CROSS REFERENCE TO RELATED APPLICATIONS

This application is a United States Application under 35 U.S.C. 371 claiming benefit of PCT Application No. PCT/EP2018/062843, filed on May 17, 2018, which claims the benefit of PCT Application No. PCT/EP2017/061987, filed on May 18, 2017.

The present invention relates to benzofurane and benzothiophene derivatives of formula (I) and their use in the treatment of cancer by modulating an immune response comprising a reactivation of the immune system in the tumor. The present invention further relates to novel benzofurane and benzothiophene derivatives of formula (II) and their use as pharmaceuticals. The invention also concerns related aspects including processes for the preparation of the compounds, pharmaceutical compositions containing one or more compounds of formula (I)/formula (II), and their use as modulators of the PGE2 receptors EP2 (alias PTGER2, alias PGE2 Receptor EP2 Subtype) and/or EP4 (alias PTGER4, alias EP4R, alias PGE2 Receptor EP4 Subtype). The compounds of formula (I)/formula (II) may especially be used as single agents or in combination with one or more therapeutic agents and/or chemotherapy and/or radiotherapy and/or immunotherapy in the prevention/prophylaxis or treatment of cancers; in particular the prevention/prophylaxis or treatment of melanoma; lung cancer; bladder cancer; renal carcinomas; gastro-intestinal cancers; endometrial cancer; ovarian cancer; cervical cancer; and neuroblastoma.

Prostaglandin E2 (PGE2) is a bioactive lipid that can elicit a wide range of biological effects associated with inflammation and cancer. PGE2 belongs to the prostanoid family of lipids. Cyclooxygenase (COX) is the rate-limiting enzyme in the synthesis of biological mediators termed prostanoids, consisting of prostaglandin PGD2, PGE2, PGF2α, prostacyclin PG12, and thromboxane TXA2. Prostanoids function via 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 stimulates adenylate cyclase, resulting in elevation of cytoplasmic cAMP levels to initiate multiple downstream events via its prototypical effector Protein kinase A. In addition, PGE2 is also able to signal via PI3K/AKT and Ras-MAPK/ERK signalling

Cancers figure among the leading causes of death worldwide. Tumors are comprised of abnormally proliferating malignant cancer cells but also of a functionally supportive microenvironment. This tumor microenvironment is comprised of a complex array of cells, extracellular matrix components, and signaling molecules and is established by the altered communication between stromal and tumor cells. As tumors expand in size, they elicit the production of diverse factors that can help the tumor to grow such as angiogenic factors (promoting ingrowth of blood vessels) or that can help to evade the attack of the host immune response. PGE2 is such an immuno-modulatory factor produced in tumors.

It is well established that COX2, mainly via PGE2, promotes overall growth of tumors and is upregulated and correlates with clinical outcome in a high percentage of common cancers, especially colorectal, gastric, esophageal, pancreatic, breast and ovarian cancer. High COX-2 and PGE2 expression levels are associated with neoplastic transformation, cell growth, angiogenesis, invasiveness, metastasis and immune evasion.

The finding that COX2is over-expressed and plays an important role in carcinogenesis in gastrointestinal (GI) cancers including among others esophagus, gastric and colorectal cancers has led to the fact that COX-inhibitors (Coxibs), including Celecoxib, and other nonsteroidal anti-inflammatory drugs (NSAID), including aspirin, are among the most studied cancer chemopreventive agents in development today (for 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 April; 15(2):113)

In addition to COX2and PGE2, also EP receptors, especially EP2 and EP4, are aberrantly over-expressed in multiple types of cancers, especially in gastro-intestinal (GI) cancers and pancreatic cancer. Furthermore, the over-expression of PGE2 and/or EP2 and/or EP4 correlates with diseases progression in some cancer types such as oesophageal squamous cell carcinoma (Kuo K T et al, Ann Surg Onc 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); head and neck squamous cell carcinoma (Gallo 0 et al, Hum Pathol. 2002, 33(7):708-14).

In accordance to studies performed with Coxibs, in mice, knockout of either COX1, COX2, microsomal prostaglandin E synthase 1 (mPTGES1), EP2 or EP4 resulted in reduced tumor incidence and progression in different tumor models. Conversely, overexpression of COX2or mPTGES1 in transgenic mice resulted in increased tumor incidence and tumor burden (for review see Nakanishi M. and Rosenberg D. W., Seminars in Immunopathology 2013, 35: 123-137; Fischer S M et al Cancer Prev Res (Phila) 2011 November; 4(11):1728-35; Fulton A M et al Cancer Res 2006; 66(20); 9794-97).

Several pharmacological studies to inhibit tumor growth and progression using EP receptor antagonists or COX2inhibitors in different tumor models have been conducted in mice. Among others, EP antagonists and/or COX2inhibitors 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), gastro-intestinal cancer (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 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 H A et al, PLOS One 2012, 7(8):e43376; Funahashi H et al, Cancer Res 2007, 67(15):7068-71). COX2inhibitors were approved for the treatment of familial adenomatous polyposis (FAP) which is an inherited pre-disposition syndrome for colorectal cancer, but later retracted due to cardiovascular side effects.

Mechanistically, PGE2 signalling is mainly involved in the crosstalk between tumor and stromal cells, thereby creating a microenvironment which is favourable for the tumor to grow. In particular, PGE2 signalling via EP2 and EP4 can for example (i) suppress the cytotoxicity and cytokine production of natural killer cells, (ii) skew the polarization of tumor-associated macrophages towards 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 MDSC (myeloid derived suppressor cells), which are potent immunosuppressive cells that accumulate in tumors both in patients and in experimental animal models (see for example 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 IFN-γ, TNF-α IL-12 and IL-2 expression in immune cells such as natural killer cells, T-cells, dendritic cells and macrophages, impairing the ability of these immune cells to induce tumor cell apoptosis and restrain tumorigenesis (see for example 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) suppress activation, IL-2 responsiveness, expansion and cytotoxicity of T-cells thereby contributing to local immunosuppression (see for example Specht C et al, Int J Cancer 200191:705-712); (vi) inhibit maturation of dendritic cells, their ability to present antigens and to 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 for nutrient and oxygen supply) by enhancing endothelial cell motility and survival as well as by increasing the expression of VEGF (vascular endothelial growth factor) (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) enhance tumor cell survival (via PI3K/AKT and MAPK signalling). For 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 e al Trends Immunol 2002, 22, 144-150).

Coxibs have been shown to render tumor cells more sensitive to radiation and chemotherapy and several clinical trials have been performed or are ongoing combining Coxibs with radio- and/or chemotherapy (for review see e.g 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).

Furthermore, there is some evidence of 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 with aromatase inhibitors (see for example Generali D et al, Br J Cancer. 2014; 111(1):46-54; Lustberg M B et all, Clin Breast Cancer. 2011 August; 11(4):221-7; Falandry C et al, Breast Cancer Res Treat. 2009 August; 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 different mouse tumor models when Aspirin (a COX1/2 inhibitor) was combined with and anti-VEGF antibody (Motz G T et al; Nat Med 2014 20(6):607) and this combination is currently under investigation in clinical trials (NCT02659384).

Recently, it has been shown that, if combined, different immunotherapeutic approaches can have enhanced anti-tumor efficacy. Due to the immune-modulatory properties of PGE2, Coxibs have thus also been used in combination with different immunotherapeutic approaches. In particular, additive or even synergistic effects could be observed when Coxibs were combined with dendritic cell vaccination in a rat glioma model and in a mouse mesothelioma or melanoma model (Zhang H et al, Oncol Res. 2013; 20(10):447-55; Veltman J D et al, BMC Cancer. 2010; 10:464; Toomey D et all, Vaccine. 2008 Jun. 25; 26(27-28):3540-9); with granulocyte-macrophage colony-stimulating factor (GM-CSF) in mouse brain tumors (Eberstål S et al, Int J Cancer. 2014 Jun. 1; 134(11):2748-53); with interferon gamma (IFN-γ) in brain tumors (Eberstål S et al, Cancer Immunol Immunother. 2012, 61(8):1191-9); with dendritic cell vaccination or with GM-CSF in a mouse breast cancer model (Hahn T et al, Int J Cancer. 2006, 118(9):2220-31); and with adenoviral interferon beta (IFN-β) therapy in a mouse mesothelioma model (DeLong P et al, Cancer Res. 2003 Nov. 15; 63(22):7845-52). Along these lines, additive or even synergistic effects of Coxibs and/or EP2 and/or EP4 antagonists can also be envisaged 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, which indicates 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 ectonucleotidases, 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 bear receptors for ADO, which are mainly of the A2a/A2b type (Hoskin D W, et al, Int J Oncol 2008, 32:527-535). Signaling via Adenosine receptors and EP2/EP4 receptors converges on the cytoplasmic adenylyl cyclase, leading to up-regulation of cAMP. It was shown that Adenosine and PGE2 cooperate in the suppression of 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 especially PD1 and/or PDL1 blockade, or other targeted therapies; for the prevention/prophylaxis or treatment of cancers, notably for the prevention/prophylaxis or treatment of skin cancer including melanoma including metastatic melanoma; lung cancer including non-small cell lung cancer; bladder cancer including urinary bladder cancer, urothelial cell carcinoma; renal carcinomas including renal cell carcinoma, metastatic renal cell carcinoma, metastatic renal clear cell carcinoma; gastro-intestinal cancers including colorectal cancer, metastatic colorectal cancer, familial adenomatous polyposis (FAP), oesophageal cancer, gastric cancer, gallbladder cancer, cholangiocarcinoma, hepatocellular carcinoma, and pancreatic cancer such as pancreatic adenocarcinoma or pancreatic ductal carcinoma; endometrial cancer; ovarian cancer; cervical cancer; neuroblastoma; prostate cancer including castrate-resistant prostate cancer; brain tumors including brain metastases, malignant gliomas, glioblastoma multiforme, medulloblastoma, meningiomas; breast cancer including triple negative breast carcinoma; oral tumors; nasopharyngeal tumors; 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; lymphoma including Burkitt's lymphoma, Hodgkin's lymphoma, MALT lymphoma; multiple myelomas; and virally induced tumors.

