attached, form a 4-6 membered carbocyclic ring (in particular, such a group -NR ^N7 R ⁿ⁸ means methylamino, dimethylamino, pyrrolidin-1-yl);

and Ar ¹ is a phenyl group of structure (Ar-I)

R

(Ar-I) where Rp is

- X1-CO-R ⁰¹ , where

X ¹ is a direct bond, (C _1-3 )alkylene (especially -CH2-, -CH(CH ₃ )-, -C(CH _{3 ) 2} -, -CH2-CH2-), -O-( C ₁ . ₃ ) alkylene-* (especially -O-CH2-*, -O-CH(CH ₃ )-*, -O-C(CH 3 _{) 2} -*, -O-CH2-CH2-* ), -NH-(C ₁ _ ₃ )alkylene-* (especially -NH-CH2-*, -NH-CH(CH ₃ )-*), —CH=CH-, -NH-CO-* or (C _3-5 )cycloalkylene; where the asterisks indicate a bond that is attached to the -CO-RO ¹ group; And

RO ¹ is

-OH;

- O-(C ₁ . ₄ )alkyl (especially ethoxy, methoxy);

- NH-SO2-RS ³ where RS ³ is (C _1-4 )alkyl, (C ₃ - ₆ ) cycloalkyl, where (C ₃ - ₆ ) cycloalkyl optionally contains a ring oxygen atom, (C ₃ . ₆ ) cycloalkyl -( _C1.3 )alkylene, where ( _C3-6 )cycloalkyl optionally contains a ring oxygen atom, ( _C1-3 )fluoroalkyl or -NH2 _;

[wherein, in particular, such a group -X1-CO-RO ¹ represents -COOH, -CO-O-CH3, -CO-OC ₂ H ₅ , -O-CH2-COOH, -O-CH(CH3)- COOH, -O-C (CH3) 2-COOH, -O-CH2-CH2-COOH, -NH-CH2-COOH, -NH-CH2CO-O-CH3, -NH-CH (CH ₃ ) -COOH, - CO-NH-SO2-CH3, -CO-NH-SO ₂ -C (CH ₃ ) ₂ , -CO-NH-SO ₂ -cyclopropyl, -CO-NH-SO ₂ -C ₂ H ₅ , -CO-NH -SO2-NH2, -CH2-COOH, -CH ₂ -CO-O-CH ₃ , -CH ₂ -CO-OC ₂ H ₅ , -CH2-CH2-COOH, -CH=CH-COOH, -NH-CO -COOH, 1-carboxycyclopropan-1-yl];

HET ¹ where HET ¹ is 5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl (including its tautomeric form 5-hydroxy-[1,2,4]oxadiazol-3- yl) or 3-oxo-2,3-dihydro-[1,2,4]oxadiazol-5-yl (including its tautomeric form 3-hydroxy-[1,2,4]oxadiazol-5-yl); or

HET, where HET is a group selected from 1H-tetrazol-5-yl, 3-hydroxyisoxazol5-yl, 2-hydroxy-[1,3,4]oxadiazol-4-yl, 3-aminoisoxazol-5-yl, 2 -aminooxazol-5-yl, 5-amino[1,3,4]thiadiazol-2-yl, 5-methylamino-[1,3,4]thiadiazol-2-yl, 5-amino-[1,2,4 ]oxadiazol-3-yl; in particular HET is 1H-tetrazol-5-yl, 3-hydroxyisoxazol-5-yl or 2-hydroxy-[1,3,4]oxadiazol-4-yl;

R ^m1 is (C1_ ₆ )alkyl (especially methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl);

(C _1-4 )alkoxy (especially methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy);

(C _1-3 )fluoroalkyl (especially trifluoromethyl);

(C _1-3 )fluoroalkoxy (especially difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy);

halogen (especially fluorine or chlorine);

(C ₃ - ₆ )cycloalkyl (especially cyclopropyl);

(C ₃ - ₆ )cycloalkyloxy (especially cyclopropyloxy, cyclobutyloxy, cyclopentyloxy);

hydroxy-(C ₂ - ₄ )alkoxy (especially 2-hydroxyethoxy); or

- S-RS ² where RS ² is (C _1-4 )alkyl (especially methyl, ethyl, n-propyl, isopropyl, isobutyl) or (C ₃ - ₆ )cycloalkyl, optionally containing one ring oxygen atom ( especially cyclobutyl, oxetan-3-yl);

R ^m2 is hydrogen, methyl, fluorine or chlorine and

R ^O1 is hydrogen;

or Ar ¹ is a 5-membered heteroaryl group of structure (Ar-II)

(Ag-P) where Y is CH or N;

R ⁷ is

-X ¹ -CO-R ^O1 , where

X ¹ is a direct bond, (C _1-3 )alkylene (especially -CH2-, -CH(CH ₃ )-, -C(CH _{3 ) 2} -, -CH2-CH2-), -O-( C ₁ . ₃ ) alkylene-* (in particular, -O-CH2-*, -O-CH ( _CH 3 )-*, -O-C (CH ₃ ) ₂ -*, -O-CH2-CH2-* ), -NH-(C ₁ . ₃ )alkylene-* (especially -NH-CH2-*, -NH-CH(CH ₃ )-*), -CH=CH-, -NH-CO-* or (C _3-5 )cycloalkylene; where the asterisks indicate a bond that is attached to the -CO-R ^O1 group; And

R ^O1 is

-OH;

-O-( _C1-4 )alkyl (especially ethoxy, methoxy);

-NH-SO2-RS ³ where RS ³ is (C _1-4 ) alkyl, (C ₃ - ₆ ) cycloalkyl, where (C ₃ - ₆ ) cycloalkyl is optional

- 21 043145 necessarily contains a ring oxygen atom, (C _3-6 )cycloalkyl-(C _1-3 )alkylene, where (C _3-6 )cycloalkyl optionally contains a ring oxygen atom, (C _1-3 )fluoroalkyl or -NH2;

[wherein, in particular, such a group -X1-CO-R ^O1 represents -COOH, -CO-O-CH3, -CO-O-C2H5, -O-CH2-COOH, -O-CH(CH ₃ )- COOH, -OC(CH ₃ ) ₂ -COOH, -O-CH2-CH2-COOH, -NH-CH2-COOH, -NH-CH2CO-O-CH3, -NH-CH(CH ₃ )-COOH, -CO -NH-SO2-CH3, -CO-NH-SO2-C(CH ₃ )2, -CO-NH-SO ₂ -cyclopropyl, -CO-NH-SO2-C2H5, -CO-NH-SO2-NH2, - CH2-COOH, -CH2-CO-O-CH3, -CH2-CO-O-C2H5, -CH2-CH2-COOH, -CH=CH-COOH, -NH-CO-COOH, 1-carboxycyclopropan-1-yl ];

HET ¹ where HET ¹ is 5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl (including its tautomeric form 5-hydroxy-[1,2,4]oxadiazol-3- yl) or 3-oxo-2,3-dihydro-[1,2,4]oxadiazol-5-yl (including its tautomeric form 3-hydroxy-[1,2,4]oxadiazol-5-yl); or

HET, where HET is a group selected from 1H-tetrazol-5-yl, 3-hydroxyisoxazol5-yl, 2-hydroxy-[1,3,4]oxadiazol-4-yl, 3-aminoisoxazol-5-yl, 2 -aminooxazol-5-yl, 5-amino[1,3,4]thiadiazol-2-yl, 5-methylamino-[1,3,4]thiadiazol-2-yl, 5-amino-[1,2,4 ]oxadiazol-3-yl; in particular, HET means 1H-tetrazol-5-yl, 3-hydroxyisoxazol-5-yl or 2-hydroxy-[1,3,4]oxadiazol-4-yl;

R ⁶ is (C _1-6 )alkyl (especially methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl);

(C _1-4 )alkoxy (especially methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy);

(C _1-3 )fluoroalkyl (especially trifluoromethyl);

(C _1-3 )fluoroalkoxy (especially difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy);

halogen (especially fluorine or chlorine);

(C _3-6 )cycloalkyl (especially cyclopropyl);

(C _3-6 )cycloalkyloxy (especially cyclopropyloxy, cyclobutyloxy, cyclopentyloxy);

hydroxy-(C _2-4 )alkoxy (especially 2-hydroxyethoxy); or

-S-RS ² where R ^S2 is (C _1-4 )alkyl (especially methyl, ethyl, n-propyl, isopropyl, isobutyl) or (C _3-6 )cycloalkyl, optionally containing one ring oxygen atom ( especially cyclobutyl, oxetan-3-yl).

Another embodiment relates to compounds for use according to embodiment 1), and to compounds of formula (III) wherein Ar ¹ is a group selected from

- 22 043145 or, in addition, Ar ¹ is a group selected from

where each of the groups A) and B) forms a separate sub-option of the invention.

Another embodiment relates to compounds for use according to embodiment 1), and to compounds of formula (III) wherein (R1)n is one, two or three substituents on the phenyl ring (i.e. n is an integer number 1, 2 or 3), wherein said substituents are independently selected from (C _1-3 )alkyl (especially methyl), (O _1-3 )alkoxy (especially methoxy, ethoxy, n-propoxy), -S -(C _1-3 )alkyl (especially methylsulfanyl), halogen (especially fluorine, chlorine or bromine), (C _1-3 )fluoroalkyl (especially trifluoromethyl), (O _1-3 )fluoroalkoxy (in especially trifluoromethoxy), cyano, hydroxy, nitro, -CO-O-(C _1-3 )alkyl (especially methoxycarbonyl), -NR ^N7 R ^N8 , where R ^N7 and R ^N8 are independently hydrogen or (O _{1 -4} )alkyl, or R ^N7 and R ^N8 together with the nitrogen atom to which they are attached, form a 4-6 membered carbocyclic ring (in particular, such a group -NR ^N7 R ^N8 means methylamino, dimethylamino, pyrrolidin-1-yl ).

Another embodiment relates to compounds for use according to embodiment 1), and to compounds of formula (III) wherein (R1) _n is one, two or three substituents on the phenyl ring (i.e. n is an integer number 1, 2 or 3), wherein said substituents are independently selected from (C _1-3 )alkyl (especially methyl), (O _1-3 )alkoxy (especially methoxy, ethoxy, n-propoxy), -S -(C _1-3 )alkyl (especially methylsulfanyl), halogen (especially fluorine, chlorine or bromine), (C _1-3 )fluoroalkyl (especially trifluoromethyl), (O _1-3 )fluoroalkoxy (in features, trifluoromethoxy), cyano or hydroxy.

Another embodiment relates to compounds for use according to embodiment 1), and to compounds of formula (III), where the moiety

(R ¹ )n is a group selected from the following:

A) phenyl, 4-bromophenyl, 3-bromophenyl, 2-bromophenyl, 4-chlorophenyl, 3chlorophenyl, 2-chlorophenyl, 4-fluorophenyl, 3-fluorophenyl, 2-fluorophenyl, 2methylphenyl, 3-methylphenyl, 4-methylphenyl, 4- hydroxyphenyl, 4-methoxyphenyl, 3-methoxyphenyl, 2-methoxyphenyl, 4-bromo-2-methylphenyl, 4-bromo-3-methylphenyl, 2,4-dimethylphenyl, 3,4-dimethylphenyl, 2,4-dichlorophenyl, 3, 4-dichlorophenyl, 2,6difluorophenyl, 4-bromo-3-chlorophenyl, 4-bromo-2-chlorophenyl, 2-bromo-5-chlorophenyl, 4-bromo-3-fluorophenyl, 4-bromo-2-fluorophenyl, 4- chloro-2,6-difluorophenyl, 3-chloro-2,6-23 043145 difluorophenyl, 2-chloro-3,6-difluorophenyl, 2,4,6-trifluorophenyl, 4-bromo-2,5difluorophenyl, 2,6-difluorophenyl, 4-bromo-2-ethylphenyl, 4-bromo-5-fluoro-2-methylphenyl, 4-bromo-2-fluoro-5-methylphenyl, 3-hydroxy-4-methoxyphenyl, 4hydroxy-3-methoxyphenyl, 3-chloro-4-methoxyphenyl, 4-bromo-3-methoxyphenyl, 3-bromo-4-methoxyphenyl, 2-fluoro-4-methoxyphenyl, 4-bromo-2-methoxyphenyl, 5-bromo2-methoxyphenyl, 2-ethoxyphenyl, 5- chloro-2-cyanophenyl, 4-chloro-2-cyanophenyl, 4fluoro-2-cyanophenyl, 4-chloro-2-methylaminophenyl, 4-trifluoromethylphenyl, 3trifluoromethylphenyl, 2-trifluoromethylphenyl, 2,5-dimethoxyphenyl, 2,3dimethoxyphenyl, 2, 4-dimethoxyphenyl, 3,5-dimethoxyphenyl, 3(methoxycarbonyl)-phenyl, 2-methoxy-5-(methylsulfanyl)-phenyl, 2-methoxy-4(methylsulfanyl)-phenyl, 4-fluoro-2-ethoxyphenyl, 4- bromo-2-ethoxyphenyl, 2-ethyl4-methoxyphenyl, 2-methoxy-4,5-dimethylphenyl, 4-chloro-6-fluoro-2-methoxyphenyl, 4-bromo-6-fluoro-2-methoxyphenyl, 4-dimethylamino- 2-fluorophenyl, 2-dimethylamino4-bromophenyl, 4-chloro-2-nitrophenyl, 2-fluoro-4-trifluoromethylphenyl, 4-bromo-2,6dimethoxyphenyl, 4-bromo-2-n-propoxyphenyl, 4-bromo-2- trifluoromethoxyphenyl, 4-bromo-2-(pyrrolidin-1-yl)phenyl and 2-ethoxy-4-trifluoromethylphenyl;

or, in addition to the groups listed above, said fragment is a group selected from the following:

IN)

3,4-dichloro-2-methylphenyl, 5-bromo-2-methylsulfanylphenyl, 2-fluoro-6methoxyphenyl, 2-methoxy-6-methylphenyl, 2-methoxy-4,6-dimethylphenyl, 4,5difluoro-2-methoxyphenyl, 2,6-difluoro-4-methoxyphenyl, 4-difluoromethoxy-2-methoxyphenyl, 4-difluoromethyl-5-fluoro-2-methoxyphenyl, 2-methoxy-4trifluoromethylphenyl, 4-difluoromethyl-2-methoxy-5-methylphenyl, 2-methoxy- 4-trifluoromethoxyphenyl, 2-fluoro-6-methoxy-4-trifluoromethylphenyl, 5-chloro-2methoxy-4-trifluoromethylphenyl and 2-difluoromethoxy-4-trifluoromethylphenyl;

where each of the groups A) and B) forms a separate sub-option of the invention.

Another embodiment relates to compounds for use according to embodiment 1), and to compounds of formula (III), where the moiety

(R ¹ ) _n is a group selected from the following:

4-bromophenyl, 4-chlorophenyl, 4-methylphenyl, 2,4-dichlorophenyl, 3,4dichlorophenyl, 2,6-difluorophenyl, 4-bromo-3-chlorophenyl, 4-bromo-2-chlorophenyl, 2bromo-5-chlorophenyl, 4-bromo-2-fluorophenyl, 4-chloro-2,6-difluorophenyl, 3-chloro-2,6-difluorophenyl, 2-chloro-3,6-difluorophenyl, 2,4,6-trifluorophenyl, 4-bromo-2, 5difluorophenyl, 4-bromo-2,6-difluorophenyl, 4-bromo-2-fluoro-5-methylphenyl, 4hydroxy-3-methoxyphenyl, 4-bromo-3-methoxyphenyl, 2-fluoro-4-methoxyphenyl, 4bromo-2- methoxyphenyl, 5-bromo-2-methoxyphenyl, 2,5-dimethoxyphenyl, 2,3-dimethoxyphenyl, 2,4-dimethoxyphenyl, 2-methoxy-4-(methylsulfanyl)-phenyl, 4-bromo-2-ethoxyphenyl, 2-ethyl-4- methoxyphenyl, 2-methoxy-4,5-dimethylphenyl, 4-chloro-6-fluoro-2-methoxyphenyl, 4-bromo-2,6-dimethoxyphenyl, 4-bromo-2-n-propoxyphenyl and 2-ethoxy-4-trifluoromethylphenyl.

Another embodiment relates to compounds of formula (II) as defined in embodiment 1), for use in accordance with embodiment 1), which are selected from the following compounds:

5-{6-[2-(4-Bromo-2,6-difluorophenyl)-ethylamino]-pyrimidin-4-yl}-thiophene-2-carboxylic acid;

2-(5-{6-[2-(4-Bromophenyl)-ethylamino]-pyrimidin-4-yl}-thiophen-2-yl)-acetamide;

2-(5-{6-[2-(4-Bromophenyl)-ethylamino]-pyrimidin-4-yl}-thiophen-2-yl)-propionic acid;

3-(5-{6-[2-(4-Bromo-2,6-difluorophenyl)-ethylamino]-pyrimidin-4-yl}-thiophen2-yl)-[1,2,4]oxadiazol-5(4Н )-one [tautomeric form: 3-(5-{6-[2-(4-bromo-2,6difluorophenyl)-ethylamino]-pyrimidin-4-yl}-thiophen-2-yl)-[1,2, 4]oxadiazol-5ol].

In addition to the compounds listed above, further compounds of formula (II) as defined in Embodiment 1) for use in accordance with Embodiment 1) are selected from the following compounds:

3-(4-{6-[2-(4-Bromo-2,6-difluorophenyl)-ethylamino]-pyrimidin-4-yl}-1-ethyl1H-pyrrol-2-yl)-[1,2,4 ]oxadiazol-5(4H)-one [tautomeric form: 3-(4-{6-[2-(4bromo-2,6-difluorophenyl)-ethylamino]-pyrimidin-4-yl}-1-ethyl-1H- pyrrol-2-yl)[1,2,4]oxadiazol-5-ol];

- 24 043145

3-(4-{6-[2-(4-Bromo-2,6-difluorophenyl)-ethylamino]-pyrimidin-4-yl}-3methoxyphenyl)-[1,2,4]oxadiazol-5(4H)- he [tautomeric form: 3-(4-{6-[2-(4bromo-2,6-difluorophenyl)-ethylamino]-pyrimidin-4-yl}-3-methoxyphenyl)[1,2,4]oxadiazol-5 -ol];

5-{6-[2-(4-Bromo-2,6-difluorophenyl)-ethylamino]-pyrimidin-4-yl}-3-ethoxy1H-pyrrole-2-carboxylic acid;

5-{6-[2-(4-Bromo-2,6-difluorophenyl)-ethylamino]-pyrimidin-4-yl}-3-cyclopropyl-1H-pyrrole-2-carboxylic acid; And

3-(5-{6-[2-(4-Bromo-2,6-difluorophenyl)-ethylamino]-pyrimidin-4-yl}pyridin-2-yl)-[1,2,4]oxadiazol-5( 4H)-one [tautomeric form: 3-(5-{6-[2-(4bromo-2,6-difluorophenyl)-ethylamino]-pyrimidin-4-yl}-pyridin-2-yl)[1,2, 4]oxadiazol-5-ol].

Another embodiment relates to compounds of formula (II) which are selected from the following compounds:

2-{6-[2-(4-Bromo-2,6-difluorophenyl)-ethylamino]-pyrimidin-4-yl}-1H-indole4-carboxylic acid;

3-(5-{6-[2-(4-Bromophenyl)-ethylamino]-pyrimidin-4-yl}-3-ethoxythiophen-2yl)-[1,2,4]oxadiazol-5(4H)-thione [ tautomeric form: 3-(5-(6-((4bromophenethyl)amino)pyrimidin-4-yl)-3-ethoxythiophen-2-yl)-[1,2,4]oxadiazol-5thiol].

In addition to compounds, further compounds of formula (II) according to embodiment 4) are selected from the following compounds:

2-{6-[2-(4-Bromo-2,6-difluorophenyl)-ethylamino]-pyrimidin-4-yl}-1H-indole 5-carboxylic acid;

4-{6-[2-(4-Bromo-2,6-difluorophenyl)-ethylamino]-pyrimidin-4-yl}-2-methylaminobenzamide;

4-{6-[2-(4-Bromo-2,6-difluorophenyl)-ethylamino]-pyrimidin-4-yl}-2-ethylaminobenzamide;

4-{6-[2-(4-Bromo-2,6-difluorophenyl)-ethylamino]-pyrimidin-4-yl}-2-methylaminobenzoic acid;

3-(4-{6-[2-(4-Bromo-2,6-difluorophenyl)-ethylamino]-pyrimidin-4-yl}-phenyl)[1,2,4]oxadiazol-5(4H)-one [tautomeric form: 3-(4-{6-[2-(4-Bromo-2,6difluorophenyl)-ethylamino]-pyrimidin-4-yl}-phenyl)-[1,2,4]oxadiazol-5-ol ];

- 25 043145

N-(4-{6-[2-(4-Bromo-2,6-diφτopφenyl)-ethylamino]-pyrimidin-4-yl}-2ethoxyphenyl)-formamide;

3-(4-{6-[2-(4-Bromo-2,6-difluorophenyl)-ethylamino]-pyrimidin-4-yl}-phenyl)4-hydroxycyclobut-3-eu-1,2-dione;

4-{6-[2-(4-Bromo-2,6-difluorophenyl)-ethylamino]-pyrimidin-4-yl}-2,6-dimethylphenol;

[2-(4-Bromo-2,6-difluorophenyl)-ethyl]-[6-(1H-indol-5-yl)-pyrimidin-4-yl]amine;

7-{6-[2-(4-Bromo-2,6-difluorophenyl)-ethylamino]-pyrimidin-4-yl}-1-methyl3,4-dihydro-1H-quinazolin-2-one;

2-{6-[2-(4-Bromo-2,6-difluorophenyl)-ethylamino]-pyrimidin-4-yl}-1H-indole7-carboxylic acid;

[2-(4-Bromo-2,6-difluorophenyl)-ethyl]-[6-(1H-indazol-5-yl)-pyrimidin-4-yl]amine;

4-{6-[2-(4-Bromo-2,6-difluorophenyl)-ethylamino]-pyrimidin-4-yl}^-(2hydroxyethyl)-2-methylaminobenzamide;

4-{6-[2-(4-Bromo-2,6-difluorophenyl)-ethylamino]-pyrimidin-4-yl}-N-(2-methoxyethyl)-2-methylaminobenzamide;

5-{6-[2-(4-Bromo-2,6-difluorophenyl)-ethylamino]-pyrimidin-4-yl}-3-ethoxythiophene-2-carboxylic acid amide;

5-{6-[2-(4-Bromo-2,6-difluorophenyl)-ethylamino]-pyrimidin-4-yl}-3-ethylthiophene-2-carboxylic acid amide;

3-(4-{6-[2-(4-Bromo-2,6-difluorophenyl)-ethylamino]-pyrimidin-4-yl}-2ethoxybenzyl)-[1,2,4]oxadiazol-5(4H)- he [tautomeric form: 3-(4-{6-[2-(4bromo-2,6-difluorophenyl)-ethylamino]-pyrimidin-4-yl}-2-ethoxybenzyl)[1,2,4]oxadiazol-5 -ol];

3-(4-{6-[2-(4-Bromo-2,6-difluorophenyl)-ethylamino]-pyrimidin-4-yl}-2ethoxyphenyl)-[1,2,4]oxadiazol-5(4H)- thione [tautomeric form: 3-(4-{6-[2-(4bromo-2,6-difluorophenyl)-ethylamino]-pyrimidin-4-yl}-2-ethoxyphenyl)[1,2,4]oxadiazol-5 -thiol];

5-{6-[2-(4-Bromo-2,6-difluorophenyl)-ethylamino]-pyrimidin-4-yl}-4chloro-3-ethoxythiophene-2-carboxylic acid amide;

1-(5-{6-[2-(4-Bromo-2,6-difluorophenyl)-ethylamino]-pyrimidin-4-yl}-3ethoxythiophen-2-yl)-1,4-dihydro-tetrazol-5- he [tautomeric form: 1-(5-(6-((4bromo-2,6-difluorophenethyl)amino)pyrimidin-4-yl)-3-ethoxythiophen-2-yl)-1Htetrazol-5-ol];

3-(5-{6-[2-(4-Bromo-2,6-difluorophenyl)-ethylamino]-pyrimidin-4-yl}-3ethoxythiophen-2-yl)-[1,2,4]oxadiazol-5 (4H)-thione [tautomeric form: 3-(5-{6[2-(4-bromo-2,6-difluorophenyl)-ethylamino]-pyrimidin-4-yl}-3-ethoxythiophen-2yl)-[1 ,2,4]oxadiazole-5-thiol];

3-(4-{6-[2-(4-Bromo-2,6-difluorophenyl)-ethylamino]-pyrimidin-4-yl}-2methylaminophenyl)-[1,2,4]oxadiazol-5(4H)- it [tautomeric form: 3-(4-{6-[2(4-bromo-2,6-difluorophenyl)-ethylamino]-pyrimidin-4-yl}-2-methylaminophenyl)[1,2,4]oxadiazol- 5-ol];

4-{6-[2-(4-Bromo-2,6-difluorophenyl)-ethylamino]-pyrimidin-4-yl}-2-propylbenzamide;

4-[6-[2-(4-Bromo-2,6-difluorophenyl (-ethylamino]-pyrimide in-4-yl}-N-(2hydroxy-2-methylpropyl)-2-propylbenzamide;

2-{6-[2-(4-Bromo-2,6-difluorophenyl)-ethylamino]-pyrimidin-4-yl}-1H-indole6-carboxylic acid;

6-{6-[2-(4-Bromo-2,6-difluorophenyl)-ethylamino]-pyrimidin-4-yl}-3H-benzooxazol-2-one;

4-{6-[2-(4-Bromo-2,6-difluorophenyl)-ethylamino]-pyrimidin-4-yl}-3-methoxybenzamide;

4-{6-[2-(4-Bromo-2,6-difluorophenyl)-ethylamino]-pyrimidin-4-yl}-2ethoxybenzamide; And

4-{6-[2-(4-Bromo-2,6-difluorophenyl)-ethylamino]-pyrimidin-4-yl}-T\T-(2hydroxyethyl)-2-propylbenzamide.

- 26 043145

Another embodiment relates to compounds of formula (III) which are selected from the following compounds:

3-Fluoro-5-[6-(2-p-tolylethylamino)-pyrimidin-4-yl]-thiophene-2-carboxylic acid;

4-{6-[2-(2-Methoxy-4-methylsulfanylphenyl)-ethylamino]-pyrimidin-4yl}-2-methylsulfanylbenzoic acid;

4-{6-[2-(2-Methoxy-4,5-dimethylphenyl)-ethylamino]-pyrimidin-4-yl}-2-methylsulfanylbenzoic acid;

-Ethoxy-5-{6-[2-(2-methoxy-4-methylsulfanylphenyl)-ethylamino]pyrimidin-4-yl}-thiophene-2-carboxylic acid;

3-Ethoxy-5-{6-[2-(2-methoxy-4,5-dimethylphenyl)-ethylamino]-pyrimidin-4yl}-thiophene-2-carboxylic acid;

2-Ethoxy-4-{6-[2-(2-methoxy-4,5-dimethylphenyl)-ethylamino]-pyrimidin-4yl}-benzoic acid;

3-(4-{6-[2-(4-Bromophenyl)-ethylamino]-pyrimidin-4-yl}-2-ethoxyphenyl)[1,2,4]oxadiazol-5(4H)-one [tautomeric form: 3-(4-(6-((4bromophenethyl)amino)pyrimidin-4-yl)-2-ethoxyphenyl)-[1,2,4]oxadiazol-5-ol];

4-{6-[2-(3,4-Dimethylphenyl)-ethylamino]-pyrimidin-4-yl}-2-methylsulfanylbenzoic acid;

4-{6-[2-(4-Bromo-2-fluorophenyl)-ethylamino]-pyrimidin-4-yl}-2-ethoxy-benzoic acid;

[2-(4-Bromo-2,6-difluorophenyl)-ethyl]-{6-[3-ethoxy-4-(1H-tetrazol-5-yl)phenyl]-pyrimidin-4-yl}-amine;

X-(4-{6-[2-(4-Bromo-2,6-difluorophenyl)-ethylamino]-pyrimidin-4-yl}-2ethoxyphenyl)-oxalamic acid;

5-{6-[2-(4-Bromo-2,6-difluorophenyl)-ethylamino]-pyrimidin-4-yl}-4-chloro-3ethoxythiophene-2-carboxylic acid;

5-{6-[2-(4-Bromo-2,6-difluorophenyl)-ethylamino]-pyrimidin-4-yl}-3-methylthiophene-2-carboxylic acid;

5-{6-[2-(4-Bromo-2,6-difluorophenyl)-ethylamino]-pyrimidin-4-yl}-3-ethylthiophene-2-carboxylic acid;

5-{6-[2-(4-Bromo-2,6-difluorophenyl)-ethylamino]-pyrimidin-4-yl}-3-chlorothiophene-2-carboxylic acid;

5-{6-[2-(4-Bromo-2,6-difluorophenyl)-ethylamino]-pyrimidin-4-yl}-3-(2hydroxyethoxy)-thiophene-2-carboxylic acid;

4-{6-[2-(4-Bromo-2,6-difluorophenyl)-ethylamino]-pyrimidin-4-yl}-2-methylsulfanylbenzoic acid;

4-{6-[2-(4-Bromo-2,6-difluorophenyl)-ethylamino]-pyrimidin-4-yl}-2isobutylbenzoic acid;

4-{6-[2-(4-Bromo-2,6-difluorophenyl)-ethylamino]-pyrimidin-4-yl}-2-difluoromethoxybenzoic acid;

3-(5-{6-[2-(4-Bromo-2,6-difluorophenyl)-ethylamino]-pyrimidin-4-yl}-3ethoxythiophen-2-yl)-propionic acid;

- 27 043145

3-(4-{6-[2-(4-Bromo-2,6-difluorophenyl)-ethylamino]-pyrimidin-4-yl}-2ethoxyphenoxy)-propionic acid;

/E/-3-(5-{6-[2-(4-Bromo-2,6-difluorophenyl)-ethylamino]-pyrimidin-4-yl}-3ethoxythiophen-2-yl)-acrylic acid;

(5-{6-[2-(4-Bromo-2,6-difluorophenyl)-ethylamino]-pyrimidin-4-yl}-3ethoxythiophen-2-yl)-acetic acid;

(4-{6-[2-(4-Bromo-2,6-difluorophenyl)-ethylamino]-pyrimidin-4-yl}-2ethoxyphenyl)-acetic acid;

5-{6-[2-(4-Bromophenyl)-ethylamino]-pyrimidin-4-yl}-3-ethoxythiophene-2-carboxylic acid;

-Ethoxy-5-{6-[2-(4-trifluoromethylphenyl)-ethylamino]-pyrimidin-4-yl}-thiophene-2-carboxylic acid;

-Ethoxy-5-{6-[2-(3-methoxyphenyl)-ethylamino]-pyrimidin-4-yl}-thiophene2-carboxylic acid;

5-[6-(2-i-Tolylethylamino)pyrimidin-4-yl]-3-trifluoromethylthiophene-2carboxylic acid;

5-{6-[2-(4-Chloro-2-nitrophenyl)-ethylamino]-pyrimidin-4-yl}-3-ethoxythiophene-2-carboxylic acid;

5-{6-[2-(2,4-Dichlorophenyl)-ethylamino]-pyrimidin-4-yl}-3-ethoxythiophene 2-carboxylic acid;

5-{6-[2-(3,4-Dimethylphenyl)-ethylamino]-pyrimidin-4-yl}-3-ethoxythiophene 2-carboxylic acid;

5-{6-[2-(5-Bromo-2-methoxyphenyl)-ethylamino]-pyrimidin-4-yl}-3-ethoxythiophene-2-carboxylic acid;

5-{6-[2-(2,5-Dimethoxyphenyl)-ethylamino]-pyrimidin-4-yl}-3-ethoxythiophene-2-carboxylic acid;

5-{6-[2-(2,4-Dimethoxyphenyl)-ethylamino]-pyrimidin-4-yl}-3-ethoxythiophene-2-carboxylic acid;

5-{6-[2-(4-Chlorophenyl)-ethylamino]-pyrimidin-4-yl}-3-ethoxythiophene-2-carboxylic acid;

3-(5-{6-[2-(4-Bromo-2-ethoxyphenyl)-ethylamino]-pyrimidin-4-yl}-3ethoxythiophen-2-yl)-[1,2,4]oxadiazol-5(4Н )-one [tautomeric form: 3-(5-{6-[2(4-bromo-2-ethoxyphenyl)-ethylamino]-pyrimidin-4-yl}-3-ethoxythiophen-2-yl)[1,2, 4]oxadiazol-5-ol];

- 28 043145

3-(5-{6-[2-(4-Chloro-2-fluoro-6-methoxyphenyl)-ethylamino]-pyrimidin-4-yl}3-ethoxythiophen-2-yl)-[1,2,4] oxadiazol-5(4H)-one [tautomeric form: 3-(5-{6[2-(4-chloro-2-fluoro-6-methoxyphenyl)-ethylamino]-pyrimidin-4-yl}-3ethoxythiophen-2- yl)-[1,2,4]oxadiazol-5-ol];

3-(5-{6-[2-(4-Bromo-2-fluoro-6-methoxyphenyl)-ethylamino]-pyrimidin-4-yl}3-ethoxythiophen-2-yl)-[1,2,4] oxadiazol-5(4H)-one [tautomeric form: 3-(5-{6[2-(4-bromo-2-fluoro-6-methoxyphenyl)-ethylamino]-pyrimidin-4-yl}-3ethoxythiophen-2- yl)-[1,2,4]oxadiazol-5-ol];

3-(5-{6-[2-(4-Bromo-2,6-dimethoxyphenyl)-ethylamino]-pyrimidin-4-yl}-3ethoxythiophen-2-yl)-[1,2,4]oxadiazol-5 (4H)-one [tautomeric form: 3-(5-{6-[2(4-bromo-2,6-dimethoxyphenyl)-ethylamino]-pyrimidin-4-yl}-3-ethoxythiophen-2yl)-[1 ,2,4]oxadiazol-5-ol];

3-(5-{6-[2-(4-Bromo-2-propoxyphenyl)-ethylamino]-pyrimidin-4-yl}-3ethoxythiophen-2-yl)-[1,2,4]oxadiazol-5(4Н )-one [tautomeric form: 3-(5-{6-[2(4-bromo-2-propoxyphenyl)-ethylamino]-pyrimidin-4-yl}-3-ethoxythiophen-2-yl)[1,2, 4]oxadiazol-5-ol];

3-(3-Ethoxy-5-{6-[2-(2-ethoxy-4-trifluoromethylphenyl)-ethylamino]pyrimidin-4-yl}-thiophen-2-yl)-[1,2,4]oxadiazol- 5(4H)-one [tautomeric form: 3-(3-ethoxy-5-{6-[2-(2-ethoxy-4-trifluoromethylphenyl)-ethylamino]-pyrimidin-4yl}-thiophen-2-yl)- [1,2,4]oxadiazol-5-ol];

3-(3-Ethoxy-5-{6-[2-(2-fluoro-4-methoxyphenyl)-ethylamino]-pyrimidin-4yl}-thiophen-2-yl)-[1,2,4]oxadiazol-5 (4H)-one [tautomeric form: 3-(3-ethoxy-5{6-[2-(2-fluoro-4-methoxyphenyl)-ethylamino]-pyrimidin-4-yl}-thiophen-2-yl)[ 1,2,4]oxadiazol-5-ol];

3-(5-{6-[2-(2-Bromo-5-chlorophenyl)-ethylamino]-pyrimidin-4-yl}-3ethoxythiophen-2-yl)-[1,2,4]oxadiazol-5(4Н )-one [tautomeric form: 3-(5-{6-[2(2-bromo-5-chlorophenyl)-ethylamino]-pyrimidin-4-yl}-3-ethoxythiophen-2-yl)[1,2, 4]oxadiazol-5-ol];

3-(3-Ethoxy-5-{6-[2-(2-ethoxy-4-fluorophenyl)-ethylamino]-pyrimidin-4-yl}thiophen-2-yl)-[1,2,4]oxadiazol- 5(4H)-one [tautomeric form: 3-(3-ethoxy-5-{6[2-(2-ethoxy-4-fluorophenyl)-ethylamino]-pyrimidin-4-yl}-thiophen-2-yl) [1,2,4]oxadiazol-5-ol];

5-Chloro-2-(2-((6-(4-ethoxy-5-(5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3yl)thiophen-2-yl)pyrimidin- 4-yl)amino)ethyl)benzonitrile [tautomeric form:

- 29 043145

5-chloro-2-(2-{6-[4-ethoxy-5-(5-hydroxy-[1,2,4]oxadiazol-3-yl)-thiophen-2-yl]pyrimidin-4-ylamino} -ethyl)-benzonitrile];

2-(2-((6-(4-Ethoxy-5-(5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl)thiophen-2yl)pyrimidin-4-yl) amino)ethyl)-5-fluorobenzonitrile [tautomeric form: 2-(2{6-[4-ethoxy-5-(5-hydroxy-[1,2,4]oxadiazol-3-yl)-thiophen-2-yl ]-pyrimidin-4ylamino}-ethyl)-5-fluorobenzonitrile];

3-(5-{6-[2-(3-Chloro-2,6-difluorophenyl)-ethylamino]-pyrimidin-4-yl}-3ethoxythiophen-2-yl)-[1,2,4]oxadiazol-5 (4H)-one [tautomeric form: 3-(5-{6-[2(3-chloro-2,6-difluorophenyl)-ethylamino]-pyrimidin-4-yl}-3-ethoxythiophen-2-yl)[ 1,2,4]oxadiazol-5-ol];

3-(3-Ethoxy-5-{6-[2-(2-ethyl-4-methoxyphenyl)-ethylamino]-pyrimidin-4yl}-thiophen-2-yl)-[1,2,4]oxadiazol-5 (4H)-one [tautomeric form: 3-(3-ethoxy-5{6-[2-(2-ethyl-4-methoxyphenyl)-ethylamino]-pyrimidin-4-yl}-thiophen-2-yl)[ 1,2,4]oxadiazol-5-ol];

3-(5-{6-[2-(2-Chloro-3,6-difluorophenyl)-ethylamino]-pyrimidin-4-yl}-3ethoxythiophen-2-yl)-[1,2,4]oxadiazol-5 (4H)-one [tautomeric form: 3-(5-{6-[2(2-chloro-3,6-difluorophenyl)-ethylamino]-pyrimidin-4-yl}-3-ethoxythiophen-2-yl)[ 1,2,4]oxadiazol-5-ol];

3-(3-Ethoxy-5-{6-[2-(2,4,6-trifluorophenyl)-ethylamino]-pyrimidin-4-yl}thiophen-2-yl)-[1,2,4]oxadiazol- 5(4H)-one [tautomeric form: 3-(3-ethoxy-5-{6[2-(2,4,6-trifluorophenyl)-ethylamino]-pyrimidin-4-yl}-thiophen-2-yl) [1,2,4]oxadiazol-5-ol];

3-(3-Ethoxy-5-{6-[2-(2-ethoxyphenyl)-ethylamino]-pyrimidin-4-yl}-thiophen2-yl)-[1,2,4]oxadiazole-5(4Н)- he [tautomeric form: 3-(3-ethoxy-5-{6-[2-(2ethoxyphenyl)-ethylamino]-pyrimidin-4-yl}-thiophen-2-yl)-[1,2,4]oxadiazol- 5ol];

3-(5-{6-[2-(2,6-Difluorophenyl)-ethylamino]-pyrimidin-4-yl}-3ethoxythiophen-2-yl)-[1,2,4]oxadiazol-5(4H)- he [tautomeric form: 3-(5-{6-[2(2,6-difluorophenyl)-ethylamino]-pyrimidin-4-yl}-3-ethoxythiophen-2-yl)[1,2,4]oxadiazol- 5-ol];

3-(5-{6-[2-(4-Chloro-2,6-difluorophenyl)-ethylamino]-pyrimidin-4-yl}-3ethoxythiophen-2-yl)-[1,2,4]oxadiazol-5 (4H)-one [tautomeric form: 3-(5-{6-[2(4-chloro-2,6-difluorophenyl)-ethylamino]-pyrimidin-4-yl}-3-ethoxythiophen-2-yl)[ 1,2,4]oxadiazol-5-ol];

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3-(5-{6-[2-(4-Bromo-3-chlorophenyl)-ethylamino]-pyrimidin-4-yl}-3ethoxythiophen-2-yl)-[1,2,4]oxadiazol-5(4Н )-one [tautomeric form: 3-(5-{6-[2(4-bromo-3-chlorophenyl)-ethylamino]-pyrimidin-4-yl}-3-ethoxythiophen-2-yl)[1,2, 4]oxadiazol-5-ol];

3-(5-{6-[2-(4-Bromo-2,5-difluorophenyl)-ethylamino]-pyrimidin-4-yl}-3ethoxythiophen-2-yl)-[1,2,4]oxadiazol-5 (4H)-one [tautomeric form: 3-(5-{6-[2(4-bromo-2,5-difluorophenyl)-ethylamino]-pyrimidin-4-yl}-3-ethoxythiophen-2-yl)[ 1,2,4]oxadiazol-5-ol];

3-(5-{6-[2-(4-Bromo-3-fluorophenyl)-ethylamino]-pyrimidin-4-yl}-3ethoxythiophen-2-yl)-[1,2,4]oxadiazol-5(4Н )-one [tautomeric form: 3-(5-{6-[2(4-bromo-3-fluorophenyl)-ethylamino]-pyrimidin-4-yl}-3-ethoxythiophen-2-yl)[1,2, 4]oxadiazol-5-ol];

3-(5-{6-[2-(4-Bromo-2,6-difluorophenyl)-ethylamino]-pyrimidin-4-yl}-3ethoxythiophen-2-yl)-[1,2,4]oxadiazol-5 (4H)-one [tautomeric form: 3-(5-{6-[2(4-bromo-2,6-difluorophenyl)-ethylamino]-pyrimidin-4-yl}-3-ethoxythiophen-2-yl)[ 1,2,4]oxadiazol-5-ol];

3-(5-{6-[2-(4-Bromo-5-fluoro-2-methylphenyl)-ethylamino]-pyrimidin-4-yl}-3ethoxythiophen-2-yl)-[1,2,4]oxadiazole -5(4H)-one [tautomeric form: 3-(5-{6-[2(4-bromo-5-fluoro-2-methylphenyl)-ethylamino]-pyrimidin-4-yl}-3-ethoxythiophen-2yl )-[1,2,4]oxadiazol-5-ol];

3-(5-{6-[2-(4-Bromo-3-methylphenyl)-ethylamino]-pyrimidin-4-yl}-3ethoxythiophen-2-yl)-[1,2,4]oxadiazol-5(4Н )-one [tautomeric form: 3-(5-{6-[2(4-bromo-3-methylphenyl)-ethylamino]-pyrimidin-4-yl}-3-ethoxythiophen-2-yl)[1,2, 4]oxadiazol-5-ol];

3-(5-{6-[2-(4-Bromo-2-fluoro-5-methylphenyl)-ethylamino]-pyrimidin-4-yl}-3ethoxythiophen-2-yl)-[1,2,4]oxadiazole -5(4H)-one [tautomeric form: 3-(5-{6-[2(4-bromo-2-fluoro-5-methylphenyl)-ethylamino]-pyrimidin-4-yl}-3-ethoxythiophen-2yl )-[1,2,4]oxadiazol-5-ol];

3-(5-{6-[2-(4-Bromo-3-methoxyphenyl)-ethylamino]-pyrimidin-4-yl}-3ethoxythiophen-2-yl)-[1,2,4]oxadiazol-5(4Н )-one [tautomeric form: 3-(5-{6-[2(4-bromo-3-methoxyphenyl)-ethylamino]-pyrimidin-4-yl}-3-ethoxythiophen-2-yl)[1,2, 4]oxadiazol-5-ol];

3-(5-{6-[2-(2,4-Dimethoxyphenyl)-ethylamino]-pyrimidin-4-yl}-3ethoxythiophen-2-yl)-[1,2,4]oxadiazol-5(4Н)- he [tautomeric form: 3-(5-{6-[2-31 043145 (2,4-dimethoxyphenyl)-ethylamino]-pyrimidin-4-yl}-3-ethoxythiophen-2-yl)[1,2,4 ]oxadiazol-5-ol];

3-(3-Ethoxy-5-{6-[2-(4-hydroxy-3-methoxyphenyl)-ethylamino]-pyrimidin4-yl}-thiophen-2-yl)-[1,2,4]oxadiazol-5 (4H)-one [tautomeric form: 3-(3-ethoxy 5-{6-[2-(4-hydroxy-3-methoxyphenyl)-ethylamino]-pyrimidin-4-yl}-thiophen-2yl)-[ 1,2,4]oxadiazol-5-ol];

3-(5-{6-[2-(2,3-Dimethoxyphenyl)-ethylamino]-pyrimidin-4-yl}-3ethoxythiophen-2-yl)-[1,2,4]oxadiazol-5(4H)- it [tautomeric form: 3-(5-{6-[2(2,3-dimethoxyphenyl)-ethylamino]-pyrimidin-4-yl}-3-ethoxythiophen-2-yl)[1,2,4]oxadiazol- 5-ol];

3-(5-{6-[2-(5-Bromo-2-methoxyphenyl)-ethylamino]-pyrimidin-4-yl}-3ethoxythiophen-2-yl)-[1,2,4]oxadiazol-5(4Н )-one [tautomeric form: 3-(5-{6-[2(5-bromo-2-methoxyphenyl)-ethylamino]-pyrimidin-4-yl}-3-ethoxythiophen-2-yl)[1,2, 4]oxadiazol-5-ol];

3-(5-{6-[2-(3,4-Dichlorophenyl)-ethylamino]-pyrimidin-4-yl}-3ethoxythiophen-2-yl)-[1,2,4]oxadiazol-5(4H)- it [tautomeric form: 3-(5-{6-[2(3,4-dichlorophenyl)-ethylamino]-pyrimidin-4-yl}-3-ethoxythiophen-2-yl)[1,2,4]oxadiazol- 5-ol];

3-(5-{6-[2-(2,4-Dichlorophenyl)-ethylamino]-pyrimidin-4-yl}-3ethoxythiophen-2-yl)-[1,2,4]oxadiazol-5(4H)- it [tautomeric form: 3-(5-{6-[2(2,4-dichlorophenyl)-ethylamino]-pyrimidin-4-yl}-3-ethoxythiophen-2-yl)[1,2,4]oxadiazol- 5-ol];

3-(5-{6-[2-(4-Bromo-2-chlorophenyl)-ethylamino]-pyrimidin-4-yl}-3ethoxythiophen-2-yl)-[1,2,4]oxadiazol-5(4Н )-one [tautomeric form: 3-(5-{6-[2(4-bromo-2-chlorophenyl)-ethylamino]-pyrimidin-4-yl}-3-ethoxythiophen-2-yl)[1,2, 4]oxadiazol-5-ol];

3-(5-{6-[2-(4-Bromo-2-fluorophenyl)-ethylamino]-pyrimidin-4-yl}-3ethoxythiophen-2-yl)-[1,2,4]oxadiazol-5(4Н )-one [tautomeric form: 3-(5-{6-[2(4-bromo-2-fluorophenyl)-ethylamino]-pyrimidin-4-yl}-3-ethoxythiophen-2-yl)[1,2, 4]oxadiazol-5-ol];

3-(5-{6-[2-(4-Bromo-2-methoxyphenyl)-ethylamino]-pyrimidin-4-yl}-3ethoxythiophen-2-yl)-[1,2,4]oxadiazol-5(4Н )-one [tautomeric form: 3-(5-{6-[2(4-bromo-2-methoxyphenyl)-ethylamino]-pyrimidin-4-yl}-3-ethoxythiophen-2-yl)[1,2, 4]oxadiazol-5-ol];

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3-(5-{6-[2-(4-Bromo-2-methylphenyl)-ethylamino]-pyrimidin-4-yl}-3ethoxythiophen-2-yl)-[1,2,4]oxadiazol-5(4Н )-one [tautomeric form: 3-(5-{6-[2(4-bromo-2-methylphenyl)-ethylamino]-pyrimidin-4-yl}-3-ethoxythiophen-2-yl)[1,2, 4]oxadiazol-5-ol];

3-(5-{6-[2-(4-Bromophenyl)-ethylamino]-pyrimidin-4-yl}-3-ethoxythiophen-2yl)-[1,2,4]oxadiazol-5(4H)-one [ tautomeric form: 3-(5-{6-[2-(4-bromophenyl)ethylamino]pyrimidin-4-yl}-3-ethoxythiophen-2-yl)-[1,2,4]oxadiazol-5-ol ];

[2-(4-Bromophenyl)-ethyl]-{6-[4-ethoxy-5-(1H-tetr-azol-5-yl)thiophen-2-yl]pyrimidin-4-yl}-amine;

3-(5-{6-[2-(4-Bromo-2,6-difluorophenyl)-ethylamino]-pyrimidin-4-yl}-3trifluoromethylthiophen-2-yl)-[1,2,4]oxadiazol-5 (4H)-one [tautomeric form: 3(5-{6-[2-(4-bromo-2,6-difluorophenyl)-ethylamino]-pyrimidin-4-yl}-3trifluoromethylthiophen-2-yl)-[1 ,2,4]oxadiazol-5-ol];

3-(5-{6-[2-(4-Bromo-2,6-difluorophenyl)-ethylamino]-pyrimidin-4-yl}-3methylthiophen-2-yl)-[1,2,4]oxadiazol-5 (4H)-one [tautomeric form: 3-(5-{6-[2(4-bromo-2,6-difluorophenyl)-ethylamino]-pyrimidin-4-yl}-3-methylthiophen-2-yl)[ 1,2,4]oxadiazol-5-ol];

2-{6-[2-(4-Bromo-2,6-difluorophenyl)-ethylamino]-pyrimidin-4-yl}-4-ethoxythiazole-5-carboxylic acid;

2-{6-[2-(4-Bromo-2,6-difluorophenyl)-ethylamino]-pyrimidin-4-yl}-4-ethylthiazole-5-carboxylic acid;

3-(2-{6-[2-(4-Bromo-2,6-difluorophenyl)-ethylamino]-pyrimidin-4-yl}-4ethoxythiazol-5-yl)-[1,2,4]oxadiazol-5 (4H)-one [tautomeric form: 3-(2-{6-[2(4-Bromo-2,6-difluorophenyl)-ethylamino]-pyrimidin-4-yl}-4-ethoxythiazol-5-yl)[ 1,2,4]oxadiazol-5-ol];

3-(2-{6-[2-(4-Bromo-2,6-difluorophenyl)-ethylamino]-pyrimidin-4-yl}-4ethylthiazol-5-yl)-[1,2,4]oxadiazol-5 (4H)-one [tautomeric form: 3-(2-{6-[2-(4bromo-2,6-difluorophenyl)-ethylamino]-pyrimidin-4-yl}-4-ethylthiazol-5-yl)[1 ,2,4]oxadiazol-5-ol];

5-(5-{6-[2-(4-Bromo-2,6-difluorophenyl)-ethylamino]-pyrimidin-4-yl}-3ethoxythiophen-2-yl)-[1,3,4]oxadiazol-2 -ol [tautomeric form: 5-(5-{6-[2-(4bromo-2,6-difluorophenyl)-ethylamino]-pyrimidin-4-yl}-3-ethoxythiophen-2-yl)[1,3, 4]-oxadiazol-2(3H)-one];

X-(5-{6-[2-(4-Bromo-2,6-difluorophenyl)-ethylamino]-pyrimidin-4-yl}-3ethoxythiophen-2-carbonyl)-methanesulfonamide;

5-(6-((4-Bromo-2,6-difluorophenethyl)amino)pyrimidin-4-yl)-3-ethoxy-Msulfamoylthiophene-2-carboxamide;

3-(5-{6-[2-(4-Bromo-2,6-difluorophenyl)-ethylamino]-2-methylpyrimidin-4-yl} 3-ethoxythiophen-2-yl)-[1,2,4] oxadiazol-5(4H)-one [tautomeric form: 3-(5-{6[2-(4-bromo-2,6-difluorophenyl)-ethylamino]-2-methylpyrimidin-4-yl}-3ethoxythiophen-2- yl)-[1,2,4]oxadiazol-5-ol];

3-(5-{6-[2-(4-Bromophenyl)-ethylamino]-2-methylpyrimidin-4-yl}-3ethoxythiophen-2-yl)-[1,2,4]oxadiazol-5(4Н)- it [tautomeric form: 3-(5-{6-[2(4-bromophenyl)-ethylamino]-2-methylpyrimidin-4-yl}-3-ethoxythiophen-2-yl)[1,2,4]oxadiazol- 5-ol]; And

3-(5-{6-[2-(4-Bromo-2,6-difluorophenyl)-ethylamino]-pyrimidin-4-yl}-3isopropoxythiophen-2-yl)-[1,2,4]oxadiazol-5 (4H)-one [tautomeric form: 3-(5{6-[2-(4-bromo-2,6-difluorophenyl)-ethylamino]-pyrimidin-4-yl}-3isopropoxythiophen-2-yl)-[1 ,2,4]oxadiazol-5-ol].

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In addition to compounds, further compounds of formula (III) which are selected from the following compounds:

4-{6-[2-(4-Bromo-2,6-difluorophenyl)-ethylamino]-pyrimidin-4-yl}-2-(2-hydroxyethoxy)-benzoic acid;

4-{6-[2-(4-Bromo-2,6-difluorophenyl)-ethylamino]-pyrimidin-4-yl}-2-propylbenzoic acid;

4-{6-[2-(4-Bromo-2,6-difluorophenyl)-ethylamino]-pyrimidin-4-yl}-2-propoxybenzoic acid;

4-{6-[2-(4-Bromo-2,6-difluorophenyl)-ethylamino]-pyrimidin-4-yl}-2-ethylsulfanylbenzoic acid;

4-{6-[2-(4-Bromo-2,6-difluorophenyl)-ethylamino]-pyrimidin-4-yl}-2-cyclobutoxybenzoic acid;

4-{6-[2-(4-Bromo-2,6-difluorophenyl)-ethylamino]-pyrimidin-4-yl}-2-butoxybenzoic acid;

4-{6-[2-(4-Bromo-2-ethoxyphenyl)-ethylamino]-pyrimidin-4-yl}-2-ethoxybenzoic acid;

5-{6-[2-(2,6-Difluorophenyl)-ethylamino]-pyrimidin-4-yl}-3-ethylthiophene-2-carboxylic acid; And

-Ethoxy-5-[6-(2-o-tolylethylamino)-pyrimidin-4-yl]-thiophene-2-carboxylic acid.

In addition to compounds, further compounds of formula (III) which are selected from the following compounds:

3-Fluoro-5-{6-[2-(4-trifluoromethylphenyl)-ethylamino]-pyrimidin-4-yl}thiophene-2-carboxylic acid;

-Ethoxy-5-{6-[2-(4-methoxyphenyl)-ethylamino]-pyrimidin-4-yl}-thiophene2-carboxylic acid;

5-{6-[2-(2,4-Dimethylphenyl)-ethylamino]-pyrimidin-4-yl}-3-trifluoromethylthiophene-2-carboxylic acid;

5-{6-[2-(3-Bromo-4-methoxyphenyl)-ethylamino]-pyrimidin-4-yl}-3-ethoxythiophene-2-carboxylic acid;

-Ethoxy-5-{6-[2-(3-methoxycarbonylphenyl)-ethylamino]-pyrimidin-4-yl}-thiophene-2-carboxylic acid;

3-(5-{6-[2-(3,4-Dimethylphenyl)-ethylamino]-pyrimidin-4-yl}-3ethoxythiophen-2-yl)-[1,2,4]oxadiazol-5(4H)- it [tautomeric form: 3-(5-{6-[2(3,4-dimethylphenyl)-ethylamino]-pyrimidin-4-yl}-3-ethoxythiophen-2-yl)[1,2,4]oxadiazol- 5-ol];

3-(3-Ethoxy-5-{6-[2-(2-fluoro-4-trifluoromethylphenyl)-ethylamino]pyrimidin-4-yl}-thiophen-2-yl)-[1,2,4]oxadiazol- 5(4H)-one [tautomeric form: 3-(3-ethoxy-5-{6-[2-(2-fluoro-4-trifluoromethylphenyl)-ethylamino]-pyrimidin-4yl}-thiophen-2-yl)- [1,2,4]oxadiazol-5-ol];

3-(3-Ethoxy-5-{6-[2-(3-hydroxy-4-methoxyphenyl)-ethylamino]-pyrimidin4-yl}-thiophen-2-yl)-[1,2,4]oxadiazol-5 (4H)-one [tautomeric form: 3-(3-ethoxy5-{6-[2-(3-hydroxy-4-methoxyphenyl)-ethylamino]-pyrimidin-4-yl}-thiophen-2yl)-[1, 2,4]oxadiazol-5-ol];

3-(5-{6-[2-(3-Chloro-4-methoxyphenyl)-ethylamino]-pyrimidin-4-yl}-3ethoxythiophen-2-yl)-[1,2,4]oxadiazol-5(4Н )-one [tautomeric form: 3-(5-{6-[2(3-chloro-4-methoxyphenyl)-ethylamino]-pyrimidin-4-yl}-3-ethoxythiophen-2-yl)[1,2, 4]oxadiazol-5-ol]; And

3-(5-{6-[2-(4-Dimethylamino-2-fluorophenyl)-ethylamino]-pyrimidin-4-yl}-3ethoxythiophen-2-yl)-[1,2,4]oxadiazol-5(4Н )-one [tautomeric form: 3-(5-{6-[2(4-dimethylamino-2-fluorophenyl)-ethylamino]-pyrimidin-4-yl}-3-ethoxythiophen-2yl)-[1,2,4 ]oxadiazol-5-ol].

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In addition to compounds, further compounds of formula (III) which are selected from the following compounds:

5-(4-{6-[2-(4-Bromo-2,6-difluorophenyl)-ethylamino]-pyrimidin-4-yl}-2methoxyphenyl)-isoxazol-3-ol [tautomeric form: 5-(4- {6-[2-(4-bromo-2,6difluorophenyl)-ethylamino]-pyrimidin-4-yl}-2-methoxyphenyl)-isoxazol-3(2H)one];

5-{6-[2-(4-Bromo-2,6-difluorophenyl)-ethylamino]-pyrimidin-4-yl}-3-methoxythiophene-2-carboxylic acid;

5-{6-[2-(3,4-Dichloro-2-methylphenyl)-ethylamino]-pyrimidin-4-yl}-3-ethoxythiophene-2-carboxylic acid;

2-Cyclobutoxy-4-{6-[2-(4-difluoromethyl-5-fluoro-2-methoxyphenyl)ethylamino]-pyrimidin-4-yl}-benzoic acid;

5-{6-[2-(4-Difluoromethyl-5-fluoro-2-methoxyphenyl)-ethylamino]-pyrimidin-4yl}-3-ethoxythiophene-2-carboxylic acid;

2-Cyclobutoxy-4-{6-[2-(2-methoxy-4,5-dimethylphenyl)-ethylamino]-pyrimidin-4-yl}-benzoic acid;

-Ethoxy-5-{6-[2-(2-methoxy-4,6-dimethylphenyl)-ethylamino]-pyrimidin-4yl}-thiophene-2-carboxylic acid;

2-Ethoxy-4-{6-[2-(2-ethoxy-4-trifluoromethylphenyl)-ethylamino]-pyrimidin4-yl}-benzoic acid;

4-{6-[2-(2-Ethoxy-4-trifluoromethylphenyl)-ethylamino]-pyrimidin-4-yl}-2-methylsulfanylbenzoic acid;

(2-Ethoxy-4-{6-[2-(2-ethoxy-4-trifluoromethylphenyl)-ethylamino]pyrimidin-4-yl}-phenyl)-acetic acid;

-Ethoxy-5-{6-[2-(2-ethoxy-4-trifluoromethylphenyl)-ethylamino]-pyrimidin4-yl}-thiophene-2-carboxylic acid;

5-{6-[2-(4-Difluoromethoxy-2-methoxyphenyl)-ethylamino]-pyrimidin-4-yl}3-ethoxythiophene-2-carboxylic acid;

-Ethoxy-5-{6-[2-(2-fluoro-6-methoxy-4-trifluoromethylphenyl)-ethylamino]pyrimidin-4-yl}-thiophene-2-carboxylic acid;

3-(4-{6-[2-(4-Bromo-2,6-difluorophenyl)-ethylamino]-pyrimidin-4-yl}-2ethoxyphenyl)-[1,2,4]oxadiazol-5(4H)- he [tautomeric form: 3-(4-{6-[2-(4bromo-2,6-difluorophenyl)-ethylamino]-pyrimidin-4-yl}-2-ethoxyphenyl)[1,2,4]oxadiazol-5 -ol];

(4-{6-[2-(4-Bromo-2,6-difluorophenyl)-ethylamino]-pyrimidin-4-yl}-2-chloro-6-ethylphenyl)-acetic acid;

(5-{6-[2-(4-Bromo-2,6-difluorophenyl)-ethylamino]-pyrimidin-4-yl}-3-ethylthiophen-2-yl)-acetic acid;

5-(4-{6-[2-(4-Bromo-2,6-difluorophenyl)-ethylamino]-pyrimidin-4-yl}-2ethoxyphenyl)-isoxazol-3-ol [tautomeric form: 5-(4- (6-((4-bromo-2,6difluorophenethyl)amino)pyrimidin-4-yl)-2-ethoxyphenyl)isoxazol-3(2H)-one];

3-(5-{6-[2-(5-Bromo-2-methylsulfanylphenyl)-ethylamino]-pyrimidin-4-yl}3-ethoxythiophen-2-yl)-[1,2,4]oxadiazol-5( 4H)-one [tautomeric form: 3-(5-{6[2-(5-bromo-2-methylsulfanylphenyl)-ethylamino]-pyrimidin-4-yl}-3ethoxythiophen-2-yl)-[1,2, 4] oxadiazol-5-ol];

(5-{6-[2-(4-Bromo-2,6-difluorophenyl)-ethylamino]-pyrimidin-4-yl}-3-propylthiophen-2-yl)-acetic acid; and (5-{6-[2-(4-Bromo-2,6-difluorophenyl)-ethylamino]-pyrimidin-4-yl}-3difluoromethoxythiophen-2-yl)-acetic acid.

- 35 043145

In addition to compounds, further compounds of formula (III) which are selected from the following compounds:

4-{6-[2-(4-Bromo-2,6-difluorophenyl)-ethylamino]-pyrimidin-4-yl}-2-butoxy6-fluorobenzoic acid;

-Ethoxy-5-{6-[2-(2-methoxy-6-methylphenyl)-ethylamino]-pyrimidin-4-yl}-thiophene-2-carboxylic acid;

4-{6-[2-(2-Ethoxy-4-trifluoromethylphenyl)-ethylamino]-pyrimidin-4-yl}-2-propylbenzoic acid;

4-{6-[2-(4-Difluoromethoxy-2-methoxyphenyl)-ethylamino]-pyrimidin-4-yl}2-methylsulfanylbenzoic acid,

4-{6-[2-(2,6-Difluoro-4-methoxyphenyl)-ethylamino]-pyrimidin-4-yl}-2-methylsulfanylbenzoic acid;

4-{6-[2-(4-Bromo-2,6-difluorophenyl)-ethylamino]-pyrimidin-4-yl}-2isobutoxybenzoic acid;

4-{6-[2-(4-Bromo-2,6-difluorophenyl)-ethylamino]-pyrimidin-4-yl}-2-cyclopropoxybenzoic acid; And

M-(4-{6-[2-(4-Bromo-2,6-difluorophenyl)-ethylamino]-pyrimidin-4-yl}-2ethoxybenzoyl)-methanesulfonamide.

In addition to compounds, further compounds of formula (III) which are selected from the following compounds:

5-{6-[2-(5-Chloro-2-methoxy-4-trifluoromethylphenyl)-ethylamino]-pyrimidin4-yl}-3-ethoxythiophene-2-carboxylic acid;

-Ethoxy-5-{6-[2-(2-methoxy-4-trifluoromethylphenyl)-ethylamino]pyrimidin-4-yl}-thiophene-2-carboxylic acid;

-Ethoxy-5-{6-[2-(2-methoxy-4-trifluoromethoxyphenyl)-ethylamino]pyrimidin-4-yl}-thiophene-2-carboxylic acid;

5-{6-[2-(2-Difluoromethoxy-4-trifluoromethylphenyl)-ethylamino]-pyrimidin4-yl}-3-ethoxythiophene-2-carboxylic acid; And

3-(2-Ethoxy-4-{6-[2-(2-methoxy-4,5-dimethylphenyl)-ethylamino]-pyrimidin4-yl}-phenoxy)-propionic acid.

Compounds of formulas (II) or (III) according to embodiments of the invention and their pharmaceutically acceptable salts can be used as drugs, for example in the form of pharmaceutical compositions for enteral (as, in particular, oral, for example, in the form of a tablet or capsule ) or parenteral administration (including topical application or inhalation).

The manufacture of pharmaceutical compositions can be carried out in a manner known to any person skilled in the art (see, for example, Remington, The Science and Practice of Pharmacy, 21st ed. (2005), part 5, Pharmaceutical Manufacturing [published by Lippincott Williams & Wilkins ]) by introducing the described compounds of formulas (II) or (III) or their pharmaceutically acceptable salts, optionally in combination with other therapeutically valuable substances, into a galenic dosage form together with suitable, non-toxic, inert, therapeutically compatible solid or liquid carrier substances and , if necessary, conventional pharmaceutical excipients.

The present invention also relates to a method for preventing/preventing or treating a disease or disorder mentioned in this application, comprising administering to a subject a pharmaceutically active amount of a compound of formulas (II) or (III) in accordance with embodiments of the invention.

In a preferred embodiment of the invention, the amount administered is between 1 mg and 2000 mg per day, in particular between 5 mg and 1000 mg per day, more preferably between 25 mg and 500 mg per day, in particular between 50 mg and 200 mg per day.

Whenever the word between is used to describe a range of numerical values, it should be understood to mean that the endpoints of the specified range are explicitly included in that range. For example: if a temperature range is described by values between 40°C and 80°C, then this means that the endpoints of 40°C and 80°C are included in that range; or if the variable is defined as an integer between 1 and 4, it means that the variable is an integer 1, 2, 3, or 4.

When not used in relation to temperatures, the term approximately before the numerical value of X in this application refers to the range that extends from X minus 10% X to X plus 10% X, and preferably to the range that extends from X minus 5 % X to X plus 5% X. In the particular case of temperatures, the term approximately before temperature Y in this application refers to the range that extends from temperature Y minus 10°C to Y plus 10°C, and preferably to an interval that extends from Y minus 5°C to Y plus 5°C.

- 36 043145

For the avoidance of any doubt, where compounds are described as being useful in the prevention/prevention or treatment of certain diseases, such compounds are likewise suitable for use in the preparation of a medicament for the prevention/prevention or treatment of said diseases. Likewise, such compounds are also useful in a method of preventing/preventing or treating such diseases, comprising administering to a subject (mammalian, especially a human) in need thereof an effective amount of such a compound.

Compounds of formulas (II) or (III) according to embodiments of the invention are useful in the prevention/prevention or treatment of disorders involving EP2 and/or EP4 receptors.

Certain compounds of formulas (II) or (III) in accordance with embodiments of the invention demonstrate their biological activity as modulators of prostaglandin-2 EP2 and/or EP4 receptors in the biological environment (i.e. in the presence of one or more enzymes capable of breaking the covalent a bond attached to a carbonyl group such as an amidase, an esterase, or any suitable equivalent capable of removing a prodrug from a carboxylic acid group).