In addition, selective or dual EP2 and/or EP4 antagonists may be useful in several other diseases or disorders responding for example to treatment with COX2inhibitors, with the advantage that EP2 and/or EP4 antagonists should not possess the potential cardiovascular side effects seen with COX2inhibitors, which are mainly due to interference with PGI2 and TXA2 synthesis (see for example Boyd M J et al, bioorganic and medicinal chemistry letters 21, 484, 2011). For example, blockade of prostaglandin production by COX inhibitors is the treatment of choice for pain, including especially inflammatory pain and painful menstruation. Thus EP2 and/or EP4 and/or dual EP2/EP4 antagonists may be useful for the treatment of pain, especially inflammatory pain. Evidence from EP2 knockout mice suggest that EP2 antagonists can be used for the treatment of inflammatory hyperalgesia (Reinold H et al, J Clin Invest 2005, 115(3):673-9). In addition, EP4 antagonists have beneficial effect in vivo in inflammatory pain models (eg Murase A, Eur J Pharmacol 2008; Clark P, J Pharmacol Exp Ther. 2008; Maubach K A 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 an EP2 in combination with an EP4 antagonist showed significant, but partial inhibition of joint inflammation in mouse collagen-induced arthritis model (Honda T et al J Exp Med 2006, 203(2):325-35).

EP2 and/or dual EP2/EP4 antagonists may be of use to decrease female fertility, i.e. they have been shown to prevent pregnancy if used as contraceptive in macaques (Peluffo M C et al Hum Reprod 2014). EP2 knockout mice have decreased 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 S L J Clin Inves 1999, 103(11):1539-45; Kennedy C R et al, Nat Med 1999 5(2):217-20).

There is also rationale that EP2 and/or EP4 antagonists may be of use to prevent or treat endometriosis: for example EP2, EP3 and EP4 and COX2are overexpressed in endometriosis cell lines and tissues (e.g. Santulli P et al J Clin Endocrinol Metab 2014, 99(3):881-90); antagonist treatment was shown to inhibit the adhesion of endometrial cells in vitro (Lee J et al Biol Reprod 2013, 88(3):77; Lee J et al Fertil Steril 201, 93(8):2498-506); COX2inhibitors have been shown to reduce endometric lesions in mice via EP2 (Chuang P C et al, Am J Pathol 2010, 176(2):850-60); and antagonist treatment has been shown to induce apoptosis of endometric cells in vitro (Banu S K et al, MOI endocrinol 2009, 23(8) 1291-305).

Dual EP2/EP4 antagonists, or the combination of a selective EP2 antagonists with a selective EP4 antagonist, may be of potential use for autoimmune disorders; e.g. they have been shown to be effective in mouse model for multiple sclerosis (MS) (Esaki Y et al PNAS 2010, 107(27):12233-8; Schiffmann 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 signalling in cells in vitro (Kojima F et al Prostaglandins Other Lipid Mediat 2009, 89:26-33) linked dual or selective EP2 and/or EP4 antagonists to the treatment of rheumatoid arthritis. Also, elevated levels of PGE(2) have been reported in synovial fluid and cartilage from patients with osteoarthritis (OA) and it has been shown that PGE2 stimulates matrix degradation in osteoarthitis chondrocytes via the EP4 receptor (Attur M et al, J Immunol. 2008; 181(7):5082-8).

EP4 overexpression is associated with enhanced inflammatory reaction in atherosclerotic plaques of patients (Cipollone F et al, Artherioscler Thromb Vasc Biol 2005, 25(9); 1925-31), thus the use of EP4 and/or dual EP2/EP4 antagonists may be indicated for plaque stabilization and prevention/prophylaxis of acute ischemic syndromes. In addition, EP4 deficiency suppresses early atherosclerosis, by compromising macrophage survival (Babaev V R et al, Cell Metab. 2008 December; 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 demonstrated that PGE(2) via EP2 accounts for subsequent impairment of lung recruitment of leukocytes and clearance ofStreptococcus pneumoniae, as well as enhanced generation of IL-10 in vivo (Medeiros A I et al J Exp Med 2009 206(1):61-8).

EP2 and/or dual EP2/EP4 antagonists may in addition be useful for the treatment of neurodegenerative diseases (for review see Cimino P J et al, Curr Med Chem. 2008; 15(19):1863-9). EP2 receptor accelerates progression of inflammation in a mouse model of amyotrophic lateral sclerosis (ALS) (Liang X et al, Ann Neurol 2008, 64(3):304-14); COX2inhibitors have been shown to be neuroprotective in rodent models of stroke, Parkinson disease and ALS (for review see Liang X et al J Mol Neurosci 2007, 33(1):94-9), decreased neurotoxicity was observed in EP2 knockout mice treated with parkinsonian toxican (Jin J et al, J Neuroinflammation 2007, 4:2), PGE2 via EP2 aggravates neurodegeneration in cultured rat cells (Takadera T et al, Life Sci 2006, 78(16): 1878-83); Reduced amyloid burden was observed in Alzheimer's disease mouse model if crossed 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 F S et al Glia 2005, 52(1):70-7); PGE2 via EP2 increases amyloid precursor protein (APP) expression in cultured rat microglial cells (Pooler A M et al Neurosci. Lett. 2004, 362(2):127-30). EP2 antagonist limits oxidative damage from activation of innate immunity (intracranial injection of LPS) in the brain and could be used for Alzheimer or HIV associated dementia (Montine T J et al, J Neurochem 2002, 83(2):463-70). In an Alzheimer's disease mouse model cognitive function could 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 to treat autosomal dominant polycystic kidney disease (ADPKD): PGE2 via EP2 induces cystogenesis of 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).

EP4 and/or dual EP2/EP4 antagonists may also be useful to treat osteoporosis: PGE2 stimulates bone resorption mainly via EP4 and partially via EP2 (Suzawa T et all, Endocrinology. 2000 April; 141(4):1554-9), EP4 knockout mice show impaired bone resorption (Miyaura C et al, J Biol Chem 2000, 275(26): 19819-23) and an EP4 antagonists showed partial inhibition of PGE(2)-stimulated osteoclastogenesis and osteoclastic bone resorption (Tomita M et al, Bone. 2002 January; 30(1):159-63).

WO2008/152093 discloses selective EP2 receptor modulators which comprise an indole ring linked to the rest of the molecule in position 3, and a pyrimidine moiety which however is not substituted with a directly linked aromatic substituent. WO2006/044732 discloses pyrimidine compounds which are modulators of PGD2 claimed to be useful e.g. in the treatment of allergic diseases; however for example the exemplified compound CAS 1001913-77-4 has been tested to be inactive on both the EP2 and the EP4 receptor in the in vitro assay set out in the experimental part below. WO2008/006583 discloses pyrimidin derivatives which are ALK-5 inhibitors. WO2006/044732 and WO2008/039882 disclose certain pyrimidine derivatives as protaglandin 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 which are claimed to be active as anti-cancer agents are disclosed in WO2006/128129, WO2008/008059 and Bioorg. Med. Chem 2013, 21(2), 540-546. WO2013/163190 WO2015/058067, and WO2015/058031 disclose certain DNA-PK inhibitors interacting with DNA repair processes. The disclosed compounds are thought to be useful to sensitize cancer cells by directly modulating cancer cell proliferation, and to enhance the efficacy of both cancer chemotherapy and radiotherapy.

The present invention provides novel benzofurane and benzothiophene derivatives of formula (I)/formula (II) which are modulators of the prostaglandin 2 receptors EP2 and/or EP4. Certain compounds of the present invention are dual antagonists of both the EP2 and the EP4 receptor. The present compounds may, thus, be useful for the prevention/prophylaxis or treatment of diseases which respond to the blockage of the EP2 receptors and/or the EP4 receptors such as especially cancers, wherein a particular aspect is the treatment of cancer by modulating an immune response comprising a reactivation of the immune system in the tumor; as well as pain including especially inflammatory pain and painful menstruation; endometriosis; acute ischemic syndromes in atherosclerotic patients; pneumonia; neurodegenerative diseases including amyotrophic lateral sclerosis, stroke; Parkinson disease, Alzheimer's disease and HIV associated dementia; autosomal dominant polycystic kidney disease; and to control female fertility.

1) A First Aspect of the Invention Relates to Compounds of the Formula (I)


for use in the treatment of a cancer, wherein said cancer is treated by modulating an immune response comprising a reactivation of the immune system in the tumor;
wherein said cancer is notably a cancer selected from melanoma including metastatic melanoma; lung cancer including non-small cell lung cancer; bladder cancer including urinary bladder cancer, urothelial cell carcinoma; renal carcinomas including renal cell carcinoma, metastatic renal cell carcinoma, metastatic renal clear cell carcinoma; gastro-intestinal cancers including colorectal cancer, metastatic colorectal cancer, familial adenomatous polyposis (FAP), oesophageal cancer, gastric cancer, gallbladder cancer, cholangiocarcinoma, hepatocellular carcinoma, and pancreatic cancer such as pancreatic adenocarcinoma or pancreatic ductal carcinoma; endometrial cancer; ovarian cancer; cervical cancer; neuroblastoma; prostate cancer including castrate-resistant prostate cancer; brain tumors including brain metastases, malignant gliomas, glioblastoma multiforme, medulloblastoma, meningiomas; breast cancer including triple negative breast carcinoma; oral tumors; nasopharyngeal tumors; 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; lymphoma including Burkitt's lymphoma, Hodgkin's lymphoma, MALT lymphoma; multiple myelomas; and virally induced tumors (especially such cancer is selected from melanoma; lung cancer; bladder cancer; renal carcinomas; gastro-intestinal cancers; endometrial cancer; ovarian cancer; cervical cancer; and neuroblastoma);
wherein said compound is optionally used in combination with one or more chemotherapy agents and/or radiotherapy and/or targeted therapy;
wherein in compounds of the formula (I)
the fragment


is substituted with R2, wherein R2represents hydrogen, (C1-4)alkyl (especially methyl, ethyl), halogen (especially chloro, bromo), or cyano; and
is optionally substituted with (R1)n; wherein (R1)nrepresents one, two or three optional substituents (i.e. said fragment is, in addition to R2, unsubstituted, or substituted with one, two or three R1), wherein said substituents R1are independently selected from (C1-3)alkyl (especially methyl), (C1-3)alkoxy (especially methoxy), halogen (especially fluoro, or chloro), (C1-3)fluoroalkyl (especially trifluoromethyl), (C1-3)fluoroalkoxy (especially trifluoromethoxy), or cyano; (for avoidance of any doubt: substituents (R1)nare in addition to the substituent R2as defined above);
X represents S or O;
R3represents hydrogen, methyl or trifluoromethyl (especially hydrogen);
R4aand R4bindependently represent hydrogen, methyl, or R4aand R4btogether with the carbon atom to which they are attached represent a cycloprop-1,1-diyl group;
R5aand R5bindependently represent hydrogen, methyl, or R5aand R5btogether with the carbon atom to which they are attached represent a cycloprop-1,1-diyl group;
Ar1representsphenyl, or 5- or 6-membered heteroaryl (notably 5-membered heteroaryl, especially thiophenyl or thiazolyl); wherein said phenyl or 5- or 6-membered heteroaryl independently is mono-, di- or tri-substituted, wherein the substituents are independently selected from(C1-6)alkyl (especially methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, 1-methyl-propan-1-yl, tert.-butyl, 3-methyl-butyl);(C1-4)alkoxy (especially methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy);(C1-3)fluoroalkyl, wherein said (C1-3)fluoroalkyl is optionally substituted with hydroxy (especially trifluoromethyl, 2,2,2-trifluoro-1-hydroxy-ethyl);(C1-3)fluoroalkoxy (especially difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy);halogen (especially fluoro, chloro, bromo);cyano;(C3-6)cycloalkyl, wherein said (C3-6)cycloalkyl is unsubstituted or mono-substituted with amino (especially cyclopropyl, 1-amino-cyclopropyl);(C4-6)cycloalkyl containing a ring oxygen atom, wherein said (C4-6)cycloalkyl containing a ring oxygen atom is unsubstituted or mono-substituted with hydroxy (especially 3-hydroxy-oxetan-3-yl);(C3-6)cycloalkyl-oxy (especially cyclobutyl-oxy, cyclopentyl-oxy);hydroxy;—X1—CO—RO1, whereinX1represents a direct bond, (C1-3)alkylene (especially —CH2—, —CH(CH3)—, —C(CH3)2—, —CH2—CH2—), —O—(C1-3)alkylene-* (especially —O—CH2—*, —O—CH(CH3)—*, —O—C(CH3)2—*, —O—CH2—CH2—*), —NH—(C1-3)alkylene* (especially —NH—CH2*, —NH—CH(CH3)—*), —S—CH2*, —CF2—, —CH═CH—, —CH≡CH—, —NH—CO—*, —CO—, or (C3-5)cycloalkylene; wherein the asterisks indicate the bond that is linked to the —CO—RO1group; andRO1represents—OH;—O—(C1-4)alkyl (especially ethoxy, methoxy);—NH—SO2—RS3wherein RS3represents (C1-4)alkyl, (C3-6)cycloalkyl wherein the (C3-6)cycloalkyl optionally contains a ring oxygen atom, (C3-6)cycloalkyl-(C1-3)alkylene wherein the (C3-6)cycloalkyl optionally contains a ring oxygen atom, (C1-3)fluoroalkyl, or —NH2;—O—CH2—CO—R4, wherein RO4represents hydroxy, or (C1-4)alkoxy, or —N[(C1-4)alkyl]2;—O—CH2—O—CO—RO5, wherein RO5represents (C1-4)alkyl or (C1-4)alkoxy;—O—CH2—CH2—N[(C1-4)alkyl]2(especially —O—CH2—CH2—N(CH3)2); or(5-methyl-2-oxo-[1,3]dioxol-4-yl)-methyloxy-;[wherein in particular such group —X1—CO—RO1represents —COOH, —COO—CH3, —CO—O—C2H5, —O—CH2—COOH, —O—CH(CH3)—COOH, —O—C(CH3)2—COOH, —O—CH2—CH2—COOH, —NH—CH2—COOH, —NH—CH2—COO—CH3, —NH—CH(CH3)—OOH, —CO—NH—SO2—CH3, —CO—NH—SO2—C(CH3)2, —CO—NH—SO2-cyclopropyl, —CO—NH—SO2—C2H5, —CO—NH—SO2—NH2, —COO—CH2—COOH, —COO—CH2—CH2—N(CH3)2, —COO—CH2—CO—N(CH3)2, —COO—CH2—O—CO—O—C2H5, —COO—CH2—O—CO-propyl, (5-methyl-2-oxo-[1,3]dioxol-4-yl)-methyl-O—CO—, —CH2—COOH, —CH2—COO—CH3, —CH2—CO—O—C2H5, —CH2—CH2—COOH, —CH═CH—COOH, —CH≡CH—CO—O—C2H5, —CF2—COOH, —NH—CO—COOH, —CO—COOH, 1-carboxy-cyclopropan-1-yl];—CO—CH2—OH;

2-hydroxy-3,4-dioxo-cyclobut-1-enyl;hydroxy-(C1-4)alkyl (especially hydroxymethyl, 1-hydroxy-ethyl);dihydroxy-(C2-4)alkyl (especially 1,2-dihydroxyethyl);hydroxy-(C2-4)alkoxy (especially 2-hydroxy-ethoxy);(C1-4)alkoxy-(C2-4)alkoxy (especially 2-methoxy-ethoxy);—(CH2)rCO—NRN3RN4wherein r represents the integer 0 or 1; and wherein RN3and RN4independently represent hydrogen, (C1-4)alkyl, hydroxy-(C2-4)alkyl, (C1-3)alkoxy-(C2-4)alkyl, or hydroxy (wherein preferably at least one of RN3and RN4represents hydrogen; and wherein particular examples of such group —CO—NRN3RN4are —CO—NH2, —CO—NH(CH3), —CO—NH(C2H5), —CH2—CO—NH2, —CO—NH—C2H4—OH, —CO—NH—C2H4—OCH3, or —CO—N(CH3)2, —CO—NH-isopropyl, or —CO—NH—OH);—X2—NRN1RN2, wherein X2represents —(CH2)m—, wherein m represents the integer 0 or 1; or X2represents —O—CH2—CH2—*, wherein the asterisk indicates the bond that is linked to the —NRN1RN2group; and whereinRN1and RN2independently represent hydrogen, (C1-4)alkyl, (C1-4)alkoxy-(C2-4)alkyl, (C3-6)cycloalkyl, or (C2-3)fluoroalkyl;or RN1independently represents hydrogen or (C1-4)alkyl, and RN2independently represents —CO—H, —CO—(C1-3)alkyl, —CO—(C1-3)alkylene-OH, or —CO—O—(C1-3)alkyl;or RN1and RN2together with the nitrogen to which they are attached form a 4-, 5- or 6-membered saturated ring optionally containing one ring oxygen or ring sulfur atom, wherein said ring is unsubstituted, or mono-substituted with oxo on a ring carbon atom, or disubstituted with oxo on a ring sulfur atom;(especially such group —X2—NRN1RN2represents amino, methylamino, ethylamino, propylamino, amino-methyl, methylamino-methyl, isobutylamino-methyl, cyclopropylamino-methyl, cyclobutylamino-methyl, (2-methoxyethyl)amino-methyl, (2,2,2-trifluoro-ethyl)-amino; or —NH—CO—H, —N(C2H5)—CO—H, —NH—CO—C2H5, —NH—CO—CH2—CH2—OH, —NH—COO—CH3, —N(CH3)—CO—O—CH3; or pyrrolidin-1-yl, 2-oxo-pyrrolidin-1-yl, 1,1-dioxo-isothiazolidin-2-yl, morpholin-4-yl, azetidin-1-yl, or piperidin-1-yl; or 2-(dimethylamino)-ethoxy);—NH—CO—NRN5RN6wherein RN5and RN6independently represent hydrogen or (C1-4)alkyl (wherein preferably at least one of RN5and RN6represents hydrogen; and wherein particular examples of such group —NH—CO—NRN5RN6are —NH—CO—NH2, —NH—CO—NH—C2H5);—SO2—RS1wherein RS1represents hydroxy, (C1-4)alkyl (especially methyl), or —NRN7RN8wherein RN7and RN8independently represent hydrogen or (C1-3)alkyl (wherein preferably at least one of RN7and RN8represents hydrogen; and wherein particular examples of such group —SO2—RS' are —SO2—CH3, —SO2—NH2, —SO2—OH, —SO2—NH—CH3);—S—RS2wherein RS2represents (C1-4)alkyl (especially methyl, ethyl, n-propyl, isopropyl, isobutyl), or (C3-6)cycloalkyl optionally containing one ring oxygen atom (especially cyclobutyl, oxetan-3-yl);—(CH2)q-HET1, wherein q represents the integer 0, 1 or 2 (especially q is 0, i.e. HET1is linked to Ar1by a direct bond); and wherein HET1represents 5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl (encompassing its tautomeric form 5-hydroxy-[1,2,4]oxadiazol-3-yl), 3-oxo-2,3-dihydro-[1,2,4]oxadiazol-5-yl (encompassing its tautomeric form 3-hydroxy-[1,2,4]oxadiazol-5-yl), or 5-thioxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl (encompassing its tautomeric form 5-mercapto-[1,2,4]oxadiazol-3-yl);—(CH2)p-HET, wherein p represents the integer 0 or 1 (especially p is 0, i.e. HET is linked to Ar1by a direct bond); and wherein HET represents a 5- or 6-membered heteroaryl (especially 5-membered heteroaryl selected from oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, imidazolyl, pyrazolyl, triazolyl, and tetrazolyl), wherein said 5- or 6-membered heteroaryl is unsubstituted, or mono- or di-substituted, wherein the substituents are independently selected from (C1-4)alkyl (especially methyl), (C1-4)alkoxy (especially methoxy), —COOH, hydroxy, hydroxy-(C1-3)alkyl (especially hydroxymethyl), (C3-5)cycloalkyl optionally containing one ring oxygen atom (especially cyclopropyl, oxetan-3-yl), or —NRN9RN10wherein RN9and RN10independently represent hydrogen, (C1-3)alkyl (especially methyl), or hydroxy-(C2-4)alkyl (especially 2-hydroxy-ethyl); (especially such group —(CH2)p-HET is 1H-tetrazol-5-yl, 3-hydroxy-isoxazol-5-yl, 2-hydroxy-[1,3,4]oxadiazol-4-yl, 3-amino-isoxazol-5-yl, 2-amino-oxazol-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-hydroxy-ethyl)]-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, 1H-imidazol-4-yl, 5-methyl-1H-imidazol-4-yl, 2,5-dimethyl-1H-imidazol-4-yl)or Ar1represents 8- to 10-membered bicyclic heteroaryl (notably 9- or 10-membered bicyclic heteroaryl; especially indazolyl, benzoimidazolyl, indolyl, benzotriazolyl, benzofuranyl, benzooxazolyl, quinoxalinyl, isoquinolinyl, quinolinyl, pyrrolopyridinyl, or imidazopyridinyl); wherein said 8- to 10-membered bicyclic heteroaryl independently is unsubstituted, mono-, or di-substituted, wherein the substituents are independently selected from (C1-4)alkyl (especially methyl); (C1-4)alkoxy (especially methoxy); (C1-3)fluoroalkyl (especially trifluoromethyl); (C1-3)fluoroalkoxy (especially trifluoromethoxy); halogen; cyano; hydroxy, or —(C0-3)alkylene-COORO2wherein RO2represents hydrogen or (C1-4)alkyl (especially such group —(C0-3)alkylene-COORO2is —COOH); (especially such 8- to 10-membered bicyclic heteroaryl, if unsubstituted, is 1H-benzoimidazol-5-yl, 1H-indol-6-yl, 1H-indol-5-yl, 1H-indol-2-yl, 1H-indazol-5-yl, isoquinolin-7-yl, quinolin-6-yl; or, if substituted, is 3-carboxy-1H-indol-6-yl, 4-carboxy-1H-indol-2-yl, 5-carboxy-1H-indol-2-yl, 6-carboxy-1H-indol-2-yl, 7-carboxy-1H-indol-2-yl, 5-(methoxycarbonyl)-1H-indol-2-yl, 6-(methoxycarbonyl)-1H-indol-2-yl), 6-carboxy-benzofuran-2-yl, 3-carboxy-benzofuran-6-yl, 2-carboxy-benzofuran-5-yl, or 2-carboxy-benzofuran-6-yl);or Ar1represents a group of the structure (Ar-III):