Diseases or disorders involving EP2 and/or EP4 receptors are, in particular, malignancy (especially melanoma, including metastatic melanoma; lung cancer, including non-small cell lung cancer; bladder cancer, including cancer of the bladder itself, urothelial cell carcinoma; renal carcinomas, including renal cell carcinoma, metastatic renal cell carcinoma, metastatic clear cell carcinoma of the kidney; gastrointestinal malignancies, including colorectal cancer, metastatic colorectal cancer, familial adenomatous polyposis (FAP), esophageal cancer, gastric cancer, gallbladder cancer, cholangiocarcinoma, hepatocellular carcinoma and pancreatic cancer such as adenocarcinoma of the pancreas or ductal carcinoma of the pancreas; endometrial cancer; ovarian cancer; cervical cancer; neuroblastoma; prostate cancer, including castration-resistant prostate cancer; brain tumors, including brain metastases, malignant gliomas, glioblastoma multiforme, medulloblastoma, meningiomas; breast cancer, including triple negative breast carcinoma; tumors of the oral cavity; tumors of the nasopharynx; thoracic cancer; head and neck cancer; leukemias, including acute myeloid leukemia, adult T-cell leukemia; carcinomas; adenocarcinomas; thyroid carcinoma, including papillary thyroid carcinoma; choriocarcinoma; Ewing's sarcoma; osteosarcoma; rhabdomyosarcoma; Kaposi's sarcoma; lymphomas including Burkitt's lymphoma, Hodgkin's lymphoma, MALT-type lymphoma; multiple myelomas; and virus-induced tumors; especially melanoma; lungs' cancer; bladder cancer; kidney carcinomas; malignant neoplasms of the gastrointestinal tract; endometrial cancer; ovarian cancer; cervical cancer; and neuroblastoma)

as well as further diseases or disorders related to EP2 and/or EP4 receptors, such as:

pain (especially inflammatory pain and painful menstruation);

endometriosis;

autosomal dominant polycystic kidney disease;

acute ischemic syndromes in patients with atherosclerosis;

pneumonia; and neurodegenerative diseases including amyotrophic lateral sclerosis, stroke; Parkinson's disease, Alzheimer's disease and HIV-related dementia;

and, in addition, EP2 and/or EP4 antagonists can be used to control female fertility.

Compounds of formulas (II) or (III) according to any of the embodiments of the invention are particularly useful as therapeutic agents for the prevention/prevention or treatment of cancer. They can be used as single therapeutic agents or in combination with one or more chemotherapeutic agents and/or radiotherapy and/or targeted therapy. Such combined treatment can be carried out simultaneously, separately or over a period of time.

Thus, the invention also relates to pharmaceutical compositions containing a pharmaceutically acceptable carrier substance, and:

a compound of formulas (II) or (III) according to any of the embodiments of the invention; and one or more cytotoxic chemotherapeutic agents.

Thus, the invention further relates to a kit containing a pharmaceutical composition, where the specified composition contains a pharmaceutically acceptable carrier substance, and:

a compound of formulas (II) or (III) according to any of the embodiments of the invention;

instructions on how to use said pharmaceutical composition for the prevention/prevention or treatment of cancer in combination with chemotherapy and/or radiotherapy and/or targeted therapy.

The terms radiotherapy or radiotherapy or radiation oncology refer to the medical use of ionizing radiation for the prevention/prevention (adjuvant therapy) and/or treatment of cancer; including external and internal radiotherapy.

The term targeted therapy refers to the prevention/prevention (adjuvant therapy) and/or treatment of cancer with one or more antineoplastic agents, such as small molecules or antibodies, that act on specific types of cancer cells or stromal cells. Some types of targeted therapies block the action of certain enzymes, proteins, or other molecules involved in the growth and spread of cancer cells. Other types of targeted therapies help the immune system kill cancer cells (immunotherapy); or inhibit angiogenesis, growth and formation of new blood vessels in the tumor; or deliver toxic substances directly to malignant cells and kill them. An example of a targeted therapy that is particularly suitable for combination with the compounds of the present invention is immunotherapy, in particular immunotherapy targeting the programmed cell death receptor 1 (PD-1 receptor) or its PD-L1 ligand (Zelenay et al. , 2015, Cell 162, 1-14; Yongkui Li et al., Oncoimmunology 2016, 5(2):e1074374).

When used in combination with compounds of formulas (II) or (III), the term targeted therapy specifically refers to agents such as:

a) epidermal growth factor receptor (EGFR) inhibitors or blocking antibodies (eg, gefinitib, erlotinib, afatinib, icotinib, lapatinib, panitumumab, zalutumumab, nimotuzumab, matuzumab, and cetuximab);

b) RAS/RAF/MEK pathway inhibitors (e.g. vemurafenib, sorafenib, dabrafenib, GDC-0879, PLX-4720, LGX818, RG7304, trametinib (GSK1120212), cobimetinib (GDC-0973/XL518), binimetinib (MEK162, ARRY- 162), selumetinib (AZD6244));

c) aromatase inhibitors (eg exemestane, letrozole, anastrozole, vorozol, formestane, fadrozole);

d) angiogenesis inhibitors, especially VEGF signaling inhibitors such as bevacuzimab (Avastin), ramucirumab, sorafenib or axitinib;

e) immune checkpoint inhibitors (eg: anti-PD1 antibodies such as pembrolizumab (lambrolizumab, MK-3475), nivolumab, pidilizumab (CT-011), AMP-514/MED10680, PDRO01, SHR-1210; REGN2810, BGBA317; fusion proteins targeting PD-1, such as AMP-224; small molecule anti-PD1 agents, such as, for example, the compounds disclosed in WO2015/033299, WO2015/044900 and WO2015/034820; anti-PD1L antibodies, such as such as BMS-936559, atezolizumab (MPDL3280A, RG7446), MEDI4736, avelumab (MSB0010718C), durvalumab (MEDI4736); anti-PDL2 antibodies such as AMP224; anti-CTLA-4 antibodies such as ipilimumab, tremilmumab; antilymphocyte-activating gene 3( LAG-3) - antibodies such as BMS-986016, IMP701, MK-4280, ImmuFact IMP321; anti-T-cell immunoglobulin mucin-3 (TIM-3) - antibodies such as MBG453; anti-CD137/4-1BB antibodies, such as BMS-663513/urelumab, PF-05082566 anti-T cell immunoreceptor with Ig and ITIM domains (TIGIT) antibodies such as RG6058 (anti-TIGIT, MTIG7192A);

f) methods involving vaccination (eg dendritic cell vaccination, peptide or protein vaccination (eg gp100 peptide or MAGE-A3 peptide);

g) re-administration of disease-derived or allogeneic (foreign) malignant cells genetically modified to secrete immunomodulatory factors, such as a granulocyte-monocyte-monocytic colony-stimulating factor (GMCSF) gene-transfected tumor cell (GVAX) gene-transfected vaccine or an fms-like ligand gene-transfected vaccine tumor cell tyrosine kinase-1 (Flt-3) (FVAX), or a Toll-like receptor enriched GM-CSF tumor cell vaccine (TEGVAX);

h) adoptive T cell immunotherapy, including engineered chimeric antigen receptor (CAR) T cells (eg, CTL019);

i) cytokine or immunocytokine based therapy (eg interferon alpha, interferon beta, interferon gamma, interleukin 2, interleukin 15);

j) Toll-like receptor (TLR) agonists (eg resiquimod, imiquimod, glucopyranosyl lipid A, CpG oligodeoxynucleotides);

k) thalidomide analogs (eg lenalidomide, pomalidomide);

l) indolamine 2,3-dioxygenase (IDO) and/or tryptophan-2,3-dioxygenase (TDO) inhibitors (e.g. RG6078/NLG919/GDC-0919; indoxymod/1MT (1-methyltryptophan), INCB024360/epacadostat, PF-06840003 (EOS200271), F001287);

m) T-cell costimulatory receptor activators (eg, anti-OX40/CD134 (tumor necrosis factor receptor superfamily, member 4, such as RG7888 (MOXRO916), 9B12; MEDI6469, GSK3174998, MEDI0562), anti-OX40 ligand/CD252; anti-family gene glucocorticoid-

- 38 043145 induced TNFR (GITR) (such as TRX518, MEDI1873, MK-4166, BMS-986156), aHTu-CD40 (TNF receptor superfamily member 5) antibodies (such as dacetuzumab (SGN-40), HCD122, CP- 870.893, rG7876, ADC-1013, APX005M, SEA-CD40); anti-CD40 ligand antibodies (such as BG9588); anti-CD27 antibodies such as varlilumab);

n) tumor-specific antigen binding molecules as well as T cell surface markers such as bispecific antibodies (e.g. RG7802 targeting CEA and CD3) or antibody fragments, antibody mimetic proteins such as engineered ankyrin repeat proteins (DARPINS), attracting T cells bispecific activator (BITE, eg AMG103, AMG330);

o) low molecular weight antibodies or inhibitors targeting the colony stimulating factor receptor (CSF-1R) (eg emactuzumab (RG7155), caberilizumab (FPA-008), PLX3397);

p) agents targeting immune cell checkpoints, natural killer cells, such as antibodies against killer cell immunoglobulin-like receptors (KIRs), eg lirilumab (IPH2102/BMS-986015);

q) agents targeting adenosine receptors or CD39 and CD73 ectonucleases that convert ATP to adenosine, such as MEDI9447 (anti-CD73 antibody), PBF-509; CPI-444 (adenosine A2a receptor antagonist).

When used in combination with compounds of formulas (II) or (III), immune checkpoint inhibitors such as those listed in d), and in particular those that target the programmed cell death receptor 1 (PD-1 receptor) or its PD-L1 ligand are preferred.

The term chemotherapy refers to the treatment of cancer with one or more cytotoxic antineoplastic agents (cytotoxic chemotherapeutic agents). Chemotherapy is often used in combination with other types of cancer treatment, such as radiation therapy or surgery. The term especially refers to conventional cytotoxic chemotherapeutic agents whose action causes the death of cells that divide too quickly, which is one of the main properties of most malignant cells. Chemotherapy can use one drug at a time (single-component chemotherapy) or several drugs at once (combination chemotherapy or polychemotherapy). Chemotherapy using drugs that acquire cytotoxic activity only when exposed to light is called photochemotherapy or photodynamic therapy.

The term cytotoxic chemotherapeutic agent or chemotherapeutic agent in the context of this application refers to an active antineoplastic agent that induces apoptosis or necrotic cell death. When used in combination with compounds of formulas (II) or (III), the term especially refers to conventional cytotoxic chemotherapeutic agents such as:

a) alkylating agents (eg mechlorethamine, chlorambucil, cyclophosphamide, ifosfamide, streptozocin, carmustine, lomustine, melphalan, dacarbazine, temozolomide, fotemustine, thiotepa or altretamine; in particular cyclophosphamide, carmustine, melphalan, dacarbazine or temozolomide);

b) platinum-based drugs (especially cisplatin, carboplatin or oxaliplatin);

c) antimetabolite drugs (eg 5-fluorouracil, folic acid/leucovorin, capecitabine, 6-mercaptopurine, methotrexate, gemcitabine, cytarabine, fludarabine or pemetrexed; in particular 5-fluorouracil, folic acid/leucovorin, capecitabine, methotrexate, gemcitabine or pemetrexed);

d) antitumor antibiotics (eg daunorubicin, doxorubicin, epirubicin, idarubicin, actinomycin-D, bleomycin, mitomycin-C or mitoxantrone; in particular doxorubicin);

e) mitosis inhibitors (eg paclitaxel, docetaxel, ixabepilone, vinblastine, vincristine, vinorelbine, vindesine or estramustine; in particular paclitaxel, docetaxel, ixabepilone or vincristine); or

f) topoisomerase inhibitors (eg etoposide, teniposide, topotecan, irinotecan, diflomotecan or elomotecan; in particular etoposide or irinotecan).

When used in combination with compounds of formulas (II) or (III), the preferred cytotoxic chemotherapeutic agents are the aforementioned alkylating agents (especially fotemustine, cyclophosphamide, ifosfamide, carmustine, dacarbazine and their prodrugs, such as especially temozolomide, or pharmaceutically acceptable salts of these compounds; in particular temozolomide); mitosis inhibitors (especially paclitaxel, docetaxel, ixabepilone; or pharmaceutically acceptable salts of these compounds; in particular paclitaxel); platinum-based drugs (especially cisplatin, oxaliplatin and carboplatin); as well as etoposide and gemcitabine.

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Chemotherapy may be provided for curative purposes or may be intended to prolong life or alleviate symptoms.

Combination chemotherapy treatment means the use of drugs along with other types of cancer treatment, such as radiation therapy or surgery.

Induction chemotherapy is a first-line treatment for cancer with a chemotherapy drug. This type of chemotherapy is used for curative purposes.

Fixative chemotherapy is given after remission to prolong overall disease-free survival and improve overall survival. The drug administered in this case is the same drug that achieved remission.

Boosted chemotherapy is identical to fixative chemotherapy, but uses a different drug than that used for induction chemotherapy.

Combination chemotherapy involves treating a patient with several different drugs at the same time. Medicines differ in their mechanism of action and side effects. The biggest benefit is minimizing the chances of developing resistance to any one drug. Also, drugs can often be used at lower doses, which reduces toxicity.

Neoadjuvant chemotherapy is given prior to local treatment, such as surgery, and is intended to shrink the primary tumor. It is also performed in malignant neoplasms with a high risk of micrometastatic disease.

Adjuvant chemotherapy is carried out after local treatment (radiotherapy or surgery). It can be used in the absence of sufficient evidence of malignancy, but in the presence of a risk of recurrence. It is also useful in inducing the death of any cancer cells that have spread to other parts of the body. These micrometastases can be treated with adjuvant chemotherapy and the recurrence rate caused by these dispersed cells can be reduced.

Maintenance chemotherapy is repeated low-dose treatment to prolong remission.

Salvage chemotherapy or palliative chemotherapy is performed without a curative purpose, but simply to reduce the tumor burden and increase life expectancy. For these regimens, a better toxicity profile is generally expected.

The term simultaneously, when it refers to the type of administration, means in this application that the specified type of administration consists in the introduction (application) of two or more active components and/or treatments at approximately the same time; and it should be understood that the simultaneous introduction (use) will result in the exposure of the subject to two or more active components and/or treatments at the same time. When the administration is carried out simultaneously, these two or more active ingredients can be administered in fixed dose combinations, or in an equivalent non-fixed dose combination (for example, using two or more different pharmaceutical compositions to be administered by the same route of administration in approximately one and the same time), or using a combination of non-fixed doses using two or more different routes of administration; wherein said administration results in substantially simultaneous exposure of the subject to two or more active ingredients and/or treatments. For example, when used in combination with chemotherapy and/or suitable targeted therapy, the EP2/EP4 antagonists of the present invention are intended to be used simultaneously.

The term fixed dose combination, when referring to the type of administration, means in this application that said type of administration consists in the administration of one single pharmaceutical composition containing two or more active ingredients.

The term separately, when it refers to the type of administration, means in this application that the specified type of administration consists in the introduction (application) of two or more active components and/or treatments at different points in time; and it should be understood that separate administration (use) will result in a treatment phase (for example, at least 1 hour, especially at least 6 hours, especially at least 12 hours) in which the subject is exposed to two or more active components and/or treatments at the same time; but separate administration (use) can also lead to a phase of treatment in which for a certain period of time (for example, at least 12 hours, in particular at least one day) the subject is exposed to only one of the two or more active components and/or methods of treatment. Separate administration (use) particularly refers to situations in which at least one of the active components and/or treatments is administered (applied) at a frequency that differs significantly from daily (such as once or twice a day).

- 40 043145 day) administration (application) (for example, where one active component and / or method of treatment is administered (applied), for example, once or twice a day, and the other is administered (applied), for example, once every two days, or once a week or at longer intervals). For example, when used in combination with radiotherapy, the EP2/EP4 antagonists of the present invention are intended to be used separately.

Under the introduction for some time in this application refers to the sequential introduction (use) of two or more active components and/or treatments at different times. The term specifically refers to a method of administration (application), in accordance with which all administration (application) of one of the active components and/or treatments is completed before the administration (application) of the other/others begins. Thus, it is possible to enter (use) one of the active components and/or methods of treatment for several months before the introduction (use) of the other(s) active(s) and/or method(s) of treatment.

The introduction for some time also covers situations in which the compound of formulas (II) or (III) will be used for treatment that begins after the cessation of the initial chemotherapeutic (for example, induction chemotherapy) and/or radiotherapy treatment and/or treatment through targeted therapy, where optionally said treatment will be carried out in combination with additional/ongoing chemotherapy and/or radiotherapy treatment and/or treatment through targeted therapy (for example, in combination with anchoring chemotherapy, boosted chemotherapy, adjuvant chemotherapy or maintenance chemotherapy; or their radiotherapeutic equivalents); where such additional/ongoing chemotherapeutic and/or radiotherapy treatment and/or targeted therapy treatment will be carried out simultaneously, separately or for some time in the sense of not being carried out with the same frequency.

Compounds of formulas (II) or (III), as defined in embodiments of the invention, are also useful in a method for modulating an immune response in a subject having a tumor, comprising administering an effective amount of a compound of formulas (II) or (III) [wherein, in particular, said administration of said effective amount results in pharmacologically active blocking of EP2 receptors, or EP4 receptors, or both EP2 and EP4 receptors]; where the specified effective amount reactivates the immune system in the tumor of the specified subject; where, in particular, the specified effective amount counteracts the polarization of tumor-associated macrophages in favor of tumor-promoting M2 macrophages; and/or down-regulates the activation, expansion and/or effector function of immunosuppressive cells that accumulate in the tumor (especially regulatory T cells (Tregs) and/or suppressor cells of myeloid origin (MDSC)); and/or upregulates IFN-γ and/or TNF-α and/or IL-12 and/or IL-2 expression in immune cells such as natural killer cells, T cells, dendritic cells and macrophages (resulting in induction of apoptosis of tumor cells and/or inhibition of oncogenesis); and/or directly or indirectly counteracts suppressed activation, IL-2 responsiveness and expansion of cytotoxic T cells (thereby reducing local immunosuppression).

Compounds of formulas (II) or (III), as defined in embodiments of the invention, are also useful in a method of reducing the rate of tumor growth and/or reducing the size of a tumor in a subject having a tumor, comprising administering an effective amount of a compound of formulas (II) or (III ) [wherein, in particular, said administration of said effective amount results in pharmacologically active blocking of EP2 receptors, or EP4 receptors, or both EP2 and EP4 receptors]; wherein said effective amount downregulates tumor angiogenesis (particularly by decreasing endothelial cell motility and/or survival and/or by decreasing VEGF (vascular endothelial growth factor) expression); and/or wherein said effective amount reduces tumor cell survival and/or induces tumor cell apoptosis (especially by inhibiting PI3K/AKT and MAPK signaling).

Compounds of formulas (II) or (III), as defined in embodiments of the invention, are also useful in a method for modulating an immune response in a subject having a tumor, comprising administering an effective amount of a compound of formulas (II) or (III) [wherein, in particular, said administration of said effective amount results in pharmacologically active blocking of EP2 receptors, or EP4 receptors, or both EP2 and EP4 receptors]; where the specified effective amount reactivates the immune system in the tumor of the specified subject; wherein said effective amount activates cytotoxicity and cytokine production of natural killer cells and/or cytotoxic T cells.

Preparation of compounds of formulas (I), (II) or (III).

Compounds of formulas (I), (II) or (III) can be obtained using well known literature methods, using the methods below, using the methods given in the experimental section below, or using similar methods. Optimum reaction conditions may vary depending on the particular reagents or solvents used, but such conditions can be determined by one skilled in the art using routine optimization techniques. In some cases, the order of the following reaction schemes and/or reaction steps may be varied in order to promote the reaction or avoid unwanted reaction products. In the general sequence of reactions set forth below, the generic groups R ¹ , R ³ , R ^4a , R ^4b , R ^5a , R ^5b and Ar ¹ are as defined for formulas (I), (II) or (III). Other abbreviations used in this application are clearly defined, or are as defined in the experimental section. In some cases, the generic groups R ¹ , R ³ , R ^4a , R ^4b , R ^5a , R ^5b and Ar ¹ may not be compatible with the set of other groups illustrated in the diagrams below, and therefore will require the use of protecting groups (PG). The use of protecting groups is well known in the art (see, for example, Protective Groups in Organic Synthesis, TW Greene, PGM Wuts, Wiley-Interscience, 1999). For the purposes of this discussion, it will be assumed that such protecting groups are in place when necessary. In some cases, the end product can be further modified, for example, by manipulating substituents to obtain a new end product. These manipulations may include, but are not limited to, reduction, oxidation, alkylation, acylation, hydrolysis, and transition metal-catalyzed cross-coupling reactions, which are well known to those skilled in the art. The resulting compounds can also be converted into salts, in particular pharmaceutically acceptable salts, by a method known per se.

Compounds of formulas (I), (II) or (III) of the present invention can be prepared according to the general reaction sequence set forth below.

The general route of synthesis, which makes it possible to obtain compounds of formula (I), is shown in scheme 1. Thus, the precursors (3) can be obtained by nucleophilic aromatic substitution reactions between primary amines (1) and pyrimidines (2) (where X means chlorine, bromine or iodine) in the presence of a base such as TEA, DIPEA or K ₂ CO ₃ in a solvent such as isopropanol, butanol, DMF or THF at RT or at elevated temperatures. Compounds of formula (I) can be prepared by metal-catalyzed cross-coupling reactions by reacting pyrimidine halide derivatives (3) with a compound of formula (4), for example, by Suzuki coupling reactions in which compounds (4) are boronic acids or boronate esters. Typical Suzuki cross-coupling reactions can be carried out in the presence of a base such as K ₂ CO ₃ , Cs ₂ CO ₃ , Na ₂ CO ₃ , K ₃ PO ₄ , or CsF and a catalyst such as Pd(PPh ₃ ) ₄ , Pd(dppf )Cl ₂ or Pd(OAc) ₂ , in a solvent such as ethanol, THF, water or mixtures thereof, typically at elevated temperatures. Boronic acids or boronate esters (4) can be obtained from commercial sources or synthesized by methods described in the literature, or methods known to a person skilled in the art.

A boronic acid derivative can be formed by a Miyaur borylation reaction, by cross-coupling bis-(pinacolato)diboron with aryl halides or triflates in the presence of a base such as potassium acetate and a catalyst such as Pd(dppf)Cl ₂ . Alternatively, the boronic acid derivative can be formed by performing a lithiation/borylation sequence, typically at low temperatures, using butyl lithium or lithium diisopropylamide as the base, and triisopropyl borate or isopropoxyboronic acid pinacol ester, in a solvent such as Et ₂ O or THF. In one embodiment, compounds of formula (I) can be obtained by nucleophilic aromatic substitution reactions between primary amines (1) and substituted pyrimidine halides (5), where X is chlorine, bromine or iodine (Scheme 1).

Alternatively, compounds of formula (I) can be synthesized by reacting a compound of formula (1) with a compound of formula (5) wherein X is OH in the presence of a coupling agent such as (benzotriazol-1-yloxy)-tris-(dimethylamino) hexafluorophosphate phosphonium (BOP), (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyBOP) or hexachlorocyclotriphosphazene in the presence of a base such as DBU, DIPEA or TEA in a solvent such as THF, MeCN or DMF at low temperatures or at RT, or at elevated temperatures.

Scheme 1. General ways to obtain compounds of formula (I)

The preparation of the desired primary amines 1 is described in Scheme 2. Aminoethylated aromatic compounds (8) can be obtained using Suzuki-Miyaura cross-coupling reactions by reacting the appropriate aromatic electrophiles (6) (bromides, iodides or trifla

- 42 043145 you) with Boc-protected potassium β-aminoethyl trifluoroborates (7). Such cross-coupling reactions can be performed using the described conditions [Pd(dppf)Cl2 or combination of Pd(OAc)2 and RuPhos as catalyst system, Cs ₂ CO ₃ as base, in toluene/H ₂ O, at elevated temperatures] . The corresponding primary amines (1) can be obtained after Boc deprotection of derivatives (8) under acidic conditions, and then they can be converted to compounds of formula (I) by following the synthesis sequences described in scheme 1. In one embodiment, shown in Scheme 2, primary amines (1) can be obtained starting from carbonyl precursors (9) and nitro compounds (10) using the Henry reaction (butylamine / acetic acid / molecular sieves / 90 ° C) and subsequent reduction of the resulting nitroalkenes (11) (lithium aluminum hydride /THF, or

NaBH ₄ /BF ₃ Et ₂ O/THF).

Scheme 2. Obtaining substituted β-aminoethyl-aromatic compounds (1)

Pyrimidines of formula (5) can be prepared by cross-coupling reactions between compounds of formula (4), typically boronic acids or esters, and dihalopyrimidines of formula (2), where X=Cl, Br or I (Scheme 3). Compounds of formula (5) where X=OH can be obtained by dealkylation of compounds of formula (13) where Alk is typically Me or Et under acidic conditions (HCl, HBr or BBr ₃ ). In turn, (13) can be formed by a cross-coupling reaction between compounds of formula (12) where X=Cl, Br, I, and compounds of formula (4), typically boronic acids or esters.

Scheme 3. Preparation of pyrimidines (5)

The following examples are given to illustrate the invention. These examples are illustrative only and should not be construed as limiting the invention in any way.

Experimental section

I. Chemistry.

All temperatures are in °C. Commercially available starting materials were used as received without further purification. Unless otherwise indicated, all reactions were carried out in oven-dried glassware under a nitrogen atmosphere. Compounds were purified by silica gel flash column chromatography or by preparative HPLC. The compounds described in the invention were characterized by data obtained by performing LC-MS (retention time t _R is given in min; molecular weight obtained from the mass spectrum is given in g/mol) using the conditions listed below. In cases where the compounds of the present invention are observed as a mixture of conformational isomers, which is especially noticeable in their LC-MS spectra, the retention time of the most common conformer is given. In some cases, the compounds are isolated after purification in the form of the corresponding ammonium salt (*1), the corresponding formic acid salt (*2) or hydrochloride (*3); such connections are marked accordingly.

Equipment for analytical LC-MS.

HPLC pump: binary gradient pump, Agilent G4220A or equivalent.

Autosampler: Gilson LH215 (with Gilson 845z injector) or equivalent.

Column compartment: Dionex TCC-3000RS or equivalent.

Degasser: Dionex SRD-3200 or equivalent.

Make-up pump: Dionex HPG-3200SD or equivalent.

DMD: Agilent G4212A or equivalent.

MS Detector: Single quadrupole mass analyzer, Thermo Finnigan MSQPlus or equivalent.

IDSR: Sedere SEDEX 90 or equivalent.

- 43 043145

LC-MS with acidic conditions.

Method A: column: Zorbax SB-aq (3.5 µm, 4.6x50 mm). Conditions: MeCN [eluent A]; water + 0.04%

TFA [eluent B]. Gradient: 95% B^5% B over 1.5 min (flow: 4.5 ml/min). Detection: UV/visible. +

MS.

Method B: column: Zorbax RRHD SB-aq (1.8 µm, 2.1x50 mm). Conditions: MeCN [eluent A]; water + 0.04% TFA [eluent B]. Gradient: 95% B^5% B over 2.0 min (flow: 0.8 ml/min). Detection: UV/visible. + MS.

Method C: Waters Acquity Binary, Solvent Manager, MS: Waters SQ Detector, DMD: Acquity UPLC PDA Detector, IDSR: Acquity UPLC ELSD. Column ACQUITY UPLC CSH C18 1.7 µm, 2.1x50 mm from Waters, thermostated in Acquity UPLC Column Manager at 60°C. Eluents: A: H ₂ O + 0.05% formic acid; B: MeCN + 0.045% formic acid. Method: Gradient: 2% B^98% B in 2.0 min. Flow: 1.0 ml/min. Detection: UV 214 nm and IDSR, and MS, t _R is given in min.

Method E: column: Waters BEH C18 (2.5 µm, 2.1x50 mm). Conditions: MeCN [eluent A]; water + 0.04% TFA [eluent B]. Gradient: 95% B^5% B over 2.0 min (flow: 0.8 ml/min). Detection: UV/visible. + MS.

LC-MS with basic conditions.

Method D: column: Waters BEH C18, 3.0x50 mm, 2.5 µm, eluents: A: water/NH ₃ [c(NH ₃ )=13 mmol/l], B: MeCN, method: 5% B to 95% B for 1.2 min, Flow 1.6 ml/min, UV detection: 214 nm.

Equipment for preparative HPLC.

HPLC pump: Gilson 333/334 equipped with Gilson LH215.

Degasser: Dionex SRD-3200.

Make-up pump: Dionex ISO-3100A.

DMD: Dionex DAD-3000.

MS detector: single quadrupole mass analyzer, Thermo Finnigan MSQ Plus.

Flow separator: MRA100-000.

IDSR: Polymer Laboratories PL-ELS 1000.

Preparative HPLC with basic conditions.

Column: Waters XBridge (10 µm, 75x30 mm). Conditions: MeCN [eluent A]; water + 0.5% NH4OH (25% aq.) [eluent B]; gradient see table. 1 (flow: 75 ml/min), the initial percentage of eluent A (x) is determined depending on the polarity of the compound to be purified. Detection: UV/visible. + MS

Table 1

t (min) 0 0.01 4.0 6.0 6.2 6.6 Eluent A (%) X X 95 95 X X Eluent B (%) 100's 100's 5 5 100's 100's

Preparative HPLC with acidic conditions.

Column: Waters Atlantis T3 (10 µm, 75x30 mm). Conditions: MeCN [eluent A]; water + 0.5% HCO2H [eluent B]; gradient see table. 2 (flow: 75 ml/min), the initial percentage of eluent A (x) is determined depending on the polarity of the compound to be purified. Detection: UV/visible. + MS

table 2

t (min) 0 0.01 4.0 6.0 6.2 6.6 Eluent A (%) X X 95 95 X X Eluent B (%) 100's 100's 5 5 100's 100's

Abbreviations (applied above or below):

AcOH - acetic acid, aq. - water atm. - atmosphere

Boc - tert-butyloxycarbonyl

BOP - (benzotriazol-1-yloxy)-tris-(dimethylamino)phosphonium hexafluorophosphate d - days

DBU - 1,8-diazabicyclo[5.4.0]undec-7-ene

DXM - dichloromethane

DIBAL/DIBAL-H - diisobutylaluminum hydride

DIPEA - diisopropylethylamine, Hunig's base

DMAP - 4-dimethylaminopyridine

DMF - dimethylformamide

DMSO - dimethyl sulfoxide dppf - 1,1'-bis-(diphenylphosphino)ferrocene

- 44 043145

EDC - 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Et - ethyl

Et2O - diethyl ether

EtOAc - ethyl acetate EtOH - ethanol Ex.-example PC - flash chromatography on silica gel h - hour(s)

HATU - (1-[bis-(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate hept - heptane(s)

HOBT - 1-hydroxybenzotriazole

HPLC - High Performance Liquid Chromatography BB - High Vacuum 'Bu - Isobutyl 'Pr - Isopropyl

LAH - lithium aluminum hydride

LC-MS - liquid chromatography - mass spectrometry Lit. - literature Me - methyl

MeCN - acetonitrile

MeOH - methanol ml - milliliter min - minute(s) MW - microwave NMP - N-methyl-2-pyrrolidone ⁿ Pr - n-propyl OAc - acetate

Pd ₂ dba ₃ - tris-(dibenzylideneacetone)diialladium(0)

Pd(dppf)Cl ₂ - [1,1'-bis-(diphenylphosphino)ferrocene]dichloropalladium (II)

Pd(dppf)Cl ₂ DCM - complex of [1,1'-bis-(diphenylphosphino)ferrocene]dichloropalladium (II) with dichloromethane

Ph - phenyl

PPh ₃ - triphenylphosphine prep. - preparative PyBOP - (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate rac - racemic PM - reaction mixture RT - room temperature s -second(s) sat. - saturated tBu tert-butyl - tertiary butyl TEA - triethylamine

TFA - trifluoroacetic acid

THF - tetrahydrofuran

TLC - thin layer chromatography tosyl - p-toluenesulfonyl t _R - retention time triflate - trifluoromethanesulfonate

General Methods

General procedure A. Nitro-aldol condensation and dehydration.

Butylamine (0.117 ml, 1.18 mmol), acetic acid (0.116 ml, 2.04 mmol) and 4A molecular sieves (100 mg) are added at RT to a solution of aromatic aldehyde (10 mmol) in nitromethane (20 ml) at RT. PM is stirred at 90°C for 1 h, then cooled to RT and concentrated in vacuo. The residue is partitioned between EtOAc and water. The organic phase is washed again with water, then with brine, dried over MgSO ₄ , filtered and concentrated in vacuo. The crude product is purified, if necessary, by preparative HPLC or by PC.

General procedure B. Reduction of nitrostyrenes with NaBH ₄ and BF ₃ . _Et2O .

BF ₃ .Et ₂ O (1.06 ml, 8.14 mmol) was added to a solution of sodium borohydride (251 mg, 6.51 mmol) in THF (7 ml) at 0°C. PM is stirred for 10 min at 0°C, then 15 min at RT. A solution of nitrostyrene (1.36 mmol) in THF (3 ml) was added dropwise and the PM was heated at reflux overnight. PM is cooled to 0°C and carefully treated with 2N. HCl (8.8 ml, 17.6 mmol). PM is heated in

- 45 043145 for 1 hour at 80°C, then cooled to RT, and the organic solvent is removed under reduced pressure. The remaining aqueous layer is extracted with Et2O. The aqueous layer is treated with 10%

NaOH until pH>12 and extracted 3 times with EtOAc. The combined organic layers are washed with brine, dried over MgSO ₄ and concentrated in vacuo. The crude product is purified, if necessary, by preparative HPLC or by PC.

General Procedure C. Suzuki-Miyaura Coupling Using Trifluoroborates.

Aryl bromide or triflate (1.91 mmol), tert-butyl N-[2(trifluoroboranuidyl)ethyl]potassium carbamate (555 mg, 2.1 mmol), cesium carbonate (2489 mg, 7.64 mmol), palladium(II) acetate ( 21.5 mg, 0.0955 mmol), RuPhos (93.8 mg, 0.191 mmol) and toluene (15 ml) and water (5 ml). The PM is purged with argon, then heated at 95° C. overnight. PM is cooled to RT and filtered through a glass microfiber filter. The filtrate is concentrated under reduced pressure. The residue is partitioned between DCM and saturated NH ₄ Cl solution. The phases are separated and the aqueous layer is extracted two more times with DCM. The combined organic layers are then washed with brine, dried over MgSO4, filtered and evaporated in vacuo. The crude product is purified, if necessary, by preparative HPLC or by PC.

General Procedure D. Boc Deprotection (Boc).

TFA (10 ml) was added to a solution of Boc-protected amine (1.91 mmol) in DCM (40 ml) at 0°C. PM is stirred for 2 h, allowing the temperature to rise to RT. Then it is concentrated in vacuo. The residue is taken up again in DCM and evaporated in vacuo (twice) to give the free amine as the TFA salt. Alternatively, the evaporation residue is taken up in DCM and washed with 1N HCl. NaOH. The organic layer is dried over MgSO4, filtered and evaporated in vacuo. The crude product is purified, if necessary, by preparative HPLC or by PC.

General Procedure E. Boc deprotection (HCl).

To a solution of Boc-protected amine (1.91 mmol) in DCM (40 ml) at 0°C was added HCl (4N in dioxane, 10 ml). PM is stirred for 2 h, allowing the temperature to rise to RT. It is then concentrated in vacuo to give the free amine as the HCl salt. Alternatively, the evaporation residue is taken up in DCM and washed with 1N HCl. NaOH. The organic layer is dried over MgSO ₄ , filtered and evaporated in vacuo. The crude product is purified, if necessary, by preparative HPLC or by PC.

General procedure F. SNAr in the case of 4,6-dihalopyrimidine.

A solution of arylethylamine (21.1 mmol), 4,6-dichloropyrimidine (3.00 g, 20.1 mmol) and TEA (3.08 ml, 22.2 mmol) in 2-propanol (50 ml) was heated at reflux for 2 h, then allowed to cool to RT and concentrated under reduced pressure. The remainder is distributed between sat. aq. NaHCO ₃ solution and EtOAc. The layers are separated and the aqueous layer is extracted again with EtOAc. The combined organic layers are washed with water, brine, dried over MgSO4, filtered and the solvent removed in vacuo. The crude product is purified, if necessary, by preparative HPLC or by PC.

General Procedure G. Suzuki Coupling Using Pd(PPh ₃ ) ₄ .

A mixture of the corresponding pyrimidine halide derivative (3) (0.15 mmol), the corresponding boronic acid derivative (4) (0.18 mmol) and 2M K2CO3 (0.3 ml, 0.6 mmol) in ethanol (3 ml) was purged with argon, tetrakis(triphenylphosphine)palladium was added (0.0075 mmol), and the reaction mixture is heated at 90°C overnight. Alternatively, the reaction can be carried out in a MW apparatus at 120°C for 15 to 30 minutes. The reaction mixture is filtered through a 0.45 μm glass microfiber filter, washed with a mixture of EtOH/MeCN and DMF. The filtrate is purified either by preparative HPLC or by PC. Alternatively, it is diluted with water, adjusted to pH if necessary, and extracted (3x) with EtOAc. The combined organic extracts are dried (MgSO4) and concentrated under reduced pressure. The residue is purified by preparative HPLC or by PC.

General Procedure H. Suzuki coupling using Pd(PPh ₃ ) ₄ followed by ester hydrolysis.

A mixture of the corresponding pyrimidine halide derivative (3) (0.15 mmol), the corresponding boronic acid derivative (4) (0.18 mmol) and 2M K2CO3 (0.3 ml, 0.6 mmol) in EtOH (3 ml) was purged with argon, Pd(PPh ₃ ) was added ₄ (0.0075 mmol), and the reaction mixture is heated at 90°C overnight. Alternatively, the reaction can be performed in a MW apparatus at 120°C for 1530 min. NaOH (32% solution, 0.5 ml) was added and the reaction mixture was stirred at RT for 2 - 20 h or at 90°C for 0.5 - 20 h PM then filtered through a 0.45 µm glass microfiber filter, washed with EtOH and water. The filtrate is either purified directly by preparative HPLC or diluted with 1N HCl. HCl and extracted 3x with EtOAc. The combined organic extracts are dried (MgSO4) and concentrated under reduced pressure. The residue is purified, if necessary, by preparative HPLC or by PC.

- 46 043145

General Procedure I. Phosphonium-mediated SNAr.

PyBOP (163 mg, 0.313 mmol) was added to a solution of 6-hydroxypyrimidine derivative (5) (0.196 mmol) in DMF (2 mL) and TEA (0.109 mL, 0.784 mmol). The yellow solution was stirred at RT for 15 min, then the appropriate arylethylamine (1) (0.245 mmol) was added and the PM was stirred at 80°C overnight. PM is cooled to RT and treated with a few drops of water and purified by preparative HPLC. Alternatively, PM is diluted with EtOAc and washed twice with brine. The organic layer is dried over MgSO ₄ , filtered and concentrated. The residue is purified, if necessary, by preparative HPLC or by PC.

Alternatively, a solution of 6-hydroxypyrimidine derivative (5) (0.1 mmol) in DMF (1 ml) is treated with DBU (0.15 mmol) and BOP (0.13 mmol). The solution is stirred at RT for 15 min - 1 h, then the appropriate arylethylamine (1) (0.125 mmol) is added and PM is stirred at 80°C for 2 - 20 h. PM is cooled to RT and treated with a few drops of water and purified with preparative HPLC. Alternatively, PM is diluted with EtOAc and washed twice with brine. The organic layer is dried over MgSO4, filtered and concentrated. The residue is purified, if necessary, by preparative HPLC or by PC.

A. Preparation of precursors and intermediates.

A.1. Synthesis of phenethylamine derivatives of formula (1).

A.1.1. 2-(4-Bromo-2-(trifluoromethoxy)phenyl)ethane-1-amine.

The title compound was prepared according to General Procedure B above using (E)-4-bromo-1-(2-nitrovinyl)-2-(trifluoromethoxy)benzene as a white solid. LCMS B: tR=0.64 min; [M+H]+=284.02.

A.1.1.1. (E)-4-Bromo-1-(2-nitrovinyl)-2-(trifluoromethoxy)benzene.

The title compound was obtained according to General Procedure A above using 4-bromo-2-(trifluoromethoxy)benzaldehyde as a yellow solid. LCMS B: tR=1.06 min; without ionization.

A.1.2. 2-(4-Bromo-2-ethoxyphenyl)ethane-1-amine.

The title compound was prepared according to General Procedure B above using (E)-4-bromo-2-ethoxy-1-(2-nitrovinyl)benzene as a brown solid. LCMS B: tR=0.62 min; [M+H]+=244.18.

A.1.2.1. (E)-4-Bromo-2-ethoxy-1-(2-nitrovinyl)benzene.

The title compound was obtained according to General Procedure A above using 4-bromo-2-ethoxybenzaldehyde as a yellow solid. LC-MS B: tR=1.09 min; without ionization. A.1.3. 2-(4-Chloro-2-fluoro-6-methoxyphenyl)ethan-1-amine The title compound was prepared according to General Procedure B above using (E)-5-chloro-1-Fluoro-3methoxy- 2-(2-nitrovinyl)benzene, as a pink solid. LCMS B: tR=0.56 min; [M+H]+=204.29.

A.1.3.1. (E)-5-Chloro-1-fluoro-3-methoxy-2-(2-nitrovinyl)benzene.

The title compound was obtained according to General Procedure A above using 4-chloro-2-fluoro-6-methoxybenzaldehyde as a pale yellow solid. LC-MS B: t _R =0.98 min; without ionization.

A.1.4. 2-(4-Bromo-2-fluoro-6-methoxyphenyl)ethane-1-amine.

The title compound was prepared according to General Procedure B above using (E)-5-bromo-1-fluoro-3-methoxy-2-(2-nitrovinyl)benzene as a pale yellow solid. LCMS B: tR=0.59 min; [M+H]+=250.08.

A.1.4.1. (E)-5-Bromo-1-fluoro-3-methoxy-2-(2-nitrovinyl)benzene.

The title compound was obtained according to General Procedure A above using 4-bromo-2-fluoro-6-methoxybenzaldehyde as a pale yellow solid. LC-MS B: tR=1.03 min; without ionization.

A.1.5. 2-(4-Bromo-2,6-dimethoxyphenyl)ethane-1-amine.

The title compound was prepared according to General Procedure B above using (E)-5-bromo-1,3-dimethoxy-2-(2-nitrovinyl)benzene as a beige solid. LCMS B: tR=0.59 min; [M+H]+=260.15.

A.1.5.1. (E)-5-bromo-1,3-dimethoxy-2-(2-nitrovinyl)benzene.

The title compound was obtained according to General Procedure A above using 4-bromo-2,6-dimethoxybenzaldehyde as a yellow solid. LCMS B: tR=1.08 min; without ionization.

A.1.6. 2-(4-Bromo-2-propoxyphenyl)ethane-1-amine.

The title compound was prepared according to General Procedure B above using (E)-4-bromo-1-(2-nitrovinyl)-2-propoxybenzene as an orange solid. LCMS B: tR=0.67 min; [M+H]+=257.99.

A.1.6.1. (E)-4-Bromo-1-(2-nitrovinyl)-2-propoxybenzene.

The title compound was prepared according to General Procedure A above using 4-bromo-2-propoxybenzaldehyde as a yellow solid. LC-MS B: t _R =1.11 min; without ionization. A.1.7. 2-(2-Ethoxy-4-(trifluoromethyl)phenyl)ethan-1-amine The title compound was prepared according to General Procedure D above using t-butyl (2ethoxy-4-(trifluoromethyl)phenethyl)carbamate, as a yellow oil. LC-MS B: t _R =0.67 min;

[M+H]+=234.30.

A.1.7.1. tert-Butyl (2-ethoxy-4-(trifluoromethyl)phenethyl)carbamate.

The title compound was obtained according to General Procedure C above using 4-bromo-3-ethoxybenzotrifluoride as a yellow solid. LC-MS B: t _R =1.09 min; [M+H] ⁺ =334.21.

A.1.8. 2-(2-Aminoethyl)-5-chloro-N-methylaniline.

The title compound was prepared according to General Procedure D above using t-butyl (4-chloro-2-(methylamino)phenethyl)carbamate as a dark oil. LC-MS B: t _R =0.56 min; [M+H]+=185.26.

A.1.8.1. tert-Butyl(4-chloro-2-(methylamino)phenethyl)carbamate.

The title compound was obtained according to General Procedure C above using N-methyl 2-bromo-5-chloroaniline hydrochloride as a pale yellow oil. LC-MS B: t _R =1.00 min; [M+H]+=284.56.

A.1.9. 2-(2-Methoxy-4-(methylthio)phenyl)ethane-1-amine hydrochloride.

The title compound was prepared according to General Procedure E above using t-butyl (2-methoxy-4-(methylthio)phenethyl)carbamate as a white solid. LCMS B: t _R =0.55 min; [M+H] ⁺ =198.18.

A.1.9.1. tert-Butyl (2-methoxy-4-(methylthio)phenethyl)carbamate.

The title compound was prepared according to General Procedure C above using 1-bromo-2-methoxy-4-(methylsulfanyl)benzene as a white foam. LC-MS B: t _R =1.01 min; [M+H]+=298.17.

A.1.10. 2-(4-(Difluoromethoxy)-2-methoxyphenyl)ethan-1-amine The title compound was prepared according to General Procedure E above using mpem-butyl (4(difluoromethoxy)-2-methoxyphenethyl)carbamate, in form of a yellow solid. LC-MS B: t _R =0.59 min; [M+H]+=218.22.

A.1.10.1. tert-Butyl (4-(difluoromethoxy)-2-methoxyphenethyl) carbamate.

The title compound was obtained according to General Procedure C above using 1-bromo-4-(difluoromethoxy)-2-methoxybenzene as a yellow oil. LCMS B: t _R =1.02 min; without ionization. A.1.11. 2-(2-Fluoro-6-methoxy-4-(trifluoromethyl)phenyl)ethan-1-amine The title compound was prepared according to General Procedure B above using (E)-1fluoro-3-methoxy-2 -(2-nitrovinyl)-5-(trifluoromethyl)benzene, as an amber oil. LC-MS B: t _R =0.64 min; [M+H]+=238.22.

A.1.11.1. (E)-1-Fluoro-3-methoxy-2-(2-nitrovinyl)-5-(trifluoromethyl)benzene.

The title compound was obtained according to General Procedure A above using 2-fluoro-6-methoxy-4-(trifluoromethyl)benzaldehyde as a light orange solid. LC-MS B: t _R =1.05 min; without ionization.

A.1.11.2. 2-Fluoro-6-methoxy-4-(trifluoromethyl)benzaldehyde.

A solution of 2-fluoro-6-hydroxy-4-(trifluoromethyl)benzaldehyde (1.00 g, 4.81 mmol) in anhydrous. DMF (20 mL) was treated at RT with cesium carbonate (1.879 g, 5.77 mmol) and iodomethane (0.604 mL, 9.61 mmol) and PM was stirred at RT under nitrogen for 2 h. Water was added and the mixture was extracted three times with Et ₂ O. The combined organic layers are then washed twice with water, dried over anhydrous. MgSO ₄ , filtered and concentrated under reduced pressure. Purification with PC (heptane/EtOAc=1/1) gave 2-fluoro-6-methoxy-4-(trifluoromethyl)benzaldehyde as a colorless solid (962 mg, 90%). LC-MS B: t _R =0.91 min; without ionization.

A.1.12. 2-(5-Chloro-2-methoxy-4-(trifluoromethyl)phenyl)ethane-1-amine.

The title compound was prepared according to General Procedure E above using t-butyl (5-chloro-2-methoxy-4-(trifluoromethyl)phenethyl)carbamate as a colorless solid. LC-MS B: t _R =0.66 min; [M+H]+=254.24.

A.1.12.1. tert-Butyl (5-chloro-2-methoxy-4-(trifluoromethyl)phenethyl)carbamate.

The title compound was obtained according to General Procedure C above using 1-bromo-5-chloro-2-methoxy-4-(trifluoromethyl)benzene as a light yellow solid. LC-MS B: t _R =1.08 min; without ionization.

A.1.12.2. 1-Bromo-5-chloro-2-methoxy-4-(trifluoromethyl)benzene.

A solution of 2-bromo-4-chloro-5-(trifluoromethyl)phenol (3.00 g, 10.40 mmol) in anhydrous. DMF (40 mL) was treated at RT with cesium carbonate (4.050 g, 12.40 mmol) and iodomethane (1.30 mL, 20.70 mmol) and PM was stirred at RT under nitrogen for 1 h. Water was added and the mixture was extracted three times with Et ₂ O. The combined organic layers are then washed twice with water, dried over anhydrous. MgSO ₄ , filtered and concentrated under reduced pressure. Purification with PC (heptane/EtOAc=7/3) gave 1-bromo-5-chloro-2-methoxy-4-(trifluoromethyl)benzene as a colorless solid (2.748 g, 92%). LC-MS B: t _R =1.06 min; without ionization.

A.1.13. 2-(2-(Difluoromethoxy)-4-(trifluoromethyl)phenyl)ethane-1-amine.

The title compound was prepared according to General Procedure E above using t-butyl (2-(difluoromethoxy)-4-(trifluoromethyl)phenethyl)carbamate as a yellow solid. LC-MS B: t _R =0.66 min; [M+H]+=256.22.

A.1.13.1. tert-Butyl (2-(difluoromethoxy)-4-(trifluoromethyl)phenethyl)carbamate.

The title compound was prepared according to General Procedure C above using 1-bromo-2-(difluoromethoxy)-4-(trifluoromethyl)benzene as a yellow oil. LC-MS B: t _R =1.06 min; without ionization.

A.1.14. 2-(3,4-Dichloro-2-methylphenyl)ethane-1-amine.

The title compound was prepared according to General Procedure E above using t-butyl (3,4-dichloro-2-methylphenethyl)carbamate as an orange solid. LC-MS B: t _R =0.62 min; [M+H] ⁺ =204.21.

A.1.14.1. tert-Butyl (3,4-dichloro-2-methylphenethyl) carbamate.

The title compound was obtained according to General Procedure C above using 1-bromo-3,4-dichloro-2-methylbenzene as a yellow oil. LC-MS B: t _R =1.08 min; without ionization.

A.1.15. 2-(4-(Difluoromethyl)-5-fluoro-2-methoxyphenyl)ethane-1-amine.

The title compound was prepared according to General Procedure E above using t-butyl (4-(difluoromethyl)-5-fluoro-2-methoxyphenethyl)carbamate as a colorless solid. LC-MS B: t _R =0.57 min; [M+H]+=220.12.

A.1.15.1. tert-Butyl (4-(difluoromethyl)-5-fluoro-2-methoxyphenethyl) carbamate.

The title compound was obtained according to General Procedure C above using 1-bromo-4-(difluoromethyl)-5-fluoro-2-methoxybenzene as a yellow oil. LCMS B: t _R =1.02 min; without ionization.

A.1.15.2. 1-Bromo-4-(difluoromethyl)-5-fluoro-2-methoxybenzene.

To a mixture of 4-bromo-2-fluoro-5-methoxybenzaldehyde (1.500 g, 6.11 mmol) in DCM (30 ml) was added dropwise (diethylamino)sulfur trifluoride (1.37 ml, 10.40 mmol) and PM was stirred overnight at RT . PM is then treated with sat. aq. NaHCO ₃ and DCM. Water layer is further extracted with DCM and the combined organic layers are dried over anhydrous. MgSO ₄ , filtered and concentrated under reduced pressure. Purification with PC (heptane/EtOAc=1/1) gave 1-bromo-4-(difluoromethyl)-5fluoro-2-methoxybenzene as a beige solid. LC-MS B: t _R =0.97 min; without ionization.

A.1.16. 2-(4-(Difluoromethyl)-2-methoxy-5-methylphenyl)ethane-1-amine.

The title compound was prepared according to General Procedure E above using t-butyl (4-(difluoromethyl)-2-methoxy-5-methylphenethyl)carbamate as a yellow solid. LCMS B: t _R =0.60 min; [M+H] ⁺ =216.17.

A.1.16.1. tert-Butyl (4-(difluoromethyl)-2-methoxy-5-methylphenethyl)carbamate.

To a mixture of tert-butyl (4-formyl-2-methoxy-5-methylphenethyl)carbamate (112 mg, 0.38 mmol) in DCM (4 mL) was added dropwise (diethylamino)sulfur trifluoride (85 μL, 0.64 mmol), and PM stirred overnight at RT. Additional (diethylamino)sulfur trifluoride (85 μl, 0.64 mmol) was then added and the PM was further stirred at RT for 2 h. The PM was then treated with sat. aq. NaHCO ₃ and DCM. Water layer is further extracted with DCM and the combined organic layers are washed with brine, dried over anhydrous. MgSO ₄ , filtered and concentrated under reduced pressure. Purification with PC (heptane/EtOAc=1/1) gave tert-butyl (4(difluoromethyl)-2-methoxy-5-methylphenethyl)carbamate as a yellow solid. LCMS B: tR=1.04 min; without ionization.

A.1.16.2. tert-Butyl (4-formyl-2-methoxy-5-methylphenethyl) carbamate.

The title compound was prepared according to General Procedure C above using 4-formyl-2-methoxy-5-methylphenyl trifluoromethanesulfonate as a pale yellow solid. LCMS B: t _R =0.96 min; without ionization.

A.1.16.3. 4-Formyl-2-methoxy-5-methylphenyl trifluoromethanesulfonate.

A solution of 4-(difluoromethyl)-2-methoxy-5-methylphenol (220 mg, 1.17 mmol) and TEA (0.42 ml, 3.04 mmol) in anhydrous. DCM (11 ml) at RT was treated with portions of 1,1,1-trifluoro-N-phenyl-N((trifluoromethyl)sulfonyl)methanesulfonamide (506 mg, 1.40 mmol) and PM was stirred at RT under nitrogen atmosphere overnight. PM is then concentrated under reduced pressure. Purification with PC (heptane to heptane/EtOAc=1/1) gave 4-formyl-2-methoxy-5-methylphenyl trifluoromethanesulfonate as a colorless oil (155 mg). LC-MS B: tR=1.01 min; without ionization.

A.1.16.4. 4-(Difluoromethyl)-2-methoxy-5-methylphenol.

A mixture of 1-(benzyloxy)-4-(difluoromethyl)-2-methoxy-5-methylbenzene (426 mg, 1.53 mmol) and 10% palladium on activated charcoal (42 mg) was placed under a nitrogen atmosphere, after which methanol (30 ml). The resulting suspension is placed under vacuum, then under a hydrogen atmosphere.

- 49 043145 (1 atm), and the reaction mixture is vigorously stirred at RT during the night. The reaction mixture was filtered through a pad of celite and concentrated under reduced pressure to give 4(difluoromethyl)-2-methoxy-5-methylphenol as a green solid which was further dried under BB (220 mg; 76%). LCMS B: tR=0.79 min; without ionization.

A.1.16.5. 1-(Benzyloxy)-4-(difluoromethyl)-2-methoxy-5-methylbenzene.

To a mixture of 4-(benzyloxy)-5-methoxy-2-methylbenzaldehyde (740 mg, 2.89 mmol) in DCM (20 mL) was added dropwise (diethylamino)sulfur trifluoride (0.64 mL, 4.91 mmol) and PM was stirred overnight at CT. Additional (diethylamino)sulfur trifluoride (0.30 mL, 2.34 mmol) was then added and the PM was further stirred at RT for 8 h. The PM was then treated with sat. aq. NaHCO ₃ and DCM. Water layer is further extracted with DCM and the combined organic layers are washed with brine, dried over anhydrous. MgSO ₄ , filtered and concentrated under reduced pressure. Purification with PC (heptane/EtOAc=1/1) gave 1-(benzyloxy)-4-(difluoromethyl)2-methoxy-5-methylbenzene as a colorless solid. LCMS B: tR=1.05 min; without ionization.

A.1.16.6. 4-(Benzyloxy)-5-methoxy-2-methylbenzaldehyde.

To a cooled (78°C) solution of 1-(benzyloxy)-4-bromo-2-methoxy-5-methylbenzene (1.130 g, 3.68 mmol) in anhydrous. THF (40 ml) was added with a solution of BuLi (1.6 M in hexanes, 3.45 ml, 5.52 mmol) and PM was further stirred at -78°C under nitrogen for 1 min. Then anhydrous is added dropwise to the previously obtained mixture. DMF (538 mg, 7.36 mmol) and stirring at -78°C was continued for 30 minutes. PM is then treated dropwise with sat. aq. NH4Cl and allowed to warm to RT. Water and Et ₂ O are then added and the layers are separated. Water layer is further extracted with Et ₂ O and the combined organic layers are dried over anhydrous. MgSO ₄ , filtered and concentrated under reduced pressure. Purification with PC (heptane/EtOAc=1/1) gave 4-(benzyloxy)-5-methoxy-2-methylbenzaldehyde as a colorless solid (0.816 g, 87%). LCMS B: tR=0.98 min; [M+H]+=257.27.

A.1.16.7. 1-(Benzyloxy)-4-bromo-2-methoxy-5-methylbenzene.

A solution of 2-(benzyloxy)-1-methoxy-4-methylbenzene (1.025 g, 4.49 mmol) in anhydrous. MeCN (20 ml) is treated with portions of N-bromosuccinimide (879 mg, 4.94 mmol). PM is further stirred at RT overnight. Add satiety. aq. NaHCO ₃ and DCM and the layers are separated. The organic layer is further washed with sat. aq. NaHCO ₃ , dried over anhydrous. MgSO ₄ , filtered and concentrated under reduced pressure. Purification with PC (heptane to EtOAc) gave 1-(benzyloxy)-4-bromo-2methoxy-5-methylbenzene as a pale yellow solid (1.35 g, 98%). LC-MS B: tR=1.09 min; [M+H] ⁺ =307.02.

A.1.16.8. 2-(Benzyloxy)-1-methoxy-4-methylbenzene.

To a solution of 2-methoxy-5-methylphenol (1.00 g, 7.09 mmol) in anhydrous. MeCN (22 mL) benzyl bromide (0.92 mL, 7.80 mmol), potassium carbonate (2.00 g, 14.20 mmol) and potassium iodide (119 mg, 0.70 mmol) are added successively at RT. PM is heated to 80° C. under nitrogen overnight. The PM is then allowed to cool to RT, filtered and the resulting filtrate concentrated under reduced pressure. Purification with PC (heptane/EtOAc=1/1) gave 2-(benzyloxy)-1-methoxy-4-methylbenzene as a colorless solid (1.65 g, quantitative). LC-MS B: tR=1.02 min; [M+H] ⁺ =229.28.

A.2. Synthesis of pyrimidine halide derivatives of formula (3).

A.2.1. 6-Chloro-N-(4-methylphenethyl)pyrimidine-4-amine.

The title compound was prepared according to General Procedure F above using 2-(p-tolyl)ethylamine and 4,6-dichloropyrimidine as an off-white solid. LCMS A: tR=0.87 min; [M+H] ⁺ =248.18.

Following the procedure described for the synthesis of A.2.1. above, the following pyrimidine halide derivatives are synthesized starting from the corresponding commercially available phenethylamines or phenethylamines A.1.1. - A.1.9. and 4,6-dichloropyrimidine or 4,6-diiodopyrimidine (see Table 3).

Table 3

Pyrimidine halide derivatives A.2.2. - A.2.11______

No. Compound i _R [min] (LC-MS) MS data, m/z [M+H] ⁺ A.2.2. X-(4-bromophenethyl)-6-iodopyrimidine-4-amine 0.84 (A) 403.95 A.2.3. 6-chloro-X-(3,4-dimethylphenethyl)pyrimidine-4amine 1.00 (V) 262.30

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A.2.4. N-(4-bromo-2-φτopφenethyl)-6-iodpyrimidine-4amine 0.93 (V) 423.87 A.2.5. 6-loro-M-(4-(trifluoromethyl)phenethyl)pyrimide and n4-amine 0.91 (A) 302.08 A.2.6. N-(4-bromo-2,6-diφτopφenethyl)-6-iodpyrimidine4-amine 0.95 (V) 440.99 A.2.7. N-(4-bromo-2-methoκciφenethyl)-6-iodpyrimidine4-amine 0.97 (V) 433.81 A.2.8. N-(4-bromo-2-etoksiφenethyl)-6-iodpyrimidine-4amine 1.01 (V) 448.06 A.2.9. N-(4-bromo-2,6-dimethocyphenethyl)-6iodopyrimidine-4-amine 1.00 (V) 463.92 A.2.10. 6-chloro-M-(2-methoxy-4- (methylthio)phenethyl)pyrimidine-4-amine 0.99 (V) 310.14 A.2.11. 6-chloro-M-(2-methoxy-4,5- dimethylphenethyl)pyrimidine-4-amine 1.02 (V) 292.15

A.2.12. 6-Chloro-K-(2-ethoxy-4-(trifluoromethyl)phenethyl)pyrimidine-4-amine.

Following General Procedure F, using 4,6-dichloropyrimidine and 2-(2-ethoxy-4(trifluoromethyl)phenyl)ethan-1-amine (A.1.7.), the title compound is obtained as a white powder. LC-MS B: t _R =1.08 min; [M+H]+=346.09.

A.2.13. 6-Chloro-N-(2,6-difluoro-4-methoxyphenethyl)pyrimidine-4-amine.

Following General Procedure F, using 4,6-dichloropyrimidine and 2-(2,6-difluoro-4-methoxyphenyl)ethan1-amine, the title compound is obtained as a brown powder. LCMS B: t _R =0.96 min; [M+H] ⁺ =300.15.

A.2.14. 6-Chloro-N-(2-methoxy-4,6-dimethylphenethyl)pyrimidine-4-amine.

The title compound was prepared according to General Procedure F above using 2-(2-methoxy-4,6-dimethylphenyl)ethan-1-amine and 4,6-dichloropyrimidine as an off-white solid. LC-MS B: t _R =1.03 min; [M+H] ⁺ =292.25.

A.2.15. 6-Chloro-K-(2-methoxy-5-(methylthio)phenethyl)pyrimidine-4-amine.

The title compound was prepared according to General Procedure F above using 2-(2-methoxy-5-(methylthio)phenyl)ethan-1-amine and 4,6-dichloropyrimidine as a yellow solid. LC-MS B: t _R =0.99 min; [M+H] ⁺ =310.14.

A.2.16. 6-Chloro-N-(4-(difluoromethoxy)-2-methoxyphenethyl)pyrimidine-4-amine.

The title compound was prepared according to general procedure F above, using 2-(4-(difluoromethoxy)-2-methoxyphenyl)ethan-1-amine (A.1.10.) and 4,6-dichloropyrimidine, as a colorless solid. LC-MS B: t _R =0.99 min; [M+H] ⁺ =330.10.

A.2.17. 6-Chloro-K-(2-methoxy-4-(trifluoromethyl)phenethyl)pyrimidine-4-amine.

The title compound was prepared according to General Procedure F above using 2-(2-methoxy-4-(trifluoromethyl)phenyl)ethan-1-amine and 4,6-dichloropyrimidine as a colorless solid. LCMS B: t _R =1.04 min; [M+H] ⁺ =332.14.

A.2.18. 6-Chloro-N-(2-fluoro-6-methoxy-4-(trifluoromethyl)phenethyl)pyrimidine-4-amine.

The title compound was prepared according to General Procedure F above using 2-(2-fluoro-6-methoxy-4-(trifluoromethyl)phenyl)ethan-1-amine (A.1.11.) and 4,6dichloropyrimidine, as a light orange solid. LC-MS B: t _R =1.05 min; [M+H] ⁺ =350.05.

A.2.19. 6-Chloro-N-(5-chloro-2-methoxy-4-(trifluoromethyl)phenethyl)pyrimidine-4-amine.

The title compound is prepared according to General Procedure F above using 2-(5-chloro-2-methoxy-4-(trifluoromethyl)phenyl)ethan-1-amine (A.1.12.) and 4,6dichloropyrimidine, as a colorless solid. LC-MS B: t _R =1.07 min; [M+H] ⁺ =366.09.

A.2.20. 6-Chloro-N-(2-(difluoromethoxy)-4-(trifluoromethyl)phenethyl)pyrimidine-4-amine.

The title compound was prepared according to General Procedure F above using 2-(2-(difluoromethoxy)-4-(trifluoromethyl)phenyl)ethan-1-amine (A.1.13.) and 4,6dichloropyrimidine, as off-white solid. LCMS B: t _R =1.04 min; [M+H] ⁺ =368.07.

A.2.21. 6-Chloro-K-(3,4-dichloro-2-methylphenethyl)pyrimidine-4-amine.

The title compound was prepared according to General Procedure F above, using 2-(3,4-dichloro-2-methylphenyl)ethan-1-amine (A.1.14.) and 4,6-dichloropyrimidine, as yellow solid. LC-MS B: t _R =1.05 min; [M+H] ⁺ =316.06.

A.2.22. 6-Chloro-N-(2-fluoro-6-methoxyphenethyl)pyrimidine-4-amine.

The title compound was prepared according to General Procedure F above using 2-(2-fluoro-6-methoxyphenyl)ethan-1-amine and 4,6-dichloropyrimidine as a colorless solid. LC-MS B: t _R =0.95 min; [M+H] ⁺ =282.23.

A.2.23. 6-Chloro-K-(4,5-difluoro-2-methoxyphenethyl)pyrimidine-4-amine.

The title compound was prepared according to General Procedure F above using 2-(4,5-difluoro-2-methoxyphenyl)ethan-1-amine and 4,6-dichloropyrimidine as a colorless solid. LC-MS B: t _R =0.97 min; [M+H] ⁺ =300.16.

A.2.24. 6-Chloro-N-(2-methoxy-4-(trifluoromethoxy)phenethyl)pyrimidine-4-amine.

The title compound was prepared according to General Procedure F above using 2-(2-methoxy-4-(trifluoromethoxy)phenyl)ethan-1-amine and 4,6-dichloropyrimidine as a colorless solid substances. LC-MS B: t _R =1.05 min; [M+H]+=348.07.

A.2.25. 6-Chloro-N-(4-(difluoromethyl)-5-fluoro-2-methoxyphenethyl)pyrimidine-4-amine.

The title compound was prepared according to General Procedure F above using 2-(4-(difluoromethyl)-5-fluoro-2-methoxyphenyl)ethan-1-amine (A.1.15.) and 4,6-dichloropyrimidine , as a colorless solid. LC-MS B: t _R =0.99 min; [M+H]+=332.13.

A.2.26. 6-Chloro-N-(4-(difluoromethyl)-2-methoxy-5-methylphenethyl)pyrimidine-4-amine.

The title compound was prepared according to General Procedure F above using 2-(4-(difluoromethyl)-2-methoxy-5-methylphenyl)ethan-1-amine (A.1.16.) and 4,6dichloropyrimidine, in as a beige solid. LC-MS B: t _R =1.00 min; [M+H]+=328.13.A.3.

Synthesis of boronic acid derivatives of formula (4).

A.3.1. 3-Fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophene-2-carboxylic acid.

To a solution of lithium diisopropylamide (2.0 M in THF/heptane/ethylbenzene, 9.84 ml, 39.4 mmol) in THF (74 ml) at -78°C was added a solution of 3-fluoro-2-thiophenecarboxylic acid (2.00 g, 13.1 mmol ) in THF (37 ml). PM is stirred for 10 min at -78°C, then a solution of 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (4.1 ml, 19.7 mmol) in THF (37 ml) is added dropwise ), PM is stirred for 20 min at -78°C, then it is allowed to warm to RT and stirred for 1 h. HCl (105 ml, 105 mmol) and stirred for 5 min. The mixture is extracted with EtOAc (3 times). The combined organic layers are washed with brine, dried over MgSO ₄ and concentrated to dryness. The crude product was purified with PC (DCM/MeOH, 1:0 to 9:1) to give the title compound as a green-yellow solid (2.64 g, 74%). LCMS A: t _R =0.46 min; without ionization.