wherein ring (B) represents a non-aromatic 5- or 6-membered ring fused to the phenyl group, wherein ring (B) comprises one or two heteroatoms independently selected from nitrogen and oxygen (notably such group (Ar-III) is 2,3-dihydro-benzofuranyl, 2,3-dihydro-1H-indolyl, 2,3-dihydro-benzo[1,4]dioxinyl, 2,3-dihydro-1H-indazolyl, 2,3-dihydro-1H-benzo[d]imidazolyl, 2,3-dihydrobenzo[d]isoxazolyl, 2,3-dihydro-isoindolyl, 2,3-dihydro-benzooxazolyl, 1,2,3,4-tetrahydro-quinazolinyl, 1,2,3,4-tetrahydro-isoquinolinyl, or 1,2,3,4-tetrahydro-phthalazinyl); wherein said ring (B) independently is unsubstituted, mono-, or di-substituted, wherein the substituents are independently selected from oxo, (C1-6)alkyl (especially methyl, ethyl, propyl, butyl, isobutyl) and —(C0-3)alkylene-COORO3wherein RO3represents hydrogen or (C1-3)alkyl (especially such group (Ar-III) is 2-oxo-2,3-dihydro-benzooxazol-6-yl, 3-methyl-2-oxo-2,3-dihydro-benzooxazol-5-yl, 1-methyl-3-oxo-2,3-dihydro-1H-indazol-6-yl, 2-oxo-1,2,3,4-tetrahydro-quinazolin-6-yl, 1-methyl-2-oxo-1,2,3,4-tetrahydro-quinazolin-6-yl, 1-oxo-1,2,3,4-tetrahydro-isoquinolin-6-yl, 1-methyl-2-oxo-1,2,3,4-tetrahydro-quinazolin-7-yl, or 1-oxo-1,2,3,4-tetrahydro-isoquinolin-7-yl).

In a sub-embodiment, Ar1especially representsphenyl, or 5- or 6-membered heteroaryl; wherein said phenyl or 5- or 6-membered heteroaryl independently is mono-, di- or tri-substituted (especially di-substituted),wherein one of said substituents is selected from (C4-6)cycloalkyl containing a ring oxygen atom, wherein said (C4-6)cycloalkyl containing a ring oxygen atom is unsubstituted or mono-substituted with hydroxy; hydroxy;

—X1—CO—RO1; 2-hydroxy-3,4-dioxo-cyclobut-1-enyl; hydroxy-(C2-4)alkoxy; —(CH2)rCO—NRN3RN4; —NH—CO—NRN5RN6; SO2—RS1; —(CH2)q-HET1; —(CH2)p-HET;and the other of said substituents, if present, independently are selected from (C1-6)alkyl; (C1-4)alkoxy; (C1-3)fluoroalkyl; (C1-3)fluoroalkoxy; halogen; cyano; (C3-6)cycloalkyl, wherein said (C3-6)cycloalkyl is unsubstituted or mono-substituted with amino; (C3-6)cycloalkyl-oxy; hydroxy; hydroxy-(C1-4)alkyl; dihydroxy-(C2-4)alkyl; hydroxy-(C2-4)alkoxy; (C1-4)alkoxy-(C2-4)alkoxy; —X2—NRN1RN2; —S—RS2;wherein the above groups and substituents are as defined in embodiment 1).or Ar1represents 8- to 10-membered bicyclic heteroaryl as defined in embodiment 1); wherein said 8- to 10-membered bicyclic heteroaryl independently is unsubstituted, mono-, or di-substituted, wherein the substituents are independently selected from (C1-4)alkyl; (C1-4)alkoxy; (C1-3)fluoroalkyl; (C1-3)fluoroalkoxy; halogen; cyano; hydroxy, or —(C0-3)alkylene-COORO2wherein RO2represents hydrogen or (C1-4)alkyl;or Ar1represents a group of the structure (Ar-III) as defined in embodiment 1).
2) A second embodiment relates to compounds according to embodiment 1), wherein R3represents hydrogen.
3) Another embodiment relates to compounds according to embodiment 1), wherein R3represents methyl.
4) Another embodiment relates to compounds according to any one of embodiments 1) to 3), wherein R4aand R4bboth represent hydrogen.
5) Another embodiment relates to compounds according to any one of embodiments 1) to 4), wherein R5aand R5bboth represent hydrogen. Particular compounds of formula (I) are compounds wherein R4aand R4bboth represent hydrogen; and R5aand R5bboth represent hydrogen.
6) Another embodiment relates to compounds according to any one of embodiments 1) to 5), wherein the characteristics defined for the fragment


according to embodiments 8), and 15) to 25) below apply mutatis mutandis.
7) Another embodiment relates to compounds according to any one of embodiments 1) to 6), wherein the characteristics defined for the substituent Ar1according to embodiments 8) to 14) below apply mutatis mutandis.
8) A second aspect of the invention relates to compounds of the formula (II)


wherein in compounds of the formula (II)
the fragment


is substituted with R2, wherein R2represents hydrogen, (C1-4)alkyl (especially methyl, ethyl), halogen (especially chloro, bromo), or cyano; and
is optionally substituted with (R1)n; wherein (R1)nrepresents one, two or three optional substituents (i.e. said fragment is, in addition to R2, unsubstituted, or substituted with one, two or three R1), wherein said substituents R1are independently selected from (C1-3)alkyl (especially methyl), (C1-3)alkoxy (especially methoxy), halogen (especially fluoro, or chloro), (C1-3)fluoroalkyl (especially trifluoromethyl), (C1-3)fluoroalkoxy (especially trifluoromethoxy), or cyano; (for avoidance of any doubt: substituents (R1)nare in addition to the substituent R2as defined above);
X represents S or O;
Ar1representsa phenyl group of the structure (Ar-I):

whereinRprepresents(C4-6)cycloalkyl containing a ring oxygen atom, wherein said (C4-6)cycloalkyl containing a ring oxygen atom is unsubstituted or mono-substituted with hydroxy (especially 3-hydroxy-oxetan-3-yl);hydroxy;—X1—CO—RO1, whereinX1represents a direct bond, (C1-3)alkylene (especially —CH2—, —CH(CH3)—, —C(CH3)2—, —CH2—CH2—), —O—(C1-3)alkylene-* (especially —O—CH2—*, —O—CH(CH3)—*, —O—C(CH3)2—*, —O—CH2—CH2—*), —NH—(C1-3)alkylene-* (especially —NH—CH2*, —NH—CH(CH3)—*), —S—CH2*, —CF2—, —CH═CH—, —CH≡CH—, —NH—CO—*, —CO—, or (C3-5)cycloalkylene; wherein the asterisks indicate the bond that is linked to the —CO—RO1group; andRO1represents—OH;—O—(C1-4)alkyl (especially ethoxy, methoxy);—NH—SO2—RS3wherein RS3represents (C1-4)alkyl, (C3-6)cycloalkyl wherein the (C3-6)cycloalkyl optionally contains a ring oxygen atom, (C3-6)cycloalkyl-(C1-3)alkylene wherein the (C3-6)cycloalkyl optionally contains a ring oxygen atom, (C1-3)fluoroalkyl, or —NH2;—O—CH2—CO—RO4, wherein RO4represents hydroxy, or (C1-4)alkoxy, or —N[(C1-4)alkyl]2;—O—CH2—O—CO—RO5, wherein RO5represents (C1-4)alkyl or (C1-4)alkoxy;—O—CH2—CH2—N[(C1-4)alkyl]2(especially —O—CH2—CH2—N(CH3)2); or(5-methyl-2-oxo-[1,3]dioxol-4-yl)-methyloxy-;[wherein in particular such group —X1—CO—RO1represents —OOH, —COO—CH3, —CO—O—C2H5, —O—CH2—COOH, —O—CH(CH3)—COOH, —O—C(CH3)2—COOH, —O—CH2—CH2—COOH, —NH—CH2—OOH, —NH—CH2—COO—CH3, —NH—CH(CH3)—COOH, —CO—NH—SO2—CH3, —CO—NH—SO2—C(CH3)2, —CO—NH—SO2-cyclopropyl, —CO—NH—SO2—C2H5, —CO—NH—SO2—NH2, —COO—CH2—OOH, —COO—CH2—CH2—N(CH3)2, —COO—CH2—CO—N(CH3)2, —COO—CH2—O—CO—O—C2H5, —CO—O—CH2—O—CO-propyl, (5-methyl-2-oxo-[1,3]dioxol-4-yl)-methyl-O—CO—, —CH2—COOH, —CH2—COO—CH3, —CH2—CO—O—C2H5, —CH2—CH2—COOH, —CH═CH—COOH, —CH≡CH—CO—O—C2H5, —CF2—COOH, —NH—CO—COOH, —CO—COOH, 1-carboxy-cyclopropan-1-yl];

2-hydroxy-3,4-dioxo-cyclobut-1-enyl;hydroxy-(C1-4)alkyl (especially hydroxymethyl, 1-hydroxy-ethyl);hydroxy-(C2-4)alkoxy (especially 2-hydroxy-ethoxy);—(CH2)rCO—NRN3RN4wherein r represents the integer 0 or 1; and wherein RN3and RN4independently represent hydrogen, (C1-4)alkyl, hydroxy-(C2-4)alkyl, (C1-3)alkoxy-(C2-4)alkyl, or hydroxy (wherein preferably at least one of RN3and RN4represents hydrogen; and wherein particular examples of such group —CO—NRN3RN4are —CO—NH2, —CO—NH(CH3), —CO—NH(C2H5), —CH2—CO—NH2, —CO—NH—C2H4—OH, —CO—NH—C2H4—OCH3, or —CO—N(CH3)2, —CO—NH-isopropyl, or —CO—NH—OH);—NRN1RN2, wherein RN1independently represents hydrogen or (C1-4)alkyl, and RN2independently represents —CO—H, —CO—(C1-3)alkyl, or —CO—(C1-3)alkylene-OH; (especially such group —(CH2)m—NRN1RN2represents-NH—CO—H, —N(C2H5)—CO—H, —NH—CO—C2H5, or —NH—CO—CH2—CH2—OH);—NH—CO—NRN5RN6wherein RN5and RN6independently represent hydrogen or (C1-4)alkyl (wherein preferably at least one of RN5and RN6represents hydrogen; and wherein particular examples of such group —NH—CO—NRN5RN6are —NH—CO—NH2, —NH—CO—NH—C2H5);—SO2—RS1wherein RS1represents (C1-4)alkyl (especially methyl), or —NRN7RN8wherein RN7and RN8independently represent hydrogen or (C1-3)alkyl (wherein preferably at least one of RN7and RN8represents hydrogen; and wherein particular examples of such group —SO2—RS1are —SO2—CH3, —SO2—NH2, —SO2—NH—CH3);—(CH2)q-HET1, wherein q represents the integer 0, 1 or 2 (especially q is 0, i.e. HET is linked to Ar1by a direct bond); and wherein HET1represents 5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl (encompassing its tautomeric form 5-hydroxy-[1,2,4]oxadiazol-3-yl), 3-oxo-2,3-dihydro-[1,2,4]oxadiazol-5-yl (encompassing its tautomeric form 3-hydroxy-[1,2,4]oxadiazol-5-yl), or 5-thioxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl (encompassing its tautomeric form 5-mercapto-[1,2,4]oxadiazol-3-yl);—(CH2)p-HET, wherein p represents the integer 0 or 1 (especially p is 0, i.e. HET is linked to Ar1by a direct bond); and wherein HET represents a 5-membered heteroaryl (especially oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, imidazolyl, pyrazolyl, triazolyl, or tetrazolyl), wherein said 5-membered heteroaryl is unsubstituted, or mono- or di-substituted, wherein the substituents are independently selected from (C1-4)alkyl (especially methyl), (C1-4)alkoxy (especially methoxy), —COOH, hydroxy, hydroxy-(C1-3)alkyl (especially hydroxymethyl), (C3-5)cycloalkyl optionally containing one ring oxygen atom (especially cyclopropyl, oxetan-3-yl), or —NRN9RN10wherein RN9and RN10independently represent hydrogen, (C1-3)alkyl (especially methyl), or hydroxy-(C2-4)alkyl (especially 2-hydroxy-ethyl); (especially such group —(CH2)p-HET is 1H-tetrazol-5-yl, 3-hydroxy-isoxazol-5-yl, 2-hydroxy-[1,3,4]oxadiazol-4-yl, 3-amino-isoxazol-5-yl, 2-amino-oxazol-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-hydroxy-ethyl)]-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, 1H-imidazol-4-yl, 5-methyl-1H-imidazol-4-yl, 2,5-dimethyl-1H-imidazol-4-yl);Rm1representshydrogen;(C1-5)alkyl (especially methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl);(C1-4)alkoxy (especially methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy);(C1-3)fluoroalkyl (especially trifluoromethyl);(C1-3)fluoroalkoxy (especially difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy);halogen (especially fluoro or chloro);(C3-6)cycloalkyl (especially cyclopropyl);(C3-6)cycloalkyl-oxy (especially cyclopropyl-oxy, cyclobutyl-oxy, cyclopentyl-oxy);hydroxy;hydroxy-(C2-4)alkoxy (especially 2-hydroxy-ethoxy);—X2—NRN1RN2, wherein X2represents a direct bond; or X2represents —O—CH2—CH2—*, wherein the asterisk indicates the bond that is linked to the —NRN1RN2group; and wherein RN1and RN2independently represent hydrogen, (C1-4)alkyl (especially methyl), or (C3-6)cycloalkyl (especially cyclopropyl); (especially such group —X2—NRN1RN2represents amino, methylamino, ethylamino, propylamino; or 2-(dimethylamino)-ethoxy);—S—RS2wherein RS2represents (C1-4)alkyl (especially methyl, ethyl, n-propyl, isopropyl, isobutyl), or (C3-6)cycloalkyl optionally containing one ring oxygen atom (especially cyclobutyl, oxetan-3-yl); wherein in a sub-embodiment, Rm1especially is different from hydrogen;Rm2represents hydrogen, methyl, fluoro, or chloro; andRo1represents hydrogen; or, in case Rm2represents hydrogen, Ro1represents hydrogen or fluoro;or Ar1represents a 5-membered heteroaryl group of the structure (Ar-II):

whereinY represents CR8wherein R8represents especially hydrogen, or halogen (notably fluoro, chloro); or Y represents N;R7represents(C4-6)cycloalkyl containing a ring oxygen atom, wherein said (C4-6)cycloalkyl containing a ring oxygen atom is unsubstituted or mono-substituted with hydroxy (especially 3-hydroxy-oxetan-3-yl);—X1—CO—RO1, whereinX1represents a direct bond, (C1-3)alkylene (especially —CH2—, —CH(CH3)—, —C(CH3)2—, —CH2—CH2—), —O—(C1-3)alkylene-* (especially —O—CH2—*, —O—CH(CH3)—*, —O—C(CH3)2—*, —O—CH2—CH2—*), —NH—(C1-3)alkylene* (especially —NH—CH2*, —NH—CH(CH3)—*), —S—CH2*, —CF2—, —CH═CH—, —CH≡CH—, —NH—CO—*, —CO—, or (C3-5)cycloalkylene; wherein the asterisks indicate the bond that is linked to the —CO—RO1group; andRO1represents—OH;—O—(C1-4)alkyl (especially ethoxy, methoxy);—NH—SO2—RS3wherein RS3represents (C1-4)alkyl, (C3-6)cycloalkyl wherein the (C3-6)cycloalkyl optionally contains a ring oxygen atom, (C3-6)cycloalkyl-(C1-3)alkylene wherein the (C3-6)cycloalkyl optionally contains a ring oxygen atom, (C1-3)fluoroalkyl, or —NH2;—O—CH2—CO—RO4, wherein RO4represents hydroxy, or (C1-4)alkoxy, or —N[(C1-4)alkyl]2;—O—CH2—O—CO—RO5, wherein RO5represents (C1-4)alkyl or (C1-4)alkoxy; or—O—CH2—CH2—N[(C1-4)alkyl]2(especially —O—CH2—CH2—N(CH3)2);(5-methyl-2-oxo-[1,3]dioxol-4-yl)-methyloxy-;[wherein in particular such group —X1—CO—RO1represents —OOH, —COO—CH3, —CO—O—C2H5, —O—CH2—COOH, —O—CH(CH3)—OOH, —O—C(CH3)2—COOH, —O—CH2—CH2—OOH, —NH—CH2—OOH, —NH—CH2—COO—CH3, —NH—CH(CH3)—OOH, —CO—NH—SO2—CH3, —CO—NH—SO2—C(CH3)2, —CO—NH—SO2-cyclopropyl, —CO—NH—SO2—C2H5, —CO—NH—SO2—NH2, —COO—CH2—OOH, —COO—CH2—CH2—N(CH3)2, —COO—CH2—CO—N(CH3)2, —COO—CH2—O—CO—O—C2H5, —COO—CH2—O—CO-propyl, (5-methyl-2-oxo-[1,3]dioxol-4-yl)-methyl-O—CO—, —CH2—COOH, —CH2—COO—CH3, —CH2—CO—O—C2H5, —CH2—CH2—OOH, —CH═CH—OOH, —CH≡CH—CO—O—C2H5, —CF2—OOH, —NH—CO—OOH, —CO—OOH, 1-carboxy-cyclopropan-1-yl];