A.3.2. Methyl 3-ethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophene-2-carboxylate.

The title compound was prepared according to Synthesis A.3.1 using methyl 3-ethylthiophene-2-carboxylate; LC-MS B: t _R =1.10 min; [M+H]+=297.27.

A.3.3. 3-Ethoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophene-2-carboxylic acid.

The title compound was prepared according to Synthesis A.3.1 using 3-ethoxythiophene-2-carboxylic acid. LCMS A: t _R =0.48 min; [M+H]+=217.07 (boronic acid, from pinacol ester hydrolysis on an LC-MS column).

A.3.4. 5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)thiophene-2-carboxylic acid.

The title compound is prepared according to the procedure described for A.3.1., starting from 3-(trifluoromethyl)thiophene-2-carboxylic acid. LC-MS A: t _R =0.59 min; without ionization.

A3.4.1. 3-(Trifluoromethyl)thiophene-2-carboxylic acid.

To a solution of 3-(trifluoromethyl)thiophene (0.4 mL, 3.68 mmol) in dry THF (10 mL) at -78°C was added a solution of butyl lithium (1.38 M in hexane, 2.93 mL, 4.05 mmol) and PM was stirred for 30 min. The reaction mixture is then poured onto an excess of freshly crushed dry ice-carbon dioxide. As soon as the temperature of PM returns to RT, add 1 N. HCl until pH<3 and the mixture is extracted with DCM (3x). The organic layer was dried over MgSO ₄ and concentrated in vacuo to give the title compound as a pale yellow solid (0.72 g, quantitative). LC-MS A: t _R =0.69 min; without ionization.

A.3.5. 5-(2-Ethoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-tetrazole.

2-ethoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)benzonitrile (500 mg, 1.83 mmol), azidotributyltin(IV) (0.768 ml, 2.75 mmol) and dry toluene (4 ml), it is sealed and heated at 180°C for 1 h under MW irradiation. The mixture is cooled to RT, treated with 0.1 N. HCl and extracted with EtOAc. The organic layer is dried over MgSO4 and concentrated in vacuo. The residue was purified with PC (heptane:EtOAc, 100:0 to 10:90) to give the title compound as a white solid (135 mg, 23%). LCMS B: t _R =0.87 min; [M+H] ⁺ =317.14.

A.3.5.1. 2-Ethoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile.

Solution of 2-hydroxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (1.50 g, 6.12 mmol), K ₂ CO ₃ (1.69 g, 12.2 mmol) in DMF (4 ml) and iodoethane (0.596 ml, 7.34 mmol) heated at 120°C for 30 min. The reaction mixture was cooled to RT, partitioned between DCM and 1N HCl. _NaHC03 . The aqueous layer is re-extracted with DCM, the combined organics are dried (MgSO ₄ ) and concentrated under reduced pressure. This gave the title compound as a beige solid (1.31 g, 78%). LCMS B: tR=0.96 min; [M+CH ₃ CN+H]+=315.10.

A.3.6. 2-(Difluoromethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid.

Bis(pinacolato)diboron (1.355 g, 5.34 mmol), KOAc (1.047 g, 10.7 mmol ) and 1,1'-bis(diphenylphosphino)ferrocene dichloropalladium(II) (208 mg, 0.285 mmol). PM is stirred at 100° C. for 17 h, then cooled to RT and filtered through a pad of celite, washing with EtOAc.

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The filtrate was washed with water and the aqueous layer was extracted (x2) with EtOAc. The organic layers are combined, washed with brine, dried over MgSO ₄ , filtered and concentrated under reduced pressure. The residue was purified with PC eluting with DCM to give the title compound as an orange solid (846 mg, 76%). LCMS A: t _R =0.37 min;

[M+H] ⁺ =313.11.

Following the procedure described for the synthesis of A.3.6. above, synthesize the following derivatives of boronic acid, starting from the corresponding commercially available halides (see table. 4).

Table 4

Boronic acid derivatives A.3.7. - A.3.11

No. Compound i _R [min] (LC-MS) MS data, m/z [M+H] ⁺ A.3.7. 2-Cyclobutoxy-5-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl)benzoic acid 0.91 (A) 319.11 A.3.8. 1-Methyl-6-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1,2-dihydro-3H-ind azol-3-one 0.77 (A) 275.27 A.3.9. 5-(4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2yl)phenyl)isoxazol-3-ol 0.85 (A) 288.17 A.3.10. 5-(4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2yl)phenyl)-[1,2,4-]oxadiazol-3-ol 0.82 (V) 290.10 A.3.11. Methyl 2-(methylthio)-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)benzoate 0.96 (A) 309.18

A.3.12. 2-Fluoro-6-propyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid.

The title compound is prepared according to the procedure described for A.3.6., starting from 4-bromo-2-fluoro-6-propylbenzoic acid. LCMS D: t _R =0.48 min; [M-N]+=307.11.

A.3.12.1. 4-Bromo-2-fluoro-6-propylbenzoic acid.

To a solution of 4-bromo-2,6-difluorobenzoic acid (5.00 g, 21.1 mmol) in THF (50 ml) at 0°С was added dropwise n-propylmagnesium bromide (2 M in THF, 21.6 ml, 43.2 mmol). The RM is allowed to reach RT and stirred for 17 h, then quenched carefully at 0° C. with MeOH (10 ml). After stirring for 5 minutes, the solvent is removed under reduced pressure. The residue was partitioned between EtOAc and 2N. HC1. The aqueous phase is re-extracted with EtOAc (2x). United org. the phases are washed with water, brine, dried over MgSO ₄ , filtered and concentrated. The residue was purified with PC (heptane/EtOAc, 100:0 to 70:30) to give the title compound as a white solid (4.45 g, 81%). LCMS A: t _R =0.84 min; without ionization.

A.3.13. 3-(2-Ethoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-[1,2,4]oxadiazol5(4H)-one.

The title compound was prepared according to the procedure described for A.3.6., starting from 3-(4-bromo-2-ethoxyphenyl)-[1,2,4]oxadiazol-5(4H)-one. LC-MS A: t _R =0.89 min; [M+H] ⁺ =333.06.

A.3.13.1. 3-(4-Bromo-2-ethoxyphenyl)-[1,2,4]oxadiazol-5(4H)-one.

A solution of 4-bromo-2-ethoxy-X'-hydroxybenzimidamide (1.395 g, 5.38 mmol), 1,-carbonyldiimidazole (1.31 g, 8.08 mmol) and DBU (1.23 ml, 8.08 mmol) in dioxane (20 ml) was stirred at 90°C for 4 h 30 min. After the mixture is cooled to RT, the product precipitates upon addition of IM HCl. The dioxane is partially evaporated with a stream of N ₂ and then the solid is filtered off in vacuo, washing with water. The title compound was obtained as a white solid (1.375 g, 90%). LC-MS A: t _R =0.81 min, [M+MeCN] ⁺ =325.89.

A.3.13.2. 4-Bromo-2-ethoxy-M'-hydroxybenzimidamide.

A suspension of 4-bromo-2-ethoxybenzonitrile (1.50 g, 6.5 mmol), hydroxylamine hydrochloride (913 mg, 13 mmol) and NaHCO ₃ (1.365 g, 16.3 mmol) in water (1.32 ml) and EtOH (26.6 ml) was stirred in a sealed tube at 90° C. for 3 hours. After the mixture has cooled to RT, the product precipitates out of the PM after the addition of water. The solid is filtered off, washing with water and some Et ₂ O. Thus, the first crop of pure title compound (947 mg) is obtained as a white solid. The filtrate is extracted with EtOAc. The organic layer is then washed twice with brine, dried over MgSO ₄ , filtered and concentrated. The residue was purified with FC (hept/EtOAc, 1:1) to give another crop of pure title compound as a white solid (448 mg) and this was combined with the first batch from the precipitation. The title compound was obtained as a white solid (1.395 g, 83%). LC-MS A: t _R =0.53 min, [M+H] ⁺ =259.03.

A.3.14. 3-(2-Ethoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)propanoic acid.

The title compound was prepared according to the procedure described for A.3.6 starting from 3-(4-bromo-2-ethoxyphenoxy)propanoic acid. LCMS D: t _R =0.45 min; [M-N] ⁺ = 335.18.

A.3.14.1. 3-(4-Bromo-2-ethoxyphenoxy)propanoic acid.

4-bromo-2-ethoxyphenol (1300 mg, 5.98 mmol), H ₂ O (5 ml), 32% NaOH (1.332 ml, 14.38 mmol) and 3-chloropropionic acid (674 mg, 6.08 mmol ). It is sealed and irradiated at 120°C for 40 minutes. PM is diluted in water and the pH is lowered to pH9 with 2N hydrochloric acid.

-53 043145

HCl, then extracted twice with EtOAc. The main aqueous layer was then acidified to pH2 and extracted twice with EtOAc, the combined organic extracts were washed with water, brine, dried over MgSO ₄ , filtered and evaporated to dryness to give the title compound as a white powder (0.448 g, 56%) . LC-MS A: t _R =0.89 min; [M+H]+=289.10.

A.3.15. Methyl (E)-3-(3-ethoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophen-2-yl)acrylate.

The title compound was prepared according to the procedure described for A.3.1., starting from methyl (E)-3-(3-ethoxythiophen-2-yl)acrylate. LC-MS A: t _R =1.02 min; [M+H]+=339.14.

A.3.15.1. Methyl (E)-3-(3-ethoxythiophen-2-yl)acrylate.

A suspension of 3-ethoxythiophene-2-carbaldehyde (2.90 g, 18.6 mmol), methyl bromoacetate (3.07 ml, 33.4 mmol) and triphenylphosphine (7.305 g, 27.8 mmol) in aq. saturated NaHCO ₃ (100 ml) was stirred at RT for 5 h. THF (30 ml) was added and PM was stirred overnight at RT. It is then extracted twice with DCM. The combined organic layers are dried over MgSO4, filtered and concentrated in vacuo. The crude product was purified with PC (Hept/EtOAc, 9:1) to give the title compound as a dark orange oil (2.9 g, 100%). LC-MS A: t _R =0.69 min; [M+MeCN]+=198.26.

A.3.16. 3-(3-Ethoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophen-2-yl)propanoic acid.

To a solution of methyl (E)-3-(3-ethoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophen-2yl)acrylate [A.3.15.] (250 mg, 0.786 mmol) in MeOH (15 ml) was added 5% wet Pd/C (50 mg). The vessel is then inerted with N ₂ and purged with H ₂ . The mixture is placed in an autoclave and stirred overnight at RT under 4 bar H ₂ pressure, then for 1 d at 50° C. under 4 bar H ₂ pressure. After filtration on a Whatman filter, 10% NaOH (1.18 ml, 11.8 mmol) is added and PM is stirred for 1 h at RT. Then it is treated with 2 N. HCl until pH<1 and extracted twice with EtOAc. The organic layer was dried over MgSO ₄ and concentrated to give the title compound as a dark yellow oil (287 mg, 74%). LC-MS A: t _R =0.86 min; [M+H]+=327.09.

A.3.17. 3-(3-Methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophen-2-yl)oxetan-3-ol.

The title compound is prepared according to the procedure described for A.3.1., starting from 3-(3-methoxythiophen-2-yl)oxetan-3-ol. LCMS A: t _R =0.78 min; [M-H2O]+=295.12.

A.3.17.1. 3-(3-Methoxythiophen-2-yl)oxetan-3-ol.

Butyllithium ₍ 1.6 M in hexane, 6.4 ml, 10.3 mmol). PM was stirred at RT for 30 min, then 3-oxetanone (0.761 ml, 12.9 mmol) was added dropwise and PM was stirred at RT for 35 min, then diluted with water, the aqueous layer was extracted three times with EtOAc and the combined organic layers dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified with PC (Hept to Hept/EtOAc, 8:2) to give the title compound as a light yellow oil (1.123 g, 70%). LCMS A: t _R =0.53 min; [MH ₂ O]+=169.04.

A.3.18. Methyl 2-(3-ethoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophen-2-yl)acetate.

Suspension of methyl 2-(3-ethoxythiophen-2-yl)acetate (815 mg, 4.07 mmol), bis-(pinacolato)diboron (633 mg, 2.44 mmol), 0.5-cyclooctadiene)(methoxy)iridium(I) dimer (28.9 mg, 0.0437 mmol) and 4,4'-ditert-butyl-2,2'-dipyridyl (26.8 mg, 0.0999 mmol) in THF (19.3 ml) are degassed with a stream of nitrogen for 15 min and then stirred at 80°C during the night. The PM is concentrated under reduced pressure and the residue is purified with PC (Hept to Hept/EtOAc, 9:1) to give the title compound as a colorless oil which crystallizes on standing. LCMS B: t _R =1.03 min; [M+H]+=327.14.

A.3.18.1. Methyl 2-(3-ethoxythiophen-2-yl)acetate.

Silver benzoate (1800 mg, 7.78 mmol) and PM was stirred at RT for 2 h. It was then diluted with EtOAc and filtered through celite. The filtrate is washed twice with sat. aq. NaHCO ₃ and once with saline. The organic layer is dried over MgSO ₄ , filtered and concentrated. The residue was purified with PC (Hept to Hept/EtOAc, 95:5) to give the title compound as a light yellow oil (817 mg, 40%). LCMS B: t _R =0.86 min, [M+H] ⁺ =201.14.

A.3.18.2. 2-Diazo-1-(3-ethoxythiophen-2-yl)ethan-1-one.

A solution of 3-ethoxythiophene-2-carboxylic acid (2500 mg, 14.1 mmol) in DCM (120 ml) was treated dropwise with thionyl chloride (1.56 ml, 21.1 mmol). PM was stirred at RT overnight, then it was concentrated in vacuo and the residue was dissolved in MeCN (80 ml). TEA (2.2 ml, 15.8 mmol) is added dropwise and the solution is cooled to 0°C. (Trimethylsilyl)diazomethane (2 M solution, 15 mL, 30 mmol) was added dropwise and PM was stirred at RT for 2 d. It was then carefully quenched by dropwise addition of AcOH until no more bubbling was observed. . PM is then concentrated and the residue partitioned between EtOAc and water. The organic layer is then washed with sat.

- 54 043145 aq. Nai ΚΌ ₃ and brine, dried (MgSO ₄ and concentrated. The residue was purified with FC (Hept to Hept/EtOAc, 8:2) to give the title compound as an intense yellow solid (2.028 g, 73%). LC-MS B: t _R =0.78 min, [M+H]+=197.15.

A.3.19. Ethyl 2-((2-ethoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)amino)-2-oxoacetate.

The title compound was prepared according to the procedure described for A.3.6., starting from ethyl 2-((4-bromo-2-ethoxyphenyl)amino)-2-oxoacetate. LCMS A: t _R =0.98 min; [M+H]+=364.21.

A.3.19.1. Ethyl 2-((4-bromo-2-ethoxyphenyl)amino)-2-oxoacetate.

To a solution of 4-bromo-2-ethoxyaniline (1.10 g, 4.84 mmol) in DCM (35 mL) was added TEA (0.748 mL, 5.32 mmol) at RT. PM is cooled to 0°C and ethyl oxalyl chloride (0.61 ml, 5.32 mmol) is added dropwise. PM is stirred for 30 min at 0° C., then allowed to warm to RT and stirred for 30 min. PM partitioned between EtOAc and sat. aq. _NaHC03 . The two layers are separated and the organic layers are washed with water, brine then dried over MgSO4, filtered and the solvent removed in vacuo to give the title compound as a brown solid (1.52 g, 99%). LCMS A: t _R =0.92 min; [M+MeCN]+=316.04.

A.3.20. 2-(2-Methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)ethan-1-ol

Cesium carbonate (456 mg, 1.4 mmol) and 2-iodoethanol (0.0563 ml, 0.72 mmol) were successively added to a solution of 4-hydroxy-3-methoxyphenylboronic acid pinacol ester (100 mg, 0.4 mmol) in DMF (4 mL). PM is then stirred at 100° C. for 4 h. PM is cooled to RT and 2-iodoethanol (0.0281 mL, 0.36 mmol) is added. PM is heated to 100°C and stirred for 1 h, then cooled to RT, diluted with EtOAc and washed with water (3x). The organic layer is dried over MgSO4, filtered and concentrated under reduced pressure. The residue is purified with acidic prep. HPLC gave the title compound as a beige solid (23 mg, 20%). LC-MS B: t _R =0.83 min; [M+H]+=295.25.

A.3.21. 3-Ethoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophene-2-sulfonamide.

3-ethoxythiophene-2-sulfonamide (308 mg, 1.49 mmol), bis(pinacolato)diboron (578 mg, 2.23 mmol), (1,5-cyclooctadiene)(methoxy)iridium(1) dimer ( 49.3 mg, 0.0743 mmol) and 4,4'-di-tert-butyl-2,2'-dipyridyl (32.6 mg, 0.119 mmol) in cyclohexane (12 mL), it was capped and PM was stirred at 120°C for 30 min with MW irradiation. PM was concentrated and purified with PC (DCM/(MeOH/NH ₃ , 98:2), 100:0 to 80:20) to give the title compound as an orange solid (670 mg, quantitative). LC-MS B: t _R =0.47 min; [M+H]+=252.26 (mass value from boronic acid resulting from pinacol ester cleavage during LC-MS analysis).

A.3.21.1. 3-Ethoxythiophene-2-sulfonamide.

To a solution of 3-fluorothiophene-2-sulfonamide (607 mg, 3.35 mmol) in DMF (3 mL) was added EtOH (2 mL, 34.3 mmol) at RT followed by NaH (241 mg, 10 mmol). PM is stirred overnight at 90°C. It is cooled to RT, NaH (241 mg, 10 mmol) and EtOH (1 ml) are added and PM is stirred at 90° C. for 4 h. It is cooled to RT, quenched with water and extracted twice with EtOAc. The combined organic layers are washed with brine, dried over anhydrous MgSO ₄ , filtered and concentrated under reduced pressure. The residue was purified with PC (heptane/EtOAc, 100:0 to 1:1) to give the title compound as a white solid (308 mg, 44%). LCMS B: t _R =0.56 min; [M+H]+=208.28.

A.3.22. Methyl 2-(2-hydroxyethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate.

The title compound was prepared according to the procedure described for A.3.6., starting from methyl 4-bromo-2-(2-hydroxyethoxy)benzoate. LC-MS B: t _R =0.89 min; [M+H]+=323.26.

A.3.22.1. Methyl 4-bromo-2-(2-hydroxyethoxy)benzoate

NaH (101 mg, 4.2 mmol) was added in portions to a solution of methyl 4-bromo-2-hydroxybenzoate (500 mg, 2.1 mmol) in DMF (5 mL) at 0°C. PM is stirred for several minutes at 0°C, then 2-bromoethanol (0.235 ml, 3.15 mmol) is added and PM is stirred at 90°C for 2 h 45 min, then cooled to RT. Water is added to PM and extracted twice with EtOAc. The combined organic layers are washed with brine, dried over MgSO ₄ , filtered and concentrated under reduced pressure. The residue was purified with PC (heptane/EtOAc, 1:0 to 6:4) to give the title compound as a colorless oil (358 mg, 62%). LC-MS B: t _R =0.77 min; [M+H]+=275.14.

A.3.23. 7-(4,4,5,5-T etramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-5H-thieno[3,2-e] [1,4]dioxepin- 5th.

The title compound is prepared according to the procedure described for A.3.21., starting from 2,3-dihydro-5H-thieno[3,2-e][1,4]dioxepin-5-one. LC-MS B: t _R =0.51 min; [M+H]+=215.41 (mass value from boronic acid resulting from pinacol ester cleavage during LC-MS analysis).

A.3.23.1. 2,3-Dihydro-5H-thieno[3,2-e][1,4]dioxepin-5-one.

K ₂ CO ₃ (623 mg, 4.5 mmol), methyl 3-hydroxythiophene-2- 55 043145 carboxylate (250 mg, 1.5 mmol) and DMF (5 ml) are loaded into a test tube for the MW instrument. PM was stirred for several minutes, then 2-bromoethanol (0.146 ml, 1.95 mmol) was added, the tube was capped and heated at 100°C for 2 h under MW irradiation. Add 2-bromoethanol (0.0319 ml, 0.45 mmol) and PM stirred at 90°C overnight at this temperature. After the mixture has cooled to RT, water is added and PM is extracted three times with EtOAc. The combined organic layers are dried over MgSO ₄ , filtered and concentrated under reduced pressure to give the crude title compound as a brownish solid (338 mg, quantitative). LC-MS B: t _R =0.61 min; [M+H]+=170.94.

A.3.24. Methyl 4-chloro-3-ethoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophene-2carboxylate.

The title compound was prepared according to the procedure described for A.3.21, starting from methyl 4-chloro-3-ethoxythiophene-2-carboxylate. LC-MS B: t _R =0.75 min; without ionization.

A.3.24.1. Methyl 4-chloro-3-ethoxythiophene-2-carboxylate.

Potassium carbonate (792 mg, 5.62 mmol) was added to a solution of methyl 4-chloro-3-hydroxythiophene-2-carboxylate (528 mg, 2.74 mmol) in DMF (27 mL) at RT. PM is stirred for 15 min at 60°C, then iodoethane (0.267 mL, 3.29 mmol) is added and PM is stirred at 60°C for 1 h 30 min, cooled to RT, and partitioned between EtOAc and water. The organic layer was washed again with water then brine, dried over MgSO ₄ , filtered and evaporated to dryness to give the title compound as a yellow oil (570 mg, 94%). LC-MS B: t _R =0.92 min; [M+H] ⁺ =221.03.

A.3.25. 3-(4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-[1,2,4]oxadiazol-5(4H)-one.

The title compound is prepared according to the procedure described for A.3.6., starting from 3-(4-bromophenyl)-[1,2,4]oxαduαzol-5(4H)-oneα. LC-MS B: t _R =0.90 min; [M+MeCN]+=330.12.

A.3.26. 3-(2-Ethoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-[1,2,4]oxadiazol5(4H)-one.

The title compound was prepared according to the procedure described for A.3.6., starting from 3-(4-bromo-2-ethoxyphenyl)-[1,2,4]oxadiazol-5(4H)-one. LC-MS B: t _R =0.98 min; [M+H]+=333.18.

A.3.26.1. 3-(4-Bromo-2-ethoxyphenyl)-[1,2,4]oxadiazol-5(4H)-one.

A solution of (Z)-4-bromo-2-ethoxy-N'-hydroxybenzimidamide (1.25 g, 4.82 mmol), 1,1'carbonyldiimidazole (1.17 g, 7.24 mmol) and 1,8-diazabicyclo[5.4.0]undec- 7-ene (1.1 ml, 7.24 mmol) in dioxane (18 ml) was stirred at 90°C for 90 min. After the mixture is cooled to RT, the product precipitates upon addition of 1M HCl. The dioxane is partially evaporated with a stream of N ₂ and then the solid is filtered off in vacuo, washing with water. The title compound was obtained as a white solid (1.096 g, 80%). LC-MS B: t _R =0.53 min, no ionization; 1H NMR (500 MHz, d6-DMSO) δ: 12.22-12.56 (m, 1H), 7.54 (d, J=8.2 Hz, 1H), 7.45 (d, J=1.7 Hz, 1H), 7.30-7.33 (m , 1H), 4.14-4.25 (m, 2H), 1.33-1.39 (m, 3H).

A.3.26.2. (Z)-4-Bromo-2-ethoxy-N'-hydroxybenzimidamide.

A suspension of 4-bromo-2-ethoxybenzonitrile (1.50 g, 6.5 mmol), hydroxylamine hydrochloride (913 mg, 13 mmol) and NaHCO ₃ (1.365 g, 16.3 mmol) in water (1.32 ml) and EtOH (26.6 ml) was stirred in a sealed tube at 90°C for 6 h. After the mixture is cooled to RT, the product precipitates from PM after adding water. The solid is filtered off under high vacuum, washing with water and some Et ₂ O. Thus, the first crop of pure title compound (947 mg) is obtained as a white solid. The filtrate is extracted with EtOAc. The organic layer is then washed twice with brine, dried over MgSO ₄ , filtered and concentrated. The residue was purified with FC (hept/EtOAc, 1:1) to give another crop of pure title compound as a white solid (448 mg) and this was combined with the first batch from the precipitation. The title compound was obtained as a white solid (1.395 g, 83%). LC-MS B: t _R =0.53 min, [M+H]+=259.12.

A.3.27. 1-Methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroquinazolin-2(1H)-one.

The title compound was prepared according to the procedure described for A.3.6., starting from 7-bromo-1-methyl-3,4-dihydroquinazolin-2(1H)-one. LCMS A: t _R =0.80 min; [M+H]+=289.18.

A.3.28. Ethyl 2-(2-ethoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-oxoacetate.

The title compound is prepared according to the procedure described for A.3.6., starting from ethyl 2-(4-bromo-2-ethoxyphenyl)-2-oxoacetate. LCMS A: t _R =0.98 min; [M+H]+=349.19.

A.3.28.1. Ethyl 2-(4-bromo-2-ethoxyphenyl)-2-oxoacetate.

Iodoethane (0.799 ml, 9.69 mmol) was added to a solution of 2-(4-bromo-2-hydroxyphenyl)-2-oxoacetic acid (1.00 g, 3.88 mmol) and K2CO3 (1.605 g) in DMF (10 ml) and PM was stirred at 50°C for 2 d. K2CO3 (1.605 g, 11.6 mmol) and iodoethane (0.799 ml, 9.69 mmol) are added and PM is stirred at 60°C for 20 h. PM is filtered, washed with DCM and concentrated at reduced pressure. The residue was purified with PC (Hept/EtOAc, 1:0 to 4:1) to give the title compound as a beige solid (0.921 g, 79%). LCMS A: t _R =0.92 min; [M+H]+=303.03.

- 56 043145

A.3.29. Methyl (2-ethoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)glycinate.

The title compound is prepared according to the procedure described for A.3.6., starting from methyl (4-bromo-2-ethoxyphenyl)glycinate. LC-MS B: t _R =0.93 min; [M+H]+=336.28.

A.3.29.1. Methyl (4-bromo-2-ethoxyphenyl) glycinate.

DiPEA (0.673 ml, 3.96 mmol) was added to a solution of 4-bromo-2-ethoxyaniline (0.60 g, 2.64 mmol) in DMF (2.5 ml), followed by methyl bromoacetate (0.275 ml, 2.9 mmol). The mixture is stirred at 90° C. for 1 hour in a microwave. The DMF was evaporated in high vacuum and the residue was purified with PC eluting with 1:0 to 17:3 Hept/EtOAc mixtures to give the title compound as a dark red oil (0.71 g, 94%). LCMS A: t _R =0.89 min; [M+H]+=288.08.

A.3.30. 3-Methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophene-2-carboxylic acid.

To a solution of methyl 3-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophene-2-carboxylate (650 mg, 1.85 mmol) in MeOH (12 ml) , THF (4 mL) and H ₂ O (4 mL) 10% NaOH (3.71 mL, 9.26 mmol) was added at RT and PM was stirred at RT overnight. Solvents are removed in vacuo. The main aqueous layer is acidified to pH=3-4 using 1N. HCl and extracted with EtOAc (2x). The combined organic layers were washed with brine, dried over MgSO ₄ , filtered and the solvent removed in vacuo to give the title compound as a brown solid, dried well under BB (365 mg, 69%). LC-MS B: t _R =0.44 min; [M+H]+=203.3 (boronic acid, from pinacol ester hydrolysis on an LC-MS column).

A.3.30.1. Methyl 3-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophene-2-carboxylate.

The title compound was prepared according to the procedure described for A.3.18, starting from methyl 3-methoxythiophene-2-carboxylate. LCMS B: t _R =0.56 min; [M+H]+=216.99 (boronic acid, from pinacol ester hydrolysis on an LC-MS column).

A.3.31. 2-Ethoxy-3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid.

Ethyl 2-ethoxy-3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (960 mg, 2.38 mmol) is dissolved in MeOH/THF (1 :1) (10 ml). Then 10% NaOH (4.77 mL, 11.9 mmol) is added and PM is stirred at RT for 4 h. HCl (~10 ml) until acidic pH (<2) and extracted with EtOAc. The resulting organic phase was dried over MgSO ₄ and concentrated to give the title compound as a yellow solid (0.735 g, 81%). LC-MS B: t _R =0.91 min; [M+H] ⁺ =311.26.

A.3.31.1. Ethyl 2-ethoxy-3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate.

The title compound is prepared according to the procedure described for A.3.6. starting from ethyl 4-bromo-2-ethoxy-3-fluorobenzoate. LC-MS B: t _R =1.10 min; [M+H]+=339.26.

A.3.31.2. Ethyl 4-bromo-2-ethoxy-3-fluorobenzoate.

Ethyl iodide (0.508 ml, 6.35 mmol) was added to a solution of 4-bromo-3-fluoro-2-hydroxybenzoic acid (750 mg, 3.1 mmol) and K ₂ CO ₃ (1070 mg, 7.74 mmol) in DMF (6 ml). The reaction mixture is stirred for 2.5 d at RT, then it is partitioned between DCM and brine. The aqueous layer was re-extracted with DCM, the combined organics were washed with brine, then dried (MgSO ₄ ) and concentrated under reduced pressure to give the title compound as a dark orange oil. LCMS B: t _R =1.03 min; [M+H]+=291.01.

A.3.32. 2-(methylamino)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide.

2-(Methylamino)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (300 mg, 1.08 mmol) is dissolved in DMF (5 ml), TEA is added (0.452 ml, 3.25 equiv.) and HATU (535 mg, 1.41 mmol) followed by the addition, after 2 min of stirring, of ammonia (0.5 M in dioxane, 2.6 ml, 1.3 mmol). PM is stirred at RT for 1 h, then treated with 1 ml of 25% ammonia and extracted with DCM. The organic layer is washed with brine, dried (MgSO4) and concentrated. The residue was purified with FC (Hept/EtOAc, 1:0 to 1:3) to give the title compound as a light yellow solid (165 mg, 55%). LC-MS E: t _R =0.80 min; [M+H]+=277.25.

A.3.33. 2-(Ethylamino)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide.

The title compound was prepared according to the procedure described for A.3.32 starting from 2-(ethylamino)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzoic acid. LCMS A: t _R =0.82 min; [M+H] ⁺ =291.25.

A.3.33.1. 2-(Ethylamino)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid.

The title compound is prepared according to the procedure described for A.3.6., starting from 4-bromo-2-(ethylamino)benzoic acid. LCMS A: t _R =0.85 min; [M+H]+=292.18.

A.3.34. N-(2-Ethoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)formamide.

The title compound is prepared according to the procedure described for A.3.6., starting from N-(4-bromo-2-ethoxyphenyl)formamide. LC-MS B: t _R =0.94 min; [M+H]+=292.23.

A.3.34.1. N-(4-Bromo-2-ethoxyphenyl)formamide.

A mixture of 4-bromo-2-ethoxyaniline (1283 mg, 5.64 mmol), ethyl formate (18.5 ml, 226 mmol) and TEA (3.14 ml, 22.6 mmol) was stirred in a sealed tube at 85°C for 5 days. PM is concentrated under reduced pressure. The residue was purified with FC (EtOAc:Hept, 0:1 to 4:6) to give the title compound as a brown solid (788 mg, 57%). LC-MS B:

- 57 043145 t _R =0.84 min; [M+H]+=285.06.

A.3.35. 2-Butoxy-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid.

The title compound is prepared according to the procedure described for A.3.6., starting from 4-bromo-2-butoxy-6-fluorobenzoic acid. LCMS A: t _R =0.92 min; [M+H] ⁺ =339.21.

A.3.35.1. 4-Bromo-2-butoxy-6-fluorobenzoic acid.

Methyl 4-bromo-2-butoxy-6-fluorobenzoate (1246 mg, 3.94 mmol) was dissolved in EtOH (15 ml). 32% NaOH (1.82 ml, 19.7 mmol) is added and PM is heated to 60°C for 1 h. It is cooled to RT and diluted with EtOAc. Add 2 n. HCl (~10 ml) until an acidic pH is reached (<2). Water layer was extracted twice with EtOAc. The resulting organic phase was dried over MgSO ₄ and concentrated to give the title compound as a white powder (1.15 g, 99%). LCMS D: tR=0.52 min; [MH] ⁺ =290.89.

A.3.35.2. Methyl 4-bromo-2-butoxy-6-fluorobenzoate.

Cs ₂ CO ₃ (2.62 g, 8.03 mmol) was added to a solution of methyl 4-bromo-2-fluoro-6-hydroxybenzoate (1.00 g, 4.02 mmol) in DMF (10 ml), after which 1-iodobutane (0.685 ml, 6.02 mmol). PM is stirred at 120° C. for 2 hours in a microwave. PM is concentrated under reduced pressure, the residue is partitioned between DCM and water. The aqueous layer is re-extracted with DCM, the combined organics are dried (MgSO ₄ ) and concentrated under reduced pressure. Purification with PC (Hept/EtOAc, 1:0 to 19:1) gave the title compound as a colorless oil (1.24 g, 99%). LCMS A: t _R =0.98 min; [M+H]+=306.84.

A.3.36. Methyl 3-(3-ethoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophen-2-yl)propanoate.

Methyl 3-(3-ethoxythiophen-2yl)propanoate (593 mg, 2.77 mmol), bis-(pinacolato)diboron (574 mg, 2.22 mmol), dimer (1,5cyclooctadiene)(methoxy )iridium(1) (91.8 mg, 0.138 mmol) and 4,4'-di-tert-butyl-2,2'-dipyridyl (59.5 mg, 0.222 mmol) in cyclohexane (20 mL). The tube is purged with argon, sealed and heated at 130°C for 15 min in a MW apparatus. PM was concentrated under reduced pressure and the residue was purified with PC (Hept/DCM, 1:1 to 0:1) to give the title compound as a clear yellow oil (2.178 g, 77%). LCMS B: t _R =1.07 min; [M+H]+=341.12.

A.3.36.1. Methyl 3-(3-ethoxythiophen-2-yl)propanoate.

To a solution of methyl (E/Z)-3-(3-ethoxythiophen-2-yl)acrylate (1818 mg, 8.31 mmol) in MeOH (30 mL) was added 10% wet Pd/C (300 mg). The vessel is then inerted with N2 and purged with H ₂ . The mixture is heated at 50° C. overnight under 5 bar H ₂ pressure. To the mixture was added 10% wet Pd/C (300 mg) and heated further at 50° C. under 6 bar H ₂ pressure for 4 days. The mixture was filtered on a 0.45 µm Whatman filter, rinsing with MeOH, and concentrated to give the title compound as a colorless oil (1.78 g, 100%). LC-MS B: t _R =0.90 min; [M+H]+=215.36.

A.3.36.2. Methyl (E/Z)-3-(3-ethoxythiophen-2-yl)acrylate

A suspension of 3-ethoxythiophene-2-carbaldehyde (2.90 g, 18.6 mmol), methyl bromoacetate (3.07 ml, 33.4 mmol) and triphenylphosphine (7.305 g, 27.8 mmol) in aq. saturated NaHCO ₃ (100 ml) was stirred at RT for 5 h. THF (30 ml) was added and PM was stirred overnight at RT. It is then extracted twice with DCM. The combined organic layers are dried over MgSO ₄ , filtered and concentrated in vacuo. The crude product was purified with PC (Hept/EtOAc, 9:1) to give the title compound as a dark orange oil (3.10 g, 79%). LC-MS A: t _R =0.86 min; [M+H]+=213.25.

A.3.37. 3-Ethoxy-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclobut-3-en-1,2-dione.

3-Ethoxy-4-(tributylstannyl)cyclobut-3-ene-1,2-dione (335 mg, 0.807 mmol) and 4-iodophenylboronic acid pinacol ester (298 mg, 0.904 mmol) are dissolved in DMF (4 ml) at bubbling N2 for 5 min. Trans-benzyl(chloro)bis-(triphenylphosphine)palladium(11) (36.7 mg, 0.0484 mmol) and CuI (15.4 mg, 0.0807 mmol) are added and PM is stirred at RT for 3 h, then filtered through a microglass filter, concentrated in vacuo and purified with PC (Hept.:EtOAc, 100:0 to 80:20) to give the title compound as a yellow solid (127 mg, 48%). LCMS A: t _R =0.97 min; [M+MeCN]+=370.07.

A.3.38. 2-(2-Propoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetic acid.

To a solution of propyl 2-(2-propoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetate (308 mg, 0.85 mmol) in EtOH (9 ml ) NaOH (10% aq. solution, 3.4 ml) was added and the mixture was stirred at RT for 2 h. EtOH was removed in vacuo. The pH value of the resulting base aqueous layer was adjusted to pH=3-4 using 1N HCl. HCl and extracted twice with EtOAc. The combined organic layers were washed with water, brine, dried over MgSO ₄ , filtered and the solvent removed in vacuo to give the title compound as a white powder (0.238 g, 87%). LCMS A: t _R =0.88 min; [M+H] ⁺ =321.08.

A.3.38.1. Propyl 2-(2-propoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetate.

The title compound was prepared according to the procedure described for A.3.6., starting from propyl 2-(4-bromo-2-propoxyphenyl)acetate. LCMS A: t _R =1.04 min; [M+H]+=363.12.

A.3.38.2. Propyl 2-(4-bromo-2-propoxyphenyl)acetate.

- 58 043145

To a solution of 4-bromo-2-hydroxyphenylacetic acid (1.50 g, 6.37 mmol) in DMF (50 ml) was added 1-iodopropane (1.38 ml, 14 mmol, 2.2 eq.) and Cs ₂ CO ₃ (6.23 g, 19.1 mmol) . PM is stirred at 100° C. overnight, then cooled to RT. Water is added and the DMF is removed under reduced pressure. The residue is partitioned between EtOAc and water. The aqueous layer is re-extracted twice with EtOAc. The combined organic extracts are washed with brine, dried (MgSO ₄ ) and concentrated in vacuo. The residue was purified with PC (Hept:EtOAc, 100:0 to 90:10) to give the title compound as a colorless oil (0.775 g, 39%). LC-MS A: t _R =1.00 min; [M+H]+=315.07.

A.3.39. 2-(2-Ethoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetic acid.

Following the synthesis of A.3.38. using ethyl 2-(2-ethoxy-4-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl)phenyl)acetate, the title compound is obtained as a white solid. LC-MS B: t _R =0.92 min; [M+H]+=307.25.

A.3.39.1. Ethyl 2-(2-ethoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetate.

The title compound was prepared according to the procedure described for A.3.6. starting from ethyl 2-(4-bromo-2-ethoxyphenyl)acetate LC-MS A: t _R =1.01 min; [M+H]+=287.04.

A.3.39.2. Ethyl 2-(4-bromo-2-ethoxyphenyl)acetate.

Following the synthesis of A.2.38.2. using 4-bromo-2-hydroxyphenylacetic acid and iodoethane, the title compound was obtained as a colorless oil. LC-MS B: t _R =1.02 min; [M+H]+=287.10.

A.3.40. 5-(2-Ethoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)isoxazol-3-ol.

To a stirred solution of 5-(4-bromo-2-ethoxyphenyl)isoxazol-3-ol (286 mg, 1.01 mmol) and 2isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.733 ml, 3.52 mmol) in dry THF (15 mL) at 78°C under nitrogen atmosphere, 2.5 M solution of butyllithium (2 mL, 5.03 mmol) was added dropwise. The PM is stirred at -78°C for 15 minutes, then water is added at -78°C and the mixture is allowed to stir at RT for 40 minutes. Saturated NH4Cl solution is added and the aqueous phase is extracted with EtOAc. The organic layer is washed twice with saline, then it is dried over MgSO ₄ , filtered and concentrated. The crude residue was purified with FQ (Hept to Hept/EtOAc, 1:1) to give the title compound as a white solid (390 mg, quant.). LCMS B: t _R =0.98 min; [M+H]+=332.34 & [M+H+MeCN]+=373.55.

A.3.40.1. 5-(4-Bromo-2-ethoxyphenyl)isoxazol-3-ol.

To a solution of ethyl 3-(4-bromo-2-ethoxyphenyl)propiolate (1017 mg, 3.42 mmol) in EtOH (30 mL) was added hydroxylamine hydrochloride (721 mg, 10.3 mmol) followed by dropwise addition of 10% NaOH (6.85 mL, 18.8 mmol); PM is stirred overnight at RT. The solvent is distilled off under reduced pressure, the residue obtained is suspended in water, and the suspension is adjusted to pH 2-3 with 2N hydrochloric acid. aqueous solution of HCl. The resulting solid was filtered off to give the title compound as a white solid (380 mg, 39%). LC-MS B: t _R =0.91 min; [M+H]+=284.17/286.25.

A.3.40.2. Ethyl 3-(4-bromo-2-ethoxyphenyl) propiolate.

A CO2 _(gas) inlet was installed in the reaction vessel and CO2 was continuously sparged into a stirred solution of ((4-bromo-2-ethoxyphenyl)ethynyl)trimethylsilane (1950 mg, 6.56 mmol) in DMSO (20 mL). Cesium fluoride (1220 mg, 7.87 mmol) is added and PM is stirred at RT for 2 h. CO2 bubbling is stopped and iodoethane (0.639 ml, 7.87 mmol) is added dropwise. PM is further stirred at RT for 3 h and then poured into water. The aqueous phase is extracted twice with EtOAc and the combined organic layers are washed back with water and finally with brine. The organic phase is dried over MgSO4 and concentrated to dryness. Purification with PC (Hept:EtOAc, 100:0 to 85:15) gave the title compound as an orange oil (1.017 g, 52%). LC-MS B: t _R =1.08 min; [M+H]+=297.20/299.23.

A.3.40.3. ((4-Bromo-2-ethoxyphenyl)ethynyl)trimethylsilane.

To a solution of 4-bromo-2-ethoxy-1-iodobenzene (2120 mg, 6.48 mmol) in THF (20 ml) was added TEA (2.71 ml, 19.5 mmol), ethynyltrimethylsilane (1.12 ml, 7.78 mmol) and copper iodide (61.7 mg , 0.324 mmol). PM is degassed and placed under argon atmosphere 3 times. Then trans-dichlorobis(triphenylphosphine)palladium(II) (91 mg, 0.13 mmol) was added and PM was degassed one last time, placed under argon and stirred at 70°C for 16 h. The mixture was cooled to RT and partitioned between EtOAc and water. The organic layer is washed with brine, dried over Na ₂ SO ₄ , filtered and the solvent is evaporated. The resulting residue was purified with PC (Hept:EtOAc, 100:0 to 90:10) to give the title compound as an orange oil (1.95 g, 100%). LCMS B: t _R =1.18 min; without ionization; 1H NMR (400 MHz, d6-DMSO) δ: 7.31 (d, J=8.2 Hz, 1H), 7.24 (d, J=1.6 Hz, 1H), 7.10 (dd, J1=1.7 Hz, J2=8.1 Hz, 1H), 4.09 (q, J=7.0 Hz, 2H), 1.33 (t, J=6.8 Hz, 3H), 0.22 (s, 9H).

A.3.41. Methyl 2-(2-(methylthio)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetate.

To a solution of methyl 2-(4-bromo-2-(methylthio)phenyl)acetate (1.45 g, 5.27 mmol) in anhydrous. DMF (12 ml) 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (1.352 g, 5.27 mmol), potassium acetate (2.069 g, 21.10 mmol) and Pd(dppf)Cl ₂ (428 mg, 0.58 mmol). PM heated to 90°C under nitrogen atmosphere

- 59 043145 for 17 hours PM then allow to cool to RT and filter through a pad of celite, washing with EtOAc. The filtrate was washed with water and the aqueous layer was extracted twice with EtOAc. The combined organic layers are then washed with brine, dried over MgSO ₄ , filtered and concentrated under reduced pressure. Purification with PC (heptane to EtOAc) gives methyl 2-(2(methylthio)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetate as pale yellow solid (664 mg, 39%). LCMS B: t _R =1.04 min; [M+H]+=323.16.

A.3.41.1. Methyl 2-(4-bromo-2-(methylthio)phenyl)acetate.

To a solution of 2-(4-bromo-2-(methylthio)phenyl)acetic acid (1.86 g, 7.12 mmol) in anhydrous. DMF (17 mL) cesium carbonate (2.901 g, 8.90 mmol) and iodomethane (0.667 mL, 10.70 mmol) are added at RT and PM is stirred at RT under nitrogen atmosphere for 1 h. Water and Et ₂ O are added and the layers are separated. The aqueous layer was extracted twice with Et ₂ O and the combined organic layers were washed with brine, dried over anhydrous. MgSO ₄ , filtered and concentrated under reduced pressure. Purification with PC (heptane to heptane/EtOAc=1/1) gave methyl 2-(4-bromo-2(methylthio)phenyl)acetate as a yellow oil (1.45 g, 74%). LC-MS B: t _R =0.97 min; without ionization.

A.3.41.2. 2-(4-Bromo-2-(methylthio)phenyl)acetic acid.

A mixture of 2-(4-bromo-2-(methylthio)phenyl)acetonitrile (1.76 g, 7.27 mmol), water (7 ml), 95% sulfuric acid (7.8 ml) and acetic acid (5.4 ml) was heated to 110°C under nitrogen for 4.5 h PM then allowed to cool to RT and poured onto ice/water. The reaction mixture is extracted twice with DCM and the combined organic layers are washed with brine, dried over anhydrous. MgSO ₄ , filtered and concentrated under reduced pressure to give 2-(4-bromo-2(methylthio)phenyl)acetic acid as a yellow solid (1.86 g, 98%). LC-MS B: t _R =0.82 min; [M+H]+=260.70.

A.3.41.3. 2-(4-Bromo-2-(methylthio)phenyl)acetonitrile.

A solution of (5-bromo-2-(chloromethyl)phenyl)(methyl)sulfane (2.45 g, 9.74 mmol) in MeCN (26 ml) and water (3.4 ml) is treated with sodium cyanide (646 mg, 12.70 mmol) and PM is heated to 80°C under nitrogen for 16 h. Additional sodium cyanide (238 mg, 4.85 mmol) is then added and the mixture heated to 80°C for 4 h PM then allowed to cool to RT and diluted with water. Acetonitrile is removed under reduced pressure and PM is extracted twice with DCM. The combined organic layers are dried over anhydrous. MgSO ₄ , filtered and concentrated under reduced pressure. Purification with PC (heptane to heptane/EtOAc=1/1) gave 2-(4-bromo-2(methylthio)phenyl)acetonitrile as a pale yellow solid (1.76 g, 75%). LC-MS B: t _R =0.95 min; [M+H] ⁺ =241.81.

A.3.41.4. (5-Bromo-2-(chloromethyl)phenyl)(methyl)sulfane.

A chilled (0°C) mixture of (4-bromo-2-(methylthio)phenyl)methanol (2.31 g, 9.91 mmol) and zinc chloride (33.8 mg, 0.248 mmol) in anhydrous DCM (20 mL) was treated dropwise with thionyl chloride (1.45 mL, 19.80 mmol) and PM was stirred at 0°C for 3 h and then at RT for 15 h. PM was concentrated under reduced pressure to give (5-bromo-2 -(chloromethyl)phenyl)(methyl)sulfane as a yellow oil (2.45 g, 98%). LC-MS B: t _R =1.04 min; without ionization.

A.3.41.5. (4-Bromo-2-(methylthio)phenyl)methanol.

To a cooled (78°C) solution of methyl 4-bromo-2-(methylthio)benzoate (2.87 g, 11.00 mmol) in anhydrous THF (30 ml) was added dropwise with a solution of diisobutylaluminum hydride (1 M in toluene, 33.0 ml, 33.0 mmol). The mixture was further stirred at -78°C under nitrogen for 15 minutes and then allowed to warm to 0°C. Stirring at 0°C was continued for 15 min and chilled PM was treated successively with water (31 ml) and 2.8 N. aq. NaOH (22 ml). The mixture is then allowed to warm to RT, EtOAc is added and the layers are separated. The aqueous layer was extracted twice with EtOAc. The combined organic layers are dried over anhydrous. MgSO4, filter and concentrate under reduced pressure. Purification with PC (heptane to heptane/EtOAc=1/1) gave (4-bromo-2(methylthio)phenyl)methanol as a colorless solid (2.31 g, 90%). LCMS B: tR=0.83 min; [M+H]+=232.99.

A.3.41.6. Methyl 4-bromo-2-(methylthio)benzoate.

To a solution of 4-bromo-2-mercaptobenzoic acid (3.00 g, 12.20 mmol) in anhydrous. DMF (20 mL) cesium carbonate (11.952 g, 36.70 mmol) was added at RT and the mixture was stirred at RT for 15 min. The cooled (0°C) mixture is then treated with iodomethane (1.92 ml, 30.60 mmol) and PM is stirred at RT for 16 h. Water and Et ₂ O are added and the layers are separated. The aqueous layer was extracted twice with Et ₂ O and the combined organic layers were washed with brine, dried over anhydrous. MgSO4, filter and concentrate under reduced pressure to give methyl 4-bromo-2(methylthio)benzoate as a pale orange solid (2.87 g, 90%). LC-MS B: t _R =0.96 min; [M+H] ⁺ =261.06.

A.3.42. Methyl 2-(2-propyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetate.

To a solution of methyl 2-(4-bromo-2-propylphenyl)acetate (2.380 g, 8.78 mmol) in anhydrous. DMF (20 ml) 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (2.251 g, 8.78 mmol), potassium acetate (3.446 g, 35.10 mmol) and Pd(dppf)Cl ₂ (714 mg, 0.96 mmol). PM is heated to 90°C under a nitrogen atmosphere during those

- 60 043145 16 hours PM then allowed to cool to RT and filtered through a pad of celite, rinsing with EtOAc. The filtrate was washed with water and the aqueous layer was extracted twice with EtOAc. The combined organic layers are then washed with brine, dried over MgSO ₄ , filtered and concentrated under reduced pressure. Purification with PC (heptane to heptane/EtOAc=1/1) gives methyl 2-(2-propyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl )phenyl)acetate as a colorless oil (2.230 g, 80%). LC-MS B: t _R =1.10 min; [M+H]+=319.31.

A.3.42.1. Methyl 2-(4-bromo-2-propylphenyl)acetate.

To a solution of 2-(4-bromo-2-propylphenyl)acetic acid (2.770 g, 10.80 mmol) in anhydrous. DMF (20 mL) cesium carbonate (5.265 g, 16.20 mmol) and iodomethane (1.02 mL, 16.20 mmol) are added at RT and PM is stirred at RT under nitrogen atmosphere for 1 h. Water and Et ₂ O are added and the layers are separated. The aqueous layer was extracted twice with Et ₂ O and the combined organic layers were washed with brine, dried over anhydrous. MgSO ₄ , filtered and concentrated under reduced pressure. Purification with PC (heptane to heptane/EtOAc=1/1) gave methyl 2-(4-bromo-2-propylphenyl)acetate as a yellow oil (2.380 g, 81%). LC-MS B: t _R =1.04 min; without ionization.

A.3.42.2. 2-(4-Bromo-2-propylphenyl)acetic acid.

A mixture of 2-(4-bromo-2-propylphenyl)acetonitrile (2.570 g, 10.80 mmol), water (10 ml), 95% sulfuric acid (11.5 ml) and acetic acid (8 ml) is heated to 110°C under nitrogen atmosphere over 3 hours PM then allowed to cool to RT and poured onto ice/water. The reaction mixture is extracted twice with DCM and the combined organic layers are washed with brine, dried over anhydrous. MgSO ₄ , filtered and concentrated under reduced pressure to give crude 2-(4-bromo-2-propylphenyl)acetic acid as a pale gray solid (3.390 g, quantitative). LCMS B: t _R =0.91 min; without ionization.

A.3.42.3. 2-(4-Bromo-2-propylphenyl)acetonitrile.

A solution of 4-bromo-1-(chloromethyl)-2-propylbenzene (2.980 g, 12.00 mmol) in MeCN (32 ml) and water (3.9 ml) is treated with sodium cyanide (767 mg, 15.60 mmol) and PM is heated to 80° C under nitrogen during the night. The PM is then allowed to cool to RT and diluted with water. Acetonitrile is removed under reduced pressure and PM is extracted twice with DCM. The combined organic layers are dried over anhydrous. MgSO ₄ , filtered and concentrated under reduced pressure. Purification with PC (heptane to EtOAc) gave 2-(4-bromo-2-propylphenyl)acetonitrile as a pale yellow oil (2.570 g, 90%). LC-MS B: t _R =1.02 min; without ionization.

A.3.42.4. 4-Bromo-1-(chloromethyl)-2-propylbenzene.

Chilled (0°C) mixture of (4-bromo-2-propylphenyl)methanol (2.650 g, 11.60 mmol) and zinc chloride (39.4 mg, 0.289 mmol) in anhydrous. DCM (23 ml) was treated dropwise with thionyl chloride (1.69 ml, 23.10 mmol) and the RM was stirred at 0° C. for 3 h and then at RT overnight. PM was concentrated under reduced pressure to give crude 4-bromo-1-(chloromethyl)-2-propylbenzene as a gray oil (2.98 g, quantitative). LC-MS B: t _R =1.10 min; without ionization.

A.3.42.5. (4-Bromo-2-propylphenyl)methanol.

To a cooled (78°C) solution of methyl 4-bromo-2-propylbenzoate (3.300 g, 12.80 mmol) in anhydrous. THF (60 ml) was added dropwise with a solution of diisobutylaluminum hydride (1 M in toluene, 38.5 ml, 38.5 mmol). The mixture was further stirred at -78°C under nitrogen for 15 minutes and then allowed to warm to 0°C. Stirring at 0°C was continued for 45 min and the chilled PM was treated successively with water (1.5 ml), 2.8 N. aq. NaOH (1.5 ml) and water (4 ml). The mixture is then allowed to warm to RT and stirring is continued for 30 minutes. The resulting mixture is filtered through celite, washing with THF, and the filtrate is concentrated to dryness under reduced pressure. Purification with PC (heptane to heptane/EtOAc=1/1) gave (4-bromo-2-propylphenyl)methanol as a colorless oil (2.650 g, 90%). LCMS B: tR=0.91 min; without ionization.

A.3.42.6. Methyl 4-bromo-2-propyl benzoate.

To a solution of 4-bromo-2-propylbenzoic acid (3.590 g, 14.80 mmol) in anhydrous. DMF (30 mL) cesium carbonate (9.623 g, 29.50 mmol) and iodomethane (1.86 mL, 29.50 mmol) are added successively at RT and PM is stirred at RT for 16 h. Water and Et ₂ O are added and the layers are separated. The aqueous layer was extracted twice with Et ₂ O and the combined organic layers were washed with brine, dried over anhydrous. MgSO ₄ , filtered and concentrated under reduced pressure. Purification with PC (heptane to heptane/EtOAc=1/1) gave methyl 4-bromo-2-propyl benzoate as a colorless oil (3.300 g, 87%). LC-MS B: t _R =1.05 min; without ionization.

A.3.42.7. 4-Bromo-2-propylbenzoic acid.

To a cooled (0°C) solution of 4-bromo-2-fluorobenzoic acid (5.000 g, 22.40 mmol) in anhydrous. THF (40 ml) was added dropwise with a solution of propyl magnesium bromide (2.0 M in THF, 33.50 ml, 67.00 mmol) and PM was further stirred at RT under nitrogen atmosphere overnight. Then, MeOH (10 ml) was added dropwise to the cooled (0°C) reaction mixture, and it was further stirred at 0°C for 5 minutes. The resulting mixture was then concentrated to dryness under reduced pressure and the residue partitioned between EtOAc and 2M aq. HCl. The layers are separated and aq. layer was extracted twice with EtOAc. The combined organic layers are then washed with brine,

- 61 043145 dried over anhydrous. MgSO ₄ , filtered and concentrated under reduced pressure. Cleaning with

PC (heptane to heptane/EtOAc=3/2) gave 4-bromo-2-propylbenzoic acid as a colorless solid (3.590 g, 66%). LC-MS B: t _R =0.93 min; without ionization.

A.3.43. Methyl 2-(2-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetate.

To a solution of methyl 2-(4-bromo-2-ethylphenyl)acetate (900 mg, 3.24 mmol) in anhydrous. DMF (15 ml) 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (832 mg, 3.24 mmol), potassium acetate (1.274 g, 13.00 mmol) and Pd(dppf)Cl ₂ (264 mg, 0.35 mmol). PM is heated to 90° C. under nitrogen overnight. The PM is then allowed to cool to RT and filtered through a pad of celite, washing with EtOAc. The filtrate was washed with water and the aqueous layer was extracted twice with EtOAc. The combined organic layers are then washed with brine, dried over MgSO ₄ , filtered and concentrated under reduced pressure. Purification with PC (heptane to heptane/EtOAc=4/1) gives methyl 2-(2-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl )phenyl)acetate as a light yellow oil (708 mg, 72%). LC-MS B: t _R =1.05 min; [M+H]+=305.22.

A.3.43.1. Methyl 2-(4-bromo-2-ethylphenyl)acetate.

To a solution of 2-(4-bromo-2-ethylphenyl)acetic acid (2.118 g, 8.05 mmol) in anhydrous. DMF (20 mL) cesium carbonate (5.246 g, 16.10 mmol) and iodomethane (1.01 mL, 16.10 mmol) are added at RT and PM is stirred at RT under nitrogen atmosphere for 1 h. Water and Et ₂ O are added and the layers are separated. The aqueous layer was extracted twice with Et ₂ O and the combined organic layers were washed with brine, dried over anhydrous. MgSO ₄ , filtered and concentrated under reduced pressure. Purification with PC (heptane to heptane/EtOAc=7/3) gave methyl 2-(4-bromo-2-ethylphenyl)acetate as a light yellow oil (2.043 g, 99%). LC-MS B: t _R =0.99 min; without ionization.

A.3.43.2. 2-(4-Bromo-2-ethylphenyl)acetic acid.

A mixture of 2-(4-bromo-2-ethylphenyl)acetonitrile (1.859 g, 7.99 mmol), water (7.5 ml), 95% sulfuric acid (8.3 ml) and acetic acid (5.8 ml) was heated to 110°C under nitrogen atmosphere over 4 hours PM then allowed to cool to RT and poured onto ice/water. The reaction mixture is extracted twice with DCM and the combined organic layers are washed with brine, dried over anhydrous. MgSO ₄ , filtered and concentrated under reduced pressure to give crude 2-(4-bromo-2-ethylphenyl)-acetic acid as an succinic solid (2.118 g, quantitative). LC-MS B: t _R =0.85 min; without ionization.

A.3.43.3. 2-(4-Bromo-2-ethylphenyl)acetonitrile.

A solution of 4-bromo-1-(chloromethyl)-2-ethylbenzene (2.050 g, 8.34 mmol) in MeCN (24 ml) and water (3 ml) is treated with sodium cyanide (553 mg, 10.80 mmol) and PM is heated to 80° C under nitrogen during the night. The PM is then allowed to cool to RT and diluted with water. Acetonitrile is removed under reduced pressure and PM is extracted twice with DCM. The combined organic layers are dried over anhydrous. MgSO ₄ , filtered and concentrated under reduced pressure. Purification with PC (heptane to heptane/EtOAc=7/3) gave 2-(4-bromo-2-ethylphenyl)acetonitrile as a colorless solid (1.859 g, 99%). LC-MS B: t _R =0.95 min; without ionization.

A.3.43.4. 4-Bromo-1-(chloromethyl)-2-ethylbenzene.

A chilled (0°C) mixture of (4-bromo-2-ethylphenyl)methanol (1.854 g, 8.30 mmol) and zinc chloride (28.3 mg, 0.208 mmol) in anhydrous DCM (20 ml) was treated dropwise with thionyl chloride (1.21 ml, 16.60 mmol) and PM was stirred at 0°C for 2 h. PM was concentrated under reduced pressure to give crude 4-bromo-1-(chloromethyl)-2-ethylbenzene as a light purple oil (2.050 g, quantitative). LCMS B: tR=1.04 min; without ionization.

A.3.43.5. (4-Bromo-2-ethylphenyl)methanol.

To a cooled (78°C) solution of methyl 4-bromo-2-ethylbenzoate (2.219 g, 9.01 mmol) in anhydrous. THF (60 ml) was added dropwise with a solution of diisobutylaluminum hydride (1 M in toluene, 27.0 ml, 27.0 mmol). The mixture was further stirred at -78°C under nitrogen for 15 minutes and then allowed to warm to 0°C. Stirring at 0°C was continued for 45 min and the chilled PM was treated successively with water (1 ml), 2.8N. aq. NaOH (1 ml) and water (3 ml). The mixture is then allowed to warm to RT and stirred for an additional 30 minutes. The resulting mixture is filtered through celite, washing with THF, and the filtrate is concentrated to dryness under reduced pressure. EtOAc and water are added and the layers are separated. The aqueous layer was extracted twice with EtOAc and the combined organic layers were dried over anhydrous. MgSO ₄ , filtered and concentrated under reduced pressure. Purification with PC (heptane to heptane/EtOAc=1/1) gave (4-bromo-2-ethylphenyl)methanol (1.854 g, 96%). LCMS B: tR=0.84 min; without ionization.

A.3.43.6. Methyl 4-bromo-2-ethyl benzoate.

To a solution of 4-bromo-2-ethylbenzoic acid (3.003 g, 12.80 mmol) in anhydrous. DMF (30 mL) cesium carbonate (8.355 g, 25.60 mmol) and iodomethane (1.61 mL, 25.60 mmol) are added at RT and PM is stirred at RT for 1 h. Water and Et2O are added and the layers are separated. The aqueous layer was extracted twice with Et2O and the combined organic layers were washed with brine, dried over anhydrous. MgSO ₄ , filtered and concentrated under reduced pressure. Purification with PC (heptane to heptane/EtOAc=7/3) gave methyl 4-bromo-2-ethyl benzoate as a clear oil (2.735 g, 88%). ZhKh- 62 043145

MS B: t _R =1.02 min; without ionization.

A.3.43.7. 4-Bromo-2-ethylbenzoic acid.

To a cooled (0°C) solution of 4-bromo-2-fluorobenzoic acid (5.000 g, 22.40 mmol) in anhydrous. THF (40 ml) was added dropwise with a solution of ethylmagnesium bromide (1.0 M in THF, 67.1 ml, 67.1 mmol) and PM was further stirred at RT under nitrogen atmosphere for 3 h. Then the cooled (0°C) reaction mixture was added dropwise MeOH (15 ml) was added and it was further stirred at 0° C. for 5 min. The resulting mixture was then concentrated to dryness under reduced pressure and the residue partitioned between EtOAc and 2M aq. HCl. The layers are separated and aq. layer was extracted twice with EtOAc. The combined organic layers are then washed with brine, dried over anhydrous. MgSO ₄ , filtered and concentrated under reduced pressure. Purification with PC (heptane to heptane/EtOAc=7/3) gave 4-bromo-2-ethylbenzoic acid as a colorless solid (3.003 g, 59%). LC-MS B: t _R =0.87 min; without ionization.

A.3.44. Methyl 2-(2-isobutyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetate.

To a solution of methyl 2-(4-bromo-2-isobutylphenyl)acetate (2.271 g, 7.13 mmol) in anhydrous. DMF (25 ml) 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (1.828 g, 7.13 mmol), potassium acetate (2.798 g, 28.50 mmol) and Pd(dppf)Cl ₂ (579 mg, 0.78 mmol). PM is heated to 95° C. under nitrogen for 16 hours. PM is then allowed to cool to RT and filtered through a Celite pad, rinsing with EtOAc. The filtrate was washed with water and the aqueous layer was extracted twice with EtOAc. The combined organic layers are then washed with brine, dried over MgSO ₄ , filtered and concentrated under reduced pressure. Purification with PC (heptane to heptane/EtOAc=1/1) gives methyl 2-(2-isobutyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl )phenyl)acetate as a yellow oil (1.822 g, 77%). LCMS B: tR=1.13 min; [M+H]+=333.24.

A.3.44.1. Methyl 2-(4-bromo-2-isobutylphenyl)acetate.

To a solution of 2-(4-bromo-2-isobutylphenyl)acetic acid (2.457 g, 8.64 mmol) in anhydrous. DMF (30 mL) cesium carbonate (5.633 g, 17.30 mmol) and iodomethane (1.09 mL, 17.30 mmol) are added at RT and PM is stirred at RT under nitrogen atmosphere for 1 h. Water and Et ₂ O are added and the layers are separated. The aqueous layer was extracted twice with Et ₂ O and the combined organic layers were washed with brine, dried over anhydrous. MgSO ₄ , filtered and concentrated under reduced pressure. Purification with PC (heptane to heptane/EtOAc=1/1) gave methyl 2-(4-bromo-2-isobutylphenyl)acetate as a clear oil (2.271 g, 92%). LC-MS B: t _R =1.06 min; without ionization.

A.3.44.2. 2-(4-Bromo-2-isobutylphenyl)acetic acid.

A mixture of 2-(4-bromo-2-isobutylphenyl)acetonitrile (2.162 g, 8.41 mmol), water (8 ml), 95% sulfuric acid (9 ml) and acetic acid (6 ml) is heated to 110°C under nitrogen atmosphere during the night. The PM is then allowed to cool to RT and poured onto an ice/water mixture. The reaction mixture is extracted twice with DCM and the combined organic layers are washed with brine, dried over anhydrous. MgSO4, filtered and concentrated under reduced pressure to give crude 2-(4-bromo-2isobutylphenyl)acetic acid as an amber oil (2.457 g, quantitative). LC-MS B: t _R =0.96 min; without ionization.

A.3.44.3. 2-(4-Bromo-2-isobutylphenyl)acetonitrile.

A solution of 4-bromo-1-(chloromethyl)-2-isobutylbenzene (2.381 g, 9.00 mmol) in MeCN (24 ml) and water (3 ml) is treated with sodium cyanide (597 mg, 11.70 mmol) and PM is heated to 80° C under nitrogen during the night. The PM is then allowed to cool to RT and diluted with water. Acetonitrile is removed under reduced pressure and PM is extracted twice with DCM. The combined organic layers are dried over anhydrous. MgSO4, filter and concentrate under reduced pressure. Purification with PC (heptane to heptane/EtOAc=1/1) gave 2-(4-bromo-2-isobutylphenyl)acetonitrile as a clear oil (2.162 g, 95%). LC-MS B: t _R =1.05 min; without ionization.

A.3.44.4. 4-Bromo-1-(chloromethyl)-2-isobutylbenzene.

A chilled (0°C) mixture of (4-bromo-2-isobutylphenyl)methanol (2.192 g, 8.83 mmol) and zinc chloride (30.1 mg, 0.221 mmol) in anhydrous DCM (20 mL) was treated dropwise with thionyl chloride (1.29 mL, 17.70 mmol) and PM was stirred at 0°C for 4 h. PM was concentrated under reduced pressure to give crude 4-bromo-1-(chloromethyl)-2-isobutylbenzene as a light pink oil (2.381 g, quantitative). LC-MS B: t _R =1.13 min; without ionization.

A.3.44.5. (4-Bromo-2-isobutylphenyl)methanol.

To a cooled (78°C) solution of methyl 4-bromo-2-isobutylbenzoate (2.712 g, 9.71 mmol) in anhydrous. THF (60 ml) was added dropwise with a solution of diisobutylaluminum hydride (1 M in toluene, 29.1 ml, 29.1 mmol). The mixture was further stirred at -78°C under nitrogen for 15 minutes and then allowed to warm to 0°C. Stirring at 0°C was continued for 30 min and the chilled PM was treated successively with water (1 ml), 2.8N. aq. NaOH (1 ml) and water (3 ml). The mixture is then allowed to warm to RT and stirred for an additional 30 minutes. The resulting mixture is filtered through celite, washing with THF, and the filtrate is concentrated to dryness under reduced pressure. EtOAc and water are added and the layers are separated. The aqueous layer was extracted twice with EtOAc and the combined organic layers were dried over anhydrous. MgSO ₄ , filtered and concentrated under reduced pressure. Purification with PC (heptane to heptane/EtOAc=1/1) gave (4-bromo-2isobutylphenyl)methanol (2.192 g, 93%). LC-MS B: t _R =0.96 min; without ionization.

A.3.44.6. Methyl 4-bromo-2-isobutyl benzoate.

To a solution of 4-bromo-2-isobutylbenzoic acid (4.254 g, 14.30 mmol) in anhydrous. DMF (50 mL) cesium carbonate (9.304 g, 28.60 mmol) and iodomethane (1.80 mL, 28.60 mmol) are added successively at RT and PM is stirred at RT for 1 h. Water and Et ₂ O are added and the layers are separated. The aqueous layer was extracted twice with Et ₂ O and the combined organic layers were washed with brine, dried over anhydrous. MgSO ₄ , filtered and concentrated under reduced pressure. Purification with PC (heptane to heptane/EtOAc=7/3) gave methyl 4-bromo-2-isobutyl benzoate as a light yellow oil (3.462 g, 89%). LC-MS B: t _R =1.11 min; without ionization.

A.3.44.7. 4-Bromo-2-isobutylbenzoic acid.

To a cooled (0°C) solution of 4-bromo-2-fluorobenzoic acid (5.000 g, 22.40 mmol) in anhydrous. THF (40 ml) is added dropwise with a solution of isobutyl magnesium bromide (2.0 M in Et ₂ O, 33.5 ml, 67.0 mmol) and PM is further stirred at RT under nitrogen atmosphere overnight. Then, MeOH (10 ml) was added dropwise to the cooled (0°C) reaction mixture, and it was further stirred at 0°C for 5 minutes. The resulting mixture was then concentrated to dryness under reduced pressure and the residue partitioned between EtOAc and 2M aq. HCl. The layers are separated and aq. layer was extracted twice with EtOAc. The combined organic layers are then washed with brine, dried over anhydrous. MgSO ₄ , filtered and concentrated under reduced pressure. Purification with PC (heptane to heptane/EtOAc=7/3) gave 4-bromo-2-isobutylbenzoic acid as a light yellow solid (4.254 g, 74%). LC-MS B: t _R =0.97 min; without ionization.

A.3.45. Methyl 2-(2-ethyl-6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetate.

To a solution of methyl 2-(4-bromo-2-ethyl-6-methylphenyl)acetate (1.176 g, 4.34 mmol) in anhydrous. DMF (15 ml) 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (1.112 g, 4.34 mmol), potassium acetate (1.703 g, 17.30 mmol) and Pd(dppf)Cl ₂ (353 mg, 0.47 mmol). The PM is heated to 90° C. under nitrogen for 16 hours. The PM is then allowed to cool to RT and filtered through a Celite pad, rinsing with EtOAc. The filtrate was washed with water and the aqueous layer was extracted twice with EtOAc. The combined organic layers are then washed with brine, dried over MgSO ₄ , filtered and concentrated under reduced pressure. Purification with PC (heptane to heptane/EtOAc=7/3) gives methyl 2-(2-ethyl-6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane -2yl)phenyl)acetate as a light green oil (895 mg, 65%). LC-MS B: t _R =1.08 min; [M+H]+=319.28.

A.3.45.1. Methyl 2-(4-bromo-2-ethyl-6-methylphenyl)acetate.

To a solution of 2-(4-bromo-2-ethyl-6-methylphenyl)acetic acid (2.993 g, 11.60 mmol) in anhydrous. DMF (20 mL) cesium carbonate (7.585 g, 23.30 mmol) and iodomethane (1.46 mL, 23.30 mmol) are added at RT and PM is stirred at RT under nitrogen atmosphere for 5 h. Water and Et2O are added and the layers are separated. The aqueous layer was extracted twice with Et2O and the combined organic layers were washed with brine, dried over anhydrous. MgSO4, filter and concentrate under reduced pressure. Purification with PC (heptane to heptane/EtOAc=7/3) gave methyl 2-(4-bromo-2-ethyl-6methylphenyl)acetate as a yellow oil (1.176 g, 37%). LCMS B: t _R =1.03 min; without ionization.

A.3.45.2. 2-(4-Bromo-2-ethyl-6-methylphenyl)acetic acid.

A mixture of 2-(4-bromo-2-ethyl-6-methylphenyl)acetonitrile (2.477 g, 10.40 mmol), water (10 ml), 95% sulfuric acid (11 ml) and acetic acid (7.5 ml) is heated to 110° C under nitrogen for 1.5 h PM then allowed to cool to RT and poured onto ice/water. The reaction mixture is extracted twice with DCM and the combined organic layers are washed with brine, dried over anhydrous. MgSO4, filtered and concentrated under reduced pressure to give crude 2-(4-bromo-2ethyl-6-methylphenyl)acetic acid as an off-white solid (2.993 g, quantitative). LC-MS B: t _R =0.81 min; without ionization.

A.3.45.3. 2-(4-Bromo-2-ethyl-6-methylphenyl)acetonitrile.

A solution of 5-bromo-2-(chloromethyl)-1-ethyl-3-methylbenzene (2.849 g, 11.50 mmol) in MeCN (30 ml) and water (3.7 ml) was treated with sodium cyanide (764 mg, 15.00 mmol), and PM heated to 80° C. under nitrogen for 1 h PM then allowed to cool to RT and diluted with water. Acetonitrile is removed under reduced pressure and PM is extracted twice with DCM. The combined organic layers are dried over anhydrous. MgSO ₄ , filtered and concentrated under reduced pressure. Purification with PC (heptane to heptane/EtOAc=7/3) gave 2-(4-bromo-2-ethyl-6-methylphenyl)acetonitrile as a clear oil (2.477 g, 90%). LC-MS B: tR=0.99 min; without ionization.

A.3.45.4. 5-Bromo-2-(chloromethyl)-1-ethyl-3-methylbenzene.

Cooled (0°C) mixture of (4-bromo-2-ethyl-6-methylphenyl)methanol (2.525 g, 11.00 mmol) and zinc chloride (37.6 mg, 0.276 mmol) in anhydrous. DCM (30 ml) was treated dropwise with thionyl chloride (1.61 ml, 22.00 mmol) and PM was stirred at 0°C for 1 h. PM was concentrated under reduced pressure to give crude 5-bromo-2-(chloromethyl)-1-ethyl -3-methylbenzene as a light brown oil (2.849 g, quantitative). LC-MS B: t _R =1.08 min; without ionization.

A.3.45.5. (4-Bromo-2-ethyl-6-methylphenyl)methanol.

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To a cooled (78°C) solution of methyl 4-bromo-2-ethyl-6-methylbenzoate (3.355 g, 13.00 mmol) in anhydrous. THF (60 ml) was added dropwise with a solution of diisobutylaluminum hydride (1 M in toluene, 39.0 ml, 39.0 mmol). The mixture was further stirred at -78°C under nitrogen for 15 minutes and then allowed to warm to 0°C. Stirring at 0°C was continued for 1 h and the chilled PM was treated successively with water (1 ml), 2.8N. aq. NaOH (1 ml) and water (3 ml). The mixture is then allowed to warm to RT and stirred for an additional 30 minutes. The resulting mixture is filtered through celite, washing with THF, and the filtrate is concentrated to dryness under reduced pressure. EtOAc and water are added and the layers are separated. The aqueous layer was extracted twice with EtOAc and the combined organic layers were dried over anhydrous. MgSO ₄ , filtered and concentrated under reduced pressure. Purification with PC (heptane to heptane/EtOAc=1/1) gave (4-bromo-2-ethyl-6methylphenyl)methanol (2.525 g, 84%). LCMS B: t _R =0.87 min; without ionization.

A.3.45.6. Methyl 4-bromo-2-ethyl-6-methylbenzoate.

To a solution of 4-bromo-2-ethyl-6-methylbenzoic acid (3.465 g, 14.30 mmol) in anhydrous. DMF (35 mL) cesium carbonate (9.288 g, 28.50 mmol) and iodomethane (1.79 mL, 28.50 mmol) are added at RT and PM is stirred at RT for 1 h. Water and Et ₂ O are added and the layers are separated. The aqueous layer was extracted twice with Et ₂ O and the combined organic layers were washed with brine, dried over anhydrous. MgSO ₄ , filtered and concentrated under reduced pressure. Purification with PC (heptane to heptane/EtOAc=3/1) gave methyl 4-bromo-2-ethyl-6-methylbenzoate as a clear oil (3.355 g, 92%). LCMS B: t _R =1.02 min; without ionization.

A.3.45.7. 4-Bromo-2-ethyl-6-methylbenzoic acid.

To a cooled (0°C) solution of 4-bromo-2-fluoro-6-methylbenzoic acid (4.000 g, 16.30 mmol) in anhydrous. THF (40 ml) was added dropwise with a solution of ethyl magnesium bromide (1.0 M in THF, 49.0 ml, 49.0 mmol) and PM was further stirred at RT under nitrogen atmosphere overnight. MeOH (15 ml) was then added dropwise to the cooled (0°C) reaction mixture, and it was further stirred at 0°C for 5 minutes. The resulting mixture was then concentrated to dryness under reduced pressure and the residue partitioned between EtOAc and 2M aq. HCl. The layers are separated and aq. layer was extracted twice with EtOAc. The combined organic layers are then washed with brine, dried over anhydrous. MgSO ₄ , filtered and concentrated under reduced pressure. Purification with PC (heptane to heptane/EtOAc=3/1) gave 4-bromo-2-ethyl-6-methylbenzoic acid as a colorless solid (3.465 g, 87%). LCMS B: t _R =0.86 min; without ionization.

A.3.46. Methyl 2-(2-chloro-6-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetate.

To a solution of methyl 2-(4-bromo-2-chloro-6-ethylphenyl)acetate (254 mg, 0.87 mmol) in anhydrous. DMF (10 ml) 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (223 mg, 0.87 mmol), potassium acetate (342 mg, 3.48 mmol) and Pd(dppf)Cl ₂ (70 mg, 0.095 mmol). The PM is heated to 90° C. under nitrogen for 5.5 hours. The PM is then allowed to cool to RT and filtered through a Celite pad, rinsing with EtOAc. The filtrate was washed with water and the aqueous layer was extracted twice with EtOAc. The combined organic layers are then washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. Purification with PC (heptane to heptane/EtOAc=1/1) gives methyl 2-(2-chloro-6-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane -2-yl)phenyl)acetate as a pale yellow oil (126 mg, 43%). LC-MS B: t _R =1.14 min; [M+H]+=339.35.

A.3.46.1. Methyl 2-(4-bromo-2-chloro-6-ethylphenyl)acetate.

To a solution of 2-(4-bromo-2-chloro-6-ethylphenyl)acetic acid (259 mg, 0.93 mmol) in anhydrous. DMF (9 mL) cesium carbonate (456 mg, 1.40 mmol) and iodomethane (70 μL, 1.12 mmol) are added at RT and PM is stirred at RT under nitrogen atmosphere for 30 min. Water and Et ₂ O are added and the layers are separated. The aqueous layer was extracted twice with Et2O and the combined organic layers were washed with brine, dried over anhydrous. MgSO ₄ , filtered and concentrated under reduced pressure. Purification with PC (heptane to heptane/EtOAc=1/1) gave methyl 2-(4-bromo-2-chloro-6-ethylphenyl)acetate as a pale yellow solid (254 mg, 93%). LC-MS B: t _R =1.03 min; without ionization.

A.3.46.2. 2-(4-Bromo-2-chloro-6-ethylphenyl)acetic acid.

A mixture of 2-(4-bromo-2-chloro-6-ethylphenyl)acetonitrile (511 mg, 1.98 mmol), potassium hydroxide (333 mg, 5.93 mmol) in EtOH (15 ml) and water (15 ml) is heated to 110° C under nitrogen for 24 h. PM is then allowed to cool to RT and concentrated under reduced pressure. Add 1 M aq. HCl and DCM, the layers are then separated and the aqueous layer is extracted twice with DCM. The combined organic layers are washed with brine, dried over anhydrous. MgSO ₄ , filtered and concentrated under reduced pressure to give crude 2-(4-bromo-2-chloro-6-ethylphenyl)acetic acid as an off-white solid (259 mg). LC-MS B: t _R =0.90 min; without ionization.

A.3.46.3. 2-(4-Bromo-2-chloro-6-ethylphenyl)acetonitrile.

A solution of 5-bromo-1-chloro-2-(chloromethyl)-3-ethylbenzene (740 mg, 2.76 mmol) in MeCN (14 mL) and water (2 mL) was treated with sodium cyanide (176 mg, 3.59 mmol) and PM heated to 80° C. under nitrogen atmosphere overnight. The PM is then allowed to cool to RT and diluted with water. The acetonitrile is removed under reduced pressure and the mixture is extracted twice with DCM. The combined organic layers are dried over anhydrous. MgSO ₄ , filtered and concentrated under reduced pressure. Cleaning with

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PC (heptane to heptane/EtOAc=1/1) gave 2-(4-bromo-2-chloro-6-ethylphenyl)acetonitrile as a colorless oil (511 mg, 72%). LC-MS B: t _R =0.99 min; without ionization.

A.3.46.4. 5-Bromo-1-chloro-2-(chloromethyl)-3-ethylbenzene.

Cooled (0°C) mixture of (4-bromo-2-chloro-6-ethylphenyl)methanol (645 mg, 2.58 mmol) and zinc chloride (9 mg, 0.064 mmol) in anhydrous. DCM (10 ml) was treated dropwise with thionyl chloride (0.37 ml, 5.17 mmol) and PM was stirred at 0° C. for 3 h and then at RT overnight. PM was concentrated under reduced pressure to give crude 5-bromo-1-chloro-2-(chloromethyl)-3-ethylbenzene as a gray oil (740 mg, quantitative). LC-MS B: t _R =1.09 min; without ionization.

A.3.46.5. (4-Bromo-2-chloro-6-ethylphenyl)methanol.

To a cooled (78°C) solution of methyl 4-bromo-2-chloro-6-ethylbenzoate (2.115 g, 7.62 mmol) in anhydrous. THF (50 ml) was added dropwise with a solution of diisobutylaluminum hydride (1 M in toluene, 45.7 ml, 45.7 mmol). The mixture was further stirred at -78°C under nitrogen for 15 minutes and then allowed to warm to 0°C. Stirring at 0°C was continued for 45 min and chilled PM was treated successively with water (2 ml), 2.8N. aq. NaOH (2 ml) and water (5 ml). The mixture is then allowed to warm to RT and stirred for an additional 30 minutes. The resulting mixture is filtered through celite, washing with THF, and the filtrate is concentrated to dryness under reduced pressure. EtOAc and water are added and the layers are separated. The aqueous layer was extracted twice with EtOAc and the combined organic layers were dried over anhydrous. MgSO ₄ , filtered and concentrated under reduced pressure. Purification with PC (heptane to heptane/EtOAc=1/1) gave pure (4bromo-2-chloro-6-ethylphenyl)methanol (645 mg, 34%). LC-MS B: t _R =0.89 min; without ionization.

A.3.46.6. Methyl 4-bromo-2-chloro-6-ethylbenzoate.

To a solution of 4-bromo-2-chloro-6-ethylbenzoic acid (2.660 g, 10.10 mmol) in anhydrous. DMF (20 mL) cesium carbonate (4.933 g, 15.10 mmol) and iodomethane (0.76 mL, 12.10 mmol) are added at RT and PM is stirred at RT for 1.5 h. Water and Et ₂ O are added and the layers are separated. The aqueous layer was extracted twice with Et ₂ O and the combined organic layers were washed with brine, dried over anhydrous. MgSO ₄ , filtered and concentrated under reduced pressure. Purification with PC (heptane to heptane/EtOAc=1/1) gave methyl 4-bromo-2-chloro-6-ethylbenzoate as a colorless oil (1.930 g, 69%). LCMS B: t _R =1.03 min; without ionization.

A.3.46.7. 4-Bromo-2-chloro-6-ethylbenzoic acid.

To a cooled (0°C) solution of 4-bromo-2-chloro-6-fluorobenzoic acid (4.530 g, 17.00 mmol) in anhydrous THF (40 mL) was added dropwise with a solution of ethyl magnesium bromide (1.0 M in THF, 67.9 mL, 67.9 mmol) and PM was further stirred at RT under nitrogen atmosphere for 50 min. Then, MeOH (20 ml) was added dropwise to the cooled (0°C) reaction mixture, and it was further stirred at 0°C for 5 minutes. The resulting mixture was then concentrated to dryness under reduced pressure and the residue partitioned between EtOAc and 2M aq. HCl. The layers are separated and aq. layer was extracted twice with EtOAc. The combined organic layers are then washed with brine, dried over anhydrous. MgSO ₄ , filtered and concentrated under reduced pressure. Purification with PC (heptane to heptane/EtOAc=1/1) gave 4-bromo-2-chloro-6-ethylbenzoic acid as a colorless solid (2.660 g, 59%). LCMS B: t _R =0.86 min; without ionization.

A.3.47. Methyl 2-(2-chloro-6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetate.

To a solution of methyl 2-(4-bromo-2-chloro-6-methylphenyl)acetate (2.614 g, 9.42 mmol) in anhydrous. DMF (25 ml) 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (2.416 g, 9.42 mmol), potassium acetate (3.697 g, 37.70 mmol) and Pd(dppf)Cl ₂ (766 mg, 1.04 mmol). PM is heated to 90° C. under nitrogen overnight. The PM is then allowed to cool to RT and filtered through a pad of celite, washing with EtOAc. The filtrate was washed with water and the aqueous layer was extracted twice with EtOAc. The combined organic layers are then washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. Purification with PC (heptane to heptane/EtOAc=7/3) gives methyl 2-(2-chloro-6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane -2yl)phenyl)acetate as a light green oil (1.939 g, 63%). LC-MS B: t _R =1.08 min; [M+H]+=325.19.

A.3.47.1. Methyl 2-(4-bromo-2-chloro-6-methylphenyl)acetate.

To a solution of 2-(4-bromo-2-chloro-6-methylphenyl)acetic acid (2.648 g, 10.00 mmol) in anhydrous. DMF (25 mL) cesium carbonate (6.548 g, 20.10 mmol) and iodomethane (1.26 mL, 20.10 mmol) are added at RT and PM is stirred at RT under nitrogen atmosphere for 1 h. Water and Et ₂ O are added and the layers are separated. The aqueous layer was extracted twice with Et ₂ O and the combined organic layers were washed with brine, dried over anhydrous. MgSO4, filter and concentrate under reduced pressure. Purification with PC (heptane to heptane/EtOAc=7/3) gave methyl 2-(4-bromo-2-chloro-6methylphenyl)acetate as a clear oil (2.614 g, 94%). LC-MS B: tR=1.00 min; without ionization.

A.3.47.2. 2-(4-Bromo-2-chloro-6-methylphenyl)acetic acid.

A mixture of 2-(4-bromo-2-chloro-6-methylphenyl)acetonitrile (2.504 g, 10.20 mmol), water (9 ml), 95% sulfuric acid (11 ml) and acetic acid (7 ml) is heated to 110° C under nitrogen for 4 h PM then allowed to cool to RT and poured onto ice/water. The reaction mixture is extracted twice with DCM and the combined organic layers are washed with brine, dried over anhydrous.

- 66 043145

MgSO ₄ , filtered and concentrated under reduced pressure to give crude 2-(4-bromo-2-chloro6-methylphenyl)acetic acid as an off-white solid (2.648 g, 98%). LC-MS B:

t _R =0.86 min; without ionization.

A.3.47.3. 2-(4-Bromo-2-chloro-6-methylphenyl)acetonitrile.

A solution of 5-bromo-1-chloro-2-(chloromethyl)-3-methylbenzene (2.752 g, 10.80 mmol) in MeCN (30 ml) and water (4 ml) was treated with sodium cyanide (719 mg, 14.10 mmol) and PM heated to 80° C. under nitrogen for 1 h PM then allowed to cool to RT and diluted with water. The acetonitrile is removed under reduced pressure and the mixture is extracted twice with DCM. The combined organic layers are dried over anhydrous. MgSO ₄ , filtered and concentrated under reduced pressure. Purification with PC (heptane to heptane/EtOAc=7/3) gave 2-(4-bromo-2-chloro-6-methylphenyl)acetonitrile as a colorless solid (2.504 g, 94%). LC-MS B: t _R =0.96 min; without ionization.

A.3.47.4. 5-Bromo-1-chloro-2-(chloromethyl)-3-methylbenzene.

Cooled (0°C) mixture of (4-bromo-2-chloro-6-methylphenyl)methanol (2.529 g, 10.70 mmol) and zinc chloride (36.6 mg, 0.268 mmol) in anhydrous. DCM (30 mL) was treated dropwise with thionyl chloride (1.57 mL, 21.50 mmol) and PM was stirred at 0°C for 4 h. PM was concentrated under reduced pressure to give crude 5-bromo-1-chloro-2-(chloromethyl) -3-methylbenzene as a dark pink solid (2.752 g, quantitative). LC-MS B: t _R =1.05 min; without ionization.

A.3.47.5. (4-Bromo-2-chloro-6-methylphenyl)methanol.

To a cooled (78°C) solution of methyl 4-bromo-2-chloro-6-methylbenzoate (3.450 g, 12.60 mmol) in anhydrous. THF (60 ml) was added dropwise with a solution of diisobutylaluminum hydride (1 M in toluene, 38.0 ml, 38.0 mmol). The mixture was further stirred at -78° C. under nitrogen for 30 minutes and then allowed to warm to RT. Stirring at RT is continued for 1.5 h and then the cooled PM is treated successively with water (1 ml), 2.8 N. aq. NaOH (1 ml) and water (3 ml). The mixture is allowed to warm to RT and stirred for an additional 30 minutes. The resulting mixture is filtered through celite, washing with THF, and the filtrate is concentrated to dryness under reduced pressure. EtOAc and water are added and the layers are separated. The aqueous layer was extracted twice with EtOAc and the combined organic layers were dried over anhydrous. MgSO ₄ , filtered and concentrated under reduced pressure. Purification with PC (heptane to heptane/EtOAc=1/1) gave pure (4bromo-2-chloro-6-methylphenyl)methanol (2.529 g, 85%). LC-MS B: t _R =0.90 min; without ionization.

A.3.47.6. Methyl 4-bromo-2-chloro-6-methylbenzoate.

To a solution of 4-bromo-2-chloro-6-methylbenzoic acid (3.500 g, 13.30 mmol) in anhydrous. DMF (35 mL) cesium carbonate (8.685 g, 26.70 mmol) and iodomethane (1.68 mL, 26.70 mmol) are added successively at RT and PM is stirred at RT for 1 h. Water and Et ₂ O are added and the layers are separated. The aqueous layer was extracted twice with Et ₂ O and the combined organic layers were washed with brine, dried over anhydrous. MgSO4, filter and concentrate under reduced pressure. Purification with PC (heptane to heptane/EtOAc=7/3) gave methyl 4-bromo-2-chloro-6-methylbenzoate as a dark orange oil (3.450 g, 98%). LC-MS B: t _R =0.99 min; without ionization.

A.3.48. Methyl 2-(2-fluoro-6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetate.

To a solution of methyl 2-(4-bromo-2-fluoro-6-methylphenyl)acetate (974 mg, 3.73 mmol) in anhydrous. DMF (15 ml) 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (957 mg, 3.73 mmol), potassium acetate (1.464 g, 14.90 mmol) and Pd(dppf)Cl ₂ (303 mg, 0.41 mmol). PM is heated to 95° C. under nitrogen overnight. The PM is then allowed to cool to RT and filtered through a pad of celite, washing with EtOAc. The filtrate was washed with water and the aqueous layer was extracted twice with EtOAc. The combined organic layers are then washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. Purification with PC (heptane to heptane/EtOAc=7/3) gives methyl 2-(2-fluoro-6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane -2-yl)phenyl)acetate as a yellow oil (918 mg, 80%). LC-MS B: t _R =1.05 min; [M+H]+=309.23.

A.3.48.1. Methyl 2-(4-bromo-2-fluoro-6-methylphenyl)acetate.

To a solution of 2-(4-bromo-2-fluoro-6-methylphenyl)acetic acid (980 mg, 3.97 mmol) in anhydrous. DMF (15 mL) cesium carbonate (2.585 g, 7.93 mmol) and iodomethane (0.499 mL, 7.93 mmol) are added at RT and PM is stirred at RT under nitrogen atmosphere for 1 h. Water and Et ₂ O are added and the layers are separated. The aqueous layer was extracted twice with Et ₂ O and the combined organic layers were washed with brine, dried over anhydrous. MgSO ₄ , filtered and concentrated under reduced pressure. Purification with PC (heptane to heptane/EtOAc=7/3) gave methyl 2-(4-bromo-2-fluoro-6methylphenyl)acetate as a clear oil (974 mg, 94%). LCMS B: tR=0.96 min; without ionization.

A.3.48.2. 2-(4-Bromo-2-fluoro-6-methylphenyl)acetic acid.

A mixture of 2-(4-bromo-2-fluoro-6-methylphenyl)acetonitrile (897 mg, 3.93 mmol), water (4 ml), 95% sulfuric acid (4 ml) and acetic acid (3 ml) is heated to 110° C under nitrogen for 2 h PM then allowed to cool to RT and poured onto ice/water. The reaction mixture is extracted twice with DCM and the combined organic layers are washed with brine, dried over anhydrous. MgSO ₄ , filtered and concentrated under reduced pressure to give crude 2-(4-bromo-2-fluoro6-methylphenyl)acetic acid as a colorless solid (980 mg, quantitative). LC- 67 043145

MS B: t _R =0.82 min; without ionization.

A.3.48.3. 2-(4-Bromo-2-fluoro-6-methylphenyl)acetonitrile.

A solution of 5-bromo-2-(chloromethyl)-1-fluoro-3-methylbenzene (1.027 g, 4.32 mmol) in MeCN (12 ml) and water (1.5 ml) is treated with sodium cyanide (287 mg, 5.62 mmol), and PM heated to 80° C. under nitrogen for 2.5 h PM then allowed to cool to RT and diluted with water. Acetonitrile is removed under reduced pressure and PM is extracted twice with DCM. The combined organic layers are dried over anhydrous. MgSO ₄ , filtered and concentrated under reduced pressure. Purification with PC (heptane to heptane/EtOAc=1/1) gave 2-(4-bromo-2-fluoro-6-methylphenyl)acetonitrile as a light yellow solid (897 mg, 91%). LC-MS B: t _R =0.91 min; without ionization.

A.3.48.4. 5-Bromo-2-(chloromethyl)-1-fluoro-3-methylbenzene.

Cooled (0°C) mixture of (4-bromo-2-fluoro-6-methylphenyl)methanol (1.000 g, 4.38 mmol) and zinc chloride (14.9 mg, 0.11 mmol) in anhydrous. DCM (10 mL) was treated dropwise with thionyl chloride (0.639 mL, 8.77 mmol) and PM was stirred at 0°C for 2 h. PM was concentrated under reduced pressure to give crude 5-bromo-2-(chloromethyl)-1-fluoro -3-methylbenzene as a brown oil (1.027 g, 99%). LC-MS B: t _R =1.02 min; without ionization.

A.3.49. Methyl 2-(2,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetate.

To a solution of methyl 2-(4-bromo-2,6-dimethylphenyl)acetate (2.575 g, 10.00 mmol) in anhydrous. DMF (25 ml) 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (2.569 g, 10.00 mmol), potassium acetate (3.931 g, 40.10 mmol) and Pd(dppf)Cl ₂ (814 mg, 1.10 mmol). PM is heated to 95° C. under nitrogen overnight. The PM is then allowed to cool to RT and filtered through a pad of celite, washing with EtOAc. The filtrate was washed with water and the aqueous layer was extracted twice with EtOAc. The combined organic layers are then washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. Purification with PC (heptane to heptane/EtOAc=3/1) gives methyl 2-(2,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2 -yl)phenyl)acetate as a light yellow solid (2.333 g, 77%). LC-MS B: t _R =1.05 min; [M+H]+=305.23.

A.3.49.1. Methyl 2-(4-bromo-2,6-dimethylphenyl)acetate.

To a solution of 2-(4-bromo-2,6-dimethylphenyl)acetic acid (2.553 g, 10.50 mmol) in anhydrous. DMF (25 mL) cesium carbonate (6.843 g, 21.00 mmol) and iodomethane (1.32 mL, 21.00 mmol) are added at RT and PM is stirred at RT under nitrogen atmosphere for 1 h. Water and Et ₂ O are added and the layers are separated. The aqueous layer was extracted twice with Et ₂ O and the combined organic layers were washed with brine, dried over anhydrous. MgSO ₄ , filtered and concentrated under reduced pressure. Purification with PC (heptane to heptane/EtOAc=7/3) gave methyl 2-(4-bromo-2,6dimethylphenyl)acetate as a clear oil (2.575 g, 95%). LC-MS B: t _R =0.99 min; without ionization.

A.3.49.2. 2-(4-Bromo-2,6-dimethylphenyl)acetic acid.

A mixture of 2-(4-bromo-2,6-dimethylphenyl)acetonitrile (3.048 g, 13.50 mmol), water (12.5 ml), 95% sulfuric acid (14 ml) and acetic acid (10 ml) was heated to 110°C in nitrogen atmosphere for 4 h PM then allowed to cool to RT and poured onto ice/water. The reaction mixture is extracted twice with DCM and the combined organic layers are washed with brine, dried over anhydrous. MgSO ₄ , filtered and concentrated under reduced pressure to give crude 2-(4-bromo-2,6dimethylphenyl)acetic acid as a colorless solid (2.553 g, 78%). LC-MS B: t _R =0.85 min; without ionization.

A.3.49.3. 2-(4-Bromo-2,6-dimethylphenyl)acetonitrile.

A solution of 5-bromo-2-(chloromethyl)-1,3-dimethylbenzene (3.328 g, 14.30 mmol) in MeCN (30 ml) and water (3.5 ml) is treated with sodium cyanide (946 mg, 18.50 mmol) and PM is heated to 80° C. under nitrogen for 2 h PM then allowed to cool to RT and diluted with water. The acetonitrile is removed under reduced pressure and the mixture is extracted twice with DCM. The combined organic layers are dried over anhydrous. MgSO4, filter and concentrate under reduced pressure. Purification with PC (heptane to heptane/EtOAc=7/3) gave 2-(4-bromo-2,6-dimethylphenyl)acetonitrile as a colorless solid (3.048 g, 95%). LC-MS B: t _R =0.95 min; without ionization.

A.3.49.4. 5-Bromo-2-(chloromethyl)-1,3-dimethylbenzene.

Chilled (0°C) mixture of (4-bromo-2,6-dimethylphenyl)methanol (3.000 g, 13.90 mmol) and zinc chloride (47.5 mg, 0.349 mmol) in anhydrous. DCM (30 mL) was treated dropwise with thionyl chloride (2.03 mL, 27.90 mmol) and PM was stirred at 0°C for 2 h. PM was concentrated to dryness under reduced pressure to give crude 5-bromo-2-(chloromethyl)-1, 3-dimethylbenzene as a colorless solid (3.328 g, quantitative). LCMS B: t _R =1.04 min; without ionization.

A.3.50. Methyl 2-(2-ethoxy-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetate.

To a solution of methyl 2-(4-bromo-2-ethoxy-6-fluorophenyl)acetate (1.370 g, 4.71 mmol) in anhydrous. DMF (12 ml) 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (1.207 g, 4.71 mmol), potassium acetate (1.847 g, 18.80 mmol) and Pd(dppf)Cl ₂ (383 mg, 0.51 mmol). PM is heated to 90° C. under nitrogen overnight. The PM is then allowed to cool to RT and filtered through a pad of celite, washing with EtOAc. The filtrate was washed with water and the aqueous layer was extracted twice with EtOAc. The combined organic layers are then washed with brine, dried over MgSO ₄ , filtered and

- 68 043145 concentrated under reduced pressure. Purification with PC (heptane to heptane/EtOAc=1/1) gives methyl 2-(2-ethoxy-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane -2yl)phenyl)acetate as a colorless solid (0.970 g, 61%). LC-MS B: t _R =1.09 min;

[M+H]+=339.21.

A.3.50.1. Methyl 2-(4-bromo-2-ethoxy-6-fluorophenyl)acetate.

To a solution of 2-(4-bromo-2-ethoxy-6-fluorophenyl)acetic acid (1.440 g, 5.20 mmol) in anhydrous. DMF (15 mL) cesium carbonate (2.117 g, 6.50 mmol) and iodomethane (0.48 mL, 7.80 mmol) are added at RT and PM is stirred at RT under nitrogen atmosphere for 15 min. Water and Et ₂ O are added and the layers are separated. The aqueous layer was extracted twice with Et ₂ O and the combined organic layers were washed with brine, dried over anhydrous. MgSO ₄ , filtered and concentrated under reduced pressure. Purification with PC (heptane to heptane/EtOAc=1/1) gave methyl 2-(4-bromo-2-ethoxy-6fluorophenyl)acetate as a colorless oil (1.370 g, 91%). LC-MS B: t _R =1.01 min; [M+H]+=290.99.

A.3.50.2. 2-(4-Bromo-2-ethoxy-6-fluorophenyl)acetic acid.

A mixture of 2-(4-bromo-2-ethoxy-6-fluorophenyl)acetonitrile (1.440 g, 5.58 mmol), water (5 ml), 95% sulfuric acid (6 ml) and acetic acid (7 ml) is heated to 110° C under nitrogen for 3 h PM then allowed to cool to RT and poured onto ice/water. The reaction mixture is extracted twice with DCM and the combined organic layers are washed with brine, dried over anhydrous. MgSO ₄ , filtered and concentrated under reduced pressure to give crude 2-(4-bromo-2ethoxy-6-fluorophenyl)acetic acid as a colorless solid (1.440 g, 93%). LCMS B: t _R =0.88 min; without ionization.

A.3.50.3. 2-(4-Bromo-2-ethoxy-6-fluorophenyl)acetonitrile.

A solution of 5-bromo-2-(chloromethyl)-1-ethoxy-3-fluorobenzene (2.860 g, 10.10 mmol) in MeCN (27 ml) and water (3.5 ml) was treated with sodium cyanide (669 mg, 13.10 mmol), and PM heated to 80° C. under nitrogen atmosphere overnight. The PM is then allowed to cool to RT and diluted with water. The acetonitrile is removed under reduced pressure and the mixture is extracted twice with DCM. The combined organic layers are dried over anhydrous. MgSO ₄ , filtered and concentrated under reduced pressure. Purification with PC (heptane to heptane/EtOAc=1/1) gave 2-(4-bromo-2-ethoxy-6-fluorophenyl)acetonitrile as a colorless solid (1.440 g, 55%). LC-MS B: t _R =0.97 min; without ionization.

A.3.50.4. 5-Bromo-2-(chloromethyl)-1-ethoxy-3-fluorobenzene.

A chilled (0°C) mixture of (4-bromo-2-ethoxy-6-fluorophenyl)methanol (2.180 g, 8.75 mmol) and zinc chloride (29.8 mg, 0.219 mmol) in anhydrous DCM (17 mL) was treated dropwise with thionyl chloride (1.28 mL, 17.50 mmol) and PM was stirred at 0°C for 2 h. PM was concentrated under reduced pressure to give crude 5-bromo-2-(chloromethyl)-1-ethoxy -3-fluorobenzene as a pale pink oil (2.330 g, 99%). LCMS B: t _R =1.07 min; without ionization.

A.3.50.5. (4-Bromo-2-ethoxy-6-fluorophenyl)methanol.

To a cooled (78°C) solution of methyl 4-bromo-2-ethoxy-6-fluorobenzoate (3.150 g, 11.40 mmol) in anhydrous. THF (30 ml) was added dropwise with a solution of diisobutylaluminum hydride (1 M in toluene, 34.1 ml, 34.1 mmol). The mixture was further stirred at -78°C under nitrogen for 15 min and then allowed to warm to 0°C. Stirring at 0° C. is continued for 45 min and then the cooled PM is treated successively with water (35 ml) and 2.8 N. aq. NaOH (25 ml). The mixture is allowed to warm to RT and stirred for an additional 30 minutes. The resulting mixture is filtered through celite, washing with THF. EtOAc and water are added and the layers are separated. The aqueous layer is extracted twice with EtOAc and the combined organic layers are dried over anhydrous. MgSO ₄ , filtered and concentrated under reduced pressure. Purification with PC (heptane to EtOAc) gave (4-bromo-2ethoxy-6-fluorophenyl)methanol as a colorless solid (2.680 g, 95%). LCMS B: tR=0.84 min; without ionization.

A.3.50.6. Methyl 4-bromo-2-ethoxy-6-fluorobenzoate.

To a solution of methyl 4-bromo-2-fluoro-6-hydroxybenzoate (2.930 g, 11.20 mmol) in anhydrous. DMF (14 mL) cesium carbonate (3.642 g, 11.20 mmol) and iodoethane (0.90 mL, 11.20 mmol) are added successively at RT and PM is stirred at RT for 30 min. Then more cesium carbonate (3.729 g, 11.40 mmol) and iodoethane (0.92 ml, 11.40 mmol) are added and PM is stirred at RT for 20 min. Water and Et ₂ O are added and the layers are separated. The aqueous layer was extracted twice with Et ₂ O and the combined organic layers were washed with brine, dried over anhydrous. MgSO ₄ , filtered and concentrated under reduced pressure. Purification with PC (heptane to heptane/EtOAc=1/1) gave methyl 4-bromo-2-ethoxy-6-fluorobenzoate as a yellow oil (3.150 g, quantitative). LC-MS B: t _R =0.97 min; [M+H]+=277.08.

A.3.51. Methyl 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethoxy)phenyl)acetate.

To a solution of methyl 2-(4-bromo-2-(trifluoromethoxy)phenyl)acetate (1.896 g, 5.58 mmol) in anhydrous. DMF (25 ml) 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (1.432 g, 5.58 mmol), potassium acetate (2.192 g, 22.30 mmol) and Pd(dppf)Cl ₂ (454 mg, 0.61 mmol). PM is heated to 95° C. under nitrogen overnight. The PM is then allowed to cool to RT and filtered through a pad of celite, washing with Et ₂ O. The filtrate is washed with water and the aqueous layer is extracted twice with Et ₂ O.

- 69 043145

The combined organic layers are then washed with brine, dried over MgSO ₄ , filtered and concentrated under reduced pressure. Purification with PC (heptane to heptane/EtOAc=7/3) gives methyl 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2( trifluoromethoxy)phenyl)acetate as a green oil (1.574 g, 78%). LC-MS B: t _R =1.09 min;

[M+H]+=361.13.

A.3.51.1. Methyl 2-(4-bromo-2-(trifluoromethoxy)phenyl)acetate.

To a solution of 2-(4-bromo-2-(trifluoromethoxy)phenyl)acetic acid (2.000 g, 6.56 mmol) in anhydrous. DMF (30 mL) cesium carbonate (4.277 g, 13.10 mmol) and iodomethane (0.82 mL, 13.10 mmol) are added at RT and PM is stirred at RT under nitrogen atmosphere for 1 h. Water and Et ₂ O are added and the layers are separated. The aqueous layer was extracted twice with Et ₂ O and the combined organic layers were washed with brine, dried over anhydrous. MgSO4, filter and concentrate under reduced pressure. Purification with PC (heptane to heptane/EtOAc=1/1) gave methyl 2-(4bromo-2-(trifluoromethoxy)phenyl)acetate as a clear oil (1.896 g, 92%). LC-MS B: t _R =1.01 min; without ionization.

A.3.52. Methyl 2-(2-(difluoromethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetate.

To a solution of methyl 2-(4-bromo-2-(difluoromethoxy)phenyl)acetate (800 mg, 2.71 mmol) in anhydrous. DMF (20 ml) 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (695 mg, 2.71 mmol), potassium acetate (1.064 g, 10.80 mmol) and Pd(dppf)Cl ₂ (220 mg, 0.29 mmol). PM is heated to 90° C. under nitrogen overnight. The PM is then allowed to cool to RT and filtered through a pad of celite, washing with EtOAc. The filtrate was washed with water and the aqueous layer was extracted twice with EtOAc. The combined organic layers are then washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. Purification with PC (heptane to heptane/EtOAc=1/1) gives methyl 2-(2-(difluoromethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl )phenyl)acetate as a yellow oil (367 mg, 40%). LCMS B: t _R =1.03 min; without ionization.

A.3.52.1. Methyl 2-(4-bromo-2-(difluoromethoxy)phenyl)acetate.

To a solution of 2-(4-bromo-2-(difluoromethoxy)phenyl)acetic acid (3.560 g, 12.70 mmol) in anhydrous. DMF (20 mL) cesium carbonate (6.191 g, 19.00 mmol) and iodomethane (0.95 mL, 15.20 mmol) are added at RT and PM is stirred at RT under nitrogen atmosphere for 1 h. Water and Et ₂ O are added and the layers are separated. The aqueous layer was extracted twice with Et ₂ O and the combined organic layers were washed with brine, dried over anhydrous. MgSO ₄ , filtered and concentrated under reduced pressure. Purification with PC (heptane to heptane/EtOAc=1/1) gave methyl 2-(4-bromo-2(difluoromethoxy)phenyl)acetate as a colorless oil (2.390 g, 64%). LCMS B: tR=0.94 min; without ionization.

A.3.52.2. 2-(4-Bromo-2-(difluoromethoxy)phenyl)acetic acid.

To a mixture of 2-(4-bromo-2-(difluoromethoxy)phenyl)acetonitrile (3.460 g, 13.20 mmol) in EtOH (100 mL) and water (100 mL) was added potassium hydroxide (2.222 g, 39.60 mmol) at RT, and PM is heated at reflux under nitrogen atmosphere overnight. The PM is then allowed to cool to RT and the ethanol is removed under reduced pressure. The resulting mixture is treated with 1M aq. HCl and extracted twice with DCM. The combined organic layers are washed with brine, dried over anhydrous. MgSO ₄ , filtered and concentrated under reduced pressure to give crude 2(4-bromo-2-(difluoromethoxy)phenyl)acetic acid as an off-white solid (3.560 g, 96%). LC-MS B: t _R =0.82 min; without ionization.

A.3.52.3. 2-(4-Bromo-2-(difluoromethoxy)phenyl)acetonitrile.

A solution of 4-bromo-1-(chloromethyl)-2-(difluoromethoxy)benzene (3.890 g, 14.30 mmol) in MeCN (38 ml) and water (5 ml) is treated with sodium cyanide (913 mg, 18.60 mmol) and PM is heated to 85° C. under nitrogen for 3 hours PM then allowed to cool to RT and diluted with water. The acetonitrile is removed under reduced pressure and the mixture is extracted twice with DCM. The combined organic layers are dried over anhydrous. MgSO4, filter and concentrate under reduced pressure. Purification with PC (heptane to EtOAc) gave 2-(4-bromo-2-(difluoromethoxy)phenyl)acetonitrile as a pale yellow solid (3.560 g, 95%). LC-MS B: t _R =0.92 min; without ionization.

A.3.52.4. 4-Bromo-1-(chloromethyl)-2-(difluoromethoxy)benzene.

Cooled (0°C) mixture of (4-bromo-2-(difluoromethoxy)phenyl)methanol (3.580 g, 14.10 mmol) and zinc chloride (48.2 mg, 0.354 mmol) in anhydrous. DCM (28 mL) was treated dropwise with thionyl chloride (2.06 mL, 28.30 mmol) and PM was stirred at 0°C for 3.5 h. PM was concentrated under reduced pressure to give crude 4-bromo-1-(chloromethyl)-2-( difluoromethoxy)benzene as a colorless oil (3.890 g, quantitative). LC-MS B: t _R =1.00 min; without ionization.

A.3.52.5. (4-Bromo-2-(difluoromethoxy)phenyl).

To a cooled (0°C) solution of 4-bromo-2-(difluoromethoxy)benzaldehyde (3.820 g, 15.20 mmol) in anhydrous MeOH (75 mL) sodium borohydride (1.727 g, 45.70 mmol) was added portionwise and the mixture was further stirred at 0° C. under nitrogen for 1 hour. The methanol was then removed under reduced pressure. DCM and water are added and the layers are separated. The aqueous layer is extracted twice with DCM and the combined organic layers are dried over anhydrous. MgSO ₄ , filtered and concentrated under reduced pressure. Purification with PC (heptane to heptane/EtOAc=1/1) gave (4-bromo-2(difluoromethoxy)phenyl)methanol as a colorless oil (3.890 g, quantitative). LC-MS B: t _R =0.81 min; without ionization.

A.3.52.6. 4-Bromo-2-(difluoromethoxy)benzaldehyde.

To a cooled (0°C) solution of 4-bromo-2-hydroxybenzaldehyde (5.000 g, 24.40 mmol) in MeCN (135 ml) and water (135 ml) was added potassium hydroxide (27.355 g, 488.00 mmol). The mixture is stirred at RT for 30 min and then cooled to -30°C. Diethyl (bromodifluoromethyl)phosphonate (13.283 g, 48.80 mmol) was added to the cooled mixture in one portion and stirring was then continued at RT for 2 h. Et ₂ O was added, the layers were separated and the aqueous layer was further extracted with Et ₂ O. The combined the organic layers are washed successively with 1M aq. NaOH, water and brine and then dried over anhydrous. MgSO ₄ , filtered and concentrated under reduced pressure. Purification with PC (heptane to heptane/EtOAc=7/3) gave 4-bromo-2(difluoromethoxy)benzaldehyde as a pale yellow solid (3.820 g, 62%). LC-MS B: t _R =0.92 min; without ionization.

A.3.53. Methyl 2-(3-ethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophen-2-yl)acetate.

A mixture of methyl 2-(3-ethylthiophen-2-yl)acetate (1.340 g, 7.27 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'bi( 1,3,2-dioxaborolane) (1.119 g, 4.36 mmol), bis-(1,5-cyclooctadiene)diiridium(I) dichloride (50.4 mg, 0.0727 mmol) and 4,4'-di-tert-butyl-2 ,2'-Bipyridine (47.8 mg, 0.175 mmol) in THF (35 ml) was degassed with nitrogen flow and then stirred at 80° C. under nitrogen atmosphere overnight. PM is concentrated under reduced pressure and the residue is purified with PC (heptane to heptane/EtOAc=4/1) to give methyl 2-(3-ethyl-5-(4,4,5,5-tetramethyl-1,3 ,2-dioxaborolan-2-yl)thiophen-2-yl)acetate as a pale yellow oil (1.781 g, 79%). LC-MS B: t _R =1.04 min; [M+H]+=311.22.

A.3.53.1. Methyl 2-(3-ethylthiophen-2-yl)acetate.

To a solution of 2-(3-ethylthiophen-2-yl)acetic acid (1.248 g, 7.33 mmol) in anhydrous. DMF (20 mL) cesium carbonate (3.581 g, 11.00 mmol) and iodomethane (0.55 mL, 8.79 mmol) are added at RT and PM is stirred at RT under nitrogen atmosphere for 40 min. Water and Et ₂ O are added and the layers are separated. The aqueous layer was extracted twice with Et ₂ O and the combined organic layers were washed with brine, dried over anhydrous. MgSO ₄ , filtered and concentrated under reduced pressure. Purification with PC (heptane to heptane/EtOAc=1/1) gave methyl 2-(3-ethylthiophen-2-yl)acetate as a yellow oil (1.340 g, 99%). LC-MS B: t _R =0.87 min; [M+H] ⁺ =185.19.

A.3.53.2. 2-(3-Ethylthiophen-2-yl)acetic acid.

To a mixture of 2-(3-ethylthiophen-2-yl)acetonitrile (1.150 g, 7.60 mmol) in EtOH (6 mL) and water (6 mL) was added potassium hydroxide (1.280 g, 22.80 mmol) at RT and PM heated to reflux flask under nitrogen atmosphere for 75 min. The PM is then allowed to cool to RT and the ethanol is removed under reduced pressure. The resulting mixture is treated with 1M aq. HCl and extracted twice with DCM. The combined organic layers are dried over anhydrous. MgSO ₄ , filtered and concentrated under reduced pressure to give crude 2-(3-ethylthiophen-2-yl)acetic acid as a yellow oil (1.247 g, 96%). LC-MS B: t _R =0.72 min; [M+H]+=170.94.

A.3.53.3. 2-(3-Ethylthiophen-2-yl)acetonitrile.

A solution of 2-(chloromethyl)-3-ethylthiophene (506 mg, 3.15 mmol) in anhydrous DMSO (20 mL) was treated with sodium cyanide (617 mg, 12.60 mmol) and PM was heated to 80°C under nitrogen for 40 min. The PM is then allowed to cool to RT and diluted with water. The resulting mixture was extracted three times with EtOAc and the combined organic layers washed with brine, dried over anhydrous. MgSO4, filter and concentrate under reduced pressure. Purification with PC (heptane to heptane/EtOAc=1/1) gave 2-(3-ethylthiophen-2-yl)acetonitrile as a yellow oil (360 mg, 76%). LC-MS B: t _R =0.83 min; without ionization.

A.3.53.4. 2-(Chloromethyl)-3-ethylthiophene.

To a cooled (0°C) solution of (3-ethylthiophen-2-yl)methanol (500 mg, 3.52 mmol) in anhydrous. DCM (18 ml) was added successively triethylamine (0.63 ml, 4.57 mmol) and 4-dimethylaminopyridine (43 mg, 0.35 mmol). Then methanesulfonyl chloride (0.32 ml, 4.22 mmol) was added dropwise and the resulting mixture was stirred at RT under nitrogen atmosphere for 1 h PM then diluted with water, the layers were separated and the aqueous layer was extracted twice with DCM. The combined organic layers are dried over anhydrous. MgSO ₄ , filtered and concentrated under reduced pressure to give crude 2-(chloromethyl)-3-ethylthiophene as a yellow oil (505 mg, 90%). LCMS B: t _R =0.86 min; without ionization.

A.3.53.5. (3-Ethylthiophen-2-yl)methanol

To a cooled (78°C) solution of methyl 3-ethylthiophene-2-carboxylate (2.270 g, 13.30 mmol) in anhydrous. THF (80 ml) was added dropwise with a solution of diisobutylaluminum hydride (1 M in toluene, 40.0 ml, 40.0 mmol). The mixture was further stirred at -78°C under nitrogen for 10 minutes and then allowed to warm to 0°C. Stirring at 0° C. was continued for 30 minutes and then the cooled PM was treated successively with water (1.5 ml), 15% aq. NaOH (1.5 ml) and water (4 ml). The mixture was allowed to warm to RT and stirred an additional 1 hour. The resulting mixture was filtered.

- 71 043145 through Celite, washing with THF. EtOAc and water are added and the layers are separated. The aqueous layer is extracted twice with EtOAc and the combined organic layers are dried over anhydrous. MgSO ₄ , filtered and concentrated under reduced pressure. Purification with PC (heptane to heptane/EtOAc=1/1) gave (3-ethylthiophen-2-yl)methanol as a colorless oil (2.030 g, quantitative).

LCMS B: t _R =0.66 min; without ionization.

A.3.53.6. Methyl 3-ethylthiophene-2-carboxylate.

To a solution of 3-ethylthiophene-2-carboxylic acid (3.130 g, 19.00 mmol) in anhydrous. DMF (20 mL) cesium carbonate (9.303 g, 28.60 mmol) and iodomethane (1.44 mL, 22.80 mmol) are added successively at RT and PM is stirred at RT for 1.5 h. Water and Et ₂ O are added and the layers are separated. The aqueous layer was extracted twice with Et ₂ O and the combined organic layers were washed with brine, dried over anhydrous. MgSO ₄ , filtered and concentrated under reduced pressure to give methyl 3-ethylthiophene-2-carboxylate as a yellow oil (3.340 g, quantitative). LC-MS B: t _R =0.89 min; [M+H]+=171.04.

A.3.54. Ethyl 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-3-carboxylate.

To a solution of ethyl 6-bromobenzofuran-3-carboxylate (1.850 g, 6.87 mmol) in anhydrous. DMF (20 ml) 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (1.763 g, 6.87 mmol), potassium acetate (2.699 g, 27.50 mmol) and Pd(dppf)Cl ₂ (559 mg, 0.75 mmol). PM is heated to 95° C. under nitrogen overnight. PM is then allowed to cool to RT and filtered through a pad of celite, washing with Et ₂ O. The filtrate is washed with water and the aqueous layer is extracted twice with Et ₂ O. The combined organic layers are then washed with brine, dried over MgSO ₄ , filtered and concentrated under reduced pressure. Purification with PC (heptane to heptane/EtOAc=7/3) gives ethyl 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-3-carboxylate in as a light yellow solid (1.528 g, 70%). LC-MSV: t _R =1.11 min; [M+H]+=317.23.

A.3.55. Methyl 2-(2-cyclopropoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetate

To a solution of methyl 2-(4-bromo-2-cyclopropoxyphenyl)acetate (2.009 g, 7.05 mmol) in anhydrous. 1,4dioxane (30 ml) at RT add 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (1.807 g , 7.05 mmol), potassium acetate (2.766 g, 28.20 mmol) and Pd(dppf)Cl ₂ (573 mg, 0.77 mmol). PM is heated to 95° C. under nitrogen overnight. The PM is then allowed to cool to RT and filtered through a pad of celite, washing with EtOAc. The filtrate was washed with water and the aqueous layer was extracted twice with EtOAc. The combined organic layers are then dried over MgSO ₄ , filtered and concentrated under reduced pressure. Purification with PC (heptane to heptane/EtOAc=7/3) gives methyl 2-(2-cyclopropoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl )phenyl)acetate as a yellow oil (1.912 g, 82%). LC-MS B: tR=1.04 min; [M+H]+=333.25.

A.3.55.1. Methyl 2-(4-bromo-2-cyclopropoxyphenyl)acetate.

Chilled (0°C) solution of diethylzinc (1 M in hexanes, 32.6 ml, 32.6 mmol) in anhydrous. DCM (30 ml) was treated dropwise with trifluoroacetic acid (1.72 ml, 22.30 mmol) and the mixture was stirred at 0° C. under nitrogen for 10 min. Diiodomethane (5.35 mL, 65.20 mmol) was then added dropwise to the cooled mixture, and stirring at 0°C was continued for 10 min. Then a solution of methyl 2-(4-bromo-2-(vinyloxy)phenyl)acetate (2.396 g, 8.57 mmol) in anhydrous was added dropwise. DCM (40 ml) and the resulting mixture was further stirred at 0° C. for 30 min and then at RT for 5 h. PM then treated with aq. sat. NH ₄ Cl and the layers are separated. The aqueous layer is extracted twice with DCM and the combined organic layers are washed with brine, dried over anhydrous. MgSO ₄ , filtered and concentrated under reduced pressure. Purification with PC (heptane to heptane/EtOAc=3/1) gave methyl 2-(4-bromo-2-cyclopropoxyphenyl)acetate as a light yellow oil (2.009 g, 82%). LC-MS B: t _R =0.99 min; without ionization.

A.3.55.2. Methyl 2-(4-bromo-2-(vinyloxy)phenyl)acetate.

To a solution of methyl 2-(4-bromo-2-hydroxyphenyl)acetate (3.160 g, 12.90 mmol) in anhydrous. toluene (35 mL) sodium carbonate (820 mg, 7.74 mmol) and bis(1,5cyclooctadiene)diiridium(1) dichloride (89.3 mg, 0.129 mmol) are added successively at RT and the mixture is degassed with nitrogen. Vinyl acetate (2.4 mL, 25.80 mmol) was then added and the resulting mixture was heated to 100° C. under nitrogen for 5 h PM, allowed to cool to RT and water was added. The mixture is extracted three times with EtOAc and the combined organic layers are washed with brine, dried over anhydrous. MgSO ₄ , filtered and concentrated under reduced pressure. Purification with PC (heptane to heptane/EtOAc=1/1) gave methyl 2-(4-bromo-2-(vinyloxy)phenyl)acetate as a yellow oil (2.253 g, 64%). LC-MS B: t _R =0.96 min; without ionization.

A.3.55.3. Methyl 2-(4-bromo-2-hydroxyphenyl)acetate.

A solution of 2-(4-bromo-2-hydroxyphenyl)acetic acid (3.000 g, 12.30 mmol) in anhydrous. MeOH (45 ml) is treated dropwise with a solution of concentrated HCl (12 M, 1.02 ml, 12.30 mmol) in anhydrous. MeOH (15 ml) and the resulting solution is heated to 70° C. under nitrogen for 2 h. PM is then allowed to cool to RT and the methanol is removed under reduced pressure. Water and Et2O are added and the layers are separated. The aqueous layer was extracted twice with Et ₂ O and the combined organic layers were washed with brine, dried over anhydrous. MgSO ₄ , filtered and concentrated under reduced

- 72 043145 pressure. Purification with PC (heptane to heptane/EtOAc=1/1) gave methyl 2-(4-bromo-2-hydroxyphenyl)acetate as a colorless solid (2.733 g, 90%). LC-MS B: t _R =0.80 min; without ionization.

A.3.56. Methyl 1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrole-2-carboxylate

To a solution of methyl 4-bromo-1-ethyl-III-pyrrole-2-carboxylate (1.567 g, 6.75 mmol) in anhydrous. DMF (15 ml) 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (1.715 g, 6.75 mmol), potassium acetate (2.651 g, 27.00 mmol) and Pd(dppf)Cl ₂ (494 mg, 0.67 mmol). PM is heated to 90° C. under nitrogen overnight. The PM is then allowed to cool to RT and filtered through a pad of celite, washing with EtOAc. The filtrate was washed with water and the aqueous layer was extracted twice with EtOAc. The combined organic layers are then washed with brine, dried over MgSO ₄ , filtered and concentrated under reduced pressure. Purification with PC (heptane to heptane/EtOAc=3/1) gives methyl 1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H -pyrrole-2-carboxylate as a light yellow oil (841 mg, 45%). LC-MS B: t _R =0.96 min; [M+H]+=280.24.

A.3.56.1. Methyl 4-bromo-1-ethyl-1H-pyrrole-2-carboxylate.

To a solution of methyl 4-bromo-III-pyrrole-2-carboxylate (1.500 g, 7.21 mmol) in anhydrous. DMF (15 mL) potassium carbonate (1.494 g, 10.80 mmol) and iodoethane (1.43 mL, 8.65 mmol) are added at RT and PM is stirred at RT under nitrogen atmosphere for 2.5 h. Water and Et ₂ O are added and the layers are separated. The aqueous layer was extracted twice with Et ₂ O and the combined organic layers were washed with brine, dried over anhydrous. MgSO ₄ , filtered and concentrated under reduced pressure. Purification with PC (heptane to heptane/EtOAc=7/3) gave methyl 4-bromo-1-ethyl-1H-pyrrole-2-carboxylate as a clear oil (1.567 g, 94%). LC-MS B: t _R =0.94 min; without ionization.

A.3.57. Methyl 1-propyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrole-2-carboxylate.

To a solution of methyl 4-bromo-1-propyl-1H-pyrrole-2-carboxylate (1.721 g, 6.99 mmol) in anhydrous. DMF (15 ml) 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (1.776 g, 6.99 mmol), potassium acetate (2.745 g, 28.00 mmol) and Pd(dppf)Cl ₂ (512 mg, 0.69 mmol). PM is heated to 90° C. under nitrogen overnight. The PM is then allowed to cool to RT and filtered through a pad of celite, washing with EtOAc. The filtrate was washed with water and the aqueous layer was extracted twice with EtOAc. The combined organic layers are then washed with brine, dried over MgSO ₄ , filtered and concentrated under reduced pressure. Purification with PC (heptane to heptane/EtOAc=3/1) gives methyl 1-propyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H -pyrrole-2-carboxylate as a yellow oil (1.036 g, 51%). LC-MS B: t _R =1.02 min; [M+H]+=294.33.

A.3.57.1. Methyl 4-bromo-1-propyl-1H-pyrrole-2-carboxylate.

To a solution of methyl 4-bromo-1H-pyrrole-2-carboxylate (1.500 g, 7.21 mmol) in anhydrous. DMF (15 mL) potassium carbonate (1.494 g, 10.80 mmol) and 1-iodopropane (0.84 mL, 8.65 mmol) are added at RT and PM is stirred at RT under nitrogen atmosphere overnight. Water and Et2O are added and the layers are separated. The aqueous layer was extracted twice with Et2O and the combined organic layers were washed with brine, dried over anhydrous. MgSO4, filter and concentrate under reduced pressure. Purification with PC (heptane to heptane/EtOAc=7/3) gave methyl 4-bromo-1-propyl-1H-pyrrole-2-carboxylate as a clear oil (1.721 g, 97%). LC-MS B: t _R =0.99 min; without ionization.

A.3.58. Methyl 3-ethoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrole-2-carboxylate.

A mixture of methyl 3-ethoxy-1H-pyrrole-2-carboxylate (265 mg, 1.57 mmol), 4,4,4',4',5,5,5',5'-octamethyl2,2'-bi(1, 3,2-dioxaborolane) (402 mg, 1.57 mmol), (1,5-cyclooctadiene)(methoxy)iridium(1) dimer (15.9 mg, 0.0235 mmol) and 4,4'-di-tert-butyl-2, 2'-bipyridine (15 mg, 0.054 mmol) in THF (5 mL) was degassed with a stream of nitrogen and then stirred at RT under nitrogen for 1 h. PM was concentrated under reduced pressure and the residue was purified with PC (heptane to heptane /EtOAc=7/3) to obtain methyl 3-ethoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrol-2-carboxylate in the form of a transparent oils (490 mg, quantitative). LCMS B: t _R =0.88 min; [M+H]+=296.25.

A.3.58.1. Methyl 3-ethoxy-1H-pyrrole-2-carboxylate.

To a solution of methyl 3-hydroxy-1H-pyrrole-2-carboxylate (300 mg, 2.06 mmol) in anhydrous. DMF (8 ml) was added at RT with potassium carbonate (299 mg, 2.17 mmol) and iodoethane (0.174 ml, 2.17 mmol) and PM was stirred at RT under nitrogen atmosphere overnight. Water and Et ₂ O are added and the layers are separated. The aqueous layer was extracted twice with Et ₂ O and the combined organic layers were washed with brine, dried over anhydrous. MgSO ₄ , filtered and concentrated under reduced pressure. Purification with PC (heptane to EtOAc) gave methyl 3-ethoxy-1H-pyrrole-2-carboxylate as a light yellow solid (265 mg, 76%). LC-MS B: t _R =0.60 min; [M+H]+=170.09.

A.3.59. Ethyl 3-cyclopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrole-2-carboxylate.

A mixture of ethyl 3-cyclopropyl-1H-pyrrole-2-carboxylate (300 mg, 1.59 mmol), 4,4,4',4',5,5,5',5'octamethyl-2,2'-bi(1 ,3,2-dioxaborolane) (408 mg, 1.59 mmol), (1,5-cyclooctadiene)(methoxy)iridium(1) dimer (16.1 mg, 0.0239 mmol) and 4,4'-di-tert-butyl-2 ,2'-bipyridine (15.2 mg, 0.055 mmol) in THF (2.5 ml) was degassed with nitrogen flow and then stirred at RT under nitrogen atmosphere for 1 h. PM was concentrated under reduced pressure and the residue was purified with PC (from heptane to heptane/BULS=7/3) to give ethyl 3-cyclopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1Hpyrrol-2-carboxylate as a yellow solid (389 mg, 80%). LCMS B: t _R =1.03 min;

[M+H]+=306.04.

L.3.60. 1-(2-Propyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclopropane-1-carboxylic acid.

The title compound is prepared according to the procedure described for K.3.6, starting from 1-(4-bromo-2-propylphenyl)cyclopropane-1-carboxylic acid. LCMS B: t _R =1.02 min; [M+MeCN]+=372.47.

L.3.60.1. 1-(4-Bromo-2-propylphenyl)cyclopropane-1-carboxylic acid.

To a flask containing 1-(4-bromo-2-propylphenyl)cyclopropane-1-carbonitrile (465 mg, 1.69 mmol) and equipped with a condenser, add H ₂ O (1.6 ml), LsOH (1.2 ml) and H ₂ SO in succession ₄ (1.8 ml). PM is stirred at 110° C. for 3 d, then cooled to RT. PM is poured into ice water and the mixture is extracted with DCM (3x). The combined organic layers are washed with 1N. NaOH solution. The main aqueous layer is extracted again with EtOLc. The aqueous layer is acidified to reach pH2-3 by adding 2N. HCl. This acidic aqueous layer is then extracted twice with EtOLc. These organic layers (acid extraction) are combined, washed with water, brine, dried over MgSO ₄ , filtered and concentrated under reduced pressure to give the title compound as a white solid (283 mg, 65%). LCMS B: tR=0.96 min; without ionization. 1H NMR (400 MHz, d6-DMSO) δ: 12.13-12.49 (m, 1H), 7.36-7.41 (m, 1H), 7.237.33 (m, 1H), 7.13-7.22 (m, 1H), 2.59- 2.67 (m, 2H), 1.61 (m, 2H), 1.43-1.56 (m, 2H), 1.06-1.15 (m, 2H), 0.810.98 (m, 3H).

L.3.60.2. 1-(4-Bromo-2-propylphenyl)cyclopropane-1-carbonitrile.

1,2-Dibromoethane (1.26 ml, 14.4 mmol), ammonium benzyl triethyl chloride (89.4 mg, 0.385 mmol) and NaOH (1346 mg, 33.6 mmol). PM is stirred for 2 nights at 110°C, then cooled to RT and 1,2-dibromoethane (1.26 ml, 14.4 mmol), ammonium benzyl triethyl chloride (89.4 mg, 0.385 mmol) and NaOH (1346 mg, 33.6 mmol) are added, and PM is stirred overnight at 110°C. After the mixture has cooled to RT, the PM is quenched with water and concentrated in vacuo. The residue is partitioned between EtOLc and water. The aqueous layer is extracted again with EtOLc. The combined organic layers are washed with water, brine, dried over MgSO ₄ , filtered and concentrated in vacuo. The residue was purified with PC (Hept:EtOLc, 100:0 to 95:5) to give the title compound as a yellow oil (468 mg, 37%). LC-MS B: t _R =1.06 min; [M+H]+=263.92.

L.3.61. 1-(2-Ethoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclopropane-1-carboxylic acid.

The title compound is prepared according to the procedure described for K.3.6, starting from 1-(4-bromo-2-ethoxy1phenyl)cyclopropane-1-carboxylic acid. LC-MS B: t _R =0.96 min; [M+H]+=333.44.

L.3.61.1. 1-(4-Bromo-2-ethoxyphenyl)cyclopropane-1-carboxylic acid.

The title compound is prepared according to the procedure described for K.3.60.1, starting from 1-(4-bromo-2-ethoxyphenyl)cyclopropane-1-carbonitrile. LC-MS B: t _R =0.90 min; [M+H]+=285.17.

L.3.61.2. 1-(4-Bromo-2-ethoxyphenyl)cyclopropane-1-carbonitrile.

The title compound was prepared according to the procedure described for K.3.60.2 starting from 2-(4-bromo-2-ethoxyphenyl)acetonitrile (Example 282-d). LC-MS B: t _R =1.00 min; [M+H]+=265.94.

L.3.62. 5-(2-Methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)isoxazol-3-ol.

Butyllithium (1.6 M in hexane) was added dropwise to a stirred solution of 5-(4-bromo-2-methoxyphenyl)isoxazol-3-ol (158 mg, 0.585 mmol) in dry THF (4 mL) at -78°C under nitrogen. , 1.1 ml, 1.76 mmol). PM is stirred at -78°C for 25 min, then isopropoxyboronic acid pinacol ester (0.418 ml, 2.05 mmol) is added dropwise and PM is stirred at -78°C for 45 min, then at RT for 40 min. PM quench sat. aq. NH4Cl and extracted with EtOLc. The organic layer is washed twice with brine, dried over MgSO ₄ , filtered and concentrated. The residue was purified with PC (Hept:EtOLc, 9:1 to 8:2) to give the expected product as a white solid (42 mg, 23%). LC-MS L: t _R =0.86 min; [M+H]+=318.14.