2-hydroxy-3,4-dioxo-cyclobut-1-enyl;hydroxy-(C1-4)alkyl (especially hydroxymethyl, 1-hydroxy-ethyl);hydroxy-(C2-4)alkoxy (especially 2-hydroxy-ethoxy);—(CH2)rCO—NRN3RN4wherein r represents the integer 0 or 1; and wherein RN3and RN4independently represent hydrogen, (C1-4)alkyl, hydroxy-(C2-4)alkyl, (C1-3)alkoxy-(C2-4)alkyl, or hydroxy (wherein preferably at least one of RN3and RN4represents hydrogen; and wherein particular examples of such group —CO—NRN3RN4are —CO—NH2, —CO—NH(CH3), —CO—NH(C2H5), —CH2—CO—NH2, —CO—NH—C2H4—OH, —CO—NH—C2H4—OCH3, or —CO—N(CH3)2, —CO—NH-isopropyl, or —CO—NH—OH);—NRN1RN2, wherein RN1independently represents hydrogen or (C1-4)alkyl, and RN2independently represents —CO—H, —CO—(C1-3)alkyl, or —CO—(C1-3)alkylene-OH; (especially such group —(CH2)m—NRN1RN2represents-NH—CO—H, —N(C2H5)—CO—H, —NH—CO—C2H5, or —NH—CO—CH2—CH2—OH);—NH—CO—NRN5RN6wherein RN5and RN6independently represent hydrogen or (C1-4)alkyl (wherein preferably at least one of RN5and RN6represents hydrogen; and wherein particular examples of such group —NH—CO—NRN5RN6are —NH—CO—NH2, —NH—CO—NH—C2H5);—SO2—RS1wherein RS1represents (C1-4)alkyl (especially methyl), or —NRN7RN8wherein RN7and RN8independently represent hydrogen or (C1-3)alkyl (wherein preferably at least one of RN7and RN8represents hydrogen; and wherein particular examples of such group —SO2—RS1are —SO2—CH3, —SO2—NH2, —SO2—NH—CH3);—(CH2)q-HET1, wherein q represents the integer 0, 1 or 2 (especially q is 0, i.e. HET is linked to Ar1by a direct bond); and wherein HET1represents 5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl (encompassing its tautomeric form 5-hydroxy-[1,2,4]oxadiazol-3-yl), 3-oxo-2,3-dihydro-[1,2,4]oxadiazol-5-yl (encompassing its tautomeric form 3-hydroxy-[1,2,4]oxadiazol-5-yl), or 5-thioxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl (encompassing its tautomeric form 5-mercapto-[1,2,4]oxadiazol-3-yl);—(CH2)p-HET, wherein p represents the integer 0 or 1 (especially p is 0, i.e. HET is linked to Ar1by a direct bond); and wherein HET represents a 5-membered heteroaryl (especially oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, imidazolyl, pyrazolyl, triazolyl, or tetrazolyl), wherein said 5-membered heteroaryl is unsubstituted, or mono- or di-substituted, wherein the substituents are independently selected from (C1-4)alkyl (especially methyl), (C1-4)alkoxy (especially methoxy), —COOH, hydroxy, hydroxy-(C1-3)alkyl (especially hydroxymethyl), (C3-5)cycloalkyl optionally containing one ring oxygen atom (especially cyclopropyl, oxetan-3-yl), or —NRN9RN10wherein RN9and RN10independently represent hydrogen, (C1-3)alkyl (especially methyl), or hydroxy-(C2-4)alkyl (especially 2-hydroxy-ethyl); (especially such group —(CH2)p-HET is 1H-tetrazol-5-yl, 3-hydroxy-isoxazol-5-yl, 2-hydroxy-[1,3,4]oxadiazol-4-yl, 3-amino-isoxazol-5-yl, 2-amino-oxazol-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-hydroxy-ethyl)]-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, 1H-imidazol-4-yl, 5-methyl-1H-imidazol-4-yl, 2,5-dimethyl-1H-imidazol-4-yl);R6represents(C1-6)alkyl (especially methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl);(C1-4)alkoxy (especially methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy);(C1-3)fluoroalkyl (especially trifluoromethyl);(C1-3)fluoroalkoxy (especially difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy);halogen (especially fluoro or chloro);hydroxy;(C3-6)cycloalkyl (especially cyclopropyl);(C3-6)cycloalkyl-oxy (especially cyclopropyl-oxy, cyclobutyl-oxy, cyclopentyl-oxy);hydroxy-(C2-4)alkoxy (especially 2-hydroxy-ethoxy);—X2—NRN1RN2, wherein X2represents a direct bond; or X2represents —O—CH2—CH2—*, wherein the asterisk indicates the bond that is linked to the —NRN1RN2group; and wherein RN1and RN2independently represent hydrogen, (C1-4)alkyl, or (C3-6)cycloalkyl; (especially such group —X2—NRN1RN2represents amino, methylamino, ethylamino, propylamino; or 2-(dimethylamino)-ethoxy);—S—RS2wherein RS2represents (C1-4)alkyl (especially methyl, ethyl, n-propyl, isopropyl, isobutyl), or (C3-6)cycloalkyl optionally containing one ring oxygen atom (especially cyclobutyl, oxetan-3-yl);or Ar1represents 8- to 10-membered bicyclic heteroaryl (notably 9- or 10-membered bicyclic heteroaryl;especially indazolyl, benzoimidazolyl, indolyl, benzofuranyl, benzooxazolyl, quinoxalinyl, isoquinolinyl, or quinolinyl); wherein said 8- to 10-membered bicyclic heteroaryl independently is mono-substituted with —(C0-3)alkylene-COORO2wherein RO2represents hydrogen or (C1-4)alkyl (especially methyl) (wherein especially such group —(C0-3)alkylene-COORO2is —COOH); (especially such 8- to 10-membered bicyclic heteroaryl is 3-carboxy-1H-indol-6-yl, 4-carboxy-1H-indol-2-yl, 5-carboxy-1H-indol-2-yl, 6-carboxy-1H-indol-2-yl, 7-carboxy-1H-indol-2-yl, 5-(methoxycarbonyl)-1H-indol-2-yl, 6-(methoxycarbonyl)-1H-indol-2-yl), 6-carboxy-benzofuran-2-yl, 3-carboxy-benzofuran-6-yl, 2-carboxy-benzofuran-5-yl, or 2-carboxy-benzofuran-6-yl);or Ar1represents a group of the structure (Ar-III):

which is selected from 2-oxo-2,3-dihydro-benzooxazol-6-yl, 3-methyl-2-oxo-2,3-dihydro-benzooxazol-5-yl, 1-methyl-3-oxo-2,3-dihydro-1H-indazol-6-yl, 2-oxo-1,2,3,4-tetrahydro-quinazolin-6-yl, 1-methyl-2-oxo-1,2,3,4-tetrahydro-quinazolin-6-yl, 1-oxo-1,2,3,4-tetrahydro-isoquinolin-6-yl, 1-methyl-2-oxo-1,2,3,4-tetrahydro-quinazolin-7-yl, and 1-oxo-1,2,3,4-tetrahydro-isoquinolin-7-yl.

The compounds of formula (I)/formula (II) may contain one or more stereogenic or asymmetric centers, such as one or more asymmetric carbon atoms, which are allowed to be present in (R)- as well as (S)-configuration. The compounds of formula (I)/formula (II) may further encompass compounds with one or more double bonds which are allowed to be present in Z— as well as E-configuration and/or compounds with substituents at a ring system which are allowed to be present, relative to each other, in cis- as well as trans-configuration. The compounds of formula (I)/formula (II) may thus be present as mixtures of stereoisomers or preferably as pure stereoisomers. Mixtures of stereoisomers may be separated in a manner known to a person skilled in the art.

In case a particular compound (or generic structure) is designated as (R)- or (S)-enantiomer, such designation is to be understood as referring to the respective compound (or generic structure) in enriched, especially essentially pure, enantiomeric form. Likewise, in case a specific asymmetric center in a compound is designated as being in (R)- or (S)-configuration or as being in a certain relative configuration, such designation is to be understood as referring to the compound that is in enriched, especially essentially pure, form with regard to the respective configuration of said asymmetric center. In analogy, cis- or trans-designations are to be understood as referring to the respective stereoisomer of the respective relative configuration in enriched, especially essentially pure, form. Likewise, in case a particular compound (or generic structure) is designated as Z- or E-stereoisomer (or in case a specific double bond in a compound is designated as being in Z- or E-configuration), such designation is to be understood as referring to the respective compound (or generic structure) in enriched, especially essentially pure, stereoisomeric form (or to the compound that is in enriched, especially essentially pure, form with regard to the respective configuration of the double bond).