L.3.62.1. 5-(4-Bromo-2-methoxyphenyl)isoxazol-3-ol.

To a stirred suspension of 3-(4-bromo-2-methoxyphenyl)-3-oxo-N-((tetrahydro-2H-pyran-2yl)oxy)propanamide (284 mg, 0.763 mmol) in MeOH (1.7 ml) at RT at dropwise add HCl conc. (6.8 ml). PM is stirred at RT for 30 min. Water (4 ml) was added and the precipitate was filtered off, washing with 1.2 ml water, to give the expected product as a white solid (169 mg, 82%) LC-MS L: t _R =0.79 min, [M+H] ⁺ =271.99 .

L.3.62.2. 3-(4-Bromo-2-methoxyphenyl)-3-oxo-N-((tetrahydro-2H-pyran-2-yl)oxy)propanamide.

- 74 043145

O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (512 mg , 4.19 mmol) and DMAP (433 mg, 3.55 mmol) at CT. PM is heated to 115° C. and stirred overnight, then cooled to RT. The mixture is partitioned between 40 ml HCl 0.5M (pH 2) and 40 ml EtOAc. The organic layer was washed three times with 40 ml sat. NaCl solution. The aqueous layer is re-extracted with 40 ml EtOAc. The organic layers are combined, dried over MgSO ₄ , filtered and concentrated. The residue was purified with FQ (Hept:EtOAc) to give the title compound as a white solid (301 mg, 25%). LC-MS A: t _R =0.76 min, [M+H]+=373.98.

A.3.62.3. Ethyl 3-(4-bromo-2-methoxyphenyl)-3-oxopropanoate.

1-(4-Bromo-2-methoxyphenyl)ethanone (1.00 g, 4.37 mmol) was dissolved in diethyl carbonate (5.6 ml, 46.2 mmol). NaH (66% suspension in oil, 384 mg, 9.6 mmol) is added carefully. PM is stirred overnight at RT. Water was added carefully and the mixture was extracted twice with EtOAc. The organic layers are washed with water, brine, dried over MgSO4, filtered and concentrated. The residue was purified with FQ (Hept-EtOAc) to give the title compound as a light yellow oil (933 mg, 71%). LC-MS A: t _R =0.87 min, [M+H] ⁺ =303.01.

A.3.63. Methyl 3-(2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanoate.

To a solution of methyl 3-(4-bromo-2-methoxyphenyl)propanoate (0.899 g, 3.26 mmol) in anhydrous. DMF (10 ml) 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (0.835 g, 3.26 mmol), potassium acetate (1.278 g, 13.00 mmol), and Pd(dppf)Cl ₂ (265 mg, 0.35 mmol). The mixture is heated to 90° C. under nitrogen overnight. The PM is allowed to cool to RT and filtered through a pad of celite, washing with EtOAc. The filtrate was washed with water and the aqueous layer was extracted twice with EtOAc. The combined organic layers are washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. Purification with PC (heptane to heptane/EtOAc=4/1) gives methyl 3-(2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl )phenyl)propanoate as a light yellow oil (0.752 g, 72%). LC-MS B: t _R =1.02 min; [M+H] ⁺ =321.22.

A.3.63.1. Methyl 3-(4-bromo-2-methoxyphenyl)propanoate.

To a solution of 3-(4-bromo-2-methoxyphenyl)propanoic acid (1.000 g, 3.86 mmol) in anhydrous. DMF (10 mL) cesium carbonate (2.515 g, 7.72 mmol) and iodomethane (0.485 mL, 7.72 mmol) are added at RT and the mixture is stirred at RT under nitrogen atmosphere for 1 h. Water and Et ₂ O are added and the layers are separated. The aqueous layer was extracted twice with Et ₂ O and the combined organic layers were washed with brine, dried over anhydrous. MgSO ₄ , filtered and concentrated under reduced pressure. Purification with PC (heptane to heptane/EtOAc=7/3) gave methyl 3-(4-bromo-2-methoxyphenyl)propanoate as a clear oil (0.899 g, 85%). LCMS B: tR=0.96 min; without ionization.

A.3.64. Methyl 2-(2-ethoxy-3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetate.

To a solution of methyl 2-(4-bromo-2-ethoxy-3-fluorophenyl)acetate (1.939 g, 6.66 mmol) in anhydrous. DMF (20 ml) 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (1.708 g, 6.66 mmol), potassium acetate (2.615 g, 26.60 mmol), and Pd(dppf)Cl ₂ (0.542 g, 0.73 mmol). The mixture is heated to 90° C. under nitrogen overnight. The PM is allowed to cool to RT and filtered through a pad of celite, washing with EtOAc. The filtrate was washed with water and the aqueous layer was extracted twice with EtOAc. The combined organic layers are washed with brine, dried over anhydrous. MgSO ₄ , filtered and concentrated under reduced pressure. Purification with PC (heptane to heptane/EtOAc=7/3) gives methyl 2-(2-ethoxy-3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane -2-yl)phenyl)acetate as a dark green oil (1.254 g, 56%). LC-MS B: t _R =1.05 min; [M+H]+=339.23.

A.3.64.1. Methyl 2-(4-bromo-2-ethoxy-3-fluorophenyl)acetate.

To a solution of 2-(4-bromo-2-ethoxy-3-fluorophenyl)acetic acid (2.186 g, 7.28 mmol) in anhydrous. DMF (20 mL) cesium carbonate (3.213 g, 9.86 mmol) and iodomethane (0.738 mL, 11.80 mmol) are added at RT and the mixture is stirred at RT under nitrogen atmosphere for 15 min. Water and Et2O are added and the layers are separated. The aqueous layer was extracted twice with Et ₂ O and the combined organic layers were washed with brine, dried over anhydrous. MgSO ₄ , filtered and concentrated under reduced pressure. Purification with PC (heptane to heptane/EtOAc=7/3) gave methyl 2-(4-bromo-2-ethoxy-3fluorophenyl)acetate as a clear oil (1.939 g, 91%). LC-MS B: t _R =0.99 min; [M+H] ⁺ =291.10.

A.3.64.2. 2-(4-Bromo-2-ethoxy-3-fluorophenyl)acetic acid.

A mixture of 2-(4-bromo-2-ethoxy-3-fluorophenyl)acetonitrile (1.879 g, 7.28 mmol), water (7 ml), 95% sulfuric acid (8 ml) and acetic acid (9 ml) is heated to 110° C under nitrogen for 1.5 h PM then allowed to cool to RT and poured onto ice/water. The reaction mixture is extracted twice with DCM and the combined organic layers are washed with brine, dried over anhydrous. MgSO ₄ , filtered and concentrated under reduced pressure to give 2-(4-bromo-2-ethoxy-3fluorophenyl)acetic acid as an off-white solid (2.186 g, quantitative). LCMS B: t _R =0.85 min; without ionization.

A.3.64.3. 2-(4-Bromo-2-ethoxy-3-fluorophenyl)acetonitrile.

Solution of 1-bromo-4-(chloromethyl)-3-ethoxy-2-fluorobenzene (2.124 g, 7.94 mmol) in MeCN (24 ml) and water

- 75 043145 (3 ml) is treated with sodium cyanide (0.527 g, 10.30 mmol) and the mixture is heated to 80° C. under nitrogen overnight. PM is allowed to cool to RT and diluted with water. The acetonitrile is removed under reduced pressure and the mixture is extracted twice with DCM. The combined organic layers are washed with brine, dried over anhydrous. MgSO ₄ , filtered and concentrated under reduced pressure. Purification with PC (heptane to heptane/EtOAc=7/3) gave 2-(4-bromo-2-ethoxy-3fluorophenyl)acetonitrile as a colorless solid (1.879 g, 92%). LC-MS B: t _R =0.97 min; without ionization.

A.3.64.4. 1-Bromo-4-(chloromethyl)-3-ethoxy-2-fluorobenzene.

Cooled (0°C) mixture of (4-bromo-2-ethoxy-3-fluorophenyl)methanol (1.947 g, 7.82 mmol) and zinc chloride (26.6 mg, 0.19 mmol) in anhydrous. DCM (25 mL) was treated dropwise with thionyl chloride (1.14 mL, 15.60 mmol) and the mixture was stirred at 0°C for 2 h. PM was concentrated under reduced pressure to give 1-bromo-4-(chloromethyl)-3-ethoxy- 2-fluorobenzene as a clear oil (2.124 g, quantitative). LC-MS B: t _R =1.06 min; without ionization.

A.3.64.5. (4-Bromo-2-ethoxy-3-fluorophenyl)methanol.

To a cooled (78°C) solution of ethyl 4-bromo-2-ethoxy-3-fluorobenzoate (2.920 g, 10.00 mmol) in anhydrous. THF (30 ml) was added dropwise with a solution of diisobutylaluminum hydride (1 M in toluene, 30.1 ml, 30.1 mmol) and the mixture was further stirred at -78° C. under nitrogen for 45 minutes. PM is then allowed to warm to 0°C and treated successively with water and 2.8N. aq. NaOH. EtOAc is added, the layers are separated and the aqueous layer is extracted twice with EtOAc. The combined organic layers are dried over anhydrous. MgSO ₄ , filtered and concentrated under reduced pressure. Purification with PC (heptane to heptane/EtOAc=7/3) gave (4-bromo-2-ethoxy-3-fluorophenyl)methanol as a colorless solid (1.947 g, 78%). LC-MS B: t _R =0.85 min; without ionization.

A.3.64.6. Ethyl 4-bromo-2-ethoxy-3-fluorobenzoate.

To a solution of 4-bromo-3-fluoro-2-hydroxybenzoic acid (3.000 g, 12.80 mmol) in anhydrous. DMF (25 ml) potassium carbonate (3.529 g, 25.50 mmol) and iodoethane (2.05 ml, 25.50 mmol) are added at RT and the mixture is stirred at 80° C. under nitrogen atmosphere overnight. Water and Et ₂ O are added and the layers are separated. The aqueous layer was extracted twice with Et ₂ O and the combined organic layers were washed with brine, dried over anhydrous. MgSO ₄ , filtered and concentrated under reduced pressure. Purification with PC (heptane to heptane/EtOAc=3/1) gave ethyl 4-bromo-2-ethoxy-3-fluorobenzoate as a yellow oil (2.920 g, 79%). LC-MS B: t _R =1.04 min; [M+H]+=291.09.

A.3.65. Methyl 2-(3-propyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophen-2-yl)acetate.

A mixture of methyl 2-(3-propylthiophen-2-yl)acetate (0.600 g, 3.03 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'bi( 1,3,2-dioxaborolane) (0.470 g, 1.82 mmol), (1,5-cyclooctadiene)(methoxy)iridium(1) dimer (21.5 mg, 0.0325 mmol) and 4,4'-di-tert-butyl- 2,2'-bipyridine (20 mg, 0.074 mmol) in THF (15 ml) was degassed with nitrogen flow and stirred at 80° C. under nitrogen atmosphere overnight. PM is concentrated under reduced pressure and the residue is purified with PC (heptane to heptane/EtOAc=7/3) to give methyl 2-(3-propyl-5-(4,4,5,5-tetramethyl-1,3 ,2-dioxaborolan-2-yl)thiophen-2-yl)acetate as a clear oil (0.671 g, 68%). LC-MS B: t _R =1.07 min; [M+H]+=325.24.

A.3.65.1. Methyl 2-(3-propylthiophen-2-yl)acetate.

A mixture of methyl 2-(3-bromothiophen-2-yl)acetate (1.655 g, 7.04 mmol), potassium n-propyl trifluoroborate (1.223 g, 7.74 mmol) and cesium carbonate (6.881 g, 21.10 mmol) in toluene (24 ml) and water (12 ml) degassed three times with nitrogen. Palladium(II) acetate (79 mg, 0.35 mmol) and RuPhos (0.346 g, 0.70 mmol) are then added and the mixture heated to 95° C. under nitrogen overnight. PM is allowed to cool to RT, water is added and the mixture is extracted three times with EtOAc. The combined organic layers are washed with brine, dried over anhydrous. MgSO4, filter and concentrate under reduced pressure. Purification with PC (heptane to heptane/EtOAc=7/3) gave methyl 2-(3-propylthiophen-2yl)acetate as a yellow oil (1.336 g, 96%). LC-MS B: t _R =0.94 min; [M+H]+=199.26.

A.3.65.2. Methyl 2-(3-bromothiophen-2-yl)acetate.

To a solution of 2-(3-bromothiophen-2-yl)acetic acid (2.000 g, 9.05 mmol) in anhydrous. DMF (20 mL) cesium carbonate (5.895 g, 18.10 mmol) and iodomethane (1.14 mL, 18.10 mmol) are added at RT and the mixture is stirred at RT under nitrogen atmosphere for 1 h. Water and Et2O are added and the layers are separated. The aqueous layer was extracted twice with Et2O and the combined organic layers were washed with brine, dried over anhydrous. MgSO ₄ , filtered and concentrated under reduced pressure. Purification with PC (heptane to heptane/EtOAc=7/3) gave methyl 2-(3-bromothiophen-2-yl)acetate as a yellow oil (2.183 g, quantitative). LC-MS B: t _R = 0.86 min; without ionization.

A.3.66. Methyl 2-(3-(difluoromethoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophen-2yl)acetate.

A mixture of methyl 2-(3-(difluoromethoxy)thiophen-2-yl)acetate (0.365 g, 1.64 mmol), 4,4,4',4',5,5,5',5'octamethyl-2,2' -bi(1,3,2-dioxaborolane) (0.253 g, 0.98 mmol), (1,5-cyclooctadiene)(methoxy)iridium(1) dimer (11 mg, 0.0164 mmol) and 4,4'-di-tert -butyl-2,2'-bipyridine (11 mg, 0.039 mmol) in THF (8 ml) was degassed with nitrogen flow and stirred at 80° C. under nitrogen atmosphere overnight. PM is concentrated under reduced pressure and the residue is purified with PC (from heptane to a mixture

- 76 043145 heptane/EUAc=4/1) to give methyl 2-(3-(difluoromethoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan2-yl)thiophen-2- yl)acetate as a yellow oil (0.473 g, 83%). LC-MS B: t _R =1.02 min; [M+H]+=349.15.

A.3.66.1. Methyl 2-(3-(difluoromethoxy)thiophen-2-yl)acetate.

To a solution of 2-(3-(difluoromethoxy)thiophen-2-yl)acetic acid (0.401 g, 1.93 mmol) in anhydrous. DMF (8 mL) cesium carbonate (0.941 g, 2.89 mmol) and iodomethane (0.145 mL, 2.31 mmol) are added at RT and the mixture is stirred at RT under nitrogen atmosphere for 30 min. Water and Et ₂ O are added and the layers are separated. The aqueous layer was extracted twice with Et ₂ O and the combined organic layers were washed with brine, dried over anhydrous. MgSO ₄ , filtered and concentrated under reduced pressure. Purification with PC (heptane to heptane/EtOAc=4/1) gave methyl 2-(3(difluoromethoxy)thiophen-2-yl)acetate as a pale yellow oil (0.364 g, 85%). LCMS B: t _R =0.83 min; without ionization.

A.3.66.2. 2-(3-(Difluoromethoxy)thiophen-2-yl)acetic acid.

A mixture of 2-(3-(difluoromethoxy)thiophen-2-yl)acetonitrile (0.306 g, 1.62 mmol), potassium hydroxide (0.272 g, 4.85 mmol) in EtOH (3 mL) and water (3 mL) was heated to 110°C under nitrogen for 2.5 h. PM is allowed to cool to RT and concentrated under reduced pressure. Add 1 M aq. HCl and DCM, the layers are separated and the aqueous layer is extracted twice with DCM. The combined organic layers are washed with brine, dried over anhydrous. MgSO ₄ , filtered and concentrated under reduced pressure to give 2-(3-(difluoromethoxy)thiophen-2-yl)acetic acid as an orange oil (0.296 g, 88%). LC-MS B: t _R =0.68 min; without ionization.

A.3.66.3. 2-(3-(Difluoromethoxy)thiophen-2-yl)acetonitrile.

A solution of 2-(chloromethyl)-3-(difluoromethoxy)thiophene (0.426 g, 2.14 mmol) in anhydrous DMSO (10.5 ml) was treated with sodium cyanide (0.217 g, 4.29 mmol) and the mixture was heated to 80°C under nitrogen for 75 min. PM is allowed to cool to RT and diluted with water. The resulting mixture was extracted three times with Et ₂ O and the combined organic layers washed with brine, dried over anhydrous. MgSO4, filter and concentrate under reduced pressure. Purification with PC (heptane to heptane/EtOAc=4/1) gave 2-(3-(difluoromethoxy)thiophen-2-yl)acetonitrile as a pale yellow oil (0.306 g, 75%). LC-MS B: t _R =0.78 min; without ionization.

A.3.66.4. 2-(Chloromethyl)-3-(difluoromethoxy)thiophene.

Cooled (0°C) mixture of (3-(difluoromethoxy)thiophen-2-yl)methanol (0.360 g, 2.00 mmol) and zinc chloride (7 mg, 0.049 mmol) in anhydrous. DCM (20 mL) was treated dropwise with thionyl chloride (0.291 mL, 3.99 mmol) and the mixture was stirred at RT for 3 h. The mixture was cooled to 0°C, treated dropwise with thionyl chloride (0.291 mL, 3.99 mmol) and stirred further at RT over 1 h. PM was concentrated under reduced pressure to give 2-(chloromethyl)-3-(difluoromethoxy)thiophene as a black oil (0.328 g, 83%). LC-MS B: t _R =0.82 min; without ionization.

A.3.66.5. (3-(Difluoromethoxy)thiophen-2-yl)methanol.

To a cooled (78°C) solution of methyl 3-(difluoromethoxy)thiophene-2-carboxylate (1.450 g, 6.97 mmol) in anhydrous. THF (50 ml) was added dropwise with a solution of diisobutylaluminum hydride (1 M in THF, 21.0 ml, 21.0 mmol). The mixture is further stirred at -78°C under nitrogen for 20 minutes and then allowed to warm to 0°C. Stirring at 0°C was continued for 20 min and PM was treated successively with water (1 ml), 2.8N. aq. NaOH (1 ml) and water (2 ml). The mixture is then allowed to warm to RT and stirred for 1 hour. The resulting mixture is filtered through celite, washing with THF, and the filtrate is concentrated to dryness under reduced pressure. Purification with PC (heptane to heptane/EtOAc=1/1) gave (3-(difluoromethoxy)thiophen-2-yl)methanol as a pale yellow oil (1.075 g, 86%). LC-MS B: t _R =0.63 min; without ionization.

A.3.66.6. Methyl 3-(difluoromethoxy)thiophene-2-carboxylate.

To a solution of 3-(difluoromethoxy)thiophene-2-carboxylic acid (0.500 g, 2.45 mmol) in anhydrous. Cesium carbonate (1.196 g, 3.67 mmol) and iodomethane (0.185 ml, 2.94 mmol) are added successively at RT with DMF (4 mL), and the mixture is stirred at RT for 40 min. Water and Et2O are added and the layers are separated. The aqueous layer was extracted twice with Et ₂ O and the combined organic layers were washed with brine, dried over anhydrous. MgSO ₄ , filtered and concentrated under reduced pressure. Purification with PC (heptane to heptane/EtOAc=1/1) gave methyl 3-(difluoromethoxy)thiophene-2carboxylate as a colorless oil (0.495 g, 97%). LC-MS B: t _R =0.81 min; without ionization.

B. Obtaining examples.

Compounds of examples 1-54, which are listed in table. 5 below is prepared by applying either General Procedure G or H to pyrimidine halide derivatives A.2.1. - A.2.11. in combination with commercially available boronic acid derivatives or with boronic acid derivatives A.3.1. - A.3.24.

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Examples 1-54

Table 5

Note. Compound t _R [min] (method) MS data, m/z [M+H] ⁺ 1 3-Fluoro-5-[6-(2-p-tolylethylamino)-pyrimidin-4yl]-thiophene-2-carboxylic acid (*1) 1.1(C) 357.9 2 4-{6-[2-(2-Methoxy-4-methylsulfanylphenyl)ethylamino]-pyrimidin-4-yl}-2methylsulfanylbenzoic acid 0.9 (C) 442.1 3 4-{6-[2-(2-Methoxy-4,5-dimethylphenyl)ethylamino]-pyrimidin-4-yl}-2methylsulfanylbenzoic acid 0.9 (C) 424.3 4 3 -Ethoxy-5 -{ 6-[2-(2-methoxy-4- methylsulfanylphenyl)-ethylamino]-pyrimidin-4yl}-thiophene-2-carboxylic acid 10(C) 446.2 5 3-Ethoxy-5-{6-[2-(2-methoxy-4,5-dimethylphenyl)ethylamino]pyrimidin-4-yl}-thiophene-2carboxylic acid 1.1(C) 428.3 6 2-Ethoxy-4-{6-[2-(2-methoxy-4- methylsulfanylphenyl)-ethylamino]-pyrimidin-4yl}-benzoic acid 0.9 (C) 440.3 7 2-Ethoxy-4-{6-[2-(2-methoxy-4,5-dimethylphenyl)ethylamino]-pyrimidin-4-yl]-benzoic acid 0.9 (C) 422.3 8 2-Cyclobutoxy-4-{6-[2-(2-methoxy-4- methylsulfanylphenyl)-ethylamino]-pyrimidin-4yl}-benzoic acid 10(C) 466.3 9 6-{6-[2-(4-Bromophenyl)-ethylamino]-pyrimidin-4yl}-1-methyl-1,2-dihydro-indazol-3-one 0.7 (C) 424.4 10 4-{6-[2-(4-Bromophenyl)-ethylamino]-pyrimidin-4yl}-2-methoxyphenol 0.7 (C) 400 eleven 4-{6-[2-(4-Bromophenyl)-ethylamino]-pyrimidin-4yl}-2-ethoxybenzoic acid (*1) 0.9 (C) 442 12 4-{6-[2-(4-Bromophenyl)-ethylamino]-pyrimidin-4yl}-2,6-difluorophenol 0.9 (C) 406 13 3-(5-{6-[2-(4-Bromophenyl)-ethylamino]-pyrimidine- 4-yl}-3-methoxythiophen-2-yl)-oxetan-3-ol 0.9 (C) 462.4 14 3-(4-{6-[2-(4-Bromophenyl)-ethylamino]-pyrimidin4-yl}-phenyl)-[1,2,4]oxadiazol-5(4H)-one [tautomeric form: 3-(4-(6-((4- bromphenethyl)amino)pyrimidin-4-yl)phenyl)[1,2,4]oxadiazol-5-ol] 0.9 (C) 438.4 15 3-(4-{6-[2-(4-Bromophenyl)-ethylamino]-pyrimidin4-yl}-2-ethoxyphenyl)-[1,2,4]oxadiazol-5(4H)-one [tautomeric form: 3 -(4-(6-((4- bromphenethyl)amino)pyrimidin-4-yl)-2ethoxyphenyl)-[1,2,4]oxadiazol-5-ol] 10(C) 482.2 16 2-(4-{6-[2-(4-Bromophenyl)-ethylamino]-pyrimidin4-yl}-2-methoxyphenoxy)-ethanol 0.7 (C) 443.9 17 (5-{6-[2-(4-Bromophenyl)-ethylamino]-pyrimidin-4yl}-3-ethoxythiophen-2-yl)-acetic acid 10(C) 462.2 18 4-{6-[2-(3,4-Dimethylphenyl)-ethylamino]pyrimidin-4-yl}-2-methylsulfanylbenzoic acid (*1) 0.9 (C) 394.1 19 4-{6-[2-(3,4-Dimethylphenyl)-ethylamino]- pyrimidin-4-yl}-2-ethoxybenzoic acid (*1) 0.9 (C) 392.3 20 2-Cyclobutoxy-4-{6-[2-(3,4-dimethylphenyl)ethylamino]-pyrimidin-4-yl}-benzoic acid (*1) 10(C) 418.4 21 4-{6-[2-(4-Bromo-2-fluorophenyl)-ethylamino]pyrimidin-4-yl}-2-ethoxybenzoic acid (*1) 0.9 (C) 460.2 22 3-Fluoro-5-{6-[2-(4-trifluoromethylphenyl)ethylamino]-pyrimidin-4-yl}-thiophene-2carboxylic acid (*1) 11(S) 412.2 23 [2-(4-Bromo-2,6-difluorophenyl)-ethyl]-{6-[3-ethoxy4-(1H-tetrazol-5-yl)-phenyl]-pyrimidin-4-yl}amine 1.0(C) 502 24 M-(4-{6-[2-(4-Bromo-2,6-difluorophenyl)-ethylamino]pyrimidin-4-yl}-2-ethoxyphenyl)-oxalamic acid 0.9 (C) 521.2

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25 4-{6-[2-(4-Bromo-2,6-difluorophenyl)-ethylamino]-pyrimidin-4-yl}-2-(2-hydroxyethoxy)-benzoic acid (*1) 0.8 (C) 494.18 26 5-{6-[2-(4-Bromo-2,6-difluorophenyl)-ethylamino]pyrimidin-4-yl}-thiophene-2-carboxylic acid (*1) 1.1(C) 440.12 27 5-{6-[2-(4-Bromo-2,6-difluorophenyl)-ethylamino]pyrimidin-4-yl}-4-chloro-3-ethoxythiophene-2carboxylic acid (*1) 1.3(C) 518.1 28 5-{6-[2-(4-Bromo-2,6-difluorophenyl)-ethylamino]pyrimidin-4-yl}-3-methylthiophene-2-carboxylic acid (*1) 11(C) 454 29 5-{6-[2-(4-Bromo-2,6-difluorophenyl)-ethylamino]pyrimidin-4-yl}-3-ethylthiophene-2-carboxylic acid (*1) 12(C) 468.1 thirty Amide 5-{6-[2-(4-bromo-2,6-difluorophenyl)- ethylamino]-pyrimidin-4-yl}-3-ethoxythiophene-2sulfonic acid 11(S) 519.1 31 5-{6-[2-(4-Bromo-2,6-difluorophenyl)-ethylamino]pyrimidin-4-yl}-3-chlorothiophene-2-carboxylic acid (*1) 12(C) 474.3 32 5-{6-[2-(4-Bromo-2,6-difluorophenyl)-ethylamino]pyrimidin-4-yl}-3-(2-hydroxyethoxy)-thiophene-2carboxylic acid (*1) 10(C) 500.1 33 5-(4-{6-[2-(4-Bromo-2,6-difluorophenyl)-ethylamino]pyrimidin-4-yl}-phenyl)-isoxazol-3-ol [tautomeric form: 5-(4-( 6-((4-bromo-2,6- difluorophenethyl)amino)pyrimidine-4- yl)phenyl)isoxazol-3 (2H)-one] 0.9 (C) 473.2 34 5-(4-(6-((4-Bromo-2,6- difluorophenethyl)amino)pyrimidin-4-yl)phenyl)[1,2,4]oxadiazol-3(2H)-one [tautomeric form: 5(4-{6-[2-(4-bromo-2,6- difluorophenyl)-ethylamino]pyrimidin-4-yl}-phenyl)-[1,2,4]oxadiazol-3-ol] 0.9 (C) 474 35 4-{6-[2-(4-Bromo-2,6-difluorophenyl)-ethylamino]pyrimidin-4-yl}-2-propylbenzoic acid 10(C) 476.4 36 4-{6-[2-(4-Bromo-2,6-difluorophenyl)-ethylamino]pyrimidin-4-yl}-2-propoxybenzoic acid 10(C) 492.2 37 4-{6-[2-(4-Bromo-2,6-difluorophenyl)-ethylamino]pyrimidin-4-yl}-2-methylsulfanylbenzoic acid 10(C) 480.2 38 4-{6-[2-(4-Bromo-2,6-difluorophenyl)-ethylamino]pyrimidin-4-yl}-2-isobutylbenzoic acid 11(S) 489.9 39 4-{6-[2-(4-Bromo-2,6-difluorophenyl)-ethylamino]pyrimidin-4-yl}-2-fluoro-6-propylbenzoic acid 11(S) 494.2 40 4-{6-[2-(4-Bromo-2,6-difluorophenyl)-ethylamino]pyrimidin-4-yl}-2-ethylsulfanylbenzoic acid 1.0(C) 494.1 41 4-{6-[2-(4-Bromo-2,6-difluorophenyl)-ethylamino]pyrimidin-4-yl}-2-difluoromethoxybenzoic acid 1.0(C) 500 42 4-{6-[2-(4-Bromo-2,6-difluorophenyl)-ethylamino]pyrimidin-4-yl}-2-cyclobutoxybenzoic acid (*1) 1.1(C) 504.3 43 4-{6-[2-(4-Bromo-2,6-difluorophenyl)-ethylamino]pyrimidin-4-yl}-2-butoxybenzoic acid 1.1(C) 506.2 44 3-(5-{6-[2-(4-Bromo-2,6-difluorophenyl)-ethylamino]pyrimidin-4-yl}-3-ethoxythiophen-2-yl)propionic acid 1.1(C) 512.3 45 3-(4-{6-[2-(4-Bromo-2,6-difluorophenyl)-ethylamino]pyrimidin-4-yl}-2-ethoxyphenoxy)-propionic acid (*1) 0.8 (C) 522.4 46 2-{6-[2-(4-Bromo-2,6-difluorophenyl)-ethylamino]pyrimidin-4-yl}-1H-indole-4-carboxylic acid 1.0(C) 473.3 47 (E)-3-(5-{6-[2-(4-Bromo-2,6-difluorophenyl)ethylamino]-pyrimidin-4-yl]-3-ethoxythiophen-2yl)-acrylic acid 1.2(C) 510.3 48 (5-{6-[2-(4-Bromo-2,6-difluorophenyl)-ethylamino]pyrimidin-4-yl}-3-ethoxythiophen-2-yl)-acetic acid 0.89 (V) 497.90 49 (4-{6-[2-(4-Bromo-2,6-difluorophenyl)-ethylamino]pyrimidin-4-yl}-2-ethoxyphenyl)-acetic acid 0.9 (C) 492.2 50 4-{6-[2-(4-Bromo-2-methoxyphenyl)-ethylamino]pyrimidin-4-yl}-2-ethoxybenzoic acid (*1) 0.9 (C) 472.2 51 4-{6-[2-(4-Bromo-2-ethoxyphenyl)-ethylamino]pyrimidin-4-yl}-2-ethoxybenzoic acid (*2) 10(C) 486.1 52 4-{6-[2-(4-Bromo-2,6-dimethoxyphenyl)-ethylamino]pyrimidin-4-yl}-2-ethoxybenzoic acid (*1) 0.9 (C) 502 53 5-{6-[2-(2,6-Difluorophenyl)-ethylamino]pyrimidin-4-yl}-3-ethylthiophene-2-carboxylic acid (*1) 11(S) 390.2 54 5-{6-[2-(4-Bromophenyl)-ethylamino]-pyrimidin-4yl} -3-ethoxythiophene-2-carboxylic acid 1.0(C) 448.2

Example 55 3-Ethoxy-5-[6-(2-o-tolylethylamino)pyrimidin-4-yl]thiophene-2-carboxylic acid (*1)

Following General Procedure F using 5-(6-chloropyrimidin-4-yl)-3-ethoxythiophene-2-carboxylic acid and 2-methylphenethylamine, the title compound is obtained as a white solid. LCMS A: tR=0.75 min; [M+H]+=285.06.

a) 5-(6-Chloropyrimidin-4-yl)-3-ethoxythiophene-2-carboxylic acid.

A mixture of 3-ethoxy-5-(6-hydroxypyrimidin-4-yl)thiophene-2-carboxylic acid (2410 mg, 9.05 mmol) and phosphorus(V) oxychloride (25 ml) was heated to 100°C for 1 h 15 min . POCl ₃ is removed under reduced pressure and the residue is diluted with EtOAc and washed with water. The organic layer is concentrated under reduced pressure and the remaining acid chloride is taken up in EtOAc and acetonitrile, then water is added. PM is stirred over the weekend. Layers separate and water

- 79 043145 layer is extracted again with EtOAc. The combined organic extracts were dried over MgSO ₄ , filtered and the solvent removed under reduced pressure to give the title compound as a beige solid (1.8860 g, 73%). LCMS A: tR=0.75 min;

[M+MeCN]+=326.02.

b) 3-Ethoxy-5-(6-hydroxypyrimidin-4-yl)thiophene-2-carboxylic acid.

A suspension of methyl 3-ethoxy-5-(6-methoxypyrimidin-4-yl)thiophene-2-carboxylate (2664 mg, 9.05 mmol) in dioxane (12.5 ml) and conc. aq. HCl (16.3 ml) is heated to 50°C and stirred for 24 h, then over the weekend at RT. The suspension is filtered and washed with heptane, then with MeOH. The filtrate was concentrated under reduced pressure and the residue was dissolved in THF/H ₂ O 10:1 (60 ml) and 2M NaOH (70 ml) was added and PM was stirred for 1 h at RT. PM is neutralized with 2 M HCl, then concentrated under reduced pressure to approximately 1/3 of its volume. Acetonitrile is added and the solid that precipitates is filtered off and washed with MeCN and dried under high vacuum to give the title compound as a light brown solid (2.718 g, quantitative). LCMS A: tR=0.54 min; [M+H] ⁺ =267.10.

c) Methyl 3-ethoxy-5-(6-methoxypyrimidin-4-yl)thiophene-2-carboxylate.

A mixture of 4-chloro-6-methoxypyrimidine (7124 mg, 48.3 mmol), methyl 3-ethoxy-5-(4,4,5,5-tetramethyl1,3,2-dioxaborolan-2-yl)thiophene-2-carboxylate ( 3141 mg, 10.1 mmol), tribasic potassium phosphate monohydrate (6951 mg, 30.2 mmol) and Pd(dppf)Cl ₂ DCM (822 mg, 1.01 mmol) in DMF (50 ml) and water (1.09 ml, 60.4 mmol) degas for 15 min under a stream of nitrogen, then stirred at RT overnight. PM is then distributed between sat. aq. NaHCO= and EtOAc. The aqueous layer was extracted twice with EtOAc, then adjusted to pH=1 with 2M HCl and extracted once with EtOAc. This last organic layer was further washed (3x) with brine, dried over MgSO ₄ , filtered and concentrated. The residue was purified with PC (heptane/EtOAc 7:1) to give the title compound as a pale yellow solid (2.402 g, 81%). LCMS A: tR=0.54 min; [M+H] ⁺ =267.10.

d) Methyl 3-ethoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophene-2-carboxylate.

The title compound was obtained according to synthesis A.3.1 using methyl 3-ethoxythiophene-2-carboxylate as a white solid; LCMS A: t _R =0.63 min; [M+H] ⁺ =313.13.

Compounds of examples 56 - 82, which are listed in table. 6 below was prepared using the same method as described for the synthesis of Example 55 by reacting 5-(6-chloropyrimidin-4-yl)-3-ethoxythiophene-2-carboxylic acid (Example 55-a) with the appropriate commercially available phenethylamines.

Table 6

Examples 56-82

Note. Compound t _R [min] (LC-MS C) MS data, m/z [M+H] ⁺ 56 3-Ethoxy-5-{6-[2-(2-fluorophenyl)-ethylamino]pyrimidin-4-yl}-thiophene-2-carboxylic acid 1.0 388.2 57 5-{6-[2-(2,4-Dimethylphenyl)-ethylamino]pyrimidin-4-yl}-3-ethoxythiophene-2-carboxylic acid (*3) 1.1 397.9 58 3-Ethoxy-5-{6-[2-(4-trifluoromethylphenyl)ethylamino]pyrimidin-4-yl}-thiophene-2carboxylic acid 1.1 438 59 3-Ethoxy-5-{6-[2-(3-methoxyphenyl)-ethylamino] pyrimidin-4-yl}-thiophene-2-carboxylic acid (*3) 0.9 400.3 60 3-Ethoxy-5-{6-[2-(4-methoxyphenyl)-ethylamino]pyrimidin-4-yl}-thiophene-2-carboxylic acid (*3) 0.9 400.4

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61 3-Ethoxy-5-{6-[2-(3-trifluoromethylphenyl)ethylamino]-pyrimidin-4-yl}-thiophene-2carboxylic acid (*3) 1.1 438.2 62 5-[6-(2-i-Tolylethylamino)-pyrimidin-4-yl]-3trifluoromethylthiophene-2-carboxylic acid (*1) 1.2 407.9 63 5-{6-[2-(3-Methoxyphenyl)-ethylamino]pyrimide in-4-yl}-3-trifluoromethylthiophene-2carboxylic acid (*1) 1.1 424.2 64 5-{6-[2-(2,4-Dimethylphenyl)-ethylamino]pyrimide in-4-yl}-3-trifluoromethylthiophene-2carboxylic acid (*1) 1.3 422.2 65 5-{6-[2-(4-Chloro-2-nitrophenyl)-ethylamino]pyrimidin-4-yl}-3-ethoxythiophene-2-carboxylic acid 1.0 449.2 66 5-{6-[2-(2,4-Dichlorophenyl)-ethylamino]pyrimidin-4-yl}-3-ethoxythiophene-2-carboxylic acid 1.1 438.3 67 5-{6-[2-(3,5-Dimethoxyphenyl)-ethylamino]pyrimidin-4-yl}-3-ethoxythiophene-2-carboxylic acid 0.9 430.1 68 5-{6-[2-(3,4-Dimethylphenyl)-ethylamino]pyrimidin-4-yl}-3-ethoxythiophene-2-carboxylic acid 1.1 398 69 3-Ethoxy-5-{6-[2-(4-hydroxyphenyl)-ethylamino]pyrimidin-4-yl}-thiophene-2-carboxylic acid 0.7 386.2 70 5-{6-[2-(2-Bromophenyl)-ethylamino]-pyrimidin-4yl} -3-ethoxythiophene-2-carboxylic acid 1.0 448.3 71 5-{6-[2-(5-Bromo-2-methoxyphenyl)-ethylamino]pyrimidin-4-yl}-3-ethoxythiophene-2-carboxylic acid 1.1 478.1 72 5-{6-[2-(2,5-Dimethoxyphenyl)-ethylamino]pyrimidin-4-yl}-3-ethoxythiophene-2-carboxylic acid 0.9 430.1 73 5-{6-[2-(2,4-Dimethoxyphenyl)-ethylamino] pyrimide in-4-yl} -3-ethoxythiophene-2-carboxylic acid 0.9 430 74 5-{6-[2-(3-Bromo-4-methoxyphenyl)-ethylamino]pyrimidin-4-yl}-3-ethoxythiophene-2-carboxylic acid 1.0 478.4 75 3-Ethoxy-5-(6-phenethylaminopyrimidin-4-yl)thiophene-2-carboxylic acid 0.9 370.2 76 3-Ethoxy-5-{6-[2-(3-methoxycarbonylphenyl)ethylamino]pyrimidin-4-yl}-thiophene-2carboxylic acid 0.9 428.1 77 5-{6-[2-(3-Chlorophenyl)-ethylamino]-pyrimidin-4yl} -3-ethoxythiophene-2-carboxylic acid 1.0 404.2 78 5-{6-[2-(2-Chlorophenyl)-ethylamino]-pyrimidin-4yl} -3-ethoxythiophene-2-carboxylic acid 1.0 404.3 79 5-{6-[2-(3-Bromophenyl)-ethylamino]-pyrimidin-4yl}-3-ethoxythiophene-2-carboxylic acid 1.0 448 80 3-Ethoxy-5-{6-[2-(4-fluorophenyl)-ethylamino]pyrimidin-4-yl}-thiophene-2-carboxylic acid 0.9 388.2 81 3-Ethoxy-5-{6-[2-(3-fluorophenyl)-ethylamino]pyrimidin-4-yl}-thiophene-2-carboxylic acid 1.0 388.2 82 5-{6-[2-(4-Chlorophenyl)-ethylamino]-pyrimidin-4yl} -3-ethoxythiophene-2-carboxylic acid 1.0 404.3

Example 83 3-(5-{6-[2-(3,4-Dimethylphenyl)ethylamino]pyrimidin-4-yl}-3-ethoxythiophen-2-yl)[1,2,4]oxadiazol-5(4H )-one [tautomeric form: 3-(5-{6-[2-(3,4-dimethylphenyl)ethylamino]pyrimidin-4yl}-3-ethoxythiophen-2-yl)-[1,2,4]oxadiazol- 5-ol].

Following general procedure I using 3-(3-ethoxy-5-(6-hydroxypyrimidin-4-yl)thiophen-2yl)-[1,2,4]oxadiazol-5-ol and 2-(3,4-dimethylphenyl )ethane-1-amine, the title compound is obtained as a yellow solid. LCMS A: tR=0.98 min; [M+H]+=438.17.

a) 3-(3-Ethoxy-5-(6-hydroxypyrimidin-4-yl)thiophen-2-yl)-[1,2,4]oxadiazol-5-ol.

Suspension of 3-(3-ethoxy-5-(6-methoxypyrimidin-4-yl)thiophen-2-yl)-[1,2,4]oxadiazol-5-ol (5180 mg, 12.1 mmol) in HCl (4M in dioxane, 100 ml) heated at 100°C overnight, cooled to RT, and the solvent is partially removed. The solid was filtered off, washing with water and dried under high vacuum to give the title compound as a light yellow solid. LCMS B: t _R =0.66 min; [M+H] ⁺ =307.01.

b) 3-(3-Ethoxy-5-(6-methoxypyrimidin-4-yl)thiophen-2-yl)-[1,2,4]oxadiazol-5-ol.

To a mixture of 3-ethoxy-K'-hydroxy-5-(6-methoxypyrimidin-4-yl)thiophene-2-carboximidamide (6930 mg, 22.6 mmol) and DBU (8.62 ml, 56.5 mmol) in dioxane/DMSO (3 :2, 220 ml) add CDI (5498 mg, 33.9 mmol). PM is stirred at 100°C for 30 min, then cooled to RT. Perform solvent evaporation and trituration in 2N. HCl afforded the title compound as a yellow solid (7.15 g, 99%). LCMS A: t _R =0.89 min; [M+H] ⁺ =321.14.

c) 3-Ethoxy-K'-hydroxy-5-(6-methoxypyrimidin-4-yl)thiophene-2-carboximidamide.

A suspension of 3-ethoxy-5-(6-methoxypyrimidin-4-yl)thiophene-2-carbonitrile (6860 mg, 24.7 mmol), TEA (10.3 ml, 74 mmol) and hydroxylamine hydrochloride (2.59 ml, 61.7 mmol) in EtOH ( 220 ml) heated at reflux for 3 h, then cooled to RT and treated with water (30 ml). The yellow solid is filtered off and dried under high vacuum. The filtrate is concentrated and the solid is triturated in water, filtered and combined with the first portion of the product. The title compound was obtained as a yellow solid (6.93 g, 95%). LC-MS B: t _R =0.62 min; [M+H] ⁺ =295.23.

d) 3-Ethoxy-5-(6-methoxypyrimidin-4-yl)thiophene-2-carbonitrile.

Cyanuric acid chloride (6248 mg, 33.5 mmol ).

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PM is then stirred at RT for 45 min. It is cooled to 0°C and diluted with water. The solid is filtered off, washing with water and then with EtOAc, and dried under high vacuum. The filtrate is extracted twice with EtOAc, the combined organic layers are washed with brine, dried over MgSO ₄ , filtered and concentrated under reduced pressure. Both portions of the solid are combined to give the title compound as a beige solid (5.49 g, 94%). LC-MS A: t _R =1.00 min; [M+H]+=262.26.

e) 3-Ethoxy-5-(6-methoxypyrimidin-4-yl)thiophene-2-carboxamide.

To a solution of 3-ethoxy-5-(6-methoxypyrimidin-4-yl)thiophene-2-carboxylic acid (7410 mg, 26.4 mmol) in THF (140 mL) was added CDI (4861 mg, 29.1 mmol) at RT. PM was stirred for 30 min, then NH4OH (25% solution, 61.1 ml, 397 mmol) was added and PM was stirred at RT for 30 min, then concentrated under reduced pressure and the residue was triturated in 2N HCl. HCl. The title compound was filtered off, dried under high vacuum to give a yellow solid (6.94 g, 94%). LCMS A: t _R =0.79 min; [M+H]+=280.22.

f) 3-Ethoxy-5-(6-methoxypyrimidin-4-yl)thiophene-2-carboxylic acid.

A suspension of methyl 3-ethoxy-5-(6-methoxypyrimidin-4-yl)thiophene-2-carboxylate (7870 mg, 26.2 mmol) in MeOH (210 ml) and 2 M NaOH (38.8 ml, 419 mmol) was stirred overnight at CT. It is then acidified with 8N. HCl (60 mL), MeOH removed in vacuo and the slurry filtered to give the title compound as a yellow solid (7.41 g, 99%). LCMS A: t _R =0.77 min; [M+H] ⁺ =281.19.

g) Methyl 3-ethoxy-5-(6-methoxypyrimidin-4-yl)thiophene-2-carboxylate.

A mixture of methyl 3-ethoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophene-2-carboxylate (10520 mg, 30 mmol), 4-chloro-6- methoxypyrimidine (4645 mg, 31.5 mmol), Pd(dppf)Cl ₂ DCM (2449 mg, 3 mmol) and tribasic potassium phosphate monohydrate (20719 mg, 90 mmol) in water (4 ml) and DMF (150 ml) are degassed for 20 min under nitrogen flow, then stirred at RT for 1 h 15 min. PM is filtered through celite, the filtrate is concentrated in vacuo, the residue is partitioned between water and EtOAc. The organic layer is washed with additional brine, dried over MgSO4, filtered and concentrated. Purification with PC (heptane/EtOAc, 1:0 to 0:1) gave the title compound as a yellow solid (7.87 g, 89%). LCMS A: t _R =0.93 min; [M+H]+=295.18.

h) Methyl 3-ethoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophene-2-carboxylate.

The title compound was obtained according to synthesis A.2.1 using methyl 3ethoxythiophene-2-carboxylate as a white solid; LCMS A: t _R =0.63 min; [M+H] ⁺ =313.13.

Following the procedure described for the synthesis of Example 83, synthesize the following examples starting from 3-(3-ethoxy-5-(6-hydroxypyrimidin-4-yl)thiophen-2-yl)-[1,2,4]oxadiazol-5 -ol and the corresponding commercially available phenethylamines or phenethylamines A1.1. - A.1.8. described above (see Table 7).

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Examples 84-127

Table 7

Note. Compound t _R [min] (method) MS data, m/z [M+H] ⁺ 84 3-(5-{6-[2-(4-Bromo-2-trifluoromethoxyphenyl)ethylamino]pyrimidin-4-yl}-3-ethoxythiophen-2yl)-[1,2,4]oxadiazol-5(4H) -one [tautomeric form: 3-(5-{6-[2-(4-bromo-2-trifluoromethoxyphenyl)ethylamino]-pyrimidin-4-yl}-3-ethoxythiophen-2- yl)-[1,2,4]oxadiazol-5-ol] 1.3(C) 572.1 85 3-(5-{6-[2-(4-Bromo-2-ethoxyphenyl)-ethylamino]pyrimidin-4-yl}-3-ethoxythiophen-2-yl)- [1,2,4]oxadiazol-5(4H)-one [tautomeric form: 3(5-{6-[2-(4-bromo-2-ethoxyphenyl)-ethylamino]pyrimidin-4-yl}-3- ethoxythiophen-2-yl)- [1,2,4]oxadiazol-5-ol] 1.2(C) 532.1 86 3-(5-{6-[2-(4-Chloro-2-fluoro-6-methoxyphenyl)ethylamino]-pyrimidin-4-yl}-3-ethoxythiophen-2yl)-[1,2,4]oxadiazol- 5(4H)-one [tautomeric form: 3-(5-{6-[2-(4-Chloro-2-fluoro-6-methoxyphenyl)ethylamino]-pyrimidin-4-yl}-3-ethoxythiophen-2yl)-[1,2,4]oxadiazol- 5-ol] 1.2(C) 492 87 3-(5-{6-[2-(4-Bromo-2-fluoro-6-methoxyphenyl)ethylamino]-pyrimidin-4-yl}-3-ethoxythiophen-2yl)-[1,2,4]oxadiazol- 5(4H)-one [tautomeric form: 3-(5-{6-[2-(4-bromo-2-fluoro-6-methoxyphenyl)ethylamino]-pyrimidin-4-yl}-3-ethoxythiophen-2yl)-[1,2,4]oxadiazol- 5-ol] 1.2(C) 536.1 88 3-(5-{6-[2-(4-Bromo-2,6-dimethoxyphenyl)ethylamino]-pyrimidin-4-yl}-3-ethoxythiophen-2yl)-[1,2,4]oxadiazol-5( 4H)-one [tautomeric form: 3-(5-{6-[2-(4-bromo-2,6-dimethoxyphenyl)- ethylamino]-pyrimidin-4-yl}-3-ethoxythiophen-2yl)-[1,2,4]oxadiazol-5-ol] 1.2(C) 547.9 89 3-(5-{6-[2-(4-Bromo-2-propoxyphenyl)-ethylamino]pyrimidin-4-yl}-3-ethoxythiophen-2-yl)- [1,2,4]oxadiazol-5(4H)-one [tautomeric form: 3(5-{6-[2-(4-bromo-2-propoxyphenyl)-ethylamino]- pyrimidin-4-yl}-3-ethoxythiophen-2-yl)- [1,2,4]oxadiazol-5-ol] 1-3 (C) 546.1 90 91 92 93 94 95 96 3-(3-Ethoxy-5-{6-[2-(2-ethoxy-4- trifluoromethylphenyl)-ethylamino]-pyrimidin-4-yl}thiophen-2-yl)-[1,2,4]oxadiazol-5(4H)-one [tautomeric form: 3-(3-ethoxy-5-{6-[2-(2-ethoxy4-trifluoromethylphenyl)-ethylamino]-pyrimidin-4yl}-thiophen-2-yl)-[1,2,4]oxadiazole -5-ol] 3-(5-{6-[2-(4-Chloro-2-methylaminophenyl)- ethylamino]-pyrimidin-4-yl}-3-ethoxythiophen-2yl)-[1,2,4]oxadiazol-5(4H)-one [tautomeric form: 3-(5-{6-[2-(4- chloro-2-methylaminophenyl)- ethylamino]-pyrimidin-4-yl}-3-ethoxythiophen-2yl)-[1,2,4]oxadiazol-5-ol] 3-(3-Ethoxy-5 -{6-[2-(2-fluoro-4-methoxyphenyl)ethylamino]-pyrimidin-4-yl}-thiophen-2-yl)- [1,2,4]oxadiazol-5(4H)-one [tautomeric form: 3(3-ethoxy-5-{6-[2-(2-fluoro-4-methoxyphenyl)- ethylamino]-pyrimidin-4-yl}-thiophen-2-yl)[1,2,4]oxadiazol-5-ol] 3-(3-Ethoxy-5-{6-[2-(2-fluoro-4- trifluoromethylphenyl)-ethylamino]-pyrimidin-4-yl}thiophen-2-yl)-[1,2,4]oxadiazol-5(4H)-one [tautomeric form: 3-(3-ethoxy-5-{6-[2-(2-fluoro-4trifluoromethylphenyl)-ethylamino]-pyrimidin-4-yl}thiophen-2-yl)-[ 1,2,4] oxadiazol-5-ol] 3-(5-{6-[2-(2-Bromo-5-chlorophenyl)-ethylamino]pyrimidin-4-yl}-3-ethoxythiophen-2-yl)- [1,2,4]oxadiazol-5(4H)-one [tautomeric form: 3(5-{6-[2-(2-bromo-5-chlorophenyl)-ethylamino]- pyrimidin-4-yl}-3-ethoxythiophen-2-yl)- [1,2,4]oxadiazol-5-ol] 3-(3-Ethoxy-5 -{6-[2-(2-ethoxy-4-fluorophenyl)ethylamino]-pyrimidin-4-yl}-thiophen-2-yl)- [1,2,4]oxadiazol-5(4H)-one [tautomeric form: 3(3-ethoxy-5-{6-[2-(2-ethoxy-4-fluorophenyl)- ethylamino]-pyrimidin-4-yl}-thiophen-2-yl)[1,2,4]oxadiazol-5-ol] 5-Chloro-2-(2-((6-(4-ethoxy-5-(5-oxo-4,5-dihydro[1,2,4]oxadiazol-3-yl)thiophen-2-yl)pyrimidine -4yl)amino)ethyl)benzonitrile [tautomeric form: 5chloro-2-(2-{6-[4-ethoxy-5-(5-hydroxy- [1,2,4]oxadiazol-3-yl)-thiophen-2-yl]-pyrimidin-4ylamino}-ethyl)-benzonitrile] 12(C) 1.2(C) 1.1(C) 1.2(C) 1.2(C) 1.2(C) 1.1(C) 522.3 473.1 458 496.2 522.1 472.1 469.2 97 2-(2-((6-(4-Ethoxy-5-(5-oxo-4,5-dihydro- [1,2,4]oxadiazol-3-yl)thiophen-2-yl)pyrimidin-4yl)amino)ethyl)-5-fluorobenzonitrile [tautomeric form: 2-(2-{6-[4-ethoxy-5- (5-hydroxy- [1,2,4]oxadiazol-3-yl)-thiophen-2-yl]-pyrimidin-4ylamino}-ethyl)-5-fluorobenzonitrile] 10(C) 453.4

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98 3-(5-{6-[2-(3-Chloro-2,6-difluorophenyl)-ethylamino]pyrimidin-4-yl}-3-ethoxythiophen-2-yl)- [1,2,4]oxadiazol-5(4H)-one [tautomeric form: 3(5-{6-[2-(3-chloro-2,6-difluorophenyl)-ethylamino]- pyrimidin-4-yl}-3-ethoxythiophen-2-yl)- [1,2,4]oxadiazol-5-ol] 1.1(C) 480.1 99 3-(3-Ethoxy-5-{6-[2-(2-ethyl-4-methoxyphenyl)ethylamino]-pyrimidin-4-yl}-thiophen-2-yl)[1,2,4]oxadiazol-5 (4H)-one [tautomeric form: 3(3-ethoxy-5-{6-[2-(2-ethyl-4-methoxyphenyl)ethylamino]-pyrimidin-4-yl}-thiophen-2-yl)[1 ,2,4]oxadiazol-5-ol] 1.1(C) 468 100 3-(5-{6-[2-(2-Chloro-3,6-difluorophenyl)-ethylamino]pyrimidin-4-yl}-3-ethoxythiophen-2-yl)- [1,2,4]oxadiazol-5(4H)-one [tautomeric form: 3(5-{6-[2-(2-chloro-3,6-difluorophenyl)-ethylamino]- pyrimidin-4-yl}-3-ethoxythiophen-2-yl)- [1,2,4]oxadiazol-5-ol] 1.1(C) 480.2 101 3-(3-Ethoxy-5 -{ 6-[2-(2,4,6-trifluorophenyl)- ethylamino]-pyrimidin-4-yl}-thiophen-2-yl)- [1,2,4]oxadiazol-5(4H)-one [tautomeric form: 3(3-ethoxy-5-{6-[2-(2,4,6-trifluorophenyl)-ethylamino]pyrimidin-4-yl }-thiophen-2-yl)-[1,2,4]oxadiazol-5ol] 1.1(C) 464.2 102 3-(3-Ethoxy-5-{6-[2-(2-ethoxyphenyl)-ethylamino]pyrimide in-4-yl}-thiophen-2-yl)-[1,2,4]oxadiazole5(4Н)- he [tautomeric form: 3-(3-ethoxy-5-{6-[2(2-ethoxyphenyl)-ethylamino]-pyrimidin-4-yl}thiophen-2-yl)-[1,2,4]oxadiazol- 5-ol] 1.1(C) 454 103 3-(5-{6-[2-(2,6-Difluorophenyl)-ethylamino]pyrimidin-4-yl}-3-ethoxythiophen-2-yl)- [1,2,4]oxadiazol-5(4H)-one [tautomeric form: 3(5-{6-[2-(2,6-difluorophenyl)-ethylamino]-pyrimidin4-yl}-3-ethoxythiophene-2 -yl)-[1,2,4]oxadiazol-5-ol] 1.1(C) 446.2 104 3-(5-{6-[2-(4-Bromo-2-ethylphenyl)-ethylamino]pyrimidin-4-yl}-3-ethoxythiophen-2-yl)- [1,2,4]oxadiazol-5(4H)-one [tautomeric form: 3(5-{6-[2-(4-bromo-2-ethylphenyl)-ethylamino]pyrimidin-4-yl}-3- ethoxythiophen-2-yl)- [1,2,4]oxadiazol-5-ol] 1.3(C) 516.2 105 3-(5-{6-[2-(4-Chloro-2,6-difluorophenyl)-ethylamino]pyrimidin-4-yl}-3-ethoxythiophen-2-yl)- [1,2,4]oxadiazol-5(4H)-one [tautomeric form: 3(5-{6-[2-(4-chloro-2,6-difluorophenyl)-ethylamino]- pyrimidin-4-yl}-3-ethoxythiophen-2-yl)- [1,2,4]oxadiazol-5-ol] 1.2(C) 480.1 106 3-(5-{6-[2-(4-Bromo-3-chlorophenyl)-ethylamino]pyrimidin-4-yl}-3-ethoxythiophen-2-yl)- [1,2,4]oxadiazol-5(4H)-one [tautomeric form: 3(5-{6-[2-(4-bromo-3-chlorophenyl)-ethylamino]- pyrimidin-4-yl}-3-ethoxythiophen-2-yl)- [1,2,4]oxadiazol-5-ol] 1.2(C) 522.1 107 3-(5-{6-[2-(4-Bromo-2,5-difluorophenyl)-ethylamino]pyrimidin-4-yl}-3-ethoxythiophen-2-yl)- [1,2,4]oxadiazol-5(4H)-one [tautomeric form: 3(5-{6-[2-(4-bromo-2,5-difluorophenyl)-ethylamino]pyrimidin-4-yl}- 3-ethoxythiophen-2-yl)- [1,2,4]oxadiazol-5-ol] 1.2(C) 524.1 108 3-(5-{6-[2-(4-Bromo-3-fluorophenyl)-ethylamino]pyrimidin-4-yl}-3-ethoxythiophen-2-yl)- [1,2,4]oxadiazol-5(4H)-one [tautomeric form: 3(5-{6-[2-(4-bromo-3-fluorophenyl)-ethylamino]- pyrimidin-4-yl}-3-ethoxythiophen-2-yl)- [1,2,4]oxadiazol-5-ol] 1.2(C) 506.2 109 3-(5-{6-[2-(4-Bromo-2-dimethylaminophenyl)ethylamino]-pyrimidin-4-yl}-3-ethoxythiophen-2yl)-[1,2,4]oxadiazol-5(4H) -one [tautomeric form: 3-(5-{6-[2-(4-bromo-2-dimethylaminophenyl)ethylamino]pyrimidin-4-yl}-3-ethoxythiophen-2yl)-[1,2,4]oxadiazol-5-ol] 1.2(C) 531.1 BY 3-(5-{6-[2-(4-Bromo-2,6-difluorophenyl)-ethylamino]pyrimidin-4-yl}-3-ethoxythiophen-2-yl)- [1,2,4]oxadiazol-5(4H)-one [tautomeric form: 3(5-{6-[2-(4-bromo-2,6-difluorophenyl)-ethylamino]- pyrimidin-4-yl}-3-ethoxythiophen-2-yl)- [1,2,4]oxadiazol-5-ol] 1.2(C) 524.1 111 3-(5-{6-[2-(4-Bromo-5-fluoro-2-methylphenyl)ethylamino]-pyrimidin-4-yl]-3-ethoxythiophen-2yl)-[1,2,4]oxadiazol- 5(4H)-one [tautomeric form: 3-(5-{6-[2-(4-bromo-5-fluoro-2-methylphenyl)ethylamino]-pyrimidin-4-yl}-3-ethoxythiophen-2yl)-[1,2,4]oxadiazol- 5-ol] 1.2(C) 520.2 112 3-(5-{6-[2-(4-Bromo-2-pyrrolidin-1-ylphenyl)ethylamino]-pyrimidin-4-yl}-3-ethoxythiophen-2yl)-[1,2,4]oxadiazol- 5(4H)-one [tautomeric form: 3-(5-{6-[2-(4-bromo-2-pyrrolidin-1-ylphenyl)ethylamino]-pyrimidin-4-yl}-3-ethoxythiophen-2yl)-[1,2,4]oxadiazol- 5-ol] 1.3(C) 556.9

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113 3-(5-{6-[2-(4-Bromo-3-methylphenyl)-ethylamino] pyrimide in-4-yl} -3-ethoxythiophen-2-yl)- [1,2,4]oxadiazol-5(4H)-one [tautomeric form: 3(5-{6-[2-(4-bromo-3-methylphenyl)-ethylamino]- pyrimide in-4-yl} -3-ethoxythiophen-2-yl)- [1,2,4]oxadiazol-5-ol] 1.2(C) 502.2 114 3-(5-{6-[2-(4-Bromo-2-fluoro-5-methylphenyl)ethylamino]-pyrimidin-4-yl}-3-ethoxythiophen-2yl)-[1,2,4]oxadiazol- 5(4H)-one [tautomeric form: 3-(5-{6-[2-(4-bromo-2-fluoro-5-methylphenyl)ethylamino]-pyrimidin-4-yl}-3-ethoxythiophen-2yl)-[1,2,4]oxadiazol- 5-ol] 1.2(C) 520 115 3-(5-{6-[2-(4-Bromo-3-methoxyphenyl)-ethylamino] pyrimide in-4-yl} -3-ethoxythiophen-2-yl)- [1,2,4]oxadiazol-5(4H)-one [tautomeric form: 3(5-{6-[2-(4-bromo-3-methoxyphenyl)-ethylamino]- pyrimide in-4-yl} -3-ethoxythiophen-2-yl)- [1,2,4]oxadiazol-5-ol] 11(S) 518.1 116 3-(5-{6-[2-(2,4-Dimethoxyphenyl)-ethylamino]pyrimide in-4-yl} -3-ethoxythiophen-2-yl)- [1,2,4]oxadiazol-5(4H)-one [tautomeric form: 3(5-{6-[2-(2,4-dimethoxyphenyl)-ethylamino]- pyrimide in-4-yl} -3-ethoxythiophen-2-yl)- [1,2,4]oxadiazol-5-ol] 1.1(C) 470 117 3-(3-Ethoxy-5-{6-[2-(3-hydroxy-4-methoxyphenyl)ethylamino]-pyrimidin-4-yl}-thiophen-2-yl)- [1,2,4]oxadiazol-5(4H)-one [tautomeric form: 3(3-ethoxy-5-{6-[2-(3-hydroxy-4-methoxyphenyl)ethylamino]-pyrimidin-4-yl }-thiophen-2-yl)- [1,2,4]oxadiazol-5-ol] 0.9 (C) 456 118 3-(3-Ethoxy-5-{6-[2-(4-hydroxy-3-methoxyphenyl)ethylamino]-pyrimidin-4-yl}-thiophen-2-yl)- [1,2,4]oxadiazol-5(4H)-one [tautomeric form: 3(3-ethoxy-5-{6-[2-(4-hydroxy-3-methoxyphenyl)ethylamino]-pyrimidin-4-yl }-thiophen-2-yl)- [1,2,4]oxadiazol-5-ol] 0.9 (C) 456.2 119 3-(5-{6-[2-(2,3-Dimethoxyphenyl)-ethylamino] pyrimide in-4-yl} -3-ethoxythiophen-2-yl)- [1,2,4]oxadiazol-5(4H)-one [tautomeric form: 3(5-{6-[2-(2,3-dimethoxyphenyl)-ethylamino]- pyrimide in-4-yl} -3-ethoxythiophen-2-yl)- [1,2,4]oxadiazol-5-ol] 10(C) 470.3 120 3-(5-{6-[2-(5-Bromo-2-methoxyphenyl)-ethylamino]pyrimidin-4-yl}-3-ethoxythiophen-2-yl)- [1,2,4]oxadiazol-5(4H)-one [tautomeric form: 3(5-{6-[2-(5-bromo-2-methoxyphenyl)-ethylamino]pyrimidin-4-yl}-3- ethoxythiophen-2-yl)- [1,2,4]oxadiazol-5-ol] 1.2(C) 518.1 121 3-(5-{6-[2-(3,4-Dichlorophenyl)-ethylamino]pyrimidin-4-yl}-3-ethoxythiophen-2-yl)- [1,2,4]oxadiazol-5(4H)-one [tautomeric form: 3(5-{6-[2-(3,4-dichlorophenyl)-ethylamino]-pyrimidin4-yl}-3-ethoxythiophene-2 -yl)-[1,2,4]oxadiazol-5-ol] 1.2(C) 478.1 122 3-(5-{6-[2-(3-Chloro-4-methoxyphenyl)-ethylamino]pyrimidin-4-yl}-3-ethoxythiophen-2-yl)- [1,2,4]oxadiazol-5(4H)-one [tautomeric form: 3(5-{6-[2-(3-chloro-4-methoxyphenyl)-ethylamino]- pyrimidin-4-yl}-3-ethoxythiophen-2-yl)- [1,2,4]oxadiazol-5-ol] 1.1(C) 474.1 123 3-(5-{6-[2-(2,4-Dichlorophenyl)-ethylamino]- pyrimidin-4-yl}-3-ethoxythiophen-2-yl)- [1,2,4]oxadiazol-5(4H)-one [tautomeric form: 3(5-{6-[2-(2,4-dichlorophenyl)-ethylamino]-pyrimidin4-yl}-3-ethoxythiophene-2 -yl)-[1,2,4]oxadiazol-5-ol] 1.2(C) 478 124 3-(5-{6-[2-(4-Bromo-2-chlorophenyl)-ethylamino]pyrimidin-4-yl}-3-ethoxythiophen-2-yl)- [1,2,4]oxadiazol-5(4H)-one [tautomeric form: 3(5-{6-[2-(4-bromo-2-chlorophenyl)-ethylamino]- pyrimidin-4-yl}-3-ethoxythiophen-2-yl)- [1,2,4]oxadiazol-5-ol] 1.02 (V) 521.89 125 3-(5-{6-[2-(4-Bromo-2-fluorophenyl)-ethylamino]pyrimidin-4-yl}-3-ethoxythiophen-2-yl)- [1,2,4]oxadiazol-5(4H)-one [tautomeric form: 3(5-{6-[2-(4-bromo-2-fluorophenyl)-ethylamino]- pyrimidin-4-yl}-3-ethoxythiophen-2-yl)- [1,2,4]oxadiazol-5-ol] 1.2(C) 506.4 126 3-(5-{6-[2-(4-Bromo-2-methoxyphenyl)-ethylamino]pyrimidin-4-yl}-3-ethoxythiophen-2-yl)- [1,2,4]oxadiazol-5(4H)-one [tautomeric form: 3(5-{6-[2-(4-bromo-2-methoxyphenyl)-ethylamino]- pyrimidin-4-yl}-3-ethoxythiophen-2-yl)- [1,2,4]oxadiazol-5-ol] 1.2(C) 518 127 3-(5-{6-[2-(4-Bromo-2-methylphenyl)-ethylamino]pyrimidin-4-yl}-3-ethoxythiophen-2-yl)- [1,2,4]oxadiazol-5(4H)-one [tautomeric form: 3(5-{6-[2-(4-bromo-2-methylphenyl)-ethylamino]- pyrimidin-4-yl}-3-ethoxythiophen-2-yl)- [1,2,4]oxadiazol-5-ol] 1.2(C) 502.2

Example 128 5-{6-[2-(4-Bromophenyl)ethylamino]pyrimidin-4-yl}-3-ethoxythiophene-2-carboxylic acid amide m.p.

To a solution of 5-{6-[2-(4-bromophenyl)ethylamino]pyrimidin-4-yl}-3-ethoxythiophene-2-carboxylic acid (Example 54, 366 mg, 0.816 mmol, 1 eq.) in DMF (3 ml) EDC.HC1 (172 mg, 0.898 mmol) and HOBT (121 mg, 0.898 mmol) are added and the RM is stirred at RT for 1 h. Then it is cooled to 0°C and 25% ammonia solution (1.24 ml) is added . The PM is stirred for 1 h at RT, then concentrated under reduced pressure and the residue partitioned between EtOAc and 1 M NaOH (pH 10). The aqueous layer is re-extracted with EtOAc. The combined organic layers were washed with brine, dried (MgSO ₄ ) and concentrated to give the title compound as a beige solid (342 mg, 94%). LCMS A: t _R =0.78 min; [M+H] ⁺ =446.98.

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Example 129 5-{6-[2-(4-Bromophenyl)ethylamino]pyrimidin-4-yl}-3-ethoxy-N-hydroxythiophene-2carboxamidine

A mixture of 5-(6-((4-bromophenethyl)amino)pyrimidin-4-yl)-3-ethoxythiophene-2-carbonitrile (84 mg, 0.196 mmol), hydroxylamine hydrochloride (27.5 mg, 0.391 mmol) and TEA (0.0545 ml , 0.391 mmol) in EtOH (2.52 ml) was stirred in a sealed tube at 90°C for 3 h. title compound as a yellow solid (49 mg, 55%). LCMS A: t _R =0.73 min; [M+H]+=463.93.

a) 5-(6-((4-Bromophenethyl)amino)pyrimidin-4-yl)-3-ethoxythiophene-2-carbonitrile.

To a suspension of 5-{6-[2-(4-bromophenyl)ethylamino]pyrimidin-4-yl}-3-ethoxythiophene-2carboxylic acid amide (example 128, 190 mg, 0.425 mmol) in DMF (1.3 ml) at 0° Cyanuric acid chloride (117 mg, 0.637 mmol) is added in portions. The PM is then allowed to warm to RT and stirred for 15 min. It is then diluted with water and extracted (3x) with EtOAc. The combined organic layers are washed with brine, dried over MgSO ₄ , filtered and concentrated. Purification with PC (heptane to heptane/EtOAc 1:4) gave the title compound as a white solid (84 mg, 46%). LCMS A: t _R =0.98 min; [M+H]+=431.05.

Example 130 3-(5-{6-[2-(4-Bromophenyl)ethylamino]pyrimidin-4-yl}-3-ethoxythiophen-2-yl)-[1,2,4]oxadiazol-5(4H) -one [tautomeric form: 3-(5-{6-[2-(4-bromophenyl)ethylamino]pyrimidin-4-yl}-3-ethoxythiophen-2-yl)-[1,2,4]oxadiazol-5 -ol].

A mixture of 5-{6-[2-(4-bromophenyl)ethylamino]pyrimidin-4-yl}-3-ethoxy-N-hydroxythiophene-2-carboxamidine (example 129, 48.6 mg, 0.105 mmol), 1,1'- carbonyldiimidazole (25.6 mg, 0.158 mmol) and DBU (0.0273 ml, 0.179 mmol) in dioxane (1 ml) was stirred at 90°C for 1 h. After the mixture had cooled to RT, 1 M HCl was added, the precipitate was filtered off, washing with water and Et ₂ O, thus obtaining the pure expected product as a yellow solid (42 mg, 81%). LCMS A: t _R =0.88 min; [M+H]+=489.88.

Example 131: [2-(4-Bromophenyl)ethyl]-{6-[4-ethoxy-5-(1H-tetrazol-5-yl)thiophen-2-yl]pyrimidin-4yl}amine

Trimethylsilyl azide ( 0.0459 ml, 0.349 mmol) and dibutyltin oxide (5.8 mg, 0.0233 mmol). PM is stirred in a sealed tube at 110°C for 8 h. It is cooled to RT, trimethylsilyl azide (0.0153 ml, 0.116 mmol) and dibutyltin oxide (5.8 mg, 0.0233 mmol) are added. PM is stirred at 110°C overnight. After the mixture is cooled to RT, PM is concentrated under reduced pressure and the residue is purified by basic preparative HPLC to give the title compound as a yellow solid (50 mg, 50%). LC-MS A: t _R =0.83 min; [M+H]+=474.01.

Example 132 thione [tautomeric form: 3-(5-(6-((4-bromophenethyl)amino)pyrimidin-4-yl)-3ethoxythiophen-2-yl)-[1,2,4]oxadiazol-5-thiol].

Following the same procedure as described for Example 130 using 1,1'-thiocarbonyldiimidazole, the title compound was obtained as a yellow solid. LCMS A: t _R =1.08 min; [M+H] ⁺ =503.91.

Example 133 3-(5-{6-[2-(4-Bromo-2,6-difluorophenyl)ethylamino]pyrimidin-4-yl}-3-trifluoromethylthiophen-2-yl)-[1,2,4] oxadiazol-5(4H)-one [tautomeric form: 3-(5-{6-[2-(4-bromo-2,6-difluorophenyl)ethylamino]pyrimidin-4-yl}-3-trifluoromethylthiophen-2-yl )-[1,2,4]oxadiazol-5-ol].

Following the same procedure as described for Example 130 using 1,1'-carbonyldiimidazole and 5(6-((4-bromo-2,6-difluorophenethyl)amino)pyrimidin-4-yl)-K'-hydroxy- 3-(trifluoromethyl)thiophene-2-carboximidamide, the title compound is obtained as a pale yellow solid. LCMS B: t _R =1.04 min; [M+H]+=547.49.

a) 5-(6-((4-Bromo-2,6-difluorophenethyl)amino)pyrimidin-4-yl)-K'-hydroxy-3-(trifluoromethyl)thiophene2-carboximidamide.

Following the same method as described for Example 129, using 5-(6-((4-bromo-2,6difluorophenethyl)amino)pyrimidin-4-yl)-3-(trifluoromethyl)thiophene-2-carbonitrile specified in The title compound is obtained as a yellow oil. LC-MS B: t _R =0.90 min; [M+H] ⁺ =521.81.

b) 5-(6-((4-Bromo-2,6-difluorophenethyl)amino)pyrimidin-4-yl)-3-(trifluoromethyl)thiophene-2-carbonitrile.

Following General Procedure F using 2-(4-bromo-2,6-difluorophenyl)ethan-1-amine and 5-(6chloropyrimidin-4-yl)-3-(trifluoromethyl)thiophene-2-carbonitrile, the title compound obtained as a red powder. LCMS B: t _R =1.19 min; [M+H]+=488.89.

c) 5-(6-Chloropyrimidin-4-yl)-3-(trifluoromethyl)thiophene-2-carbonitrile.

Following the procedure described for Example 83-d using 5-(6-chloropyrimidin-4-yl)-3(trifluoromethyl)thiophene-2-carboxamide, the title compound was obtained as a white solid. LCMS A: t _R =0.94 min; without ionization.

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d) 5-(6-Chloropyrimidin-4-yl)-3-(trifluoromethyl)thiophene-2-carboxamide.

Following the procedure described for Example 83-e, using 5-(6-chloropyrimidin-4-yl)-3(trifluoromethyl)thiophene-2-carboxylic acid, the title compound was obtained as a white solid. LC-MS B: t _R =0.75 min; [M+H]+=307.97.

e) 5-(6-Chloropyrimidin-4-yl)-3-(trifluoromethyl)thiophene-2-carboxylic acid.

Following the procedure described for Example 55-c using 4,6-dichloropyrimidine and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)thiophene-2- carboxylic acid (A.3.4.), the title compound is obtained as a beige solid. LC-MS B: t _R =0.83 min; [M+MeCN] ⁺ =349.91.

Example 134 5-{6-[2-(4-Bromo-2,6-difluorophenyl)ethylamino]pyrimidin-4-yl}-3-trifluoromethylthiophene-2-carboxylic acid amide m.p.

The title compound was formed as a by-product in the synthesis of Example 133-a and was isolated as a white powder. LCMS A: t _R =0.95 min; [M+H]+=506.81.

Example 135 3-(5-{6-[2-(4-Bromo-2,6-difluorophenyl)ethylamino]pyrimidin-4-yl}thiophen-2-yl)[1,2,4]oxadiazol-5( 4H)-one [tautomeric form: 3-(5-{6-[2-(4-bromo-2,6-difluorophenyl)ethylamino]pyrimidin-4-yl}thiophen-2-yl)-[1,2, 4]oxadiazol-5-ol].

Following the same procedure as described for Example 130 using 1,1'-carbonyldiimidazole and 5(6-((4-bromo-2,6-difluorophenethyl)amino)pyrimidin-4-yl)-N'-hydroxythiophen- 2-carboximidamide, the title compound is obtained as a white solid. LC-MS B: t _R =0.91 min; [M+H]+=479.9.

a) 5-(6-((4-Bromo-2,6-difluorophenethyl)amino)pyrimidin-4-yl)-N'-hydroxythiophene-2-carboximidamide.

Following the same procedure as described for Example 129, using 5-(6-((4-bromo-2,6difluorophenethyl)amino)pyrimidin-4-yl)thiophene-2-carbonitrile, the title compound was obtained as a gray powder. LC-MS B: t _R =0.74 min; [M+H]+=455.93.

b) 5-(6-((4-Bromo-2,6-difluorophenethyl)amino)pyrimidin-4-yl)thiophene-2-carbonitrile.

Following the procedure described for Example 55-c using N-(4-bromo-2,6-difluorophenethyl)-6iodopyrimidine-4-amine (A.2.6.) and 5-cyanothiophene-2-boronic acid, the title compound obtained as a beige powder. LC-MS B: t _R =1.04 min; [M+H]+=420.78.

Example 136 3-(5-{6-[2-(4-Bromo-2,6-difluorophenyl)ethylamino]pyrimidin-4-yl}-3-methylthiophen-2yl)-[1,2,4]oxadiazol- 5(4H)-one [tautomeric form: 3-(5-{6-[2-(4-bromo-2,6-difluorophenyl)ethylamino]pyrimidin-4-yl}-3-methylthiophen-2-yl)- [1,2,4]oxadiazol-5-ol].

Following the same method as described for example 130 using 1,1'-carbonyldiimidazole and 5-(6-((4bromo-2,6-difluorophenethyl)amino)pyrimidin-4-yl)-N'-hydroxy-3 -methylthiophene-2-carboximidamide, the title compound is obtained as a white solid. LC-MS B: t _R =0.94 min; [M+H]+=493.89.

a) 5-(6-((4-Bromo-2,6-difluorophenethyl)amino)pyrimidin-4-yl)-N'-hydroxy-3-methylthiophene-2-carboximidamide.

Following the same procedure as described for Example 129, using 5-(6-((4-bromo-2,6difluorophenethyl)amino)pyrimidin-4-yl)-3-methylthiophene-2-carbonitrile, the title compound was obtained as a crude mixture, which is used without further purification. LC-MS B: t _R =0.72 min; [M+H]+=467.75.

b) 5-(6-((4-Bromo-2,6-difluorophenethyl)amino)pyrimidin-4-yl)-3-methylthiophene-2-carbonitrile.

Following the procedure described for Example 55-c, using N-(4-bromo-2,6-difluorophenethyl)-6-iodopyrimidine-4-amine (A.2.6.) and 5-cyano-4-methylthiophene-2-boronic acid, the title compound is obtained as a pale yellow powder. LCMS B: t _R =1.07 min; [M+H]+=436.81.

Example 137 3-(5-{6-[2-(4-Bromophenyl)ethylamino]pyrimidin-4-yl}-3-ethoxythiophen-2-ylmethyl)[1,2,4]oxadiazol-5(4H)- he [tautomeric form: 3-(5-{6-[2-(4-bromophenyl)ethylamino]pyrimidin-4-yl}-3ethoxythiophen-2-ylmethyl)-[1,2,4]oxadiazol-5-ol] .

Following the same method as described for example 130 using 1,1'-carbonyldiimidazole and 2(5-(6-((4-bromophenethyl)amino)pyrimidin-4-yl)-3-ethoxythiophen-2-yl) -N'-hydroxyacetimidamide, the title compound is obtained as a white solid. LC-MS B: t _R =0.81 min; [M+H]+=502.08.

a) 2-(5-(6-((4-Bromophenethyl)amino)pyrimidin-4-yl)-3-ethoxythiophen-2-yl)-N'-hydroxyacetimidamide.

Following the same procedure as described for Example 129, using 2-(5-(6-((4-bromophenethyl)amino)pyrimidin-4-yl)-3-ethoxythiophen-2-yl)acetonitrile, the title compound was obtained in form of a white solid. LCMS B: t _R =0.66 min; [M+H]+=476.16.

b) 2-(5-(6-((4-Bromophenethyl)amino)pyrimidin-4-yl)-3-ethoxythiophen-2-yl)acetonitrile.

A solution of sodium cyanide (83.1 mg, 1.7 mmol) in water (0.4 ml). PM is stirred at RT for 30 min, then diluted with EtOAc and washed twice with sat. aq. NaHCO ₃ and once with brine 87 043145 rum. The organic layer is dried over MgSO ₄ , filtered and concentrated. The remainder is purified with

PC (heptane to heptane/EtOAc 1:1) to give the title compound as a white powder (117 mg, 63%). LC-MS B: t _R =0.89 min; [M+H]+=443.22.

c) N-(4-Bromophenethyl)-6-(5-(chloromethyl)-4-ethoxythiophen-2-yl)pyrimidin-4-αmin.

Thionyl chloride ( 0.0191 ml, 0.259 mmol) and PM was stirred for 1 h. It was then concentrated in vacuo to give the crude expected product as a greyish solid (82 mg, quantitative). LC-MS B: t _R =0.88 min; [M+H]+=450.06.

d) (5-(6-((4-Bromophenethyl)amino)pyrimidin-4-yl)-3-ethoxythiophen-2-yl)methanol.

To a solution of methyl 5-(6-((4-bromophenethyl)amino)pyrimidin-4-yl)-3-ethoxythiophene-2-carboxylate (550 mg, 1.13 mmol) in THF (20 ml) at -78°C dropwise diisobutylaluminum hydride (1.0 M in DCM, 6.2 ml, 6.78 mmol) is added and PM is stirred for 3 h. Diisobutylaluminum hydride (1.0 M in DCM, 3.1 ml, 3.39 mmol) is added dropwise and PM is stirred for 3 h. Then it is carefully quenched at -78°C by adding dropwise sat. aq. NH4C1. After the mixture has cooled to RT, DCM and saturated Rochelle's salt solution are added, the biphasic mixture is stirred vigorously at RT, then filtered through celite. The layers are separated, then the organic layer is washed twice with brine, separated by passing through a phase separator cartridge, and concentrated. The solid residue is triturated in Et ₂ O. The solid is filtered off, washing with Et ₂ O and dried in vacuo to give the pure expected product as a beige solid (375 mg, 76%). LCMS A: t _R =0.78 min; [M+H]+=434.09.

e) Methyl 5-(6-((4-bromophenethyl)amino)pyrimidin-4-yl)-3-ethoxythiophene-2-carboxylate.

Following the procedure described for Example 55-c using N-(4-bromophenethyl)-6-iodopyrimidine-4amine (A.2.2.) and methyl 3-ethoxy-5-(4,4,5,5-tetramethyl-1 ,3,2-Dioxaborolan-2-yl)thiophene-2-carboxylate (Example 83-h), title compound was obtained as a beige powder. LC-MS B: t _R =0.96 min; [M+H]+=462.15.

Example 138 3-(5-{6-[2-(4-Bromo-2,6-difluorophenyl)ethylamino]pyrimidin-4-yl}-3-ethoxythiophen-2ylmethyl)-[1,2,4]oxadiazol- 5(4H)-one [tautomeric form: 3-(5-{6-[2-(4-bromo-2,6-difluorophenyl)ethylamino]pyrimidin-4-yl}-3-ethoxythiophen-2-ylmethyl)- [1,2,4]oxadiazol-5-ol].

Following the same method as described for example 130 using 1,1'-carbonyldiimidazole and 2(5-(6-((4-bromo-2,6-difluorophenethyl)amino)pyrimidin-4-yl)-3- ethoxythiophen-2-yl)-N'-hydroxyacetimidamide, the title compound is obtained as a beige solid. LCMS B: t _R =0.86 min; [M+H]+=538.02.

a) 2-(5-(6-((4-Bromo-2,6-difluorophenethyl)amino)pyrimidin-4-yl)-3-ethoxythiophen-2-yl)-N'-hydroxyacetimidamide.

Following the same method as described for example 129 using 2-(5-(6-((4-bromo-2,6difluorophenethyl)amino)pyrimidin-4-yl)-3-ethoxythiophen-2-yl)acetonitrile, the title compound is obtained as a light yellow solid. LC-MS B: t _R =0.70 min; [M+H] ⁺ =511.90.

b) 2-(5-(6-((4-Bromo-2,6-difluorophenethyl)amino)pyrimidin-4-yl)-3-ethoxythiophen-2-yl)acetonitrile.

Following general procedure I using 2-(3-ethoxy-5-(6-hydroxypyrimidin-4-yl)thiophen-2yl)acetonitrile and 2-(4-bromo-2,6-difluorophenyl)ethane-1-amine, the indicated in the title compound is obtained as a yellow solid. LC-MS B: t _R =0.94 min; [M+H]+=479.07.

c) 2-(3-Ethoxy-5-(6-hydroxypyrimidin-4-yl)thiophen-2-yl)acetonitrile.

Following the same procedure as described for Example 83-a using 2-(3-ethoxy-5-(6methoxypyrimidin-4-yl)thiophen-2-yl)acetonitrile, the title compound was obtained as a pink solid. LC-MS B: t _R =0.70 min; [M+H]+=262.07.

d) 2-(3-Ethoxy-5-(6-methoxypyrimidin-4-yl)thiophen-2-yl)acetonitrile.

Following the same procedure as described for Example 137-b using 4-(5-(chloromethyl)-4ethoxythiophen-2-yl)-6-methoxypyrimidine, the title compound was obtained as a light yellow solid. LC-MS B: t _R =0.93 min; [M+H]+=276.12.

e) 4-(5-(Chloromethyl)-4-ethoxythiophen-2-yl)-6-methoxypyrimidine.

Following the same procedure as described for Example 137-c using (3-ethoxy-5-(6methoxypyrimidin-4-yl)thiophen-2-yl)methanol, the title compound was obtained as a greyish solid. LC-MS B: t _R =0.94 min; without ionization.

f) (3-Ethoxy-5-(6-methoxypyrimidin-4-yl)thiophen-2-yl)methanol.

Following the same procedure as described for Example 137-d using methyl 3-ethoxy-5-(6methoxypyrimidin-4-yl)thiophene-2-carboxylate (Example 83-g), the title compound was obtained as light yellow solid. LC-MS B: t _R =0.78 min; [M+H]+=267.10.

Example 139: {6-[5-(5-Amino-[1,2,4]oxadiazol-3-yl)-4-ethoxythiophen-2-yl]pyrimidin-4-yl}-[2-(4bromophenyl)ethyl ]amine.

N-(4-Bromophenethyl)-6-(4-ethoxy-5-(5-(trichloromethyl)-[1,2,4]oxadiazol-3-yl)thiophen-2-yl)pyrimidin-4-amine (17 mg, 0.0259 mmol) at RT was dissolved in NH ₃ (7 M in MeOH, 0.5 mL) and PM was stirred at RT for 1 h. It was then concentrated and the residue was purified with prep. HPLC with obtaining

No. 88 043145 of the title compound as a white solid. LC-MS B: t _R =0.83 min;

[M+H]+=487.07.

a) N(4-Bromophenethyl)-6-(4-ethoxy-5-(5-(trichloromethyl)-[1,2,4]oxadiazol-3-yl)thiophen-2-yl)pyrimidin-4-amine.

Trichloroacetic acid anhydride (0.0169 ml, 0.0908 mmol) was added at RT to a suspension of 5-{6[2-(4-bromophenyl)ethylamino]pyrimidin-4-yl}-3-ethoxy-N-hydroxythiophene-2-carboxamidine (Example 129 , 50 mg, 0.0757 mmol) in toluene (0.35 ml). The suspension is stirred at 115°C for 30 min, then cooled to RT. It is then diluted with EtOAc and washed twice with sat. aq. NaHCO3 and once with saline. The organic layer is dried over MgSO ₄ , filtered and concentrated. The residue was purified with PC (heptane to heptane/EtOAc 1:1) to give the title compound as a light yellow solid (17 mg, 38%). LC-MS B: t _R =1.16 min; [M+H]+=590.20.

Example 140 [2-(4-Bromophenyl)ethyl]-{6-[4-ethoxy-5-(5-methoxy-[1,2,4]oxadiazol-3-yl)thiophen-2yl]pyrimidin-4- yl}amine.

To a solution of N-(4-bromophenethyl)-6-(4-ethoxy-5-(5-(trichloromethyl)-[1,2,4]oxadiazol-3-yl)thiophen-2yl)pyrimidin-4-amine (example 139-a, 18 mg, 0.0275 mmol) in DMF (0.275 mL), sodium methoxide (0.5 M in methanol, 0.082 mL, 0.0412 mmol) was added dropwise at RT. PM is stirred at RT for 1 h, quenched with water, and purified with prep. HPLC gave the title compound as a white solid (3 mg, 20%). LCMS D: t _R =1.15 min; [MH] ⁺ =501.90.

Example 141 2-[3-(5-{6-[2-(4-Bromophenyl)ethylamino]pyrimidin-4-yl}-3-ethoxythiophen-2-yl)[1,2,4]oxadiazol-5- ylamino]ethanol.

Following the same method as described for Example 139 using N-(4-bromophenethyl)-6-(4ethoxy-5-(5-(trichloromethyl)-[1,2,4]oxadiazol-3-yl)thiophene- 2-yl)pyrimidin-4-amine (139-a) and ethanolamine, the compound is obtained as a white solid. LC-MS B: t _R =0.81 min; [M+H] ⁺ =531.07.

Example 142 [2-(4-Bromophenyl)ethyl]-{6-[4-ethoxy-5-(5-oxetan-3-yl-[1,2,4]oxadiazol-3-yl)thiophen2-yl] pyrimidin-4-yl}amine.

Oxetane-3-carboxylic acid (9.27 mg, 0.0908 mmol) was dissolved in DMF (0.746 ml) and TBTU (29.2 mg, 0.0908 mmol) and DIPEA (0.0311 ml, 0.182 mmol) were added successively. After 5 min stirring at RT, add 5-{6-[2-(4-bromophenyl)ethylamino]pyrimidin-4-yl}-3-ethoxy-Nhydroxythiophene-2-carboxamidine (example 129, 40 mg, 0.0606 mmol), and the RM is stirred at RT overnight, then at 120° C. for 1 h 40 min. After cooling to RT, PM is directly purified with prep. HPLC afforded the title compound as a yellow solid (4 mg, 12%). LC-MS B: t _R =0.95 min; [M+H]+=527.95.

Example 143 [3-(5-{6-[2-(4-Bromophenyl)ethylamino]pyrimidin-4-yl}-3-ethoxythiophen-2-yl)[1,2,4]oxadiazol-5-yl] methanol

Acetoxyacetic acid (5.42 mg, 0.0454 mmol) was dissolved in DMF (0.561 ml) and TBTU (14.6 mg, 0.0454 mmol) and DIPEA (0.0183 ml, 0.107 mmol) were added successively. After 5 min stirring at RT, add 5-{6-[2-(4-bromophenyl)ethylamino]pyrimidin-4-yl}-3-ethoxy-N-hydroxythiophene-2-carboxamidine (example 129, 30 mg, 0.0454 mmol ) and PM is stirred at RT for 1 h, then at 120°C for 1 h. After cooling to RT, PM is directly purified with prep. HPLC. to give the title compound as a yellow solid (2.4 mg, 11%). LC-MS D: t _R =1.01 min; [MH] ⁺ =501.87.

Example 144 3-[2-(5-{6-[2-(4-Bromophenyl)ethylamino]pyrimidin-4-yl}-3-ethoxythiophen-2-yl)ethyl][1,2,4]oxadiazol- 5(4H)-one [tautomeric form: 3-[2-(5-{6-[2-(4-bromophenyl)ethylamino]pyrimidin-4yl}-3-ethoxythiophen-2-yl)ethyl] - [1, 2,4]oxadiazol-5-ol].

Following the same method as described for example 130, using 3-(5-(6-((4bromophenethyl)amino)pyrimidin-4-yl)-3-ethoxythiophen-2-yl)-N'-hydroxypropanimidamide and 1, 1'carbonyldiimidazole, the compound is obtained as a white solid. LCMS B: tR=0.83 min; [M+H]+=515.90.

a) 3-(5-(6-((4-Bromophenethyl)amino)pyrimidin-4-yl)-3-ethoxythiophen-2-yl)-N'-hydroxypropanimidamide.

Following the same procedure as described for example 129, starting from 3-(5-(6-((4-bromophenethyl)amino)pyrimidin-4-yl)-3-ethoxythiophen-2-yl)propanenitrile, the title compound is obtained as a light yellow solid. LC-MS B: t _R =0.68 min; [M+H]+=490.12.

b) 3-(5-(6-((4-Bromophenethyl)amino)pyrimidin-4-yl)-3-ethoxythiophen-2-yl)propanenitrile.

To a mixture of (5-(6-((4-bromophenethyl)amino)pyrimidin-4-yl)-3-ethoxythiophen-2-yl)methanol (example 137-d, 266 mg, 0.612 mmol) and (cyanomethyl)trimethylphosphine iodide (391 mg, 1.53 mmol) propionitrile (1.22 ml) and DIPEA (0.335 ml, 1.96 mmol) are added. PM is stirred at 95°C in a sealed tube for 3 h. At RT, water (66 mg, 3.67 mmol) is added carefully and PM is stirred at 95°C for 2 h. PM is cooled to RT, diluted with water (10 ml) and HCl (1 M, 1 ml), and extracted with EtOAc (3 times). The combined extracts are washed with brine, dried (MgSO ₄ ) and concentrated. The residue was purified with PC to give the title compound as a yellow solid (43 mg, 15%). LC-MS B: t _R =0.89 min; [M+H]+=457.10.

- 89 043145

Example 145 1-(5-{6-[2-(4-Bromophenyl)ethylamino]pyrimidin-4-yl}-3-ethoxythiophen-2-yl)ethanol m.p.

To a solution of 1 -(5-(6-((4-bromophenethyl)amino)pyrimidin-4-yl)-3-ethoxythiophen-2-yl)ethan-1-one (65 mg, 0.146 mmol) in EtOH (2 ml ) at 0°C sodium borohydride (27.5 mg, 0.728 mmol) is added and then PM is stirred at RT over the weekend. Sodium borohydride (27.5 mg, 0.728 mmol) is added and stirring is continued for 1 h. The PM is quenched by dropwise addition of acetone and concentrated under reduced pressure. The residue is partitioned between water and EtOAc, then the organic layer is dried over MgSO ₄ , filtered and concentrated. Cleaning with Prep. HPLC gave the title compound as a white solid (38 mg, 57%). LCMS A: tR=0.77 min; [M+H]+=447.87.

a) 1-(5-(6-((4-Bromophenethyl)amino)pyrimidin-4-yl)-3-ethoxythiophen-2-yl)ethan-1-one.

To a flame-dried flask containing 5-(6-((4-bromophenethyl)amino)pyrimidin-4-yl)-3ethoxy-N-methoxy-N-methylthiophene-2-carboxamide (115 mg, 0.234 mmol) in THF (2 ml) at 0°C, bromomethylmagnesium (3 M in THF, 0.25 ml, 0.75 mmol) was added dropwise, then the solution was stirred at RT for 1 h, and quenched with sat. aq. NH ₄ Cl and diluted with EtOAc. Some product remains insoluble at the interface of the two layers and is therefore filtered off to give 24 mg (23%) of pure product as a beige solid. The filtrate phases are separated, the organic layer is washed with brine (2x), dried over anhydrous MgSO ₄ , filtered and concentrated to give the expected product as a light yellow solid (65 mg, 62%). LCMS A: tR=0.90 min; [M+H]+=446.03.

b) 5-(6-((4-Bromophenethyl)amino)pyrimidin-4-yl)-3-ethoxy-N-methoxy-N-methylthiophene-2-carboxamide.

A mixture of 5-{6-[2-(4-bromophenyl)ethylamino]pyrimidin-4-yl}-3-ethoxythiophene-2-carboxylic acid (example 54, 194 mg, 0.427 mmol), N,O-dimethyl hydroxylamine hydrochloride (63.8 mg, 0.641 mmol), TEA (0.178 ml, 1.28 mmol) and HATU (244 mg, 0.641 mmol) in DMF (1.5 ml) were stirred at RT for 1 h, and purified with prep. HPLC afforded the title compound as a beige solid (115 mg, 55%). LCMS A: tR=0.81 min; [M+H]+=490.96.

Example 146 (5-{6-[2-(4-Bromophenyl)ethylamino]pyrimidin-4-yl}-3-ethoxythiophen-2-yl)urea

TEA ( 0.01 ml, 0.0718 mmol) and trichloroacetyl isocyanate (0.01 ml, 0.0809 mmol). PM is stirred at RT for 1 h 30 min, concentrated and the residue is taken up in NH ₃ (7 M in MeOH, 0.5 ml) and stirred at RT for 1 h. PM is diluted with DCM and water. The product precipitated as a yellow solid which was filtered off and dried under high vacuum (11 mg, 58%). LCMS A: tR=0.72 min; [M+H]+=462.00.

a) 6-(5-Amino-4-ethoxythiophen-2-yl)-N-(4-bromophenethyl)pyrimidin-4-amine hydrochloride.

Solution of tert-butyl (5-(6-((4-bromophenethyl)amino)pyrimidin-4-yl)-3-ethoxythiophen-2-yl)carbamate (22 mg, 0.0424 mmol) in 4M HCl in dioxane (1 ml) stirred at RT for 2 h, then concentrated under reduced pressure to give the title compound as an orange solid (19.3 mg, 99%). LCMS A: tR=0.75 min; [M+H]+=419.09.

b) tert-Butyl (5-(6-((4-bromophenethyl)amino)pyrimidin-4-yl)-3-ethoxythiophen-2-yl)carbamate.

5-{6-[2-(4-Bromophenyl)ethylamino]pyrimidin-4-yl}-3-ethoxythiophene-2-carboxylic acid (example 54.100 mg, 0.22 mmol) was suspended in mpem-butanol (0.75 ml) and at RT diphenylphosphoryl azide (0.0474 ml, 0.22 mmol) was added followed by TEA (0.0311 ml, 0.221 mmol). PM is heated at 90° C. and stirred for 5 hours. After the mixture has cooled to RT, it is diluted with sat. aq. NaHCO ₃ and extracted with EtOAc. The organic layer is washed twice with brine, dried over MgSO ₄ , filtered and concentrated. Purification with PC (heptane to heptane/EtOAc 1:1) gave the title compound as a light yellow solid (23 mg, 20%). LCMS A: tR=0.86 min; [M+H]+=519.06.

Example 147 3-(3-{6-[2-(4-Bromophenyl)ethylamino]pyrimidin-4-yl}phenyl)-[1,2,4]oxadiazol-5(4H)one [tautomeric form: 3- (3-{6-[2-(4-bromophenyl)ethylamino]pyrimidin-4-yl}phenyl)-[1,2,4]oxadiazol5-ol].

Following the same procedure as described for Example 130 using 1,1'-carbonyldiimidazole and 3(6-((4-bromophenethyl)amino)pyrimidin-4-yl)-N-hydroxybenzimidamide, the title compound was obtained as white solid. LCMS A: tR=0.72 min; [M+H]+=437.99.

a) 3-(6-((4-Bromophenethyl)amino)pyrimidin-4-yl)-N'-hydroxybenzimidamide.

Following the same procedure as described for example 129, using 3-(6-((4-bromophenethyl)amino)pyrimidin-4-yl)benzonitrile, the title compound was obtained as a white solid. LCMS A: tR=0.59 min; [M+H]+=412.07.

b) 3-(6-((4-Bromophenethyl)amino)pyrimidin-4-yl)benzonitrile.

Following general procedure G using N-(4-bromophenethyl)-6-iodopyrimidin-4-amine (A.2.2.) and 3-cyanophenylboronic acid, the title compound is obtained as a white solid. LCMS A: tR=0.76 min; [M+H] ⁺ =381.05.

- 90 043145

Example 148 2-{6-[2-(4-Bromo-2,6-difluorophenyl)ethylamino]pyrimidin-4-yl}-4-ethoxythiazole-5carboxylic acid m.p.

TEA (0.151 ml, 1.08 mmol) and PyBop (150 mg , 0.288 mmol). PM is stirred until complete dissolution at RT for several minutes and 2-(4-bromo-2,6difluorophenyl)ethan-1-amine (59 mg, 0.25 mmol) is added. PM is heated at 100° C. for 30 min in a MW apparatus. Add 10% NaOH (0.721 ml, 2 mmol) and PM stirred at 70°C overnight. Cleaning with prep. LC-MS gives the title compound as a yellow solid. LC-MS B: t _R =0.97 min; [M+H]+=486.95.

a) Ethyl 4-ethoxy-2-(6-hydroxypyrimidin-4-yl)thiazole-5-carboxylate.

Following the procedure described for the synthesis of Example 83-a using ethyl 4-ethoxy-2-(6methoxypyrimidin-4-yl)thiazol-5-carboxylate, the title compound was obtained as a yellow solid. LCMS B: t _R =0.78 min; [M+H]+=296.15.

b) Ethyl 4-ethoxy-2-(6-methoxypyrimidin-4-yl)thiazole-5-carboxylate.

K2CO3 (2168 mg, 15.4 mmol) was added to a solution of ethyl 4-hydroxy-2-(6-methoxypyrimidin-4-yl)thiazol-5-carboxylate (1730 mg, 6.15 mmol) in DMF (40 mL) at RT under argon. , and PM is heated at 60°C. Iodoethane (0.749 ml, 9.23 mmol) is added and PM is stirred at 75° C. overnight. It is then cooled to RT and water (75 ml) is added. Water layer was extracted with DCM, the organic extracts were dried (MgSO ₄ ), filtered and concentrated under reduced pressure to give the crude title compound as an orange solid (1.75 g, 76%). LCMS B: t _R =1.04 min; [M+H]+=310.24.

c) Ethyl 4-hydroxy-2-(6-methoxypyrimidin-4-yl)thiazole-5-carboxylate.

Pyridine (1.9 ml, 23.4 mmol) was added to a solution of 6-methoxypyrimidine-4-carbothioamide (1000 mg, 5.85 mmol) in toluene (40 ml) at RT, after which diethyl bromomalonate (1.52 ml, 8.19 mmol) was added. PM is heated at reflux overnight, then cooled to RT and treated with 2N HCl. HCl. The product is filtered off. The filtrate layers are separated and aq. layer was extracted twice with EtOAc. The combined organic layers are dried over MgSO ₄ , filtered, evaporated to dryness. The residue was combined with the first crop of product to give the title compound as a brown solid (1.73 g, 99%). LC-MS B: t _R =0.89 min; [M+H]+=282.18.

Example 149 2-{6-[2-(4-Bromo-2,6-difluorophenyl)ethylamino]pyrimidin-4-yl}-4-ethylthiazole-5-carboxylic acid m.p.

Following the procedure described for the synthesis of Example 148 using ethyl 4-ethyl-2-(6hydroxypyrimidin-4-yl)thiazol-5-carboxylate and 2-(4-bromo-2,6-difluorophenyl)ethan-1-amine, indicated in the title compound is obtained as a white solid. LCMS B: tR=0.97 min; [M+H]+=470.90.

a) Ethyl 4-ethyl-2-(6-hydroxypyrimidin-4-yl)thiazole-5-carboxylate.

Following the procedure described for the synthesis of Example 83-a using ethyl 4-ethyl-2-(6ethoxypyrimidin-4-yl)thiazole-5-carboxylate, the title compound was obtained as a beige solid. LC-MS B: t _R =0.73 min; [M+H]+=266.26.

b) Ethyl 4-ethyl-2-(6-ethoxypyrimidin-4-yl)thiazole-5-carboxylate.

To a solution of methyl 2-chloro-3-oxovalerianate (0.96 ml, 6.5 mmol) in EtOH (30 ml) was added 6-methoxypyrimidine-4-carbothioamide (1000 mg, 5.91 mmol) and the mixture was refluxed overnight. Methyl 2-chloro-3-oxovalerianate (1.31 mL, 8.86 mmol) was added and PM was heated further at reflux for 24 h, then cooled to RT and treated with water (15 mL), cooled to 0°C. The precipitate was filtered off, washing with MeOH and dried under high vacuum to give the title compound as a pinkish solid (485 mg, 28%). LC-MS B: t _R =1.07 min; [M+H]+=294.20.

Example 150 3-(2-{6-[2-(4-Bromo-2,6-difluorophenyl)ethylamino]pyrimidin-4-yl}-4-ethoxythiazol-5yl)-[1,2,4]oxadiazol- 5(4H)-one [tautomeric form: 3-(2-{6-[2-(4-bromo-2,6-difluorophenyl)ethylamino]pyrimidin-4-yl}-4-ethoxythiazol-5-yl)- [1,2,4]oxadiazol-5-ol].

Following the procedure described for the synthesis of Example 148 using 3-(4-ethoxy-2-(6hydroxypyrimidin-4-yl)thiazol-5-yl)-[1,2,4]oxadiazol-5-ol and 2-(4 -bromo-2,6-difluorophenyl)ethane-1-amine, the title compound is obtained as a yellow solid. LC-MS B: t _R =1.10 min; [M+H]+=524.05.

a) 3-(4-Ethoxy-2-(6-hydroxypyrimidin-4-yl)thiazol-5-yl)-[1,2,4]oxadiazol-5-ol.

Following the procedure described for the synthesis of example 83-a, using 3-(4-ethoxy-2-(6methoxypyrimidin-4-yl)thiazol-5-yl)-[1,2,4]oxadiazol-5-ol, indicated in the title compound is obtained as a yellowish solid. LC-MS B: t _R =0.68 min; [M+H]+=308.17.

b) 3-(4-Ethoxy-2-(6-methoxypyrimidin-4-yl)thiazol-5-yl)-[1,2,4]oxadiazol-5-ol.

Following the procedure described for the synthesis of Example 83-b using 4-ethoxy-N'-hydroxy-2(6-methoxypyrimidin-4-yl)thiazole-5-carboximidamide, the title compound was obtained as a beige solid. LC-MS B: t _R =0.94 min; [M+H] ⁺ =321.93.

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c) 4-Ethoxy-N'-hydroxy-2-(6-methoxypyrimidin-4-yl)thiαzol-5-carboximideαamide.

Following the procedure described for the synthesis of Example 83-c using 4-ethoxy-2-(6methoxypyrimidin-4-yl)thiazole-5-carbonitrile, the title compound was obtained as a dark yellow solid. LC-MS B: t _R =0.67 min; [M+H]+=296.17.

d) 4-Ethoxy-2-(6-methoxypyrimidin-4-yl)thiazole-5-carbonitrile.

NH ₄ OH (25%, 4.05 ml, 26.3 mmol) and I ₂ (1824 mg, 7.19 mmol) and the mixture was stirred at RT for 3 h. Then it was poured into 10 ml of 40% NaHSO ₃ (15 ml) and extracted with EtOAc, dried over MgSO ₄ and concentrated in vacuo to give the title compound as an orange solid. LCMS B: t _R =1.02 min; [M+H]+=263.25.

e) 4-Ethoxy-2-(6-methoxypyrimidin-4-yl)thiazole-5-carbaldehyde.

A mixture of ethyl 4-ethoxy-2-(6-methoxypyrimidin-4-yl)thiazol-5-carboxylate (example 148-b, 706 mg, 2.64 mmol) in THF (20 ml) was cooled to -78°C and added dropwise DiBAl-H (1M in THF, 5.28 ml, 5.28 mmol). The mixture is stirred at RT overnight. The mixture is quenched at 0°C by adding dropwise water (200 µl), then 10% NaOH (400 µl) and finally water (600 µl). The precipitate containing aluminum is filtered off on a Celite pad and washed with EtOAc. The filtrate is dried over MgSO ₄ , filtered and concentrated under reduced pressure. The residue was dissolved in DCM (20 ml) and MnO ₂ (2701 mg, 26.4 mmol) was added. The mixture is stirred for 5 hours at RT, then filtered through a pad of celite and washed with EtOAc. The filtrate was concentrated under reduced pressure to give the title compound as a light orange solid. LC-MS B: t _R =0.97 min; [M+H]+=266.25.

Example 151 3-(2-{6-[2-(4-Bromo-2,6-difluorophenyl)ethylamino]pyrimidin-4-yl}-4-ethylthiazol-5-yl)[1,2,4]oxadiazole -5(4H)-one [tautomeric form: 3-(2-{6-[2-(4-bromo-2,6-difluorophenyl)ethylamino]pyrimidin-4-yl}-4-ethylthiazol-5-yl) -[1,2,4]oxadiazol-5-ol].

Following the procedure described for the synthesis of Example 148 using 3-(4-ethyl-2-(6hydroxypyrimidin-4-yl)thiazol-5-yl)-[1,2,4]oxadiazol-5-ol and 2-(4 -bromo-2,6-difluorophenyl)ethane-1-amine, the title compound is obtained as a yellow solid. LC-MS B: t _R =1.03 min; [M+H]+=510.98.

a) 3-(4-Ethyl-2-(6-hydroxypyrimidin-4-yl)thiazol-5-yl)-[1,2,4]oxadiazol-5-ol.

Following the procedure described for the synthesis of example 83-a, using 3-(4-ethyl-2-(6ethoxypyrimidin-4-yl)thiazol-5-yl)-[1,2,4]oxadiazol-5-ol, indicated in the title compound is obtained as a gray solid. LC-MS B: t _R =0.64 min; [M+H]+=292.17.

b) 3-(4-Ethyl-2-(6-ethoxypyrimidin-4-yl)thiazol-5-yl)-[1,2,4]oxadiazol-5-ol

Following the procedure described for the synthesis of Example 83-b using 4-ethyl-N'-hydroxy-2-(6ethoxypyrimidin-4-yl)thiazol-5-carboximidamide, the title compound was obtained as a light orange solid. LC-MS B: t _R =0.92 min; [M+H]+=320.21.

c) 4-Ethyl-N'-hydroxy-2-(6-ethoxypyrimidin-4-yl)thiαzol-5-carboximideαamide.

Following the procedure described for the synthesis of Example 83-c using 4-ethyl-2-(6ethoxypyrimidin-4-yl)thiazole-5-carbonitrile, the title compound was obtained as a light yellow solid. LC-MS B: t _R =0.66 min; [M+H]+=294.21.

d) 4-Ethyl-2-(6-ethoxypyrimidin-4-yl)thiazole-5-carbonitrile.

Following the procedure described for the synthesis of Example 83-d using 2-(6-ethoxypyrimidin-4yl)-4-ethylthiazole-5-carboxamide, the title compound was obtained as a beige solid. LCMS B: t _R =1.04 min; [M+H] ⁺ =261.29.

e) 2-(6-Ethoxypyrimidin-4-yl)-4-ethylthiazol-5-carboxamide.

Following the procedure described for the synthesis of Example 83-e using 2-(6-ethoxypyrimidin-4yl)-4-ethylthiazole-5-carboxylic acid, the title compound was obtained as an orange solid. LC-MS B: t _R =0.79 min; [M+H]+=279.25.

f) 2-(6-Ethoxypyrimidin-4-yl)-4-ethylthiazole-5-carboxylic acid.

An ice-cold solution of ethyl 4-ethyl-2-(6-ethoxypyrimidin-4-yl)thiazole-5-carboxylate (Example 149b, 1000 mg, 3.09 mmol) in THF/MeOH 1:1 (15 mL) was treated with 10% NaOH (5.58 ml, 15.5 mmol) and stirred at RT for 20 h. The solvents are removed under reduced pressure, the aqueous phase is extracted once with Et ₂ O. The aqueous phase is then acidified with 2N. HCl and extracted with EtOAc (3x). The combined organic extracts are dried over MgSO ₄ , filtered and concentrated under reduced pressure to give the title compound as a greenish solid (522 mg, 64%). LCMS B: t _R =0.88 min; [M+H]+=280.24.

Example 152 5-(5-{6-[2-(4-Bromo-2,6-difluorophenyl)ethylamino]pyrimidin-4-yl}-3-ethoxythiophen-2yl)-[1,3,4]oxadiazol- 2-ol [tautomeric form: 5-(5-{6-[2-(4-bromo-2,6-difluorophenyl)ethylamino]pyrimidin-4-yl}-3-ethoxythiophen-2-yl)-[1, 3,4]oxadiazol-2(3H)-one].

Following the procedure described for the synthesis of Example 83 using 5-(3-ethoxy-5-(6hydroxypyrimidin-4-yl)thiophen-2-yl)-[1,3,4]oxadiazol-2-ol, 2-(4 -bromo-2,6-difluorophenyl)ethan-1-amine and BOP, the title compound is obtained as a yellow solid. LC-MS B: t _R =0.94 min; [M+H]=526.01.

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a) 5-(3-Ethoxy-5-(6-hydroxypyrimidin-4-yl)thiophen-2-yl)-[1,3,4]oxadiazol-2-ol.

Following the procedure described for the synthesis of example 83-a using tert-butyl 2-yl)carbonate, the title compound is obtained as a yellow solid. LC-MS B: t _R =0.64 min; [M+H]+=307.04.

b) tert-Butyl (5-(3-ethoxy-5-(6-methoxypyrimidin-4-yl)thiophen-2-yl)-[1,3,4]oxadiazol-2-yl) carbonate.

Di- tert-butyl dicarbonate (693 mg, 3.18 mmol). PM was stirred at RT overnight, then partitioned between DCM and sat. aq. _NaHC03 . The two layers are separated using a phase separating syringe and the organic layer is concentrated to dryness. Cleaning with Prep. HPLC gave the title compound as a yellow solid (31 mg, 43%). LC-MS B: t _R =1.10 min; [M+H]+=421.16.

c) 3-Ethoxy-5-(6-methoxypyrimidin-4-yl)thiophene-2-carbohydrazide.

Hydrazine monohydrate (0.216 ml, 4.37 mmol) ). PM was stirred at 80° C. for 3 h and then concentrated to dryness to give the title compound as a yellow solid (253 mg, 99%). LC-MS B: t _R =0.68 min; [M+H]+=295.16.

Example 153 5-(6-((4-Bromo-2,6-difluorophenethyl)amino)pyrimidin-4-yl)-3-ethoxythiophene-2carboxylic acid

Following the general procedure G, using N-(4-bromo-2,6-difluorophenethyl)-6-iodopyrimidine-4-amine (A.2.6.) and 3-ethoxy-5-(4,4,5,5-tetramethyl -1,3,2-dioxaborolan-2-yl)thiophene-2-carboxylic acid (A.3.3.), the title compound is obtained as a light yellow solid. LC-MS B: t _R =0.89 min; [M+H]+=485.96.

Example 154 N-(5-{6-[2-(4-Bromo-2,6-difluorophenyl)ethylamino]pyrimidin-4-yl}-3-ethoxythiophene-2carbonyl)methanesulfonamide m.p.

5-(6-((4-Bromo-2,6-difluorophenethyl)amino)pyrimidin-4-yl)-3-ethoxythiophene-2-carboxylic acid (example 153, 70 mg, 0.145 mmol) is dissolved in DMSO/THF (2:1) (3 ml) and add CDI (35.2 mg, 0.217 mmol). PM is heated at 60°C for 1 h, cooled to RT and treated with methanesulfonamide (31.2 mg, 0.318 mmol) and DBU (0.054 ml, 0.361 mmol). PM is stirred at RT for 2 hours 30 minutes. The THF is removed under reduced pressure, a few drops of TEA are added and the mixture is filtered through a Whatman filter and purified with prep. HPLC to give the title compound as a white solid. LC-MS B: t _R =1.03 min; [M+H]+=563.03.

Example 155 5-(6-((4-Bromo-2,6-difluorophenethyl)amino)pyrimidin-4-yl)-3-ethoxy-N-sulfamoylthiophene-2-carboxamide

Following the procedure described for the synthesis of Example 154 using 5-(6-((4-bromo-2,6difluorophenethyl)amino)pyrimidin-4-yl)-3-ethoxythiophene-2-carboxylic acid (Example 153) and the sulfamide indicated in the title compound is obtained as a white solid. LCMS B: tR=0.94 min; [M+H] ⁺ =561.78.

Example 156 3-(5-{6-[2-(4-Bromo-2,6-difluorophenyl)ethylamino]-2-methylpyrimidin-4-yl}-3ethoxythiophen-2-yl)-[1,2,4 ]oxadiazol-5(4H)-one [tautomeric form: 3-(5-{6-[2-(4-bromo-2,6difluorophenyl)ethylamino]-2-methylpyrimidin-4-yl}-3-ethoxythiophene-2 -yl)-[1,2,4]oxadiazol-5-ol].

Following the procedure described for the synthesis of Example 83 using 3-(3-ethoxy-5-(6-hydroxy-2-methylpyrimidin-4-yl)thiophen-2-yl)-[1,2,4]oxadiazol-5-ol and 2-(4-bromo-2,6-difluorophenyl)ethan-1-amine, the title compound is obtained as a pale yellow solid. LC-MS B: t _R =0.90 min; [M+H]+=540.05.

a) 3-(3-Ethoxy-5-(6-hydroxy-2-methylpyrimidin-4-yl)thiophen-2-yl)-[1,2,4]oxadiazol-5-ol.

Following the procedure described for the synthesis of Example 83-a using 3-(3-ethoxy-5-(6-methoxy-2methylpyrimidin-4-yl)thiophen-2-yl)-[1,2,4]oxadiazol-5- ol, the title compound is obtained as a yellow solid. LCMS B: t _R =0.71 min; [M+H]+=321.04.

b) 3-(3-Ethoxy-5-(6-methoxy-2-methylpyrimidin-4-yl)thiophen-2-yl)-[1,2,4]oxadiazol-5-ol.

Following the procedure described for the synthesis of Example 83-b using 3-ethoxy-N'-hydroxy-5-(6methoxy-2-methylpyrimidin-4-yl)thiophene-2-carboximidamide, the title compound was obtained as a yellow solid . LC-MS B: t _R =0.95 min; [M+H]+=335.05.

c) 3-Ethoxy-N'-hydroxy-5-(6-methoxy-2-methylpyrimidin-4-yl)thiophene-2-carboximidamide.

Following the procedure described for the synthesis of Example 83-c using 3-ethoxy-5-(6-methoxy-2methylpyrimidin-4-yl)thiophene-2-carbonitrile, the title compound was obtained as a yellow solid. LC-MS B: t _R =0.66 min; [M+H]+=309.09.

d) 3-Ethoxy-5-(6-methoxy-2-methylpyrimidin-4-yl)thiophene-2-carbonitrile.

Following the procedure described for the synthesis of Example 83-d using 3-ethoxy-5-(6-methoxy-2methylpyrimidin-4-yl)thiophene-2-carboxamide, the title compound was obtained as a beige solid. LC-MS B: t _R =1.06 min; [M+H]+=276.18.

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e) 3-Ethoxy-5-(6-methoxy-2-methylpyrimidin-4-yl)thiophene-2-carbonitrile.

A solution of methyl 3-ethoxy-5-(6-methoxy-2-methylpyrimidin-4-yl)thiophene-2-carboxylate (450 mg, 1.46 mmol) in NH ₃ (7 M in MeOH, 15 ml) was stirred at 80°C over 3 d, then it is concentrated under reduced pressure to give the title compound as a yellow solid (449 mg, 99%). LC-MS B: t _R =0.84 min; [M+H]+=294.13.

f) Methyl 3-ethoxy-5-(6-methoxy-2-methylpyrimidin-4-yl)thiophene-2-carboxylate.

Following the procedure described for the synthesis of Example 83-g using methyl 3-ethoxy-5-(4,4,5,5tetramethyl-1,3,2-dioxaborolan-2-yl)thiophene-2-carboxylate (Example 83-h ) and 4-chloro-6-methoxy-2-methylpyrimidine, the title compound is obtained as a yellow solid. LCMS B: t _R =0.99 min; [M+H]+=309.10.

Example 157 3-(5-{6-[2-(4-Bromophenyl)ethylamino]-2-methylpyrimidin-4-yl}-3-ethoxythiophen-2-yl)[1,2,4]oxadiazol-5( 4H)-one [tautomeric form: 3-(5-{6-[2-(4-bromophenyl)ethylamino]-2-methylpyrimidin-4-yl}-3-ethoxythiophen-2-yl)-[1,2, 4]oxadiazol-5-ol].

Following the procedure described for the synthesis of Example 83 using 3-(3-ethoxy-5-(6-hydroxy-2methylpyrimidin-4-yl)thiophen-2-yl)-[1,2,4]oxadiazol-5-ol ( example 156-a) and 4-bromophenethylamine, the title compound is obtained as a pale yellow solid. LCMS B: t _R =0.86 min; [M+H]+=504.07.

Example 158 2-(5-{6-[2-(4-Bromophenyl)ethylamino]pyrimidin-4-yl}thiophen-2-yl)acetamide

Following the procedure described for the synthesis of Example 156-e, using methyl 2-(5-(6-((4bromophenethyl)amino)pyrimidin-4-yl)thiophen-2-yl)acetate and NH3 in MeOH, the title compound is obtained as a beige solid. LC-MS B: t _R =0.69 min; [M+H]+=417.05.

a) Methyl 2-(5-(6-((4-bromophenethyl)amino)pyrimidin-4-yl)thiophen-2-yl)acetate.

Following the procedure described for the synthesis of example 83-g using N-(4-bromophenethyl)-6iodopyrimidine-4-amine (A.2.2.) and methyl 2-(5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)thiophen-2yl)acetate, the title compound is obtained as a beige solid. LC-MS B: t _R =0.82 min; [M+H]+=431.94.

b) Methyl 2-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophen-2-yl)acetate.

Following the procedure described for the synthesis of A.3.18., using methylthiophene-2-acetate, the title compound was obtained as a white solid. LC-MS B: t _R =0.97 min; [M+H]+=283.14.

Example 159 rac-2-(5-{6-[2-(4-Bromophenyl)ethylamino]pyrimidin-4-yl}thiophen-2-yl)propionic acid

A mixture of 2-(5-(6-((4-bromophenethyl)amino)pyrimidin-4-yl)thiophen-2-yl)propanenitrile (30 mg, 0.0726 mmol) in HCl conc. (0.35 ml) stirred in a sealed tube at 85°C for 45 min. It is then cooled to 0°C, made basic with NH4OH and purified with prep. HPLC yielding the title compound as a white solid (23 mg, 73%). LCMS B: t _R =0.78 min; [M+H]+=432.06.

a) 2-(5-(6-((4-Bromophenethyl)amino)pyrimidin-4-yl)thiophen-2-yl)propanenitrile.

Following the procedure described for the synthesis of Example 83-g using N-(4-bromophenethyl)-6iodopyrimidine-4-amine (A.2.2.) and 2-(5-(4,4,5,5-tetramethyl-1, 3,2-dioxaborolan-2-yl)thiophen-2yl)propanenitrile, the title compound is obtained as a beige solid. LCMS B: t _R =0.87 min; [M+H]+=413.07.

b) 2-(5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)thiophen-2-yl)propanenitrile.

Following the procedure described for the synthesis of A.3.18., using 2-(thiophen-2-yl)propanenitrile, the title compound is obtained as a white solid. LCMS A: tR=1.00 min; without ionization.

Example 160 4-Chloro-2-(2-{6-[4-ethoxy-5-(5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl)thiophen-2yl] pyrimidin-4-ylamino}ethyl)benzonitrile [tautomeric form: 4-chloro-2-(2-{6-[4-ethoxy-5-(5hydroxy-[1,2,4]oxadiazol-3-yl)thiophen- 2-yl]pyrimidin-4-ylamino}ethyl)benzonitrile].

3-(5-{6-[2-(2-Bromo-5-chlorophenyl)ethylamino]pyrimidin-4yl}-3-ethoxythiophen-2-yl)-[1,2,4]oxadiazole -5(4H)-one (example 94, 28 mg, 0.0536 mmol), copper(T) cyanide (0.00415 ml, 0.134 mmol) and DMF (1 ml). It is capped and heated at 160°C for 30 min under MW irradiation. Copper(I) cyanide (0.0124 mL, 0.402 mmol) was added and the mixture was heated further at 180°C for 30 min, then at 170°C for 1 h. PM treated with 0.5 mL of 25% NH ₄ OH and filtered through 0.45 µm Whatman filter, rinsing with MeOH, and cleaned with prep. HPLC gave the title compound as a beige solid (1 mg, 4%). LCMS B: t _R =0.95 min; [M+H]+=469.16.

Example 161 3-(5-{6-[2-(4-Dimethylamino-2-fluorophenyl)ethylamino]pyrimidin-4-yl}-3-ethoxythiophen-2-yl)-[1,2,4]oxadiazol- 5(4H)-one [tautomeric form: 3-(5-{6-[2-(4-dimethylamino-2-fluorophenyl)ethylamino]pyrimidin-4-yl}-3-ethoxythiophen-2-yl)-[1 ,2,4]oxadiazol-5-ol].

3-(5-{6-[2-(4-bromo-2-fluorophenyl)ethylamino]pyrimidin-4yl}-3-ethoxythiophen-2-yl)-[1,2,4]oxadiazole -5(4H)-one (example 125, 15 mg, 0.0296 mmol), dimethylamine (2.0 M in THF, 0.02 ml, 0.04 mmol), XPhos (3 mg, 0.0061 mmol), tris-(dibenzylideneace-94 043145 tone) dipalladium(0) (3 mg, 0.00328 mmol) and Cs ₂ CO ₃ (30 mg, 0.0921 mmol) in toluene (1 ml). The tube is capped, evacuated and filled with N ₂ (3x). PM is heated at 120° C. for 15 min under MW irradiation. Dimethylamine (2.0 M in THF, 0.075 mL, 0.148 mmol) is added and PM is heated further at 125°C for 30 min. Dimethylamine (2.0 M in THF, 0.15 ml, 0.296 mmol) is added and PM is heated at 130°C for 30 min. Dimethylamine (2.0 M in THF, 0.15 ml, 0.296 mmol), XPhos (3 mg, 0.0061 mmol) and tris-(dibenzylideneacetone)dipalladium(0) (3 mg, 0.00328 mmol) are added and the mixture is heated at 150°C for 1 h PM is filtered on a 0.45 μm glass fiber filter, the filtrate is concentrated and the residue is purified with prep. HPLC yielding the title compound as a beige solid (1 mg, 7%). LC-MS B: t _R =0.85 min; [M+H]+=471.06.

Example 162 3-(5-{6-[2-(4-Bromo-2,6-difluorophenyl)ethylamino]pyrimidin-4-yl}-3-isopropoxythiophen-2-yl)-[1,2,4] oxadiazol-5(4H)-one [tautomeric form: 3-(5-{6-[2-(4-bromo-2,6-difluorophenyl)ethylamino]pyrimidin-4-yl}-3-isopropoxythiophen-2-yl )-[1,2,4]oxadiazol-5-ol].

Following the procedure described for the synthesis of Example 83 using 3-(5-(6-hydroxypyrimidin-4-yl)3-isopropoxythiophen-2-yl)-[1,2,4]oxadiazol-5-ol and 2-(4 -bromo-2,6-difluorophenyl)ethane-1-amine, the title compound is obtained as a beige solid. LC-MS B: t _R =1.03 min; [M+H]+=538.06.

a) 3-(5-(6-Hydroxypyrimidin-4-yl)-3-isopropoxythiophen-2-yl)-[1,2,4]oxadiazol-5-ol.

Following the procedure described for the synthesis of example 83-a, using 3-(5-(6-methoxypyrimidin-4-yl)3-isopropoxythiophen-2-yl)-[1,2,4]oxadiazol-5-ol specified in The title compound is obtained as a brown solid. LCMS B: t _R =0.71 min; [M+H]+=321.16.

b) 3-(5-(6-Methoxypyrimidin-4-yl)-3-isopropoxythiophen-2-yl)-[1,2,4]oxadiazol-5-ol.

Following the procedure described for the synthesis of Example 83-b using N'-hydroxy-3-isopropoxy-5-(6methoxypyrimidin-4-yl)thiophene-2-carboximidamide, the title compound was obtained as a yellow solid. LC-MS B: t _R =0.95 min; [M+H]+=335.23.

c) N'-Hydroxy-3-isopropoxy-5-(6-methoxypyrimidin-4-yl)thiophene-2-carboximidamide.

Following the procedure described for the synthesis of Example 83-c using 3-isopropoxy-5-(6methoxypyrimidin-4-yl)thiophene-2-carbonitrile, the title compound was obtained as a yellow solid. LC-MS B: t _R =0.66 min; [M+H]+=309.26.

d) 3-Isopropoxy-5-(6-methoxypyrimidin-4-yl)thiophene-2-carbonitrile.

Following the procedure described for the synthesis of Example 83-d using 3-isopropoxy-5-(6methoxypyrimidin-4-yl)thiophene-2-carboxamide, the title compound was obtained as a beige solid. LCMS B: t _R =1.04 min; [M+H]+=276.27.

e) 3-Isopropoxy-5-(6-methoxypyrimidin-4-yl)thiophene-2-carboxamide.

Following the procedure described for the synthesis of Example 83-e using 3-isopropoxy-5-(6methoxypyrimidin-4-yl)thiophene-2-carboxylic acid, the title compound was obtained as a brown solid. LC-MS B: t _R =0.85 min; [M+H]+=294.23.

f) 3-Isopropoxy-5-(6-methoxypyrimidin-4-yl)thiophene-2-carboxylic acid.

To a solution of methyl 3-isopropoxy-5-(6-methoxypyrimidin-4-yl)thiophene-2-carboxylate (500 mg, 1.62 mmol) in MeOH (16 ml) and THF (10 ml) was added 1 N. NaOH (16.2 ml, 16.2 mmol). PM is stirred at RT overnight, then concentrated in vacuo. The residue is partitioned between EtOAc and water. The main aqueous layer was acidified to pH=2 using 1N HCl. HCl and extracted twice with EtOAc. The combined organic layers are then washed with brine, dried over MgSO ₄ , filtered and concentrated under reduced pressure to give the title compound as a beige solid (322 mg, 68%). LC-MS B: t _R =0.93 min; [M+H]+=295.20.

g) Methyl 3-isopropoxy-5-(6-methoxypyrimidin-4-yl)thiophene-2-carboxylate.

Following the procedure described for the synthesis of Example 83-g using methyl 3-isopropoxy-5-(4,4,5,5tetramethyl-1,3,2-dioxaborolan-2-yl)thiophene-2-carboxylate and 4-chloro- 6-methoxypyrimidine, the title compound is obtained as a yellow solid. LC-MS B: t _R =0.98 min; [M+H]+=309.06.

h) Methyl 3-isopropoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophene-2-carboxylate.

Following the procedure described for the synthesis of A.3.3., using methyl 3-isopropoxythiophene-2-carboxylate, the title compound was obtained as a beige solid. LC-MS B: t _R =0.73 min; [M+H]+=259.12 (boronic acid, from pinacol ester hydrolysis on an LC-MS column).

i) Methyl 3-isopropoxythiophene-2-carboxylate.

NaH (60% in oil, 2529 mg, 63.2 mmol) was added in portions to a solution of methyl 3-hydroxythiophene-2-carboxylate (8000 mg, 50.6 mmol) in DMF (100 ml) at 0°C. After gas evolution is complete, 2-bromopropane (15.84 mL, 166.8 mmol) is added dropwise. After 5 minutes at 0°C, PM is allowed to warm to RT, then to 50°C over the weekend. It is cooled to RT, quenched with a few drops of water, then concentrated under reduced pressure. The residue is partitioned between water and EtOAc. The aqueous layer is re-extracted twice with EtOAc. The combined organic phases were washed with water, brine, dried over MgSO ₄ , filtered and concentrated in vacuo to give the title compound as a brown liquid (9.80 g, 97%). LC-MS B:

tR=0.78 min; [M+H]+=201.24.

Example 163 5-{6-[2-(4-Bromo-2,6-difluorophenyl)ethylamino]pyrimidin-4-yl}-3-(2-dimethylaminoethoxy)thiophene-2-carboxylic acid m.p.

To a solution of methyl 5-(6-((4-bromo-2,6-difluorophenethyl)amino)pyrimidin-4-yl)-3-hydroxythiophene-2carboxylate (20 mg, 0.0458 mmol), Cs ₂ CO ₃ (44.8 mg, 0.137 mmol) and TBAI (3.42 mg, 0.00917 mmol) in DMF (1 mL) was added (2-bromoethyl)dimethylamine (33.7 mg, 0.137 mmol) and PM heated at 120°C overnight. PM is cooled to RT and treated with 10% NaOH (0.0917 mL, 0.229 mmol) and stirred an additional 4 h at RT. PM is filtered, rinsing with MeOH and purified with prep. HPLC gave the title compound as a red solid (3 mg, 16%). LC-MS B: tR=0.70 min; [M+H] ⁺ =527.07.

a) Methyl 5-(6-((4-bromo-2,6-difluorophenethyl)amino)pyrimidin-4-yl)-3-hydroxythiophene-2carboxylate.

Following the general procedure G using N-(4-bromo-2,6-difluorophenethyl)-6-iodopyrimidine-4amine (A.2.6.) and methyl 3-hydroxy-5-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)thiophene-2carboxylate, the title compound, is obtained as an ocher solid. LCMS B: t _R =1.00 min; [M+H] ⁺ =471.99.

b) Methyl 3-hydroxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophene-2-carboxylate.

Following the procedure described for the synthesis of A.3.3., using methyl 3-hydroxythiophene-2-carboxylate, the title compound was obtained as a brown solid. LC-MS B: t _R =0.56 min; without ionization.

Example 164 3-Ethoxy-5-{6-[2-(2-methoxy-5-methylsulfanylphenyl)ethylamino]pyrimidin-4yl}thiophene-2-carboxylic acid m.p.

Following the general procedure G, using 6-chloro-N-(2-methoxy-4-(methylthio)phenethyl)pyrimidine-4amine (A.2.10.) and 3-ethoxy-5-(4,4,5,5-tetramethyl -1,3,2-dioxaborolan-2-yl)thiophene-2-carboxylic acid (A.3.3.), title compound is obtained as a white solid. LCMS A: t _R =0.84 min; [M+H] ⁺ =446.12.

Example 165 4-{6-[2-(2-Methoxy-5-methylsulfanylphenyl)ethylamino]pyrimidin-4-yl}-2methylsulfanylbenzoic acid

Following the general procedure H, using 6-chloro-N-(2-methoxy-4-(methylthio)phenethyl)pyrimidine-4amine (A.2.10.) and methyl 2-(methylthio)-4-(4,4,5, 5-Tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (A.3.11.), title compound is obtained as a white solid. LCMS A: t _R =0.78 min; [M+H] ⁺ =442.13.

Compounds of examples 166-274, which are listed in table. 8 below is prepared by applying either General Procedure G or H to pyrimidine halide derivatives A.2.1. - A.2.26. in combination with commercially available boronic acid derivatives or with boronic acid derivatives A.3.1. - A.3.59.