The term “enriched”, when used in the context of stereoisomers, is to be understood in the context of the present invention to mean that the respective stereoisomer is present in a ratio of at least 70:30, especially of at least 90:10 (i.e., in a purity of at least 70% by weight, especially of at least 90% by weight), with regard to the respective other stereoisomer/the entirety of the respective other stereoisomers.

The term “essentially pure”, when used in the context of stereoisomers, is to be understood in the context of the present invention to mean that the respective stereoisomer is present in a purity of at least 95% by weight, especially of at least 99% by weight, with regard to the respective other stereoisomer/the entirety of the respective other stereoisomers.

The present invention also includes isotopically labelled, especially2H (deuterium) labelled compounds of formula (I)/formula (II) according to embodiments 1) to 34), which compounds are identical to the compounds of formula (I)/formula (II) except that one or more atoms have each been replaced by an atom having the same atomic number but an atomic mass different from the atomic mass usually found in nature. Isotopically labelled, especially2H (deuterium) labelled compounds of formula (I)/formula (II) and salts thereof are within the scope of the present invention. Substitution of hydrogen with the heavier isotope2H (deuterium) may lead to greater metabolic stability, resulting e.g. in increased in-vivo half-life or reduced dosage requirements, or may lead to reduced inhibition of cytochrome P450 enzymes, resulting e.g. in an improved safety profile. In one embodiment of the invention, the compounds of formula (I)/formula (II) are not isotopically labelled, or they are labelled only with one or more deuterium atoms. In a sub-embodiment, the compounds of formula (I)/formula (II) are not isotopically labelled at all. Isotopically labelled compounds of formula (I)/formula (II) may be prepared in analogy to the methods described hereinafter, but using the appropriate isotopic variation of suitable reagents or starting materials.

In this patent application, a bond drawn as a dotted line shows the point of attachment of the radical drawn. For example, the radical drawn below


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

In some instances, the compounds of formula (I)/formula (II) may contain tautomeric forms. Such tautomeric forms are encompassed in the scope of the present invention. In case tautomeric forms exist of a certain residue, and only one form of such residue is disclosed or defined, the other tautomeric form(s) are understood to be encompassed in such disclosed residue. For example the group 2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl is to be understood as also encompassing its tautomeric forms 2-hydroxy-1H-benzo[d]imidazol-5-yl and 2-hydroxy-3H-benzo[d]imidazol-5-yl. Similarly, 5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl (alternatively named 5-oxo-4H-[1,2,4]oxadiazol-3-yl) encompasses its tautomeric form 5-hydroxy-[1,2,4]oxadiazol-3-yl, and 3-oxo-2,3-dihydro-[1,2,4]oxadiazol-5-yl (alternatively named 3-oxo-2H-[1,2,4]oxadiazol-5-yl) encompasses its tautomeric form 3-hydroxy-[1,2,4]oxadiazol-5-yl.

Where the plural form is used for compounds, salts, pharmaceutical compositions, diseases and the like, this is intended to mean also a single compound, salt, or the like.

Any reference to compounds of formula (I)/formula (II) according to embodiments 1) to 34) is to be understood as referring also to the salts (and especially the pharmaceutically acceptable salts) of such compounds, as appropriate and expedient.

The term “pharmaceutically acceptable salts” refers to salts that retain the desired biological activity of the subject compound and exhibit minimal undesired toxicological effects. Such salts include inorganic or organic acid and/or base addition salts depending on the presence of basic and/or acidic groups in the subject compound. For reference see for example “Handbook of Pharmaceutical Salts. Properties, Selection and Use.”, P. Heinrich Stahl, Camille G. Wermuth (Eds.), Wiley-VCH, 2008; and “Pharmaceutical Salts and Co-crystals”, Johan Wouters and Luc Quéré (Eds.), RSC Publishing, 2012.

Definitions provided herein are intended to apply uniformly to the compounds of formula (I)/formula (II), as defined in any one of embodiments 1) to 25), and, mutatis mutandis, throughout the description and the claims unless an otherwise expressly set out definition provides a broader or narrower definition. It is well understood that a definition or preferred definition of a term defines and may replace the respective term independently of (and in combination with) any definition or preferred definition of any or all other terms as defined herein. Whenever the group Ar1or 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.

Whenever a substituent is denoted as optional, it is understood that such substituent may be absent (i.e. the respective residue is unsubstituted with regard to such optional substituent), in which case all positions having a free valency (to which such optional substituent could have been attached to; such as for example in an aromatic ring the ring carbon atoms and/or the ring nitrogen atoms having a free valency) are substituted with hydrogen where appropriate. Likewise, in case the term “optionally” is used in the context of (ring) heteroatom(s), the term means that either the respective optional heteroatom(s), or the like, are absent (i.e. a certain moiety does not contain heteroatom(s)/is a carbocycle/or the like), or the respective optional heteroatom(s), or the like, are present as explicitly defined.

The term “halogen” means fluorine, chlorine, bromine, or iodine; especially fluorine, chlorine, or bromine; preferably fluorine or chlorine.

The term “alkyl”, used alone or in combination, refers to a saturated straight or branched chain hydrocarbon group containing one to six carbon atoms. The term “(Cx-y)alkyl” (x and y each being an integer), refers to an alkyl group as defined before, containing x to y carbon atoms. For example a (C1-6)alkyl group contains from one to six carbon atoms. Examples of alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert.-butyl, 3-methyl-butyl, 2,2-dimethyl-propyl and 3,3-dimethyl-butyl. For avoidance of any doubt, in case a group is referred to as e.g. propyl or butyl, it is meant to be n-propyl, respectively n-butyl. Preferred are methyl and ethyl. Most preferred is methyl. Preferred for substituents of Ar1being phenyl or 5- or 6-membered heteroaryl are methyl, ethyl, propyl, isobutyl, 1-methyl-propan-1-yl, tert.-butyl, 3-methyl-butyl.

The term “—(Cx-y)alkylene-”, used alone or in combination, refers to bivalently bound alkyl group as defined before containing x to y carbon atoms. Preferably, the points of attachment of a —(C1-y)alkylene group are in 1,1-diyl, in 1,2-diyl, or in 1,3-diyl arrangement. In case a (C0-y)alkylene group is used in combination with another substituent, the term means that either said substituent is linked through a (C1-y)alkylene group to the rest of the molecule, or it is directly attached to the rest of the molecule (i.e. a (C0)alkylene group represents a direct bond linking said substituent to the rest of the molecule). The alkylene group —C2He refers to —CH2—CH2— if not explicitly indicated otherwise. For the linker X1, examples of (C1-3)alkylene groups are —CH2—, —CH(CH3)—, —C(CH3)2—, and —CH2—CH2—, especially —CH2— and —CH2—CH2-. Examples of (C0-3)alkylene groups as used in the substituents —(C0-3)alkylene-COORO2and (C0-3)alkylene-COORO3, respectively, are (C0)alkylene, and methylene, respectively.

The term “alkoxy”, used alone or in combination, refers to an alkyl-O— group wherein the alkyl group is as defined before. The term “(Cx-y)alkoxy” (x and y each being an integer) refers to an alkoxy group as defined before containing x to y carbon atoms. For example a (C1-4)alkoxy group means a group of the formula (C1-4)alkyl-O— in which the term “(C1-4)alkyl” has the previously given significance. Examples of alkoxy groups are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec.-butoxy and tert.-butoxy. Preferred are ethoxy and especially methoxy. Preferred for substituents of Ar1being 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 before containing one to three carbon atoms in which one or more (and possibly all) hydrogen atoms have been replaced with fluorine. The term “(Cx-y)fluoroalkyl” (x and y each being an integer) refers to a fluoroalkyl group as defined before containing x to y carbon atoms. For example a (C1-3)fluoroalkyl group contains from one to three carbon atoms in which one to seven hydrogen atoms have been replaced with 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-hydroxy-ethyl.

The term “fluoroalkoxy”, used alone or in combination, refers to an alkoxy group as defined before containing one to three carbon atoms in which one or more (and possibly all) hydrogen atoms have been replaced with fluorine. The term “(Cx-y)fluoroalkoxy” (x and y each being an integer) refers to a fluoroalkoxy group as defined before containing x to y carbon atoms. For example a (C1-3)fluoroalkoxy group contains from one to three carbon atoms in which one to seven hydrogen atoms have been replaced with fluorine. Representative examples of fluoroalkoxy groups include trifluoromethoxy, difluoromethoxy, 2-fluoroethoxy, 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 “(Cx-y)cycloalkyl” (x and y each being an integer), refers to a cycloalkyl group as defined before containing x to y carbon atoms. For example a (C3-6)cycloalkyl group contains from 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 especially oxetanyl. Examples of (C3-6)cycloalkyl groups wherein said (C3-6)cycloalkyl is optionally mono-substituted with amino are cyclopropyl, 1-amino-cyclopropyl. Examples of (C3-6)cycloalkyl groups wherein said (C3-6)cycloalkyl is mono-substituted with —COOH are 1-carboxy-cyclopropyl, 1-carboxy-cyclopentyl.

The term “—(Cx-y)cycloalkylene-”, used alone or in combination, refers to bivalently bound cycloalkyl group as defined before containing x to y carbon atoms. Preferably, the points of attachment of any bivalently bound cycloalkyl group are in 1,1-diyl, or in 1,2-diyl arrangement. Examples are cyclopropan-1,1-diyl, cyclopropan-1,2-diyl, and cyclopentan-1,1-diyl; preferred is cyclopropan-1,1-diyl.