Table 8

Examples 166-274

Note. Compound t _R [min] (method C) MS data, m/z [M+H] ⁺ 166 3-(4-{6-[2-(4-Bromo-2,6-difluorophenyl)- ethylamino]-pyrimidin-4-yl}-2-methoxyphenyl)propionic acid (*1) 0.849 492.2 167 4-{6-[2-(4-Bromo-2,6-difluorophenyl)-ethylamino]pyrimidin-4-yl}-2-butoxy-6-fluorobenzoic acid 1.17 524.2 168 2-{6-[2-(4-Bromo-2,6-difluorophenyl)-ethylamino]pyrimidin-4-yl}-1H-indole-5-carboxylic acid (*1) 0.977 471.9

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169 2-{6-[2-(4-Bromo-2,6-difluorophenyl)-ethylamino]pyrimidin-4-yl}-1H-indole-6-carboxylic acid 1.027 473.4 170 [2-(4-Bromo-2,6-difluorophenyl)-ethyl]-[6-(1Nindol-6-yl)-pyrimidin-4-yl]-amine 0.814 429.1 171 1-(4-{6-[2-(4-Bromo-2,6-difluorophenyl)- ethylamino]-pyrimidin-4-yl}-2-ethoxyphenyl)-cyclopropanecarboxylic acid (*1) 0.935 518.2 172 1-(4-{6-[2-(4-Bromo-2,6-difluorophenyl)- ethylamino]-pyrimidin-4-yl}-2-propylphenyl)cyclopropanecarboxylic acid (*1) 0.98 516.3 173 2-Cyclobutoxy-4-{6-[2-(2-methoxy-5methylsulfanylphenyl)-ethylamino]-pyrimidine- 4-yl}-benzoic acid (*1) 0.987 464.1 174 5-(4-{6-[2-(4-Bromo-2,6-difluorophenyl)- ethylamino]-pyrimidin-4-yl}-2-methoxyphenyl)isoxazol-3-ol [tautomeric form: 5-(4-{6-[2(4-bromo-2,6-difluorophenyl)-ethylamino]- pyrimidin-4-yl}-2-methoxyphenyl)-isoxazol- 3(2Н)-one] 0.985 503.1 175 (4-{6-[2-(4-Bromo-2,6-difluorophenyl)-ethylamino]pyrimidin-4-yl}-2-ethoxy-3-fluorophenyl)acetic acid (*1) 0.945 510.0 176 5-{6-[2-(4-Bromo-2,6-difluorophenyl)-ethylamino]pyrimidin-4-yl}-3-methoxythiophene-2-carboxylic acid (*1) 1.057 470.1 177 3-Ethoxy-5-{6-[2-(2-fluoro-6-methoxyphenyl)ethylamino]-pyrimidin-4-yl}-thiophene-2carboxylic acid 0.997 418.3 178 3-Ethoxy-5-{6-[2-(2-methoxy-6-methylphenyl)ethylamino]pyrimidin-4-yl}-thiophene-2carboxylic acid 1.037 414.3 179 5-{6-[2-(4,5-Difluoro-2-methoxyphenyl)- ethylamino]-pyrimidin-4-yl}-3-ethoxythiophene-2carboxylic acid 1.022 436.2 180 4-{6-[2-(4-Bromo-2,6-difluorophenyl)-ethylamino]pyrimidin-4-yl}-2-ethoxybenzoic acid (*1) 0.982 478.2 181 5-{6-[2-(3,4-Dichloro-2-methylphenyl)-ethylamino]pyrimidin-4-yl}-3-ethoxythiophene-2-carboxylic acid (*1) 1.193 450.1 182 (4-{6-[2-(4-Bromo-2,6-difluorophenyl)-ethylamino]pyrimidin-4-yl}-2-ethoxyphenylamino)-acetic acid 0.829 507 183 4-{6-[2-(4-Difluoromethyl-5-fluoro-2- methoxyphenyl)-ethylamino]-pyrimidin-4-yl}-2ethoxybenzoic acid (*1) 0.908 460.2 184 2-Cyclobutoxy-4-{6-[2-(4-difluoromethyl-5-fluoro2-methoxyphenyl)-ethylamino]-pyrimidin-4-yl}benzoic acid (*1) 1.002 486.1 185 5-{6-[2-(4-Difluoromethyl-5-fluoro-2- methoxyphenyl)-ethylamino]-pyrimidin-4-yl}-3ethoxythiophene-2-carboxylic acid (*1) 1.047 466.2 186 (4-{6-[2-(4-Difluoromethyl-5-fluoro-2- methoxyphenyl)-ethylamino]-pyrimidin-4-yl}-2ethoxyphenyl)-acetic acid (*1) 0.834 474.1 187 4-{6-[2-(4-Difluoromethyl-5-fluoro-2- methoxyphenyl)-ethylamino]-pyrimidin-4-yl}-2-methylsulfanylbenzoic acid (*1) 0.913 462 188 2-Cyclobutoxy-4-{6-[2-(2-methoxy-4,5dimethylphenyl)-ethylamino]-pyrimidin-4-yl}benzoic acid (*1) 1.027 446.2 189 4-{6-[2-(2-Methoxy-4,5-dimethylphenyl)- ethylamino]-pyrimidin-4-yl}-2-propylbenzoic acid (*1) 0.987 418 190 (2-Ethoxy-4-{6-[2-(2-methoxy-4,5-dimethylphenyl)ethylamino]-pyrimidin-4-yl}-phenyl)-acetic acid (*1) 0.859 434.2 191 (4-{6-[2-(2-Methoxy-4,5-dimethylphenyl)ethylamino]-pyrimidin-4-yl}-2- methylsulfanylphenyl)-acetic acid (*1) 0.869 436.3 192 (4-{6-[2-(2-Methoxy-4,5-dimethylphenyl)ethylamino]-pyrimidin-4-yl}-2-propylphenyl)acetic acid (*1) 0.908 432.2 193 (2-Ethoxy-6-fluoro-4-{6-[2-(2-methoxy-4,5- dimethylphenyl)-ethylamino]-pyrimidin-4-yl}phenyl)-acetic acid (*1) 0.972 452.9 194 (4-{6-[2-(2-Methoxy-4,5-dimethylphenyl)- ethylamino]-pyrimidin-4-yl}-2-propoxyphenyl)acetic acid (*1) 0.913 448 195 4-{6-[2-(5-Chloro-2-methoxy-4- trifluoromethylphenyl)-ethylamino]-pyrimidin-4yl}-2-ethoxybenzoic acid (*1) 1.042 494 196 4-{6-[2-(5-Chloro-2-methoxy-4- trifluoromethylphenyl)-ethylamino]-pyrimidin-4yl}-2-methylsulfanylbenzoic acid (*1) 1.047 496 197 4-{6-[2-(5-Chloro-2-methoxy-4- trifluoromethylphenyl)-ethylamino]-pyrimidin-4yl}-2-propylbenzoic acid (*1) 1.091 492.3 198 5-{6-[2-(5-Chloro-2-methoxy-4- trifluoromethylphenyl)-ethylamino]-pyrimidin-4yl}-3-ethoxythiophene-2-carboxylic acid (*1) 1.17 500.1

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199 4-{6-[2-(4-Difluoromethyl-2-methoxy-5- methylphenyl)-ethylamino]-pyrimidin-4-yl}-2ethoxybenzoic acid (*1) 0.923 456 200 4-{6-[2-(2-Methoxy-4,6-dimethylphenyl)ethylamino]-pyrimidin-4-yl}-2methylsulfanylbenzoic acid (*1) 0.947 422.1 201 4-{6-[2-(2-Methoxy-4,6-dimethylphenyl)- ethylamino]-pyrimidin-4-yl}-2-propylbenzoic acid (*1) 0.992 418 202 (2-Ethoxy-4-{6-[2-(2-methoxy-4,6-dimethylphenyl)ethylamino]-pyrimidin-4-yl}-phenyl)-acetic acid (*1) 0.864 434.1 203 3-Ethoxy-5-{6-[2-(2-methoxy-4,6-dimethylphenyl)ethylamino]-pyrimidin-4-yl}-thiophene-2carboxylic acid (*1) 1.101 426 204 (4-{6-[2-(2-Methoxy-4,6-dimethylphenyl)- ethylamino]-pyrimidin-4-yl}-2-propoxyphenyl)acetic acid (*1) 0.918 448.2 205 2-Ethoxy-4-{6-[2-(2-methoxy-4- trifluoromethylphenyl)-ethylamino]-pyrimidin-4yl}-benzoic acid (*1) 0.967 460 206 4-{6-[2-(2-Methoxy-4-trifluoromethylphenyl)ethylamino]-pyrimidin-4-yl}-2methylsulfanylbenzoic acid (*1) 0.972 462.4 207 4-{6-[2-(2-Methoxy-4-trifluoromethylphenyl)ethylamino]-pyrimidin-4-yl}-2-propylbenzoic acid (*1) 1.022 458.1 208 3-Ethoxy-5-{6-[2-(2-methoxy-4- trifluoromethylphenyl)-ethylamino]-pyrimidin-4yl}-thiophene-2-carboxylic acid (*1) 1.106 466.2 209 2-Isobutyl-4-{6-[2-(2-methoxy-4- trifluoromethylphenyl)-ethylamino]-pyrimidin-4yl}-benzoic acid (*1) 1.066 472 210 3-Ethoxy-5-{6-[2-(2-methoxy-4- trifluoromethoxyphenyl)-ethylamino]-pyrimidin4-yl}-thiophene-2-carboxylic acid (*1) 1.131 482.1 211 2-Ethoxy-4-{6-[2-(2-ethoxy-4- trifluoromethylphenyl)-ethylamino]-pyrimidin-4yl}-benzoic acid (*1) 1.042 476.2 212 4-{6-[2-(2-Ethoxy-4-trifluoromethylphenyl)ethylamino]-pyrimidin-4-yl}-2methylsulfanylbenzoic acid (*1) 1.042 475.9 213 4-{6-[2-(2-Ethoxy-4-trifluoromethylphenyl)ethylamino]-pyrimidin-4-yl}-2-propylbenzoic acid (*1) 1.081 472.1 214 (2-Ethoxy-4-{6-[2-(2-ethoxy-4- trifluoromethylphenyl)-ethylamino]-pyrimidin-4yl}-phenyl)-acetic acid (*1) 0.943 490.2 215 3-Ethoxy-5-{6-[2-(2-ethoxy-4- trifluoromethylphenyl)-ethylamino]-pyrimidin-4yl}-thiophene-2-carboxylic acid (*1) 1.18 480 216 4-{6-[2-(4-Bromo-2,6-difluorophenyl)-ethylamino]pyrimidin-4-yl}-2-methylaminobenzamide 0.809 462.1 217 4-{6-[2-(4-Bromo-2,6-difluorophenyl)-ethylamino]pyrimidin-4-yl}-2-ethylaminobenzamide 0.868 476.4 218 4-{6-[2-(2-Difluoromethoxy-4- trifluoromethylphenyl)-ethylamino]-pyrimidin-4yl}-2-methylsulfanylbenzoic acid (*1) 1.002 498.3 219 5-{6-[2-(2-Difluoromethoxy-4- trifluoromethylphenyl)-ethylamino]-pyrimidin-4yl}-3-ethoxythiophene-2-carboxylic acid (*1) 1.126 502.1 220 4-{6-[2-(4-Difluoromethoxy-2-methoxyphenyl)ethylamino]-pyrimidin-4-yl}-2-ethoxybenzoic acid (*1) 0.883 458.3 221 4-{6-[2-(4-Difluoromethoxy-2-methoxyphenyl)ethylamino]-pyrimidin-4-yl}-2methylsulfanylbenzoic acid (*1) 0.888 460.1 222 4-{6-[2-(4-Difluoromethoxy-2-methoxyphenyl)ethylamino]-pyrimidin-4-yl}-2-propylbenzoic acid (*1) 0.937 456.2 223 (4-{6-[2-(4-Difluoromethoxy-2-methoxyphenyl)ethylamino]-pyrimidin-4-yl}-2-ethoxyphenyl)acetic acid (*1) 0.819 472.2 224 5-{6-[2-(4-Difluoromethoxy-2-methoxyphenyl)ethylamino]-pyrimidin-4-yl}-3-ethoxythiophene-2carboxylic acid (*1) 1.022 464.1 225 3-(2-Ethoxy-4-{6-[2-(2-methoxy-4,5- dimethylphenyl)-ethylamino]-pyrimidin-4-yl}phenoxy)-propionic acid (*1) 0.834 464 226 2-Ethoxy-4-{6-[2-(2-fluoro-6-methoxy-4- trifluoromethylphenyl)-ethylamino]-pyrimidin-4ylJ-benzoic acid (*1) 1.007 478 227 3-Ethoxy-5-{6-[2-(2-fluoro-6-methoxy-4trifluoromethylphenyl)-ethylamino]-pyrimidin-4yl}-thiophene-2-carboxylic acid (*1) 1.136 484.1 228 4-{6-[2-(2,6-Difluoro-4-methoxyphenyl)- ethylamino]-pyrimidin-4-yl}-2-ethoxybenzoic acid (*1) 0.873 430.3 229 4-{6-[2-(2,6-Difluoro-4-methoxyphenyl)ethylamino]-pyrimidin-4-yl}-2methylsulfanylbenzoic acid (*1) 0.883 432.3

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230 4-{6-[2-(2-Fluoro-6-methoxy-4- trifluoromethylphenyl)-ethylamino]-pyrimidin-4yl}-2-methylsulfanylbenzoic acid (*1) 1.012 479.9 231 4-{6-[2-(4-Bromo-2,6-difluorophenyl)-ethylamino]pyrimidin-4-yl}-2-methylaminobenzoic acid 0.913 463.3 232 6-{6-[2-(4-Bromo-2,6-difluorophenyl)-ethylamino]pyrimidin-4-yl}-1-methyl-1,3-dihydroindol-2- He 0.839 459 233 3-(4-(6-((2,6-Difluorophenethyl)amino)pyrimidin4-yl)-2-ethoxyphenyl)-[1,2,4]oxadiazol-5(4H)-one [tautomeric form: 3-( 4-(6-((2,6- difluorophenethyl)amino)pyrimidin-4-yl)-2ethoxyphenyl)-[1,2,4]oxadiazol-5-ol] 0.937 440.3 234 3-(4-{6-[2-(4-Bromo-2,6-difluorophenyl)- ethylamino]-pyrimidin-4-yl}-2-ethoxyphenyl)[1,2,4]oxadiazol-5(4H)-one [tautomeric form 3-(4-{6-[2-(4-bromo-2, 6-difluorophenyl)- ethylamino]-pyrimidin-4-yl}-2-ethoxyphenyl)[1,2,4]oxadiazol-5-ol] 1.066 518 235 3-(4-{6-[2-(4-Bromo-2,6-difluorophenyl)ethylamino]-pyrimidin-4-yl}-phenyl)- [1,2,4]oxadiazol-5(4H)-one [tautomeric form: 3-(4-{6-[2-(4-bromo-2,6-difluorophenyl)- ethylamino]-pyrimidin-4-yl}-phenyl)[1,2,4]oxadiazol-5-ol] 0.957 474.2 236 (4-{6-[2-(4-Bromo-2,6-difluorophenyl)-ethylamino]pyrimidin-4-yl}-2-trifluoromethoxyphenyl)acetic acid (*1) 1.081 532 237 4-{6-[2-(4-Bromo-2,6-difluorophenyl)-ethylamino]pyrimidin-4-yl}-2-isobutoxybenzoic acid (*1) 1.131 506.1 238 M-(4-{6-[2-(4-Bromo-2,6-difluorophenyl)ethylamino]-pyrimidin-4-yl}-phenyl)-formamide 0.765 433.2 239 (4-{6-[2-(4-Bromo-2,6-difluorophenyl)-ethylamino]pyrimidin-4-yl}-2-ethoxyphenyl)-oxoacetic acid 0.918 506 240 X-(4-{6-[2-(4-Bromo-2,6-difluorophenyl)ethylamino]pyrimidin-4-yl}-2-ethoxyphenyl)formamide 0.883 477.2 241 (4-{6-[2-(4-Bromo-2,6-difluorophenyl)-ethylamino]pyrimidin-4-yl}-2-ethylphenyl)-acetic acid (*1) 0.873 476.2 242 (4-{6-[2-(4-Bromo-2,6-difluorophenyl)-ethylamino]pyrimidin-4-yl}-2-propylphenyl)-acetic acid (*1) 0.928 489.9 243 3-(4-{6-[2-(4-Bromo-2,6-difluorophenyl)ethylamino]-pyrimidin-4-yl}-phenyl)-4hydroxycyclobut-3-ene-1,2-dione 0.973 486.1 244 (4-{6-[2-(4-Bromo-2,6-difluorophenyl)-ethylamino]pyrimidin-4-yl}-2-isobutylphenyl)-acetic acid (*1) 0.977 504.1 245 4-{6-[2-(4-Bromo-2,6difluorophenyl)-ethylamino]-pyrimidin-4-yl}-2-ethylbenzoic acid methyl ester 1.161 476.3 246 4-{6-[2-(4-Bromo-2,6difluorophenyl)-ethylamino]-pyrimidin-4-yl}-2-methylsulfanylbenzoic acid methyl ester 1.17 494 247 3-(5-{6-[2-(4-Bromo-2,6difluorophenyl)-ethylamino]-pyrimidin-4-yl}-3ethoxythiophen-2-yl)-propionic acid ethyl ester 1.299 540.2 248 (4-{6-[2-(4-Bromo-2,6-difluorophenyl)-ethylamino]pyrimidin-4-yl}-2-propoxyphenyl)acetic acid (*1) 0.942 506.2 249 4-{6-[2-(4-Bromo-2,6-difluorophenyl)-ethylamino]pyrimidin-4-yl}-2-ethylbenzoic acid (*1) 0.972 462.4 250 4-{6-[2-(4-Bromo-2,6-difluorophenyl)-ethylamino]pyrimidin-4-yl}-2,6-dimethylphenol 0.829 434.2 251 4-{6-[2-(4-Bromo-2,6-difluorophenyl)-ethylamino]pyrimidin-4-yl}-2-isopropoxybenzoic acid (*1) 1.056 492.2 252 (4-{6-[2-(4-Bromo-2,6-difluorophenyl)-ethylamino]pyrimidin-4-yl}-2-difluoromethoxyphenyl)acetic acid (*1) 0.972 514 253 (4-{6-[2-(4-Bromo-2,6-difluorophenyl)-ethylamino]pyrimidin-4-yl}-2-chloro-6-ethylphenyl)-acetic acid (*1) 1.042 510.2 254 (4-{6-[2-(4-Bromo-2,6-difluorophenyl)-ethylamino]pyrimidin-4-yl}-2-methylphenyl)-acetic acid (*1) 0.824 462.1 255 (4-{6-[2-(4-Bromo-2,6-difluorophenyl)-ethylamino]pyrimidin-4-yl}-2,6-dimethylphenyl)-acetic acid (*1) 0.844 476.4 256 (4-{6-[2-(4-Bromo-2,6-difluorophenyl)-ethylamino]pyrimidin-4-yl}-2-fluoro-6-methylphenyl)acetic acid (*1) 0.938 480.4 257 (4-{6-[2-(4-Bromo-2,6-difluorophenyl)-ethylamino]pyrimidin-4-yl}-2-ethyl-6-methylphenyl)acetic acid (*1) 0.893 490.2 258 [2-(4-Bromo-2,6-difluorophenyl)-ethyl]-[6-(1Nindol-5-yl)-pyrimidin-4-yl]-amine 0.809 429.2

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259 4-{6-[2-(4-Bromo-2,6-difluorophenyl)-ethylamino]pyrimidin-4-yl}-2-cyclopropoxybenzoic acid (*1) 0.992 490.4 260 (4-{6-[2-(4-Bromo-2,6-difluorophenyl)-ethylamino]pyrimidin-4-yl}-2-cyclopropoxyphenyl)acetic acid (*1) 0.903 504.1 261 (5-{6-[2-(4-Bromo-2,6-difluorophenyl)-ethylamino]pyrimidin-4-yl}-3-ethylthiophen-2-yl)-acetic acid (*1) 1.022 482.2 262 7-{6-[2-(4-Bromo-2,6-difluorophenyl)-ethylamino]pyrimidin-4-yl}-1-methyl-3,4-dihydro-1Hquinazolin-2-one 0.809 474 263 2-{6-[2-(4-Bromo-2,6-difluorophenyl)-ethylamino]pyrimidin-4-yl}-1H-indole-7-carboxylic acid (*1) 1.141 473.2 264 (4-{6-[2-(4-Bromo-2,6-difluorophenyl)-ethylamino]pyrimidin-4-yl}-2-chloro-6-methylphenyl)acetic acid (*1) 0.992 496.1 265 (4-{6-[2-(4-Bromo-2,6-difluorophenyl)-ethylamino]pyrimidin-4-yl}-phenyl)-urea 0.71 448.2 266 6-{6-[2-(4-Bromo-2,6-difluorophenyl)-ethylamino]pyrimidin-4-yl}-3H-benzooxazol-2-one 0.824 447.2 267 [2-(4-Bromo-2,6-difluorophenyl)-ethyl]-[6-(1Nindazol-5-yl)-pyrimidin-4-yl]-amine 0.77 430.2 268 5-{6-[2-(4-Bromo-2,6-difluorophenyl)-ethylamino]pyrimidin-4-yl}-3-ethoxy-1H-pyrrole-2carboxylic acid (*1) 0.933 467.3 269 4-{6-[2-(4-Bromo-2,6-difluorophenyl)-ethylamino]pyrimidin-4-yl}-1-ethyl-1H-pyrrole-2carboxylic acid (*1) 0.775 451.2 270 4-{6-[2-(4-Bromo-2,6-difluorophenyl)-ethylamino]pyrimidin-4-yl}-1-propyl-1H-pyrrole-2carboxylic acid (*1) 0.819 465.2 271 5-{6-[2-(4-Bromo-2,6-difluorophenyl)-ethylamino]pyrimidin-4-yl}-3-cyclopropyl-1H-pyrrole-2carboxylic acid (*1) 0.987 463 272 6-{6-[2-(4-Bromo-2,6-difluorophenyl)-ethylamino]pyrimidin-4-yl}-benzofuran-3-carboxylic acid (*1) 0.933 474.2 273 5-(4-{6-[2-(4-Bromo-2,6-difluorophenyl)- ethylamino]-pyrimidin-4-yl}-2-ethoxyphenyl)isoxazol-3-ol [tautomeric form: 5-(4-(6-((4bromo-2,6-difluorophenethyl)amino)pyrimidin-4yl)-2- ethoxyphenyl)isoxazol-3(2H)-one] 1.051 517.4 274 4-{6-[2-(4-Bromo-2,6-difluorophenyl)-ethylamino]pyrimidin-4-yl}-2-ethoxy-3-fluorobenzoic acid (*1) 1.032 496.1

Example 275 3-(5-{6-[2-(5-Bromo-2-methylsulfanylphenyl)ethylamino]pyrimidin-4-yl}-3-ethoxythiophen-2-yl)-[1,2,4]oxadiazol- 5(4H)-one [tautomeric form: 3-(5-{6-[2-(5-bromo-2-methylsulfanylphenyl)ethylamino]pyrimidin-4-yl}-3-ethoxythiophen-2-yl)-[1 ,2,4]oxadiazol-5-ol].

Following general procedure I using 3-(3-ethoxy-5-(6-hydroxypyrimidin-4-yl)thiophen-2yl)-[1,2,4]oxadiazol-5-ol (Example 83-a) and hydrochloride 2 -(5-bromo-2-(methylthio)phenyl)ethane-1-amine, the title compound is obtained as a pale yellow powder. LCMS D: tR=1.25 min; [M+H]+=534.1.

Example 276 4-{6-[2-(4-Bromo-2,6-difluorophenyl)ethylamino]pyrimidin-4-yl}-N-(2-hydroxyethyl)-2methylaminobenzamide m.p.

4-{6-[2-(4-Bromo-2,6-difluorophenyl)ethylamino]pyrimidin-4-yl}-2-methylaminobenzoic acid (Example 231) (51 mg, 0.11 mmol) and ethanolamine (8 µl, 0.132 mmol) was dissolved in DMF (2 ml). N-ethyldiisopropylamine (57 µl, 0.33 mmol) is added, after which HATU (52 mg, 0.138 mmol) and PM are stirred at RT for 1 h. It is then diluted with water and MeCN, and purified with prep. HPLC afforded the title compound as a light yellow solid (52 mg, 93%). LCMS D: tR=0.789 min; [M+H]+=506.0.

Example 277 4-{6-[2-(4-Bromo-2,6-difluorophenyl)ethylamino]pyrimidin-4-yl}-N-(2-methoxyethyl)-2methylaminobenzamide.

Following the procedure described for Example 276 using 2-methoxyethylamine, the title compound was obtained as a light yellow powder. LCMS D: tR=0.878 min; [M+H] ⁺ =520.3.

Example 278 3-(4-{6-[2-(4-Bromo-2,6-difluorophenyl)ethylamino]pyrimidin-4-yl}-1-ethyl-1H-pyrrol-2yl)-[1,2, 4]oxadiazol-5(4H)-one [tautomeric form: 3-(4-{6-[2-(4-bromo-2,6-difluorophenyl)ethylamino]pyrimidin-4-yl}-1-ethyl-1 N-pyrrol-2-yl)-[1,2,4]oxadiazol-5-ol].

Following the procedure described for example 83-b using 4-(6-((4-bromo-2,6difluorophenethyl)amino)pyrimidin-4-yl)-1-ethyl-N'-hydroxy-1H-pyrrole-2 -carboximidamide, the title compound is obtained as a white powder. LCMS D: tR=0.834 min; [M+H] ⁺ =491.2.

a) 4-(6-((4-Bromo-2,6-difluorophenethyl)amino)pyrimidin-4-yl)-1-ethyl-N'-hydroxy-1H-pyrrole-2-carboximidamide.

Following the procedure described for Example 83-c, using 4-(6-((4-bromo-2,6difluorophenethyl)amino)pyrimidin-4-yl)-1-ethyl-1H-pyrrole-2-carbonitrile as indicated in the title the compound is obtained as a gray solid. LCMS B: tR=0.68 min; [M+H] ⁺ =467.42.

b) 4-(6-((4-Bromo-2,6-difluorophenethyl)amino)pyrimidin-4-yl)-1-ethyl-1H-pyrrole-2-carbonitrile.

Following the general procedure G, using N-(4-bromo-2,6-difluorophenethyl)-6-iodopyrimidine-4-amine (A.2.6.) and 1-ethyl-4-(4,4,5,5-tetramethyl -1,3,2-dioxaborolan-2-yl)-1H-pyrrole-2-carbonitrile specified in

- 100 043145 heading the compound is obtained in the form of an ocher-colored powder. LC-MS B: t _R =0.84 min; [M+H]+=432.37.

c) 1-Ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrole-2-carbonitrile.

The title compound was prepared according to the procedure described for A.3.6., starting from 4-bromo-1-ethyl-1H-pyrrole-2-carbonitrile. LC-MS B: t _R =0.97 min; without ionization; 1H NMR (400 MHz, d6-DMSO) δ: 7.50-7.58 (m, 1H), 6.99-7.14 (m, 1H), 3.99-4.19 (m, 2H), 1.33-1.43 (m, 3H), 1.21- 1.29(m, 12H).

Example 279 5-{6-[2-(4-Bromo-2,6-difluorophenyl)ethylamino]pyrimidin-4-yl}-3-ethoxythiophene2-carboxylic acid amide.

To a solution of 5-(6-((4-bromo-2,6-difluorophenethyl)amino)pyrimidin-4-yl)-3-ethoxythiophene-2-carboxylic acid (example 153, 64 mg, 0.128 mmol) in DMF (3 ml) HATU (72.8 mg, 0.191 mmol) is added at RT. PM is stirred for 30 min. Then add 25% ammonia solution (0.197 ml, 1.28 mmol) and PM stirred at RT overnight. Then it is directly cleaned with prep. LC-MS gave the title compound as a white solid (55 mg, 89%). LC-MS C: t _R =1.072 min; [M+H]+=483.4.

Example 280 N-(4-{6-[2-(4-Bromo-2,6-difluorophenyl)ethylamino]pyrimidin-4-yl}-2ethoxybenzoyl)methanesulfonamide m.p.

A mixture of 4-{6-[2-(4-bromo-2,6-difluorophenyl)ethylamino]pyrimidin-4-yl}-2-ethoxybenzoic acid (example 180) (36 mg, 0.0727 mmol), methanesulfonamide (9.27 mg, 0.0945 mmol), EDC (25.1 mg, 0.131 mmol) and DMAP (26.6 mg, 0.218 mmol) were dissolved in DCM (0.7 ml) and stirred at RT for 2 days. PM is concentrated and purified with prep. LC-MS gave the title compound as a white solid (17 mg, 42%). LC-MS C: t _R =1.081 min; [M+H] ⁺ =555.1.

Example 281 5-{6-[2-(4-Bromo-2,6-difluorophenyl)ethylamino]pyrimidin-4-yl}-3-ethylthiophene-2carboxylic acid amide.

Following the procedure described for example 83-e using 5-{6-[2-(4-bromo-2,6difluorophenyl)ethylamino]pyrimidin-4-yl}-3-ethylthiophene-2-carboxylic acid (example 29) and 25% ammonium hydroxide solution, the title compound is obtained as a white solid. LC-MS C: t _R =1.056 min; [M+H]+=467.2.

Example 282 3-(4-{6-[2-(4-Bromo-2,6-difluorophenyl)ethylamino]pyrimidin-4-yl}-2-ethoxybenzyl)[1,2,4]oxadiazol-5(4H )-one [tautomeric form: 3-(4-{6-[2-(4-bromo-2,6-difluorophenyl)ethylamino]pyrimidin-4-yl}-2-ethoxybenzyl)-[1,2,4] oxadiazol-5-ol].

Following the procedure described for example 83-b using (E/Z)-2-(4-(6-((4-bromo-2,6difluorophenethyl)amino)pyrimidin-4-yl)-2-ethoxyphenyl)-N '-Hydroxyacetimidamide, the title compound is obtained as a white solid. LC-MS C: t _R =0.928 min; [M+H] ⁺ =532.1.

a) (E/Z)-2-(4-(6-((4-Bromo-2,6-difluorophenethyl)amino)pyrimidin-4-yl)-2-ethoxyphenyl)-N'-hydroxyacetimidamide.

Following the procedure described for example 83-c, using 2-(4-(6-((4-bromo-2,6difluorophenethyl)amino)pyrimidin-4-yl)-2-ethoxyphenyl)acetonitrile, the title compound is obtained in form of a white solid. LC-MS B: t _R =0.66 min; [M+H]+=506.10.

b) 2-(4-(6-((4-Bromo-2,6-difluorophenethyl)amino)pyrimidin-4-yl)-2-ethoxyphenyl)acetonitrile.

Following the general procedure G using N-(4-bromo-2,6-difluorophenethyl)-6-iodopyrimidine-4-amine (A.2.6.) and 2-(2-ethoxy-4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetonitrile, the title compound is obtained as a beige powder. LCMS B: t _R =0.88 min; [M+H]+=473.33.

c) 2-(2-Ethoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetonitrile.

The title compound is prepared according to the procedure described for A.3.6., starting from 2-(4-bromo-2-ethoxyphenyl)acetonitrile. LC-MS B: t _R =1.05 min; [M+H]+=288.4.

d) 2-(4-Bromo-2-ethoxyphenyl)acetonitrile.

The title compound was prepared according to the procedure described for Example 83-d starting from 2-(4-bromo-2-ethoxyphenyl)acetamide. LC-MS B: t _R =0.97 min; without ionization. 1H NMR (400 MHz, d6-DMSO) δ: 7.22-7.42 (m, 2H), 6.96-7.21 (m, 1H), 4.13 (q, J=6.9 Hz, 2H), 3.78-3.86 (m, 2H) , 1.36 (m, 3H).

e) 2-(4-Bromo-2-ethoxyphenyl)acetamide.

The title compound was prepared according to the procedure described for Example 83-e starting from 2-(4-bromo-2-ethoxyphenyl)acetic acid. LCMS B: t _R =0.76 min; [M+H]+=257.85.

Example 283 3-(4-{6-[2-(4-Bromo-2,6-difluorophenyl)ethylamino]pyrimidin-4-yl}-2-ethoxybenzyl)[1,2,4]oxadiazol-5(4H )-thione [tautomeric form: 3-(4-{6-[2-(4-bromo-2,6-difluorophenyl)ethylamino]pyrimidin-4-yl}-2-ethoxybenzyl)-[1,2,4] oxadiazole-5-thiol].

Following the procedure described for example 83-b using (E/Z)-2-(4-(6-((4-bromo-2,6difluorophenethyl)amino)pyrimidin-4-yl)-2-ethoxyphenyl)-N '-hydroxyacetimidamide (Example 282-a) and 1,1'-thiocarbonyldiimidazole, the title compound is obtained as a white solid. LC-MS C: t _R =1.007 min; [M+H]+=548.0.

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Example 284 3-(4-{6-[2-(4-Bromo-2,6-difluorophenyl)ethylamino]pyrimidin-4-yl}-2-propylbenzyl)[1,2,4]oxadiazol-5(4H )-one [tautomeric form: 3-(4-{6-[2-(4-bromo-2,6-difluorophenyl)ethylamino]pyrimidin-4-yl}-2-propylbenzyl)-[1,2,4] oxadiazol-5-ol].

Following the procedure described for Example 83-b using (E/Z)-2-(4-(6-((4-6pom-2,6difluorophenethyl)amino)pyrimidin-4-yl)-2-propylphenyl)-N '-Hydroxyacetimidamide, the title compound is obtained as a white solid. LC-MS C: t _R =0.963 min; [M+H]+=530.2.

a) (E/Z)-2-(4-(6-((4-Bromo-2,6-difluorophenethyl)amino)pyrimidin-4-yl)-2-propylphenyl)-N'-hydroxyacetimidamide.

Following the procedure described for example 83-c, using 2-(4-(6-((4-bromo-2,6difluorophenethyl)amino)pyrimidin-4-yl)-2-propylphenyl)acetonitrile, the title compound was obtained in form of a white solid. LC-MS B: t _R =0.70 min; [M+H]+=504.16.

b) 2-(4-(6-((4-Bromo-2,6-difluorophenethyl)amino)pyrimidin-4-yl)-2-propylphenyl)acetonitrile.

Following the general procedure G using Na(4-bromo-2,6-difluorophenethyl)-6-iodopyrimidine-4amine (A.2.6.) and 2-(2-propyl-4-(4,4,5,5-tetramethyl -1,3,2-dioxaborolan-2-yl)phenyl)acetonitrile, the title compound is obtained as a white powder. LC-MS B: t _R =0.91 min; [M+H] ⁺ =471.14.

c) 2-(2-Propyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetonitrile.

The title compound was prepared according to the procedure described for A.3.6., starting from 2-(4-bromo-2-propylphenyl)acetonitrile. LC-MS B: t _R =1.09 min; [M+H]+=327.25.

Example 285 3-(4-{6-[2-(4-Bromo-2,6-difluorophenyl)ethylamino]pyrimidin-4-yl}-2-propylbenzyl)[1,2,4]oxadiazol-5(4H )-thione [tautomeric form: 3-(4-{6-[2-(4-bromo-2,6-difluorophenyl)ethylamino]pyrimidin-4-yl}-2-propylbenzyl)-[1,2,4] oxadiazole-5-thiol].

Following the procedure described for Example 83-b using (E/Z)-2-(4-(6-((4-6pom-2,6difluorophenethyl)amino)pyrimidin-4-yl)-2-propylphenyl)-No. -hydroxyacetimidamide (Example 284-a) and 1,1'-thiocarbonyldiimidazole, the title compound was obtained as a white solid. LC-MS C: t _R =1.037 min; [M+H]+=546.4.

Example 286 2-(4-{6-[2-(4-Bromo-2,6-difluorophenyl)ethylamino]pyrimidin-4-yl}-2-ethoxyphenyl)acetamide m.p.

A solution of ethyl 2-(4-(6-((4-bromo-2,6-difluorophenethyl)amino)pyrimidin-4-yl)-2-ethoxyphenyl)acetate (91 mg, 0.175 mmol) in NH ₃ (7M in MeOH , 3 ml) stirred in a sealed tube for 3 d at 85°C. PM is then concentrated under reduced pressure and purified with FQ (Hept/EtOAc 1:0 to 0:1) to give the expected product as a white solid (71 mg, 82%). LC-MS C: t _R =0.804 min; [M+H]+=491.4.

a) Ethyl 2-(4-(6-((4-bromo-2,6-difluorophenethyl)amino)pyrimidin-4-yl)-2-ethoxyphenyl)acetate.

Following the general procedure G using N-(4-bromo-2,6-difluorophenethyl)-6-iodopyrimidine-4amine (A.2.6.) and ethyl 2-(2-ethoxy-4-(4,4,5,5 -tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetate (A.3.39.1.), the title compound is obtained as a white powder. LC-MS B: t _R =0.92 min; [M+H]+=520.0.

Example 287 2-(5-{6-[2-(4-Bromophenyl)ethylamino]pyrimidin-4-yl}-3-ethoxythiophen-2-yl)acetamide

Following the procedure described for Example 276 using (5-{6-[2-(4-bromophenyl)ethylamino]pyrimidin-4-yl}-3-ethoxythiophen-2-yl)acetic acid (Example 17) and title ammonia the compound is obtained as a white powder. LC-MS C: t _R =0.903 min; [M+H] ⁺ =461.3.

Example 288 [2-(4-Bromophenyl)ethyl]-{6-[5-(1H-tetrazol-5-ylmethyl)thiophen-2-yl]pyrimidin-4yl}amine

Trimethylsilyl azide ( 0.0247 ml, 0.188 mmol) and dibutyltin oxide (3.12 mg, 0.0125 mmol). PM is stirred at 110° C. overnight in a sealed tube. It is then cooled to RT, diluted with EtOAc and washed twice with 1M HCl and once with brine. The organic layer is dried over MgSO ₄ , filtered and concentrated. The residue is purified with prep. LC-MS gave the expected product as a white solid (22 mg, 39%). LC-MS C: t _R =0.868 min; [M+H]+=442.2.

a) 2-(5-(6-((4-Bromophenethyl)amino)pyrimidin-4-yl)thiophen-2-yl)acetonitrile.

N-(4-bromophenethyl)-6-iodopyrimidin-4-amine mixture (A.2.2., 438 mg, 1.08 mmol), 2-(5-(4,4,5,5tetramethyl-1,3,2-dioxaborolane -2-yl)thiophen-2-yl)acetonitrile (297 mg, 1.19 mmol), [1,1'bis-(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (88.6 mg, 0.108 mmol), and trisubstituted potassium phosphate (749 mg, 3.25 mmol) in water (0.117 ml, 6.51 mmol) and DMF (11.7 ml) are degassed for 15 min under nitrogen flow, then stirred at RT overnight. [1,1'-Bis-(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (88.6 mg, 0.108 mmol) was added to PM and it was again degassed and stirred at RT for 4 h. PM was then diluted with EtOAc and washed with saline. The organic phase is dried over MgSO ₄ , filtered and concentrated. The residue was purified with PC (Hept to Hept/EtOAc 1:1) to give the expected product as a beige solid (192 mg, 44%). LC-MS B: t _R =0.82 min; [M+H]+=399.04.

- 102 043145

b) 2-(5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)thiophen-2-yl)acetonitrile.

A mixture of 2-thiopheneacetonitrile (199 mg, 1.57 mmol), bis-(pinacolato)diboron (244 mg, 0.941 mmol), (1,5-cyclooctαdiene)(methoxy)iridium(I) dimer (5.5 mg, 0.0083 mmol) and 4 ,4'-di-tert-butyl-2,2'-dipyridyl (5.5 mg, 0.0205 mmol) in THF (7.5 ml) was degassed with nitrogen flow for 15 min and then stirred at 80° C. overnight. It is then cooled to RT, concentrated under reduced pressure and the residue is purified with PC (Hept to Hept/EtOAc, 9:1) to give the expected product as a colorless oil which crystallizes on standing (300 mg, 77%). LC-MS B: t _R =0.94 min; without ionization. 1H NMR (500 MHz, d6-DMSO) δ: 7.45 (d, J=3.5 Hz, 1H), 7.17 (d, J=3.5 Hz, 1H), 4.36 (d, J=0.7 Hz, 2H), 1.29 ( s, 12H).

Example 289 3-(5-{6-[2-(4-Bromo-2,6-difluorophenyl)ethylamino]pyrimidin-4-yl}-pyridin-2-yl)[1,2,4]oxadiazol-5 (4H)-one [tautomeric form: 3-(5-{6-[2-(4-bromo-2,6-difluorophenyl)ethylamino]pyrimidin-4-yl}-pyridin-2-yl)-[1, 2,4]oxadiazol-5-ol].

Following the procedure described for Example 83-b using (E/Z)-5-(6-((4-6pom-2,6difluorophenethyl)amino)pyrimidin-4-yl)-K'-hydroxypicolinimidamide, the title compound obtained as a white solid. LC-MS C: t _R =1.037 min; [M+H]+=475.3.

a) (E/Z)-5-(6-((4-Bromo-2,6-difluorophenethyl)amino)pyrimidin-4-yl)-N'-hydroxypicolinimidamide.

Following the procedure described for example 83-c, using 5-(6-((4-bromo-2,6-difluorophenethyl)amino)pyrimidin-4-yl)picolinonitrile, the title compound was obtained as a beige solid. LC-MS B: t _R =0.70 min; [M+H]+=450.98.

5-(6-((4-Bromo-2,6-difluorophenethyl)amino)pyrimidin-4-yl)picolinonitrile.

Following the procedure described for the synthesis of Example 288-a, using N-(4-bromo-2,6-difluorophenethyl)6-iodopyrimidin-4-amine (A.2.6.) and 2-cyano-5-pyridinylboronic acid specified in The title compound is obtained as a brown solid. LC-MS B: t _R =0.90 min; [M+H]+=417.85.

Example 290 3-(4-{6-[2-(4-Bromo-2,6-difluorophenyl)ethylamino]pyrimidin-4-yl}-2-ethoxyphenyl)[1,2,4]oxadiazol-5(4H )-thione [tautomeric form: 3-(4-{6-[2-(4-bromo-2,6-difluorophenyl)ethylamino]pyrimidin-4-yl}-2-ethoxyphenyl)-[1,2,4] oxadiazole-5-thiol].

Following the procedure described for Example 83-b using (E/Z)-4-(6-((4-6pom-2,6difluorophenethyl)amino)pyrimidin-4-yl)-2-ethoxy-K'-hydroxybenzimidamide and 1,1'-thiocarbonyldiimidazole, the title compound is obtained as a pale yellow solid. LCMS C: t _R =1.145 min; [M+H]+=534.0.

a) (E/Z)-4-(6-((4-Bromo-2,6-difluorophenethyl)amino)pyrimidin-4-yl)-2-ethoxy-N'-hydroxybenzimidamide.

Following the procedure described for Example 83-c, using 4-(6-((4-bromo-2,6difluorophenethyl)amino)pyrimidin-4-yl)-2-ethoxybenzonitrile, the title compound was obtained as a yellow solid. LC-MS B: t _R =0.67 min; [M+H]+=491.83.

b) 4-(6-((4-Bromo-2,6-difluorophenethyl)amino)pyrimidin-4-yl)-2-ethoxybenzonitrile.

Following the general procedure G using N-(4-bromo-2,6-difluorophenethyl)-6-iodopyrimidine-4-amine (A.2.6.) and 4-cyano-3-ethoxyphenylboronic acid, the title compound is obtained as a white powder . LC-MS B: t _R =0.93 min; [M+H]+=458.83.

Example 291 3-(4-{6-[2-(4-Bromo-2,6-difluorophenyl)ethylamino]pyrimidin-4-yl}-3-methoxyphenyl)[1,2,4]oxadiazol-5(4H )-one [tautomeric form: 3-(4-{6-[2-(4-bromo-2,6-difluorophenyl)ethylamino]pyrimidin-4-yl}-3-methoxyphenyl)-[1,2,4] oxadiazol-5-ol].

Following the procedure described for Example 83-b, using 4-(6-((4-bromo-2,6difluorophenethyl)amino)pyrimidin-4-yl)-N-hydroxy-3-methoxybenzimidamide, the title compound was obtained as white solid. LC-MS C: t _R =0.834 min; [M+H]+=504.2.

a) 4-(6-((4-Bromo-2,6-difluorophenethyl)amino)pyrimidin-4-yl)-N-hydroxy-3-methoxybenzimidamide.

Following the procedure described for example 83-c, using 4-(6-((4-bromo-2,6difluorophenethyl)amino)pyrimidin-4-yl)-3-methoxybenzonitrile, the title compound was obtained as a yellow solid. LC-MS B: t _R =0.66 min; [M+H]+=478.09.

b) 4-(6-((4-Bromo-2,6-difluorophenethyl)amino)pyrimidin-4-yl)-3-methoxybenzonitrile.

Following the general procedure G, using N-(4-bromo-2,6-difluorophenethyl)-6-iodopyrimidine-4-amine (A.2.6.) and 3-methoxy-4-(4,4,5,5-tetramethyl -1,3,2-dioxaborolan-2-yl)benzonitrile, the title compound is obtained as a white solid. LC-MS B: t _R =0.84 min; [M+H]+=447.3.

c) 3-Methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile.

Following the procedure described for the synthesis of A.3.6., using 4-bromo-3-methoxybenzonitrile, the title compound was obtained as a dark purple solid. LC-MS B: t _R =0.97 min; without ionization.

Example 292 4-{6-[2-(4-Bromo-2,6-difluorophenyl)ethylamino]pyrimidin-4-yl}-3-methoxybenzamide

The title compound was isolated as a by-product in the synthesis of 4-(6-((4bromo-2,6-difluorophenethyl)amino)pyrimidin-4-yl)-N-hydroxy-3-methoxybenzimidamide (Example 291-a) as white powder. LC-MS C: t _R =0.715 min; [M+H]+=463.2.

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Example 293 5-{6-[2-(4-Bromo-2,6-difluorophenyl)ethylamino]pyrimidin-4-yl}-4-chloro-3ethoxythiophene-2-carboxylic acid amide.

Following the procedure described for the synthesis of Example 279 using 5-{6-[2-(4-bromo-2,6difluorophenyl)ethylamino]pyrimidin-4-yl}-4-chloro-3-ethoxythiophene-2-carboxylic acid (example 27), the title compound was obtained as a white solid. LC-MS C: t _R =1.215 min; [M+H]+=517.1.

Example 294 1-(5-{6-[2-(4-Bromo-2,6-difluorophenyl)ethylamino]pyrimidin-4-yl}-3-ethoxythiophen-2yl)-1,4-dihydrotetrazol-5-one [tautomeric form: 1-(5-(6-((4-bromo-2,6-difluorophenethyl)amino)pyrimidin-4-yl)-3-ethoxythiophen-2-yl)-1H-tetrazol-5-ol] (*1).

N-(4-Bromo-2,6-difluorophenethyl)-6-(4-ethoxy-5-isocyanatothiophen-2-yl)pyrimidin-4-amine (78 mg, 0.162 mmol) is suspended in dioxane (2 ml) then added azidotrimethylsilane (0.906 ml, 6.48 mmol), and the mixture is heated at 90°C for 4 h. PM is concentrated and purified with prep. LCMS to give the title compound as a yellow solid (5 mg, 6%). LCMS C: t _R =1.141 min; [M+H]+=524.0.

a) N-(4-Bromo-2,6-difluorophenethyl)-6-(4-ethoxy-5-isocyanatothiophen-2-yl)pyrimidin-4-amine.

To a solution of 5-{6-[2-(4-bromo-2,6-difluorophenyl)ethylamino]pyrimidin-4-yl}-3-ethoxythiophene-2carboxylic acid (example 153, 130 mg, 0.268 mmol) in THF (10 ml) add TEA (0.1 ml, 0.718 mmol) and diphenylphosphoryl azide (0.07 ml, 0.325 mmol). PM is heated in a vessel under reflux at 70°C for 2 h, cooled to RT and concentrated to dryness. The residue was purified with PC (Hept:EtOAc 1:0 to 1:1) to give the expected isocyanate as a white solid (78 mg, 60%). LC-MS E: t _R =1.13 min; without ionization.

Example 295 5(4H)-thione [tautomeric form: 3-(5-{6-[2-(4-bromo-2,6-difluorophenyl)ethylamino]pyrimidin-4-yl}-3-ethoxythiophen-2-yl)- [1,2,4]oxadiazole-5-thiol].

Following the procedure described for Example 83-b using (E/Z)-5-(6-((4-6pom-2,6difluorophenethyl)amino)pyrimidin-4-yl)-3-ethoxy-K'-hydroxythiophene- 2-carboximidamide and 1,1'thiocarbonyldiimidazole, the title compound, were obtained as a brown solid. LC-MS C: t _R =1.296 min; [M+H]+=540.2.

a) (E/Z)-5-(6-((4-Bromo-2,6-difluorophenethyl)amino)pyrimidin-4-yl)-3-ethoxy-N'-hydroxythiophene-2carboximidamide.

Following the procedure described for the synthesis of example 83-c using 5-(6-((4-bromo-2,6difluorophenethyl)amino)pyrimidin-4-yl)-3-ethoxythiophene-2-carbonitrile, the title compound is obtained in form of a yellow solid. LC-MS B: t _R =0.81 min; [M+H]+=497.87.

b) 5-(6-((4-Bromo-2,6-difluorophenethyl)amino)pyrimidin-4-yl)-3-ethoxythiophene-2-carbonitrile.

Following the procedure described for the synthesis of Example 83-d using 5-{6-[2-(4-Bromo-2,6difluorophenyl)ethylamino]pyrimidin-4-yl}-3-ethoxythiophene-2-carboxylic acid amide (Example 279 ), the title compound was obtained as a light yellow solid. LC-MS B: t _R =1.14 min; [M+H]+=467.19.

Example 296 3-(4-{6-[2-(4-Bromo-2,6-difluorophenyl)ethylamino]pyrimidin-4-yl}-2-methylaminophenyl)-[1,2,4]oxadiazol-5( 4H)-one [tautomeric form: 3-(4-{6-[2-(4-bromo-2,6difluorophenyl)ethylamino]pyrimidin-4-yl}-2-methylaminophenyl)-[1,2,4]oxadiazole -5-ol].

Following the procedure described for Example 83-b using (E/Z)-4-(6-((4-6pom-2,6difluorophenethyl)amino)pyrimidin-4-yl)-K'-hydroxy-2-(methylamino )benzimidamide, the title compound is obtained as a yellow solid. LC-MS C: t _R =0.963 min; [M+H]+=502.9.

a) (E/Z)-4-(6-((4-Bromo-2,6-difluorophenethyl)amino)pyrimidin-4-yl)-N'-hydroxy-2-(methylamino)benzimidamide.

Following the procedure described for the synthesis of Example 83-c using 4-(6-((4-bromo-2,6difluorophenethyl)amino)pyrimidin-4-yl)-2-(methylamino)benzonitrile, the title compound is obtained as yellow solid. LC-MS B: t _R =0.67 min; [M+H]+=477.25.

b) 4-(6-((4-Bromo-2,6-difluorophenethyl)amino)pyrimidin-4-yl)-2-(methylamino)benzonitrile.

Following the procedure described for the synthesis of Example 83-d using 4-{6-[2-(4-bromo-2,6difluorophenyl)ethylamino]pyrimidin-4-yl}-2-methylaminobenzamide (Example 216), the title compound obtained as a light yellow solid. LCMS B: t _R =0.86 min; [M+H]+=444.24.

Example 297 4-{6-[2-(4-Bromo-2,6-difluorophenyl)ethylamino]pyrimidin-4-yl}-2-ethoxybenzamide

To a solution of 4-{6-[2-(4-bromo-2,6-difluorophenyl)ethylamino]pyrimidin-4-yl}-2-ethoxybenzoic acid (example 180, 0.08 mmol), ammonium chloride (5.7 mg, 0.096 mmol ) and DIPEA (0.0438 ml, 0.256 mmol) in DMF (0.6 ml), a solution of HATU (31.9 mg, 0.084 mmol) in DMF (0.2 ml) is added. PM is stirred for 3 d at RT, then purified directly with prep. LC-MS gave the title compound as a white solid (20.3 mg, 53%). LC-MS C: t _R =0.91 min; [M+H]+=477.4.

Following the procedure described for Example 297, using 4-{6-[2-(4-bromo-2,6difluorophenyl)ethylamino]pyrimidin-4-yl}-2-ethoxybenzoic acid (Example 180) and the corresponding commercially available amines, synthesize the following examples.

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Note. Compound t _R [min] (LC-MS C) MS data, m/z [M+H] ⁺ 298 4-{6-[2-(4-Bromo-2,6-difluorophenyl)-ethylamino]pyrimidin-4-yl}-2-ethoxy-N-methylbenzamide 0.955 491.3 299 4-{6-[2-(4-Bromo-2,6-difluorophenyl)-ethylamino]pyrimidin-4-yl}-2-ethoxy-N-ethylbenzamide 1.031 505.2 300 4-{6-[2-(4-Bromo-2,6-difluorophenyl)-ethylamino]pyrimidin-4-yl}-2-ethoxy-K-(2- hydroxyethyl)-benzamide 0.869 521.4 301 4-{6-[2-(4-Bromo-2,6-difluorophenyl)-ethylamino]pyrimidin-4-yl}-2-ethoxy-N-(2-methoxyethyl)benzamide 1.011 535 302 4-{6-[2-(4-Bromo-2,6-difluorophenyl)-ethylamino]pyrimidin-4-yl}-2-ethoxy-M-(2-hydroxy-2methylpropyl)-benzamide 0.955 549.1

Following the procedure described for Example 297 using 4-{6-[2-(4-bromo-2,6-difluorophenyl)ethylamino]pyrimidin-4-yl}-2-propoxybenzoic acid (Example 36) and the corresponding commercially available amines , synthesize the following examples.

Note. Compound t _R [min] (LC-MS C) MS data, m/z [M+H] ⁺ 303 4-{6-[2-(4-Bromo-2,6-difluorophenyl)-ethylamino]pyrimidin-4-yl}-2-propylbenzamide 0.859 475.3 304 4-{6-[2-(4-Bromo-2,6-difluorophenyl)-ethylamino]pyrimidin-4-yl}-M-methyl-2-propylbenzamide 0.9 489.3 305 4-{6-[2-(4-Bromo-2,6-difluorophenyl)-ethylamino]pyrimidin-4-yl}-M-ethyl-2-propylbenzamide 0.96 503.3 306 4-{6-[2-(4-Bromo-2,6-difluorophenyl)-ethylamino]pyrimidin-4-yl}-M-(2-hydroxyethyl)-2propylbenzamide 0.834 519.2 307 4-{6-[2-(4-Bromo-2,6-difluorophenyl)-ethylamino]pyrimidin-4-yl}-M-(2-methoxyethyl)-2-propylbenzamide 0.945 533.1 308 4-{6-[2-(4-Bromo-2,6-difluorophenyl)-ethylamino]pyrimidin-4-yl}-M-(2-hydroxy-2methylpropyl)-2-propylbenzamide 0.91 547.3

By applying either general procedure G or H to pyrimidine halide derivatives A.2.1. - A.2.26. in combination with commercially available boronic acid derivatives or with boronic acid derivatives A.3.1. - A.3.66, synthesize the following examples.

Note. Compound t _R [min] (method C) MS data, m/z [M+H] ⁺ 309 [2-(4-Bromo-2,6-difluorophenyl)-ethyl]-(6imidazo[1,2-a]pyridin-6-ylpyrimidin-4-yl)amine 0.683 430.3 310 [6-(1H-Benzoimidazol-5-yl)-pyrimidin-4-yl]-[2- (4-bromo-2,6-difluorophenyl)-ethyl]-amine 0.653 430.2 311 2-(4-{6-[2-(4-Bromo-2,6-difluorophenyl)-ethylamino]pyrimidin-4-yl}-phenoxy)-ethanol 0.738 450.2 312 5-{6-[2-(4-Bromo-2,6-difluorophenyl)-ethylamino]pyrimidin-4-yl}-1,3-dihydroindol-2-one 0.718 445.2 313 (4-{6-[2-(4-Bromo-2,6difluorophenyl)-ethylamino]-pyrimidin-4-yl}phenyl)-carbamic acid methyl ester 0.819 463.2 314 (5-{6-[2-(4-Bromo-2,6-difluorophenyl)-ethylamino]pyrimidin-4-yl}-3-propylthiophen-2-yl)-acetic acid(*1) 1.086 496.2 315 (5-{6-[2-(4-Bromo-2,6-difluorophenyl)-ethylamino]pyrimidin-4-yl}-3-difluoromethoxythiophen-2-yl)acetic acid (*1) 1.126 520

II. biological analyses.

The compounds of the present invention can be further characterized with respect to their general pharmacokinetic and pharmacological properties using conventional assays well known in the art, such as angiogenesis assays or tumor growth inhibition assays, or, for example, assays regarding their bioavailability in different species (such like a rat or a dog); or regarding their drug safety and/or toxicological properties using conventional assays well known in the art, such as assays for cytochrome P450 enzyme inhibition and time dependent inhibition, pregnane X receptor (PXR) activation, glutathione binding, or phototoxic behavior.

EMT-6 mouse tumor model.

The EMT-6 cell line is generated from a transplantable murine mammary carcinoma that arose in a BALB/cCRGL mouse after implantation of a hyperplastic mammary alveolar nodule (Volence FJ, et al., J Surg Oncol. 1980, 13(1):39-44) obtained from ATCC (American Type Culture Collection, Manassas, Virginia, USA).

EMT-6 tumor cells are grown as a monolayer at 37° C. in a humid atmosphere (5% CO ₂ , 95% air) in RPMI 1640 containing 2 mM L-glutamine and supplemented with 10% fetal bovine serum. For experimental use, tumor cells are separated from the culture flask using trypsin. Cells are counted in a hemocytometer and their viability is assessed by trypan blue exclusion.

Tumors are induced in female BALB/c mice either by subcutaneous injection of 1 x 10 ⁶ EMT-6 cells in 200 µl of RPMI 1640 into the right flank, or by injection of 2.5 x 10 ⁵ EMT-6 cells into 50 µl of RPMI1640 into

- 105 043145 adipose tissue of the mammary gland. For the final injection, female BALB/c mice are anesthetized with isoflurane and a 5 mm incision is made over the lateral chest in the skin to expose the mammary fat. After injection of tumor cells, a cotton swab moistened with 95% ethanol is lightly pressed against the chest surface to kill tumor cells that may leak from the injection site. The skin of mice is closed with 4-0 Crinerce surgical sutures.

The behavior and survival of the animals are monitored daily, and body weight and tumor growth are measured twice a week. Tumor sizes are measured with a caliper and tumor volume is calculated using the following formula: tumor volume=(width ² χ length)/2.

When tumor volumes reach a range between 60 and 100 mm ³ (depending on the experiment), treatment with EP2 and/or EP4 antagonists is initiated and the compound is given daily for at least 3 weeks.

Tumor weight is measured at the end of the study.

In vitro assays.

The values of the antagonistic activity of the compounds of formula (I) at EP2 and EP4 receptors are determined in accordance with the following experimental method.

The assay uses PathHunterTM HEK 293 PTGER2 and PTGER4 b-arrestin cell lines from DiscoverX. The system is based on the procedure of complementation of enzyme fragments. Two complementary fragments of the b-galactosidase enzyme are expressed in stably transfected cells. A large portion of b-gal, called the enzyme acceptor AF, is fused to the C-terminus of barrestin 2. A smaller fragment, called the ProLinkTM marker, is fused to PTGER2 (EP2) or PTRGER4 (EP4) at the C-terminus. Upon activation, β-arrestin is recruited, which triggers the interaction between ProLink and AF, allowing the complementation of the two β-gal fragments and the formation of a functional enzyme that is able to hydrolyze the substrate and generate a chemiluminescent signal.

hEP2 b-arrestin based assay.

HEK 293 PTGER2 b-arrestin cells (DiscoverX 93-021-4C1) are separated from culture dishes with cell dissociation buffer (Invitrogen, 13151-014), and harvested in growth medium (CP: DMEM + Glutamax-I (Invitrogen 32430) /10% FCS, 1% penicillin/streptomycin). Seeding 5000 cells per well of a 384 well plate (white with white bottom, Greiner 781080) in 20 μl of CP per well. The plate is incubated at 37°C, 5% CO ₂ for 24 h.

Stock solutions of test compounds are prepared at a concentration of 10 mM in DMSO and serially diluted in DMSO to concentrations required for dose-inhibition-response curves (test concentration range: 10 μM - 2 nM or 1 μM - 0.2 nM).

PGE2 (Cayman 14010, stock solution: 10 mM in DMSO) was used as agonist at a final concentration of 5 μM corresponding to EC80.

Five microliters of diluted compounds are transferred to an assay plate. The tablet is pre-incubated for 15 min at 37°C. Then five microliters of PGE2 (cuonic conc. 5 μM) are transferred to the assay plate. The plate is incubated for 120 min at 37°C.

Components of the PathHunter Glo Detection Kit are thawed and mixed according to the manufacturer's instructions: 1 part Galacton Star Substrate with 5 parts Emerald IITM Solution and 19 parts PathHunter Cell Assay Buffer, respectively. Twelve µl of the reagent is transferred to an assay plate and incubated for 1 hour at room temperature in the dark. Luminescence pulses are read on a BMG Fluostar Optima reader according to the manufacturer's instructions.

For each compound concentration, calculate the percentage of activity compared to the DMSO control as mean ± STDEV (each concentration is measured in duplicate).

IC ₅₀ values and curves are generated by XLfit software (IDBS) using the Dose-Response One Site model 203. When compounds have been measured multiple times, average values are given.

hEP4 b-arrestin based assay:

HEK 293 PTGER4 b-arrestin cells (DiscoverX 93-030-4C1) are separated from culture dishes with cell dissociation buffer (Invitrogen, 13151-014) and harvested in growth medium (CP: DMEM + Glutamax-I (Invitrogen 32430) /10% FCS, 1% penicillin/streptomycin). Seeding 5000 cells per well of a 384 well plate (white with white bottom, Greiner 781080) in 20 μl of CP per well. The tablet is incubated at 37°C, 5% CO ₂ for 24 hours.

Stock solutions of test compounds are prepared at a concentration of 10 mM in DMSO and serially diluted in DMSO to concentrations required for dose-inhibition-response curves (test concentration range: 10 μM - 2 nM or 1 μM - 0.2 nM).

PGE2 (Cayman 14010, stock solution: 100 μM in DMSO) was used as agonist at a final concentration of 20 nM corresponding to EC80.

- 106 043145

Five microliters of diluted compounds are transferred to an assay plate. The tablet is pre-incubated for 15 min at 37°C. Then five microliters of PGE2 (final conc.

nM) are transferred to an assay plate. The tablet is incubated for 120 min at 37°C.

Components of the PathHunter Glo Detection Kit are thawed and mixed according to the manufacturer's instructions: 1 part Galacton Star Substrate with 5 parts Emerald IITM Solution and 19 parts PathHunter Cell Assay Buffer, respectively. Twelve µl of the reagent is transferred to an assay plate and incubated for 1 hour at room temperature in the dark. Luminescence pulses are read on a BMG Fluostar Optima reader according to the manufacturer's instructions.

For each compound concentration, calculate the percentage of activity compared to the DMSO control as mean ± STDEV (each concentration is measured in duplicate).

IC ₅₀ values and curves are generated by XLfit software (IDBS) using the Dose-Response One Site model 203. When compounds have been measured multiple times, average values are given.

The values of the antagonistic activity of the compounds of formula (I) at EP2 and EP4 receptors are also determined in accordance with the following experimental method.

Human tumor cell lines endogenously expressing either EP4 or EP2 are used and the accumulation of cAMP in cells upon PGE2 stimulation is monitored. Glioblastoma SF295 cells express high endogenous levels of EP2 and do not express EP4, while breast cancer BT549 cells express high endogenous levels of EP4 and very low levels of EP2.

HTRF (Time-Resolved Homogeneous Fluorescence) is used as a detection method for cAMP, working with the Cisbio kit (HTRF cAMP dynamic 2 kit 20'000 tests Cisbio Cat. #62AM4PEC), which is based on a competitive immunoassay using a cryptate-labeled anti-cAMP antibody. and d2-labeled cAMP. Native cell-produced cAMP or unlabeled cAMP (for standard curve) competes with exogenously added d2-labeled cAMP (acceptor) for binding to the anti-cAMP-Eu3+ monoclonal antibody cryptate (donor). A FRET signal (fluorescence resonance energy transfer) is only obtained if a labeled anti-cAMP antibody binds d2 labeled cAMP, thus the specific signal (i.e. energy transfer) is inversely proportional to the cAMP concentration in the standard or sample.

hEP2 cAMP based analysis.

SF295 cells (NCI/#0503170) are separated from culture dishes with cell dissociation buffer (Invitrogen, 13151-014) and harvested in growth medium (CP: RPMI1640 (Invitrogen 21875)/10% FCS, 1% penicillin/streptomycin) . Cells are counted, washed and resuspended in assay buffer (AB; HBSS, 20 mM HEPES, 0.2% BSA; 2 mM IBMX). 4'000 cells in 5 µl of AB are plated in a small volume well of a 384 well plate (black flat bottom, Greiner 784076).

Stock solutions of test compounds are prepared at a concentration of 10 mM in DMSO and serially diluted in DMSO to the concentrations required for dose-inhibition-response curves (test concentration range: 30 μM - 0.4 nM; 30 μM - 0.015 nM or 1 μM 0.01 nM).

PGE2 (Cayman 14010, stock solution: 75 μM in DMSO) was used as agonist at a final concentration of 75 nM corresponding to EC80.

2.5 µl of diluted compounds are transferred to the assay plate. The tablet is pre-incubated for 45 minutes at room temperature. Following this, 2.5 microliters of PGE2 (final conc. 75 nM) is transferred to the assay plate. The plate is incubated for 30 minutes at room temperature. Five µl of each reagent, donor (anti-cAMP cryptate) and acceptor (cAMP-d2) is added and the plate is incubated for an additional hour at room temperature in the dark and then read using a BMG LABTECH PHERAstar reader (excitation: 337 nm, emission: 620 and 665 nm).

The obtained delta F (fluorescence) values (665 nm/620 nm) are converted to % cAMP values using the measurements of the cAMP calibrator supplied with the kit. For each compound concentration, the percentage cAMP was calculated compared to the DMSO control as mean ± STDEV (each concentration measured in duplicate).

IC ₅₀ values and curves are generated by XLfit software (IDBS) using the Dose-Response One Site model 203. When compounds have been measured multiple times, average values are given.

hEP4 cAMP based analysis.

BT549 cells (NCI/#0507282) are separated from culture dishes with cell dissociation buffer (Invitrogen, 13151-014), and harvested in growth medium (CP: RPMI1640 (Invitrogen 21875)/10% FCS, 1% penicillin/streptomycin) . Cells are counted, washed and resuspended in assay buffer (AB; HBSS, 20 mM HEPES, 0.2% BSA; 2 mM IBMX). 4'000 cells in 5 µl of AB are plated in a small volume well of a 384 well plate (flat bottom black, Greiner 784076).

- 107 043145

Stock solutions of test compounds are prepared at a concentration of 10 mM in DMSO and serially diluted in DMSO to the concentrations required for dose-inhibition-response curves (test concentration range: 30 μM - 0.4 nM; 30 μM - 0.015 nM or 1 μM 0.01 nM).

PGE2 (Cayman 14010, stock solution: 6 μM in DMSO) was used as agonist at a final concentration of 6 nM corresponding to EC80.

2.5 microliters of diluted compounds are transferred to an assay plate. The tablet is pre-incubated for 45 minutes at room temperature. Following this, 2.5 microliters of PGE2 (final conc. 6 nM) is transferred to the assay plate. The plate is incubated for 30 minutes at room temperature. Five µl of each reagent, donor (anti-cAMP cryptate) and acceptor (cAMPd2) is added and the plate is incubated for an additional hour at room temperature in the dark and then read using a BMG LABTECH PHERAstar reader (excitation: 337 nm, emission: 620 and 665 nm ).

The obtained delta F (fluorescence) values (665 nm/620 nm) are converted to % cAMP values using the measurements of the cAMP calibrator supplied with the kit. For each compound concentration, the percentage cAMP was calculated compared to the DMSO control as mean ± STDEV (each concentration measured in duplicate).

IC ₅₀ values and curves are generated by XLfit software (IDBS) using the Dose-Response One Site model 203. When compounds have been measured multiple times, average values are given.

Antagonist activity values (IC ₅₀ in nM) in beta-arrestin and cAMP assays of exemplary compounds are shown in Table 1. 9.

Table 9

Note. LEP4 b-app. 1C ₅₀ LEP2 b-app. IC50 LEP2 cAMP IC50 LEP4 cAMP IC50 Note. LEP4 b-app. IC50 LEP2 b-app. 1С ₅₀ LEP2 cAMP 1C ₅₀ LEP4 cAMP 1C ₅₀ 1 402 240 86 65 159 392 602 2 550 438 79 112 160 134 318 256 3 420 86 45 46 161 10 713 40 4 38 5 162 2 20 46 5 5 45 6 163 3250 234 636 792 6 1210 1350 702 573 164 102 37 77 39 7 759 441 205 140 165 582 62 163 480 8 340 262 166 326 154 9 642 1080 167 431 42 198 1080 10 931 798 168 196 190 1690 2000 eleven 1090 358 311 440 169 457 21 74 1380 12 885 617 170 746 424 13 294 636 171 582 680 14 257 262 172 401 440 15 56 368 198 42 173 519 107 16 795 914 174 108 36 265 94 17 147 202 189 293 175 461 258 18 168 481 130 173 176 75 22 9 6 19 705 7990 649 712 177 343 126 20 446 498 574 178 404 29 10 134 21 779 248 193 80 179 315 140 22 187 759 68 180 674 119 52 221 23 60 73 28 61 181 96 165 92 34 24 45 35 93 110 182 208 163 25 2070 203 71 454 183 661 695 26 104 149 46 115 184 140 127 630 250 27 168 23 50 97 185 8 51 41 6 28 80 49 41 41 186 238 945 29 20 29 23 12 187 216 130 260 200 thirty 46 239 132 213 188 117 179

- 108 043145

31 100 39 8 14 189 338 295 32 55 thirty 190 181 486 33 156 ISO 149 191 145 322 34 261 437 676 192 193 380 35 242 109 86 433 193 159 797 36 684 70 91 951 194 207 548 37 215 43 thirty 185 195 269 837 38 202 277 128 81 196 FROM 235 400 107 39 349 122 164 697 197 163 539 40 333 84 25 298 198 4 329 41 342 92 20 107 199 283 163 42 241 59 50 297 200 526 114 43 208 55 66 514 201 482 140 44 62 44 120 38 202 365 597 45 50 81 184 165 203 92 81 27 AND 46 148 105 303 470 204 699 433 47 AND 50 129 85 205 681 966 48 25 28 46 51 206 372 315 49 143 139 246 159 207 491 721 50 1310 264 259 910 208 18 207 51 39 72 684 209 156 557 52 343 626 210 20 294 615 21 53 472 437 63 221 211 126 106 148 170 54 17 60 31 10 212 50 26 62 93 55 1000 89 65 396 213 217 71 184 300 56 3030 717 512 775 214 62 184 57 1160 295 166 215 3 10 12 8 58 And 454 127 20 216 17 21 23 67 59 169 359 131 51 217 29 20 134 79 60 139 376 81 218 917 690 61 363 715 161 219 96 302 332 42 62 108 324 176 79 220 839 401 63 233 644 105 221 268 92 64 205 316 244 38 222 286 231 65 136 111 102 53 223 232 367 66 133 16 27 53 224 23 37 67 261 712 245 225 97 277 68 33 145 165 25 226 273 907 69 915 382 170 227 5 81 120 8 70 260 139 554 228 777 502 71 100 85 70 53 229 273 81 72 104 77 40 42 230 152 662 73 136 54 thirty 35 231 94 16 13 43 74 90 533 33 232 325 711 75 2180 727 568 918 233 398 222 76 310 488 234 88 234 49 77 93 23 77 121 415 108 235 89 43 203 149 78 176 149 458 236 351 265 79 203 408 106 237 419 72 128 668 80 255 366 238 438 251 81 554 318 125 239 387 300 82 103 74 66 46 240 72 127 511 405 83 14 208 13 241 431 215 574 506 84 116 358 166 242 231 145 526 223 85 6 8 7 12 243 61 41 86 thirty 16 84 89 244 251 364 ISO 280 87 5 AND 28 17 245 307 392 4630 6720 88 2 9 31 6 246 277 479 89 3 17 10 58 247 278 799 90 3 26 24 10 248 311 226 635 299 91 42 2840 335 249 467 110 92 4 48 68 4 250 169 78 856 887

- 109 043145

93 3 509 6 251 831 254 94 90 79 82 93 252 484 214 1910 959 95 59 thirty 15 166 253 170 191 96 43 24 58 106 254 880 753 97 95 131 144 127 255 283 344 98 14 53 83 50 256 584 574 99 45 75 80 69 257 239 212 100 27 17 50 59 258 174 77 101 103 44 62 82 259 351 46 45 76 102 91 34 17 122 260 755 204 103 36 62 39 39 261 42 58 165 101 104 101 956 399 262 149 88 105 9 AND 40 25 263 73 31 167 73 106 1 35 49 10 264 465 372 107 2 10 AND 7 265 452 242 108 5 28 FROM 15 266 368 65 109 558 254 267 183 70 BUT 2 6 9 3 268 294 19 21 225 111 6 31 137 26 269 768 258 112 80 892 192 270 700 316 113 3 47 FROM 29 271 380 36 151 1760 114 3 15 27 8 272 426 174 115 16 44 51 12 273 56 45 364 211 116 5 10 14 8 274 646 160 117 16 692 244 26 275 90 125 163 18 118 316 488 266 148 276 37 23 59 72 119 5 10 17 AND 277 68 74 221 241 120 21 35 13 69 278 42 64 150 89 121 9 66 60 42 279 5 46 72 12 122 8 906 19 280 289 20 48 257 123 27 29 32 19 281 37 56 47 81 124 46 36 282 83 135 1030 380 125 3 AND 49 5 283 245 118 959 595 126 7 22 74 20 284 199 295 127 14 29 129 47 285 272 163 128 34 629 235 286 287 217 129 45 372 247 287 315 868 1210 130 4 22 63 24 288 1190 739 775 131 3 18 54 AND 289 308 80 234 320 132 6 594 60 290 28 48 133 13 13 92 44 291 77 88 774 154 134 98 284 718 292 893 100 135 8 26 15 34 293 41 138 900 326 136 6 18 17 18 294 18 27 47 22 137 411 371 963 295 2 12 84 2 138 130 34 123 247 296 9 12 44 14 139 6 290 149 297 236 21 140 12 345 218 298 301 128 141 8 381 168 299 255 145 142 700 571 300 230 155 143 604 344 301 640 118 144 126 1000 433 302 565 121 145 1120 690 303 163 44 146 14 39 249 189 304 339 126 147 490 834 305 628 203 148 9 20 19 8 306 403 97 149 43 199 67 73 307 781 219 150 2 13 15 9 308 164 156 151 3 69 43 29 309 875 352 152 5 12 9 thirty 310 302 400 153 21 5 7 4 311 776 216 154 33 13 8 66 312 703 175 155 35 12 20 62 313 333 143 156 31 9 28 16 314 61 55 169 27 157 57 64 99 34 315 38 25 17 28 158 2270 643 913

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Claims (18)

1 . Use of a compound of formula (II) wherein said compound of formula (II) is a prostaglandin-2 (PGE2) EP2 and/or EP4 receptor modulator for treating cancer by modulating an immune response, including reactivation of the immune system in a tumor, and wherein said cancer is selected from melanoma; lung cancer; bladder cancer; renal carcinoma; malignant neoplasms of the gastrointestinal tract; endometrial cancer; ovarian cancer; cervical cancer; neuroblastoma and prostate cancer; and (R ¹ )n represents zero, one, two or three substituents on the phenyl ring, wherein said substituents are independently selected from (C1-3)alkyl, (C1-3)alkoxy, -S-(C1-3)alkyl, halogen, (C1-3)fluoroalkyl, (C1-3)fluoroalkoxy, cyano, hydroxy, nitro, -CO-O-(C1-3)alkyl, and -NR ^N7 R ^N8 where R ^N7 and RN ⁸ are independently hydrogen or (C1_ ₄ )alkyl or R ^N7 and RN ⁸ together with the nitrogen atom to which they are attached form a 4-6 membered carbocyclic ring; R ³ is hydrogen or methyl; Ar ¹ is a phenyl group of structure (Ar-I) where Rp represents a (C ₄ . ₆ )cycloalkyl containing a ring oxygen atom, where the specified (C _4-6 )cycloalkyl containing a ring oxygen atom is not substituted or monosubstituted by hydroxy; hydroxy; X-CO-RO ¹ , where X ¹ is a direct bond, (C ₁ . ₃ )alkylene, -O-(C ₁ . ₃ )alkylene-*, -NH-(C ₁ _ ₃ )alkylene-*, -CH=CH- or -NH- CO-*; where the asterisks indicate a bond that is attached to the -CO-R ^O1 group; And R ^O1 is -OH; - O-(C ₁ . ₄ )alkyl; - NH-SO2-RS ³ where RS ³ is (C ₁ . ₄ )αlkyl, (C ₃ . ₆ ) cycloalkyl, where (C ₃ . ₆ ) cycloalkyl contains zero or one ring oxygen atom, (C ₃ . ₆ )cycloalkyl-(C _{1 .3} )alkylene, where (C _{3 .6} )cycloalkyl contains zero or one ring oxygen atom, (C _{1 .3} )fluoroalkyl or -NH2; Ν'™ Άνη ₂ . - (CH ₂ ) _q -HET ¹ where q is the integer 0, 1 or 2 and HET ¹ is 5-oxo4,5-dihydro-[1,2,4]oxadiazol-3-yl or the tautomeric form 5 -hydroxy-[1,2,4]oxadiazol-3-yl, 3-oxo2,3-dihydro-[1,2,4]oxadiazol-5-yl or the tautomeric form of 3-hydroxy-[1,2,4] oxadiazol-5-yl, or 5-thioxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl or the tautomeric form of 5-mercapto-[1,2,4]oxadiazol-3-yl; - (CH ₂ ) _p -HET, where p is the integer 0 or 1 and HET is a group selected from 1H-tetrazol-5-yl, 3-hydroxyisoxazol-5-yl, 2-hydroxy-[1,3 ,4]oxadiazol-4-yl, 3-aminoisoxazol-5-yl, 2-aminooxazol-5-yl, 5-amino-[1,3,4]thiadiazol-2-yl, 5-methylamino-[1,3 ,4]thiadiazol-2-yl, 5-methoxy[1,2,4]oxadiazol-3-yl, 5-amino-[1,2,4]oxadiazol-3-yl, 5-[(2-hydroxyethyl) ]amino)-[1,2,4]oxadiazol-3-yl, 5hydroxymethyl-[1,2,4]oxadiazol-3-yl and 5-(oxetan-3-yl)-[1,2,4]oxadiazole -3 -ila; R ^m1 is hydrogen; (C ₁ . ₆ )alkyl; (C ₁ . ₄ )alkoxy; (C ₁ . ₃ )fluoroalkyl; (C ₁ . ₃ )fluoroalkoxy; halogen; (C ₃ . ₆ )cycloalkyloxy; hydroxy; hydroxy-(C ₂ . ₄ )alkoxy; - X ² -NR ^N1 R ^N2 , where X ² is a direct bond or X ² is -O-CH2-CH2-*, where the asterisk indicates a bond that is attached to the -NR ^N1 R ^N2 group; and where R ^N1 and RN ² independently represent hydrogen, (C _{1 .4} )alkyl or (C _{3 .6} )cycloalkyl; - S-RS ² where RS ² represents (C ₁ . ₄ )alkyl or (C _{3 .6} )cycloalkyl containing zero or one ring oxygen atom; - 111 043145 R ^m2 is hydrogen, methyl, fluorine or chlorine and R ⁰¹ is hydrogen; or if R ^m2 is hydrogen, R ^O1 is hydrogen or fluorine; or Ar ¹ is a 5-membered heteroaryl group of structure (Ar-II) ^R6 (Ag-11) where Y is CR ⁸ where R ⁸ is hydrogen or halogen; or Y is N; R ⁷ is a (C4-6)cycloalkyl containing a ring oxygen atom, wherein said (C4.6)cycloalkyl containing a ring oxygen atom is unsubstituted or monosubstituted by hydroxy; - X ¹ -CO-R ^O1 , where X ¹ is a direct bond, (C ₁ . ₃ )alkylene, -O-(C _{1 .3} )alkylene-*, -NH-(C _{1 .3} )alkylene-*, -CH=CH-, -NH- CO-* or (C ₃ . ₅ )cycloalkylene; where the asterisks indicate a bond that is attached to the -CO-R ^O1 group; And R ^O1 is -OH; -O-(C _1-4 )alkyl; - NH-SO2-RS ³ where RS ³ is (C _1-4 )alkyl, (C _{3 .6} )cycloalkyl, where (C _{3 .6} )cycloalkyl contains zero or one ring oxygen atom, (C _{3 .6} )cycloalkyl-(C _{1 .3} )alkylene, where (C _{3 .6} )cycloalkyl contains zero or one ring oxygen atom, (C _{1 .3} )fluoroalkyl or -NH ₂ ; - O-CH ₂ -CO-R ^{O 4} , where R ^{O 4} is hydroxy or (Cl. ₄ )alkoxy, or -N[(C ₁ . ₄ )alkyl] ₂ ; - O-CH ₂ -O-CO-R ^O5 , where R ^O5 is (C _{1 .4} )alkyl or (C _{1 .4} )alkoxy; -O-CH ₂ -CH ₂ -N[(C ₁ . ₄ )alkyl] ₂ or (5-methyl-2-oxo-[1,3]dioxol-4-yl)methyloxy-; hydroxy-(C ₁ . ₄ )alkyl; hydroxy-(C ₂ . ₄ )alkoxy; - (CH ₂ ) _r -CO-NR ^N3 R ^N4 , where r is the integer 0 or 1 and R ^N3 and R ^N4 are independently hydrogen or (C ₁ . ₄ )alkyl; - NH-CO-NR ^N5 R ⁿ⁶ , where R ^N5 and R ^N6 independently represent hydrogen or (C ₁ . ₄ )alkyl; - SO2-RS ¹ where R ^S1 is (C1.4) alkyl or -NR ^N7 R ⁿ⁸ where R ^N7 and R ^N8 are independently hydrogen or ( _C1.3 ) alkyl; - (CH ₂ ) _q -HET ¹ where q is the integer 0, 1 or 2 and HET ¹ is 5-oxo4,5-dihydro-[1,2,4]oxadiazol-3-yl or the tautomeric form 5 -hydroxy-[1,2,4]oxadiazol-3-yl, 3-oxo2,3-dihydro-[1,2,4]oxadiazol-5-yl or the tautomeric form of 3-hydroxy-[1,2,4] oxadiazol-5-yl, or 5-thioxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl or the tautomeric form of 5-mercapto-[1,2,4]oxadiazol-3-yl; - (CH ₂ ) _p -HET, where p is the integer 0 or 1 and HET is a group selected from 1H-tetrazol-5-yl, 3-hydroxyisoxazol-5-yl, 2-hydroxy-[1,3 ,4]oxadiazol-4-yl, 3aminoisoxazol-5-yl, 2-aminooxazol-5-yl, 5-amino-[1,3,4]thiadiazol-2-yl, 5-methylamino[1,3,4] thiadiazol-2-yl, 5-methoxy-[1,2,4]oxadiazol-3-yl, 5-amino-[1,2,4]oxadiazol-3-yl, 5-[(2hydroxyethyl)]amino)- [1,2,4]oxadiazol-3-yl, 5-hydroxymethyl-[1,2,4]oxadiazol-3-yl and 5-(oxetan-3yl)-[1,2,4]oxadiazol-3-yl ; R ⁶ is (C ₁ . ₆ )alkyl; (C ₁ . ₄ )alkoxy; (C ₁ . ₃ )fluoroalkyl; (C ₁ . ₃ )fluoroalkoxy; halogen; (C ₃ . ₆ )cycloalkyloxy; hydroxy-(C ₂ . ₄ )alkoxy; - X ² -NR ⁿ¹ R ⁿ² , where X ² is a direct bond or X ² is -O-CH2-CH2-*, where the asterisk indicates a bond that is attached to the -NR ⁿ¹ R ⁿ² group; and where _R ^N1 and R ^N2 independently represent hydrogen, ( _C1.4 )alkyl or ( _C3.6 )cycloalkyl; - S-RS ² where RS ² represents (C ₁ . ₄ )alkyl or (C _{3 .6} )cycloalkyl containing zero or one ring oxygen atom; or Ar ¹ is an 8-10 membered bicyclic heteroaryl selected from indazolyl, benzoimidazolyl, indolyl, benzofuranyl, and benzoxazolyl; where the specified 8-10-membered bicyclic heteroaryl is independently monosubstituted -(C0.3)alkylene-COOR ^{O 2} where R ^{O 2} represents hydrogen or (C1. ₄ ) alkyl; or - 112 043145 Ar ¹ is a structure group (Ar-III) Αν (Ar-III), which is selected from 2-oxo-2,3-dihydrobenzooxazol-6-yl, 3-methyl-2-oxo-2,3-dihydrobenzooxazol-5 -yl, 1-methyl-3-oxo-2, 3-dihydro-1 H-indazol-6-yl, 2-oxo-1,2,3,4-tetrahydroquinazolin-6-yl, 1-methyl-2-oxo-1,2,3,4-tetrahydroquinazolin-6 -yl, 1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl, 1-methyl-2-oxo-1,2,3,4-tetrahydroquinazolin-7-yl and 1-oxo-1,2 ,3,4-tetrahydroisoquinolin7-yl; or a pharmaceutically acceptable salt thereof. 2. Use of a compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein Ar ¹ is a group selected from - 113 043145 - 114 043145 3. The use of a compound or a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein (R1)n represents one, two or three substituents on the phenyl ring, wherein said substituents are independently selected from (C _1-3 )alkyl, (C _{1 -3} )αlkoxy, -S-(C _1-3 )alkyl, halogen, (C _1-3 )fluoroalkyl, (C _1-3 )fluoroalkoxy, cyano, hydroxy, nitro, -CO-O-(C _1-3 )αkyl, and -NR ^N7 R ^N8 where R ^N7 and R ^N8 are independently hydrogen or (C _1-4 )alkyl or R ^N7 and R ^N8 together with the nitrogen atom to which they are attached form a 4-6 membered carbocyclic ring. 4. Compound of formula (III) (R ¹ ) _n Formula (III), where in the compounds of formula (III) (R1) _n represents zero, one, two or three substituents on the phenyl ring (i.e. n represents the integer 0, 1, 2 or 3), where the specified substituents independently selected from (C _1-3 )alkyl, (C _1-3 )alkoxy, -S-(C _1-3 )alkyl, halogen, (C _1-3 )fluoroalkyl, (C _1-3 )fluoroalkoxy, cyano , hydroxy, nitro, -CO-O-(C _1-3 )alkyl, and -NR ^N7 R ^N8 where R ^N7 and R ^N8 are independently hydrogen or (C _1-4 ) alkyl or R ^N7 and R ^N8 together with the nitrogen atom to which they are attached, they form a 4-6-membered carbocyclic ring; And Ar ¹ is a phenyl group of structure (Ar-I) R ^m1 to X (Ar-I), where R ^p is - X ¹ -CO-R ^O1 , where X ¹ is a direct bond, (C _1-3 )alkylene, -O-(C _1-3 )alkylene-*, -NH-(C _1-3 )alkylene-*, -CH=CH-, -NH- CO-* or (C _3-5 )cycloalkylene; where the asterisks indicate a bond that is attached to the -CO-R ^O1 group; And R ^O1 is -OH; -O-(C _1-4 )alkyl; - NH-SO ₂ -R ^S3 where R ^S3 is (C _1-4 )alkyl, (C _3-6 )cycloalkyl, where (C _3-6 )cycloalkyl contains zero or one ring oxygen atom, (C _{3- 6} ) cycloαalkyl-(C _1-3 ) alkylene, where (C _3-6 ) cycloalkyl co- - 115 043145 holds zero or one ring oxygen atom, (C _1-3 )fluoroalkyl or -NH2; HET ¹ where HET ¹ is 5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl or 3-oxo-2,3dihydro-[1,2,4]oxadiazol-5- silt; or HET, where HET is a group selected from 1H-tetrazol-5-yl, 3-hydroxyisoxazol5-yl, 2-hydroxy-[1,3,4]oxadiazol-4-yl, 3-aminoisoxazol-5-yl, 2 -aminooxazol-5-yl, 5-amino[1,3,4]thiadiazol-2-yl and 5-methylamino-[1,3,4]thiadiazol-2-yl, 5-amino-[1,2,4 ]oxadiazol-3-yl; R ^m1 is (C _1-6 )alkyl; (C _1-4 )alkoxy; (C _1-3 )fluoroalkyl; (C _1-3 )fluoroalkoxy; halogen; (C _3-6 )cycloalkyl; (C _3-6 )cycloalkyloxy; hydroxy-(C _2-4 )alkoxy or - S-RS ² where R ^S2 represents (C _1-4 )alkyl or (C _3-6 )cycloalkyl containing zero or one ring oxygen atom; Rm ² is hydrogen, methyl, fluorine or chlorine and R ^O1 is hydrogen or Ar ¹ is a 5-membered heteroaryl group of structure (Ar-II) where Y is CH or N; R ⁷ is -X1-CO-R ^O1 , where X ¹ is a direct bond, (C _1-3 )alkylene, -O-(C _1-3 )alkylene-*, -NH-(C _1-3 )alkylene-*, -CH=CH-, -NH- CO-* or (C _3-5 )cycloalkylene; where the asterisks indicate a bond that is attached to the -CO-R ^O1 group; And R ^O1 is -OH; -O-(C _1-4 )alkyl; -NH-SO2-RS ³ where R ^S3 is (C _1-4 )alkyl, (C _3-6 )cycloalkyl, where (C _3-6 )cycloalkyl contains zero or one ring oxygen atom, (C _3-6 )cycloalkyl-(C _1-3 )alkylene, where (C _3-6 )cycloalkyl contains zero or one ring oxygen atom, (C _1-3 )fluoroalkyl or -NH2; HET ¹ where HET ¹ is 5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl or 3-oxo-2,3dihydro-[1,2,4]oxadiazol-5- silt; or HET, where HET is a group selected from 1H-tetrazol-5-yl, 3-hydroxyisoxazol5-yl, 2-hydroxy-[1,3,4]oxadiazol-4-yl, 3-aminoisoxazol-5-yl, 2 -aminooxazol-5-yl, 5-amino[1,3,4]thiadiazol-2-yl and 5-methylamino-[1,3,4]thiadiazol-2-yl, 5-amino-[1,2,4 ]oxadiazol-3-yl; R ⁶ is (C _1-6 )alkyl; (C _1-4 )alkoxy; (C _1-3 )fluoroalkyl; (C _1-3 )fluoroalkoxy; halogen; (C _3-6 )cycloalkyl; (C _3-6 )cycloalkyloxy; hydroxy-(C _2-4 )alkoxy or -S-RS ² where R ^S2 is (C _1-4 )alkyl or (C _3-6 )cycloalkyl containing zero or one ring oxygen atom; or a pharmaceutically acceptable salt thereof. 5. The compound according to claim 4, where Ar ¹ represents a group selected from - 116 043145 or a pharmaceutically acceptable salt thereof. 6. The compound according to claim 4 or 5, where (R ¹ )n represents one, two or three substituents on the phenyl ring, where these substituents are independently selected from (O _1-3 )alkyl, (O _1-3 )alkoxy, -S-(Cl _-3 )alkyl, halogen, (O _1-3 )fluoroalkyl, (O _1-3 )fluoroalkoxy, cyano and hydroxy; or a pharmaceutically acceptable salt thereof. 7. Connection according to claim 4 or 5; where fragment ( ^Rl )n is a group selected from phenyl, 4-bromophenyl, 3-bromophenyl, 2-bromophenyl, 4chlorophenyl, 3-chlorophenyl, 2-chlorophenyl, 4-fluorophenyl, 3-fluorophenyl, 2-fluorophenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 4-hydroxyphenyl, 4-methoxyphenyl, 3-methoxyphenyl, 2methoxyphenyl, 4-bromo-2-methylphenyl, 4-bromo-3-methylphenyl, 2,4-dimethylphenyl, 3,4-dimethylphenyl, 2,4- dichlorophenyl, 3,4-dichlorophenyl, 2,6-difluorophenyl, 4-bromo-3-chlorophenyl, 4-bromo-2-chlorophenyl, 2bromo-5-chlorophenyl, 4-bromo-3-fluorophenyl, 4-bromo-2- fluorophenyl, 4-chloro-2,6-difluorophenyl, 3-chloro-2,6difluorophenyl, 2-chloro-3,6-difluorophenyl, 2,4,6-trifluorophenyl, 4-bromo-2,5-difluorophenyl, 4- bromine-2,6difluorophenyl, 4-bromo-2-ethylphenyl, 4-bromo-5-fluoro-2-methylphenyl, 4-bromo-2-fluoro-5-methylphenyl, 3hydroxy-4-methoxyphenyl, 4-hydroxy-3- methoxyphenyl, 3-chloro-4-methoxyphenyl, 4-bromo-3methoxyphenyl, 3-bromo-4-methoxyphenyl, 2-fluoro-4-methoxyphenyl, 4-bromo-2-methoxyphenyl, 5-bromo-2methoxyphenyl, 2-ethoxyphenyl, 5-chloro-2-cyanophenyl, 4-chloro-2-cyanophenyl, 4-fluoro-2-cyanophenyl, 4-chloro-2-methylaminophenyl, 4-trifluoromethylphenyl, 3-trifluoromethylphenyl, 2-trifluoromethylphenyl, 2,5-dimethoxyphenyl, 2,3-dimethoxyphenyl, 2,4-dimethoxyphenyl, 3,5-dimethoxyphenyl, 3(methoxycarbonyl)phenyl, 2-methoxy-5-(methylsulfanyl)phenyl, 2-methoxy-4-(methylsulfanyl)phenyl, 4-fluoro- 2-ethoxyphenyl, 4-bromo-2-ethoxyphenyl, 2-ethyl-4-methoxyphenyl, 2-methoxy-4,5-dimethylphenyl, 4-chloro-6-fluoro-2-methoxyphenyl, 4-bromo-6-fluoro- 2-methoxyphenyl, 4-dimethylamino-2-fluorophenyl, 2dimethylamino-4-bromophenyl, 4-chloro-2-nitrophenyl, 2-fluoro-4-trifluoromethylphenyl, 4-bromo-2,6dimethoxyphenyl, 4-bromo-2-n- propoxyphenyl, 4-bromo-2-trifluoromethoxyphenyl, 4-bromo-2(pyrrolidin-1-yl)phenyl, 2-ethoxy-4-trifluoromethylphenyl, 3,4-dichloro-2-methylphenyl, 5-bromo-2methylsulfanylphenyl, 2- fluoro-6-methoxyphenyl, 2-methoxy-6-methylphenyl, 2-methoxy-4,6dimethylphenyl, 4,5-difluoro-2-methoxyphenyl, 2,6-difluoro-4-methoxyphenyl, 4-difluoromethoxy-2methoxyphenyl, 4- difluoromethyl-5-fluoro-2-methoxyphenyl, 2-methoxy-4-trifluoromethylphenyl, 4-difluoromethyl-2-methoxy-5-methylphenyl, 2-methoxy-4-trifluoromethoxyphenyl, 2-fluoro-6-methoxy-4trifluoromethylphenyl, 5-chloro- 2-methoxy-4-trifluoromethylphenyl and 2-difluoromethoxy-4trifluoromethylphenyl; or a pharmaceutically acceptable salt thereof. - 117 043145 8. Connection according to claim 4 or 5, where the fragment (H')n is a group selected from 4-bromophenyl, 4-chlorophenyl, 4-methylphenyl, 2,4-dichlorophenyl, 3,4-dichlorophenyl, 2,6-difluorophenyl, 4-bromo-3-chlorophenyl, 4-bromo -2-chlorophenyl, 2-bromo-5chlorophenyl, 4-bromo-2-fluorophenyl, 4-chloro-2,6-difluorophenyl, 3-chloro-2,6-difluorophenyl, 2-chloro-3,6difluorophenyl, 2,4 ,6-trifluorophenyl, 4-bromo-2,5-difluorophenyl, 4-bromo-2,6-difluorophenyl, 4-bromo-2-fluoro-5methylphenyl, 4-hydroxy-3-methoxyphenyl, 4-bromo-3-methoxyphenyl , 2-fluoro-4-methoxyphenyl, 4-bromo-2-methoxyphenyl, 5-bromo-2-methoxyphenyl, 2,5-dimethoxyphenyl, 2,3-dimethoxyphenyl, 2,4-dimethoxyphenyl, 2methoxy-4-(methylsulfanyl)phenyl, 4-bromo-2-ethoxyphenyl, 2-ethyl-4-methoxyphenyl, 2-methoxy-4,5dimethylphenyl, 4-chloro-6-fluoro-2-methoxyphenyl, 4-bromo-2,6-dimethoxyphenyl, 4-bromo- 2-n-propoxyphenyl and 2-ethoxy-4-trifluoromethylphenyl; or a pharmaceutically acceptable salt thereof. 9. The compound according to claim 4, selected from the group consisting of 3-fluoro-5-[6-(2-p-tolylethylamino)pyrimidin-4-yl]thiophene-2-carboxylic acid; 4-{6-[2-(2-methoxy-4-methylsulfanylphenyl)ethylamino]pyrimidin-4-yl}-2-methylsulfanylbenzoic acid; 4-{6-[2-(2-methoxy-4,5-dimethylphenyl)ethylamino]pyrimidin-4-yl}-2-methylsulfanylbenzoic acid; 3-ethoxy-5-{6-[2-(2-methoxy-4-methylsulfanylphenyl)ethylamino]pyrimidin-4-yl}thiophene-2-carboxylic acid; 3-ethoxy-5-{6-[2-(2-methoxy-4,5-dimethylphenyl)ethylamino]pyrimidin-4-yl}thiophene-2-carboxylic acid; 2-ethoxy-4-{6-[2-(2-methoxy-4,5-dimethylphenyl)ethylamino]pyrimidin-4-yl}benzoic acid; 3-(4-{6-[2-(4-bromophenyl)ethylamino]pyrimidin-4-yl}-2-ethoxyphenyl)-[1,2,4]oxadiazol-5(4H)-one; 3-(4-(6-((4-Bromophenethyl)amino)pyrimidin-4-yl)-2-ethoxyphenyl)-[1,2,4]oxadiazol-5-ol; 4-{6-[2-(3,4-dimethylphenyl)ethylamino]pyrimidin-4-yl}-2-methylsulfanylbenzoic acid; 4-{6-[2-(4-bromo-2-fluorophenyl)ethylamino]pyrimidin-4-yl}-2-ethoxybenzoic acid; [2-(4-bromo-2,6-difluorophenyl)ethyl]-{6-[3-ethoxy-4-(1H-tetrazol-5-yl)phenyl]pyrimidin-4-yl}amine; N-(4-{6-[2-(4-bromo-2,6-difluorophenyl)ethylamino]pyrimidin-4-yl}-2-ethoxyphenyl)oxalamic acid; 5-{6-[2-(4-bromo-2,6-difluorophenyl)ethylamino]pyrimidin-4-yl}-4-chloro-3-ethoxythiophene-2-carboxylic acid; 5-{6-[2-(4-bromo-2,6-difluorophenyl)ethylamino]pyrimidin-4-yl}-3-methylthiophene-2-carboxylic acid; 5-{6-[2-(4-bromo-2,6-difluorophenyl)ethylamino]pyrimidin-4-yl}-3-ethylthiophene-2-carboxylic acid; 5-{6-[2-(4-bromo-2,6-difluorophenyl)ethylamino]pyrimidin-4-yl}-3-chlorothiophene-2-carboxylic acid; 5-{6-[2-(4-bromo-2,6-difluorophenyl)ethylamino]pyrimidin-4-yl}-3-(2-hydroxyethoxy)thiophene-2-carboxylic acid; 4-{6-[2-(4-bromo-2,6-difluorophenyl)ethylamino]pyrimidin-4-yl}-2-methylsulfanylbenzoic acid; 4-{6-[2-(4-bromo-2,6-difluorophenyl)ethylamino]pyrimidin-4-yl}-2-isobutylbenzoic acid; 4-{6-[2-(4-bromo-2,6-difluorophenyl)ethylamino]pyrimidin-4-yl}-2-difluoromethoxybenzoic acid; 3-(5-{6-[2-(4-bromo-2,6-difluorophenyl)ethylamino]pyrimidin-4-yl}-3-ethoxythiophen-2-yl)propionic acid; 3-(4-{6-[2-(4-bromo-2,6-difluorophenyl)ethylamino]pyrimidin-4-yl}-2-ethoxyphenoxy)propionic acid; (E)-3-(5-{6-[2-(4-bromo-2,6-difluorophenyl)ethylamino]pyrimidin-4-yl}-3-ethoxythiophen-2-yl)acrylic acid; (5-{6-[2-(4-bromo-2,6-difluorophenyl)ethylamino]pyrimidin-4-yl}-3-ethoxythiophen-2-yl)acetic acid; (4-{6-[2-(4-bromo-2,6-difluorophenyl)ethylamino]pyrimidin-4-yl}-2-ethoxyphenyl)acetic acid; 5-{6-[2-(4-bromophenyl)ethylamino]pyrimidin-4-yl}-3-ethoxythiophene-2-carboxylic acid; 3-ethoxy-5-{6-[2-(4-trifluoromethylphenyl)ethylamino]pyrimidin-4-yl}thiophene-2-carboxylic acid; 3-ethoxy-5-{6-[2-(3-methoxyphenyl)ethylamino]pyrimidin-4-yl}thiophene-2-carboxylic acid; 5-[6-(2-p-tolylethylamino)pyrimidin-4-yl]-3-trifluoromethylthiophene-2-carboxylic acid; 5-{6-[2-(4-chloro-2-nitrophenyl)ethylamino]pyrimidin-4-yl}-3-ethoxythiophene-2-carboxylic acid; 5-{6-[2-(2,4-dichlorophenyl)ethylamino]pyrimidin-4-yl}-3-ethoxythiophene-2-carboxylic acid; - 118 043145 5-{6-[2-(3,4-dimethylphenyl)ethylamino]pyrimidin-4-yl}-3-ethoxythiophene-2-carboxylic acid; 5-{6-[2-(5-bromo-2-methoxyphenyl)ethylamino]pyrimidin-4-yl}-3-ethoxythiophene-2-carboxylic acid; 5-{6-[2-(2,5-dimethoxyphenyl)ethylamino]pyrimidin-4-yl}-3-ethoxythiophene-2-carboxylic acid; 5-{6-[2-(2,4-dimethoxyphenyl)ethylamino]pyrimidin-4-yl}-3-ethoxythiophene-2-carboxylic acid; 5-{6-[2-(4-chlorophenyl)ethylamino]pyrimidin-4-yl}-3-ethoxythiophene-2-carboxylic acid; 3-(5-{6-[2-(4-bromo-2-ethoxyphenyl)ethylamino]pyrimidin-4-yl}-3-ethoxythiophen-2-yl)-[1,2,4]oxadiazol-5(4Н )-she; 3-(5-{6-[2-(4-bromo-2-ethoxyphenyl)ethylamino]pyrimidin-4-yl}-3-ethoxythiophen-2-yl)-[1,2,4]oxadiazol-5-ol ; 3-(5-{6-[2-(4-Chloro-2-fluoro-6-methoxyphenyl)ethylamino]pyrimidin-4-yl}-3-ethoxythiophen-2-yl)-[1,2,4]oxadiazole -5(4H)-she; 3-(5-{6-[2-(4-Chloro-2-fluoro-6-methoxyphenyl)ethylamino]pyrimidin-4-yl}-3-ethoxythiophen-2-yl)-[1,2,4]oxadiazole -5-ola; 3-(5-{6-[2-(4-bromo-2-fluoro-6-methoxyphenyl)ethylamino]pyrimidin-4-yl}-3-ethoxythiophen-2-yl)-[1,2,4]oxadiazole -5(4H)-she; 3-(5-{6-[2-(4-bromo-2-fluoro-6-methoxyphenyl)ethylamino]pyrimidin-4-yl}-3-ethoxythiophen-2-yl)-[1,2,4]oxadiazole -5-ola; 3-(5-{6-[2-(4-Bromo-2,6-dimethoxyphenyl)ethylamino]pyrimidin-4-yl}-3-ethoxythiophen-2-yl)-[1,2,4]oxadiazol-5 (4H) - she; 3-(5-{6-[2-(4-Bromo-2,6-dimethoxyphenyl)ethylamino]pyrimidin-4-yl}-3-ethoxythiophen-2-yl)-[1,2,4]oxadiazol-5 -ola; 3-(5-{6-[2-(4-bromo-2-propoxyphenyl)ethylamino]pyrimidin-4-yl}-3-ethoxythiophen-2-yl)-[1,2,4]oxadiazole5(4H)- she; 3-(5-{6-[2-(4-bromo-2-propoxyphenyl)ethylamino]pyrimidin-4-yl}-3-ethoxythiophen-2-yl)-[1,2,4]oxadiazol-5ol; 3-(3-ethoxy-5-{6-[2-(2-ethoxy-4-trifluoromethylphenyl)ethylamino]pyrimidin-4-yl}thiophen-2-yl)-[1,2,4]oxadiazol-5( 4H)-she; 3-(3-ethoxy-5-{6-[2-(2-ethoxy-4-trifluoromethylphenyl)ethylamino]pyrimidin-4-yl}thiophen-2-yl)-[1,2,4]oxadiazol-5- ola; 3-(3-ethoxy-5-{6-[2-(2-fluoro-4-methoxyphenyl)ethylamino]pyrimidin-4-yl}thiophen-2-yl)-[1,2,4]oxadiazole5(4H) -she; 3-(3-ethoxy-5-{6-[2-(2-fluoro-4-methoxyphenyl)ethylamino]pyrimidin-4-yl}thiophen-2-yl)-[1,2,4]oxadiazol5-ol; 3-(5-{6-[2-(2-bromo-5-chlorophenyl)ethylamino]pyrimidin-4-yl}-3-ethoxythiophen-2-yl)-[1,2,4]oxadiazol-5(4H )-she; 3-(5-{6-[2-(2-bromo-5-chlorophenyl)ethylamino]pyrimidin-4-yl}-3-ethoxythiophen-2-yl)-[1,2,4]oxadiazol-5-ol ; 3-(3-ethoxy-5-{6-[2-(2-ethoxy-4-fluorophenyl)ethylamino]pyrimidin-4-yl}thiophen-2-yl)-[1,2,4]oxadiazol-5( 4H)-she; 3-(3-ethoxy-5-{6-[2-(2-ethoxy-4-fluorophenyl)ethylamino]pyrimidin-4-yl}thiophen-2-yl)-[1,2,4]oxadiazol-5- ola; 5-chloro-2-(2-((6-(4-ethoxy-5-(5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl)thiophen-2-yl) pyrimidin-4yl)amino)ethyl)benzonitrile; 5-chloro-2-(2-{6-[4-ethoxy-5-(5-hydroxy-[1,2,4]oxadiazol-3-yl)thiophen-2-yl]pyrimidin-4-ylamino}ethyl ) benzonitrile; 2-(2-{6-[4-ethoxy-5-(5-hydroxy-[1,2,4]oxadiazol-3-yl)thiophen-2-yl]pyrimidin-4-ylamino}ethyl)-5fluorobenzonitrile; 2-(2-((6-(4-ethoxy-5-(5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl)thiophen-2-yl)pyrimidin-4- yl)amino)ethyl)-5-fluorobenzonitrile; 3-(5-{6-[2-(3-chloro-2,6-difluorophenyl)ethylamino]pyrimidin-4-yl}-3-ethoxythiophen-2-yl)-[1,2,4]oxadiazol-5 (4H)-she; 3-(5-{6-[2-(3-chloro-2,6-difluorophenyl)ethylamino]pyrimidin-4-yl}-3-ethoxythiophen-2-yl)-[1,2,4]oxadiazol-5 -ola; 3-(3-ethoxy-5-{6-[2-(2-ethyl-4-methoxyphenyl)ethylamino]pyrimidin-4-yl}thiophen-2-yl)-[1,2,4]oxadiazol-5( 4H)-she; 3-(3-ethoxy-5-{6-[2-(2-ethyl-4-methoxyphenyl)ethylamino]pyrimidin-4-yl}thiophen-2-yl)-[1,2,4]oxadiazol-5- ola; 3-(5-{6-[2-(2-chloro-3,6-difluorophenyl)ethylamino]pyrimidin-4-yl}-3-ethoxythiophen-2-yl)-[1,2,4]oxadiazol-5 (4H)-she; 3-(5-{6-[2-(2-chloro-3,6-difluorophenyl)ethylamino]pyrimidin-4-yl}-3-ethoxythiophen-2-yl)-[1,2,4]oxadiazol-5 -ola; - 119 043145 3-(3-ethoxy-5-{6-[2-(2,4,6-trifluorophenyl)ethylamino]pyrimidin-4-yl}thiophen-2-yl)-[1,2,4]oxadiazol-5( 4H) - she; 3-(3-ethoxy-5-{6-[2-(2,4,6-trifluorophenyl)ethylamino]pyrimidin-4-yl}thiophen-2-yl)-[1,2,4]oxadiazol-5- ola; 3-(3-ethoxy-5-{6-[2-(2-ethoxyphenyl)ethylamino]pyrimidin-4-yl}thiophen-2-yl)-[1,2,4]oxadiazol5(4H)-one; 3-(3-ethoxy-5-{6-[2-(2-ethoxyphenyl)ethylamino]pyrimidin-4-yl}thiophen-2-yl)-[1,2,4]oxadiazol-5ol; 3-(5-{6-[2-(2,6-difluorophenyl)ethylamino]pyrimidin-4-yl}-3-ethoxythiophen-2-yl)-[1,2,4]oxadiazol5(4H)-one; 3-(5-{6-[2-(2,6-difluorophenyl)ethylamino]pyrimidin-4-yl}-3-ethoxythiophen-2-yl)-[1,2,4]oxadiazol5-ol; 3-(5-{6-[2-(4-chloro-2,6-difluorophenyl)ethylamino]pyrimidin-4-yl}-3-ethoxythiophen-2-yl)-[1,2,4]oxadiazol-5 (4H)-she; 3-(5-{6-[2-(4-chloro-2,6-difluorophenyl)ethylamino]pyrimidin-4-yl}-3-ethoxythiophen-2-yl)-[1,2,4]oxadiazol-5 -ola; 3-(5-{6-[2-(4-bromo-3-chlorophenyl)ethylamino]pyrimidin-4-yl}-3-ethoxythiophen-2-yl)-[1,2,4]oxadiazol-5(4H )-she; 3-(5-{6-[2-(4-bromo-3-chlorophenyl)ethylamino]pyrimidin-4-yl}-3-ethoxythiophen-2-yl)-[1,2,4]oxadiazol-5-ol ; 3-(5-{6-[2-(4-bromo-2,5-difluorophenyl)ethylamino]pyrimidin-4-yl}-3-ethoxythiophen-2-yl)-[1,2,4]oxadiazol-5 (4H)-she; 3-(5-{6-[2-(4-bromo-2,5-difluorophenyl)ethylamino]pyrimidin-4-yl}-3-ethoxythiophen-2-yl)-[1,2,4]oxadiazol-5 -ola; 3-(5-{6-[2-(4-bromo-3-fluorophenyl)ethylamino]pyrimidin-4-yl}-3-ethoxythiophen-2-yl)-[1,2,4]oxadiazol-5(4H )-she; 3-(5-{6-[2-(4-bromo-3-fluorophenyl)ethylamino]pyrimidin-4-yl}-3-ethoxythiophen-2-yl)-[1,2,4]oxadiazol-5-ol ; 3-(5-{6-[2-(4-bromo-2,6-difluorophenyl)ethylamino]pyrimidin-4-yl}-3-ethoxythiophen-2-yl)-[1,2,4]oxadiazol-5 (4H)-she; 3-(5-{6-[2-(4-bromo-2,6-difluorophenyl)ethylamino]pyrimidin-4-yl}-3-ethoxythiophen-2-yl)-[1,2,4]oxadiazol-5 -ola; 3-(5-{6-[2-(4-bromo-5-fluoro-2-methylphenyl)ethylamino]pyrimidin-4-yl}-3-ethoxythiophen-2-yl)-[1,2,4]oxadiazole -5(4H)-she; 3-(5-{6-[2-(4-bromo-5-fluoro-2-methylphenyl)ethylamino]pyrimidin-4-yl}-3-ethoxythiophen-2-yl)-[1,2,4]oxadiazole -5-ola; 3-(5-{6-[2-(4-bromo-3-methylphenyl)ethylamino]pyrimidin-4-yl}-3-ethoxythiophen-2-yl)-[1,2,4]oxadiazole5(4H)- she; 3-(5-{6-[2-(4-bromo-3-methylphenyl)ethylamino]pyrimidin-4-yl}-3-ethoxythiophen-2-yl)-[1,2,4]oxadiazol-5-ol ; 3-(5-{6-[2-(4-bromo-2-fluoro-5-methylphenyl)ethylamino]pyrimidin-4-yl}-3-ethoxythiophen-2-yl)-[1,2,4]oxadiazole -5(4H)-she; 3-(5-{6-[2-(4-bromo-2-fluoro-5-methylphenyl)ethylamino]pyrimidin-4-yl}-3-ethoxythiophen-2-yl)-[1,2,4]oxadiazole -5-ola; 3-(5-{6-[2-(4-bromo-3-methoxyphenyl)ethylamino]pyrimidin-4-yl}-3-ethoxythiophen-2-yl)-[1,2,4]oxadiazole5(4H)- she; 3-(5-{6-[2-(4-bromo-3-methoxyphenyl)ethylamino]pyrimidin-4-yl}-3-ethoxythiophen-2-yl)-[1,2,4]oxadiazol5-ol; 3-(5-{6-[2-(2,4-dimethoxyphenyl)ethylamino]pyrimidin-4-yl}-3-ethoxythiophen-2-yl)-[1,2,4]oxadiazol5(4H)-one; 3-(5-{6-[2-(2,4-dimethoxyphenyl)ethylamino]pyrimidin-4-yl}-3-ethoxythiophen-2-yl)-[1,2,4]oxadiazol-5ol; 3-(3-ethoxy-5-{6-[2-(4-hydroxy-3-methoxyphenyl)ethylamino]pyrimidin-4-yl}thiophen-2-yl)-[1,2,4]oxadiazol-5( 4H)-she; 3-(3-ethoxy-5-{6-[2-(4-hydroxy-3-methoxyphenyl)ethylamino]pyrimidin-4-yl}thiophen-2-yl)-[1,2,4]oxadiazol-5- ola; 3-(5-{6-[2-(2,3-dimethoxyphenyl)ethylamino]pyrimidin-4-yl}-3-ethoxythiophen-2-yl)-[1,2,4]oxadiazol-5(4H)- she; 3-(5-{6-[2-(2,3-dimethoxyphenyl)ethylamino]pyrimidin-4-yl}-3-ethoxythiophen-2-yl)-[1,2,4]oxadiazol-5-ol; 3-(5-{6-[2-(5-bromo-2-methoxyphenyl)ethylamino]pyrimidin-4-yl}-3-ethoxythiophen-2-yl)-[1,2,4]oxadiazole5(4H)- she; - 120 043145 3-(5-{6-[2-(5-bromo-2-methoxyphenyl)ethylamino]pyrimidin-4-yl}-3-ethoxythiophen-2-yl)-[1,2,4]oxadiazol5-ol; 3-(5-{6-[2-(3,4-dichlorophenyl)ethylamino]pyrimidin-4-yl}-3-ethoxythiophen-2-yl)-[1,2,4]oxadiazol5(4H)-one; 3-(5-{6-[2-(3,4-dichlorophenyl)ethylamino]pyrimidin-4-yl}-3-ethoxythiophen-2-yl)-[1,2,4]oxadiazol5-ol; 3-(5-{6-[2-(2,4-dichlorophenyl)ethylamino]pyrimidin-4-yl}-3-ethoxythiophen-2-yl)-[1,2,4]oxadiazol5(4H)-one; 3-(5-{6-[2-(2,4-dichlorophenyl)ethylamino]pyrimidin-4-yl}-3-ethoxythiophen-2-yl)-[1,2,4]oxadiazol5-ol; 3-(5-{6-[2-(4-bromo-2-chlorophenyl)ethylamino]pyrimidin-4-yl}-3-ethoxythiophen-2-yl)-[1,2,4]oxadiazole5(4Н)- she; 3-(5-{6-[2-(4-bromo-2-chlorophenyl)ethylamino]pyrimidin-4-yl}-3-ethoxythiophen-2-yl)-[1,2,4]oxadiazol-5ol; 3-(5-{6-[2-(4-bromo-2-fluorophenyl)ethylamino]pyrimidin-4-yl}-3-ethoxythiophen-2-yl)-[1,2,4]oxadiazole5(4Н)- she; 3-(5-{6-[2-(4-bromo-2-fluorophenyl)ethylamino]pyrimidin-4-yl}-3-ethoxythiophen-2-yl)-[1,2,4]oxadiazol-5ol; 3-(5-{6-[2-(4-bromo-2-methoxyphenyl)ethylamino]pyrimidin-4-yl}-3-ethoxythiophen-2-yl)-[1,2,4]oxadiazole5(4Н)- she; 3-(5-{6-[2-(4-bromo-2-methoxyphenyl)ethylamino]pyrimidin-4-yl}-3-ethoxythiophen-2-yl)-[1,2,4]oxadiazol5-ol; 3-(5-{6-[2-(4-bromo-2-methylphenyl)ethylamino]pyrimidin-4-yl}-3-ethoxythiophen-2-yl)-[1,2,4]oxadiazole5(4H)- she; 3-(5-{6-[2-(4-bromo-2-methylphenyl)ethylamino]pyrimidin-4-yl}-3-ethoxythiophen-2-yl)-[1,2,4]oxadiazol-5ol; 3-(5-{6-[2-(4-bromophenyl)ethylamino]pyrimidin-4-yl}-3-ethoxythiophen-2-yl)-[1,2,4]oxadiazol5(4H)-one; 3-(5-{6-[2-(4-bromophenyl)ethylamino]pyrimidin-4-yl}-3-ethoxythiophen-2-yl)-[1,2,4]oxadiazol-5ol; [2-(4-bromophenyl)ethyl]-{6-[4-ethoxy-5-(1H-tetrazol-5-yl)thiophen-2-yl]pyrimidin-4-yl}amine; 3-(5-{6-[2-(4-bromo-2,6-difluorophenyl)ethylamino]pyrimidin-4-yl}-3-trifluoromethylthiophen-2-yl)[1,2,4]oxadiazol-5( 4H) - she; 3-(5-{6-[2-(4-bromo-2,6-difluorophenyl)ethylamino]pyrimidin-4-yl}-3-trifluoromethylthiophen-2-yl)[1,2,4]oxadiazol-5- ola; 3-(5-{6-[2-(4-bromo-2,6-difluorophenyl)ethylamino]pyrimidin-4-yl}-3-methylthiophen-2-yl)-[1,2,4]oxadiazole5(4Н )-she; 3-(5-{6-[2-(4-bromo-2,6-difluorophenyl)ethylamino]pyrimidin-4-yl}-3-methylthiophen-2-yl)-[1,2,4]oxadiazol5-ol ; 2-{6-[2-(4-bromo-2,6-difluorophenyl)ethylamino]pyrimidin-4-yl}-4-ethoxythiazole-5-carboxylic acid; 2-{6-[2-(4-bromo-2,6-difluorophenyl)ethylamino]pyrimidin-4-yl}-4-ethylthiazole-5-carboxylic acid; 3-(2-{6-[2-(4-bromo-2,6-difluorophenyl)ethylamino]pyrimidin-4-yl}-4-ethoxythiazol-5-yl)-[1,2,4]oxadiazole5(4H )-she; 3-(2-{6-[2-(4-bromo-2,6-difluorophenyl)ethylamino]pyrimidin-4-yl}-4-ethoxythiazol-5-yl)-[1,2,4]oxadiazol5-ol ; 3-(2-{6-[2-(4-bromo-2,6-difluorophenyl)ethylamino]pyrimidin-4-yl}-4-ethylthiazol-5-yl)-[1,2,4]oxadiazole5(4H ) - she; 3-(2-{6-[2-(4-bromo-2,6-difluorophenyl)ethylamino]pyrimidin-4-yl}-4-ethylthiazol-5-yl)-[1,2,4]oxadiazol-5ol ; 5-(5-{6-[2-(4-bromo-2,6-difluorophenyl)ethylamino]pyrimidin-4-yl}-3-ethoxythiophen-2-yl)-[1,3,4]oxadiazol-2ol ; 5-(5-{6-[2-(4-bromo-2,6-difluorophenyl)ethylamino]pyrimidin-4-yl}-3-ethoxythiophen-2-yl)-[1,3,4]oxadiazole2(3H )-she; N-(5-{6-[2-(4-bromo-2,6-difluorophenyl)ethylamino]pyrimidin-4-yl}-3-ethoxythiophene-2-carbonyl)methanesulfonamide; 5-(6-((4-bromo-2,6-difluorophenethyl)amino)pyrimidin-4-yl)-3-ethoxy-N-sulfαmoylthiophene-2-carboxamide; 3-(5-{6-[2-(4-bromo-2,6-difluorophenyl)ethylamino]-2-methylpyrimidin-4-yl}-3-ethoxythiophen-2-yl)[1,2,4]oxadiazole -5(4H)-she; 3-(5-{6-[2-(4-bromo-2,6-difluorophenyl)ethylamino]-2-methylpyrimidin-4-yl}-3-ethoxythiophen-2-yl)[1,2,4]oxadiazole -5-ola; - 121 043145 3-(5-{6-[2-(4-bromophenyl)ethylamino]-2-methylpyrimidin-4-yl}-3-ethoxythiophen-2-yl)-[1,2,4]oxadiazol-5(4Н) -she; 3-(5-{6-[2-(4-bromophenyl)ethylamino]-2-methylpyrimidin-4-yl}-3-ethoxythiophen-2-yl)-[1,2,4]oxadiazol-5-ol; 3-(5-{6-[2-(4-bromo-2,6-difluorophenyl)ethylamino]pyrimidin-4-yl}-3-isopropoxythiophen-2-yl)-[1,2,4]oxadiazol-5 (4H) - she; 3-(5-{6-[2-(4-bromo-2,6-difluorophenyl)ethylamino]pyrimidin-4-yl}-3-isopropoxythiophen-2-yl)-[1,2,4]oxadiazol-5 -ola; 4-{6-[2-(4-bromo-2,6-difluorophenyl)ethylamino]pyrimidin-4-yl}-2-(2-hydroxyethoxy)benzoic acid; 4-{6-[2-(4-bromo-2,6-difluorophenyl)ethylamino]pyrimidin-4-yl}-2-propylbenzoic acid; 4-{6-[2-(4-bromo-2,6-difluorophenyl)ethylamino]pyrimidin-4-yl}-2-propoxybenzoic acid; 4-{6-[2-(4-bromo-2,6-difluorophenyl)ethylamino]pyrimidin-4-yl}-2-ethylsulfanylbenzoic acid; 4-{6-[2-(4-bromo-2,6-difluorophenyl)ethylamino]pyrimidin-4-yl}-2-cyclobutoxybenzoic acid; 4-{6-[2-(4-bromo-2,6-difluorophenyl)ethylamino]pyrimidin-4-yl}-2-butoxybenzoic acid; 4-{6-[2-(4-bromo-2-ethoxyphenyl)ethylamino]pyrimidin-4-yl}-2-ethoxybenzoic acid; 5-{6-[2-(2,6-difluorophenyl)ethylamino]pyrimidin-4-yl}-3-ethylthiophene-2-carboxylic acid; 3-ethoxy-5-[6-(2-o-tolylethylamino)pyrimidin-4-yl]thiophene-2-carboxylic acid; 3-fluoro-5-{6-[2-(4-trifluoromethylphenyl)ethylamino]pyrimidin-4-yl}thiophene-2-carboxylic acid; 3-ethoxy-5-{6-[2-(4-methoxyphenyl)ethylamino]pyrimidin-4-yl}thiophene-2-carboxylic acid; 5-{6-[2-(2,4-dimethylphenyl)ethylamino]pyrimidin-4-yl}-3-trifluoromethylthiophene-2-carboxylic acid; 5-{6-[2-(3-bromo-4-methoxyphenyl)ethylamino]pyrimidin-4-yl}-3-ethoxythiophene-2-carboxylic acid; 3-ethoxy-5-{6-[2-(3-methoxycarbonylphenyl)ethylamino]pyrimidin-4-yl}thiophene-2-carboxylic acid; 3-(5-{6-[2-(3,4-dimethylphenyl)ethylamino]pyrimidin-4-yl}-3-ethoxythiophen-2-yl)-[1,2,4]oxadiazol-5(4H)one ; 3-(5-{6-[2-(3,4-dimethylphenyl)ethylamino]pyrimidin-4-yl}-3-ethoxythiophen-2-yl)-[1,2,4]oxadiazol-5-ol; 3-(3-ethoxy-5-{6-[2-(2-fluoro-4-trifluoromethylphenyl)ethylamino]pyrimidin-4-yl}thiophen-2-yl)-[1,2,4]oxadiazol-5( 4H) - she; 3-(3-ethoxy-5-{6-[2-(2-fluoro-4-trifluoromethylphenyl)ethylamino]pyrimidin-4-yl}thiophen-2-yl)-[1,2,4]oxadiazol-5- ola; 3-(3-ethoxy-5-{6-[2-(3-hydroxy-4-methoxyphenyl)ethylamino]pyrimidin-4-yl}thiophen-2-yl)-[1,2,4]oxadiazol-5( 4H) - she; 3-(3-ethoxy-5-{6-[2-(3-hydroxy-4-methoxyphenyl)ethylamino]pyrimidin-4-yl}thiophen-2-yl)-[1,2,4]oxadiazol-5- ola; 3-(5-{6-[2-(3-Chloro-4-methoxyphenyl)ethylamino]pyrimidin-4-yl}-3-ethoxythiophen-2-yl)-[1,2,4]oxadiazol-5(4Н )-she; 3-(5-{6-[2-(3-Chloro-4-methoxyphenyl)ethylamino]pyrimidin-4-yl}-3-ethoxythiophen-2-yl)-[1,2,4]oxadiazol-5-ol ; 3-(5-{6-[2-(4-dimethylamino-2-fluorophenyl)ethylamino]pyrimidin-4-yl}-3-ethoxythiophen-2-yl)-[1,2,4]oxadiazol-5(4Н )-She and 3-(5-{6-[2-(4-dimethylamino-2-fluorophenyl)ethylamino]pyrimidin-4-yl}-3-ethoxythiophen-2-yl)-[1,2,4]oxadiazol-5-ol ; or a pharmaceutically acceptable salt thereof. 10. The compound according to claim 4, selected from the group consisting of 5-(4-{6-[2-(4-bromo-2,6-difluorophenyl)ethylamino]pyrimidin-4-yl}-2-methoxyphenyl)isoxazol-3-ol; 5-(4-{6-[2-(4-bromo-2,6-difluorophenyl)ethylamino]pyrimidin-4-yl}-2-methoxyphenyl)uzoxazol-3(2H)-one; 5-{6-[2-(4-bromo-2,6-difluorophenyl)ethylamino]pyrimidin-4-yl}-3-methoxythiophene-2-carboxylic acid; 5-{6-[2-(3,4-dichloro-2-methylphenyl)ethylamino]pyrimidin-4-yl}-3-ethoxythiophene-2-carboxylic acid; 2-cyclobutoxy-4-{6-[2-(4-difluoromethyl-5-fluoro-2-methoxyphenyl)ethylamino]pyrimidin-4-yl}benzoic acid; 5-{6-[2-(4-difluoromethyl-5-fluoro-2-methoxyphenyl)ethylamino]pyrimidin-4-yl}-3-ethoxythiophene-2carboxylic acid; 2-cyclobutoxy-4-{6-[2-(2-methoxy-4,5-dimethylphenyl)ethylamino]pyrimidin-4-yl}benzoic acid; 3-ethoxy-5-{6-[2-(2-methoxy-4,6-dimethylphenyl)ethylamino]pyrimidin-4-yl}thiophene-2-carboxylic acid; - 122 043145 2-ETOXY-4-{6-[2-(2-ethoxy-4-trifluoromethylphenyl)ethylamino]pyrimidin-4-yl}benzoic acid; 4-{6-[2-(2-ethoxy-4-trifluoromethylphenyl)ethylamino]pyrimidin-4-yl}-2-methylsulfanylbenzoic acid; (2-ETOXY-4-{6-[2-(2-ethoxy-4-trifluoromethylphenyl)ethylamino]pyrimidin-4-yl}phenyl)acetic acid; 3-ethoxy-5-{6-[2-(2-ethoxy-4-trifluoromethylphenyl)ethylamino]pyrimidin-4-yl}thiophene-2-carboxylic acid; 5-{6-[2-(4-difluoromethoxy-2-methoxyphenyl)ethylamino]pyrimidin-4-yl}-3-ethoxythiophene-2-carboxylic acid; 3-ethoxy-5-{6-[2-(2-fluoro-6-methoxy-4-trifluoromethylphenyl)ethylamino]pyrimidin-4-yl}thiophene-2carboxylic acid; 3-(4-{6-[2-(4-bromo-2,6-difluorophenyl)ethylamino]pyrimidin-4-yl}-2-ethoxyphenyl)-[1,2,4]oxadiazol-5(4H)one ; 3-(4-{6-[2-(4-bromo-2,6-difluorophenyl)ethylamino]pyrimidin-4-yl}-2-ethoxyphenyl)-[1,2,4]oxadiazol-5-ol; (4-{6-[2-(4-bromo-2,6-difluorophenyl)ethylamino]pyrimidin-4-yl}-2-chloro-6-ethylphenyl)acetic acid; (5-{6-[2-(4-bromo-2,6-difluorophenyl)ethylamino]pyrimidin-4-yl}-3-ethylthiophen-2-yl)acetic acid; 5-(4-{6-[2-(4-bromo-2,6-difluorophenyl)ethylamino]pyrimidin-4-yl}-2-ethoxyphenyl)isoxazol-3-ol; 5-(4-(6-((4-bromo-2,6-difluorophenethyl)amino)pyrimidin-4-yl)-2-ethoxyphenyl)isoxazol-3(2H)-one; 3-(5-{6-[2-(5-bromo-2-methylsulfanylphenyl)ethylamino]pyrimidin-4-yl}-3-ethoxythiophen-2-yl)- [ 1,2,4]ox-sadiazol-5(4H)-one; 3-(5-{6-[2-(5-bromo-2-methylsulfanylphenyl)ethylamino]pyrimidin-4-yl}-3-ethoxythiophen-2-yl)[1,2,4]oxadiazol-5-ol; (5-{6-[2-(4-bromo-2,6-difluorophenyl)ethylamino]pyrimidin-4-yl}-3-propylthiophen-2-yl)acetic acid; (5-{6-[2-(4-bromo-2,6-difluorophenyl)ethylamino]pyrimidin-4-yl}-3-difluoromethoxythiophen-2-yl)acetic acid; 4-{6-[2-(4-bromo-2,6-difluorophenyl)ethylamino]pyrimidin-4-yl}-2-butoxy-6-fluorobenzoic acid; 3-ethoxy-5-{6-[2-(2-methoxy-6-methylphenyl)ethylamino]pyrimidin-4-yl}thiophene-2-carboxylic acid; 4-{6-[2-(2-ethoxy-4-trifluoromethylphenyl)ethylamino]pyrimidin-4-yl}-2-propylbenzoic acid; 4-{6-[2-(4-difluoromethoxy-2-methoxyphenyl)ethylamino]pyrimidin-4-yl}-2-methylsulfanylbenzoic acid, 4-{6-[2-(2,6-difluoro-4-methoxyphenyl)ethylamino]pyrimidin-4-yl}-2-methylsulfanylbenzoic acid; 4-{6-[2-(4-bromo-2,6-difluorophenyl)ethylamino]pyrimidin-4-yl}-2-isobutoxybenzoic acid; 4-{6-[2-(4-bromo-2,6-difluorophenyl)ethylamino]pyrimidin-4-yl}-2-cyclopropoxybenzoic acid; N-(4-{6-[2-(4-bromo-2,6-difluorophenyl)ethylamino]pyrimidin-4-yl}-2-ethoxybenzoyl)methanesulfonamide; 5-{6-[2-(5-Chloro-2-methoxy-4-trifluoromethylphenyl)ethylamino]pyrimidin-4-yl}-3-ethoxythiophene-2carboxylic acid; 3-ethoxy-5-{6-[2-(2-methoxy-4-trifluoromethylphenyl)ethylamino]pyrimidin-4-yl}thiophene-2-carboxylic acid; 3-ethoxy-5-{6-[2-(2-methoxy-4-trifluoromethoxyphenyl)ethylamino]pyrimidin-4-yl}thiophene-2-carboxylic acid; 5-{6-[2-(2-difluoromethoxy-4-trifluoromethylphenyl)ethylamino]pyrimidin-4-yl}-3-ethoxythiophene-2carboxylic acid and 3-(2-ethoxy-4-{6-[2-(2-methoxy-4,5-dimethylphenyl)ethylamino]pyrimidin-4-yl}phenoxy)propionic acid; or a pharmaceutically acceptable salt thereof. 11. A pharmaceutical composition that modulates PGE2 EP2 and/or EP4 receptors, containing as an active principle a compound according to any one of claims 4 to 10 or a pharmaceutically acceptable salt thereof and at least one therapeutically inert excipient. 12. The use of a compound according to any one of claims 4 to 10 or a pharmaceutically acceptable salt thereof as a drug which is a modulator of PGE2 EP2 and/or EP4 receptors. 13. The use of a compound according to any one of paragraphs.4-10 or its pharmaceutically acceptable salt for the treatment of diseases selected from the group consisting of malignant neoplasm; pain; endometriosis; autosomal dominant polycystic kidney disease; acute ischemic syndromes in patients with atherosclerosis; pneumonia and neurodegenerative diseases. 14. The use of a compound according to any one of claims 4 to 10, or a pharmaceutically acceptable salt thereof, for the treatment of a cancer selected from melanoma; lung cancer; bladder cancer- - 123 043145 rya; renal carcinoma; malignant neoplasms of the gastrointestinal tract; endometrial cancer; ovarian cancer; cervical cancer; neuroblastoma and prostate cancer. 15. The use of a compound according to any one of claims 4-10 or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment of diseases selected from the group consisting of cancer; pain; endometriosis; autosomal dominant polycystic kidney disease; acute ischemic syndromes in patients with atherosclerosis; pneumonia and neurodegenerative diseases. 16. The use of a compound according to any one of claims 4-10, or a pharmaceutically acceptable salt thereof, for the treatment of cancer by modulating an immune response, including reactivation of the immune system in the tumor. 17. A method for modulating an immune response in a subject having a tumor, comprising administering an effective amount of a compound of formula (III) according to any one of pi.4-10 or a pharmaceutically acceptable salt thereof; where the specified effective amount reactivates the immune system in the tumor of the specified subject. 18. A method for treating a malignant neoplasm; pain; endometriosis; autosomal dominant polycystic kidney disease; acute ischemic syndromes in patients with atherosclerosis; pneumonia and neurodegenerative diseases; comprising administering to a subject in need thereof a compound of formula (III) according to any one of claims 4-10, or a pharmaceutically acceptable salt thereof.