Examples of (C3-6)cycloalkyl-oxy are cyclobutyl-oxy, and cyclopentyl-oxy.

Alkylated amino groups —N[(C1-4)alkyl]2as used in groups —X—CO—RO1, wherein RO1represents —O—CH2—CO—RO4, wherein RO4represents —N[(C1-4)alkyl]2; or wherein RO1represents —O—CH2—CH2—N[(C1-4)alkyl]2are such that the two respective (C1-4)alkyl groups are independently selected. A preferred example of such amino group —N[(C1-4)alkyl]2is —N(CH3)2.

The term “heterocycle”, used alone or in combination, and if not explicitly defined in a broader or more narrow way, refers to a saturated monocyclic hydrocarbon 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 “(Cx-y)heterocycle” refers to such a heterocycle containing x to y ring atoms. Heterocycles are unsubstituted or substituted as explicitly defined.

A group composed of a “non-aromatic 5- or 6-membered ring fused to the phenyl group, wherein ring (B) comprises one or two heteroatoms independently selected from nitrogen and oxygen” as used for (Ar-III) refers to phenyl groups which are fused to a (C5-6)heterocycle as defined before. Examples are 2,3-dihydro-benzofuranyl, 2,3-dihydro-1H-indolyl, 2,3-dihydro-benzo[1,4]dioxinyl, 2,3-dihydro-1H-indazolyl, 2,3-dihydro-1H-benzo[d]imidazolyl, 2,3-dihydrobenzo[d]isoxazolyl, 2,3-dihydro-isoindolyl, 3-dihydro-benzooxazol-6-yl, 2,3-dihydro-benzooxazol-5-yl, 1,2,3,4-tetrahydro-quinazolin-6-yl, 1,2,3,4-tetrahydro-quinazolin-7-yl, 1,2,3,4-tetrahydro-isoquinolin-6-yl, and 1,2,3,4-tetrahydro-phthalazin-6-yl. The above groups are unsubstituted, mono-, or di-substituted, wherein the substituents are independently selected from oxo, (C1-6)alkyl, and —(C0-3)alkylene-COORO3wherein RO3represents hydrogen or (C1-3)alkyl (especially methyl); especially substituents are independently selected from oxo, methyl, ethyl, propyl, butyl, isobutyl, or —COOH; wherein the substituents are attached to the fused 5- or 6-membered non-aromatic ring. Oxo substituents are preferably attached to a ring carbon atom which is in alpha position to a ring nitrogen atom. Preferred examples of such groups are 2,3-dihydro-benzofuranyl, 2,3-dihydro-1H-indolyl, 2,3-dihydro-benzo[1,4]dioxinyl; as well as the oxosubstituted heterocyclyl groups 3-oxo-2,3-dihydro-1H-indazolyl, 2-oxo-2,3-dihydro-1H-benzo[d]imidazolyl, 3-oxo-2,3-dihydrobenzo[d]isoxazolyl, 2-oxo-1,3-dihydro-indolyl, 1-oxo-2,3-dihydro-isoindolyl, 2-oxo-2,3-dihydro-benzooxazolyl, 2-oxo-1,2,3,4-tetrahydro-quinazolinyl, 1-oxo-1,2,3,4-tetrahydro-isoquinolinyl, 1,4-dioxo-1,2,3,4-tetrahydro-phthalazinyl; wherein the above groups optionally carry one (further) substituent independently selected from (C1-6)alkyl, and —(C0-3)alkylene-COORO3wherein RO3represents hydrogen or (C1-3)alkyl (especially methyl). Particular examples are 2-oxo-2,3-dihydro-benzooxazol-6-yl, 3-methyl-2-oxo-2,3-dihydro-benzooxazol-5-yl, 1-methyl-3-oxo-2,3-dihydro-1H-indazol-6-yl, 2-oxo-1,2,3,4-tetrahydro-quinazolin-6-yl, 1-methyl-2-oxo-1,2,3,4-tetrahydro-quinazolin-6-yl, 1-oxo-1,2,3,4-tetrahydro-isoquinolin-6-yl, 1-methyl-2-oxo-1,2,3,4-tetrahydro-quinazolin-7-yl, or 1-oxo-1,2,3,4-tetrahydro-isoquinolin-7-yl.

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

The term “aryl”, used alone or in combination, means phenyl or naphthyl, especially phenyl. The above-mentioned aryl groups are unsubstituted or substituted as explicitly defined.

Examples of the substituent Ar1representing phenyl are especially those which are at least mono-substituted in para position with respect to the point of attachment of the rest of the molecule. In addition, such group Ar1representing phenyl may carry one or two further substituents, especially in one or both meta positions with respect to the point of attachment of the rest of the molecule. The respective substituents of such phenyl groups are as explicitly defined.

The term “heteroaryl”, used alone or in combination, means a 5- to 10-membered monocyclic or bicyclic aromatic ring containing 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- to 10-membered bicyclic heteroaryl groups such as indolyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzothiophenyl, indazolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzoisothiazolyl, benzotriazolyl, benzoxadiazolyl, benzothiadiazolyl, thienopyridinyl, quinolinyl, isoquinolinyl, naphthyridinyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, pyrrolopyridinyl, pyrazolopyridinyl, pyrazolopyrimidinyl, pyrrolopyrazinyl, imidazopyridinyl, imidazopyridazinyl, and imidazothiazolyl. The above-mentioned heteroaryl groups are unsubstituted or substituted as explicitly defined.

For the substituent Ar1representing a “5- or 6-membered heteroaryl”, the term means the above-mentioned 5- or 6-membered groups such as especially pyridinyl, pyrimidinyl, pyrrolyl, pyrazolyl, isoxazolyl, thiazolyl or thiophenyl. Notably, the term refers to 5-membered groups such as especially thiazolyl or thiophenyl; in particular thiophen-2-yl, thiophen-3-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl. Preferred is thiophenyl, especially thiophen-2-yl; or thiazolyl, especially thiazol-2-yl. The above groups are substituted as explicitly defined. Thiophen-2-yl or thiazol-2-yl are especially di-substituted with one substituent being in position 5, and a second substituent in position 4 (and, for thiophen-2-yl, optionally a halogen substituent in position 3).

For the substituent Ar1representing a “8- to 10-membered bicyclic heteroaryl” the term means the above-mentioned 8- to 10-membered heteroaryl groups. Notably, the term refers to 9- or 10-membered heteroaryl groups, such as especially indazolyl, benzoimidazolyl, indolyl, benzotriazolyl, benzooxazolyl, quinoxalinyl, isoquinolinyl, quinolinyl, pyrrolopyridinyl, and imidazopyridinyl, as well as benzofuranyl, benzothiophenyl, and benzothiazolyl. The above groups are unsubstituted or substituted as explicitly defined. Particular examples are 1H-indol-2-yl, 1H-indol-3-yl, 1H-indol-4-yl, 1H-indol-5-yl, 1H-indol-6-yl, 1-methyl-1H-indol-5-yl, 1H-indazol-5-yl, 1H-indazol-6-yl, 1-methyl-1H-indazol-6-yl, 3-methyl-1H-indazol-6-yl, 3-methoxy-1H-indazol-6-yl, 6-methoxy-1H-indazol-5-yl, 1H-benzoimidazol-5-yl, 2-methyl-1H-benzoimidazol-5-yl, 2-trifluoromethyl-1H-benzoimidazol-5-yl, 1H-benzotriazol-5-yl, 2-methyl-benzooxazol-5-yl, 2-methyl-benzooxazol-6-yl, quinoxalin-6-yl, isoquinolin-7-yl, quinolin-6-yl, 1H-pyrrolo[2,3-c]pyridin-3-yl, 1H-pyrrolo[2,3-b]pyridin-3-yl, 1H-pyrrolo[2,3-b]pyridin-5-yl, 1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl, imidazo[1,2-a]pyridin-6-yl, 2-carboxy-1H-indol-5-yl, 3-carboxy-1H-indol-6-yl, 4-carboxy-1H-indol-2-yl, 5-carboxy-1H-indol-2-yl, 6-carboxy-1H-indol-2-yl, 7-carboxy-1H-indol-2-yl, 7-carboxy-1H-indol-4-yl, 7-carboxy-1-methyl-1H-indol-4-yl, 5-(methoxycarbonyl)-1H-indol-2-yl, 6-(methoxycarbonyl)-1H-indol-2-yl), 6-carboxy-benzofuran-2-yl, 3-carboxy-benzofuran-6-yl, 2-carboxy-benzofuran-5-yl, and 2-carboxy-benzofuran-6-yl. Preferred examples are 1H-benzoimidazol-5-yl, 1H-indol-6-yl, 1H-indol-5-yl, 1H-indol-2-yl, 1H-indazol-5-yl, as well as 8- to 10-membered bicyclic heteroaryl which are mono-substituted with —(C0-3)alkylene-COORO2such as 3-carboxy-1H-indol-6-yl, 4-carboxy-1H-indol-2-yl, 5-carboxy-1H-indol-2-yl, 6-carboxy-1H-indol-2-yl, 7-carboxy-1H-indol-2-yl, 5-(methoxycarbonyl)-1H-indol-2-yl, 6-(methoxycarbonyl)-1H-indol-2-yl), 6-carboxy-benzofuran-2-yl, 3-carboxy-benzofuran-6-yl, 2-carboxy-benzofuran-5-yl, and 2-carboxy-benzofuran-6-yl. In addition, a further example is 7-carboxy-benzothiophen-2-yl.

For the substituent “—(CH2)p-HET, wherein p represents the integer 0 or 1, and wherein HET represents a 5- or 6-membered heteroaryl”, such 5- or 6-membered heteroaryl is as defined before; notably a nitrogen containing 5-membered heteroaryl such as especially tetrazolyl, or oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, imidazolyl, pyrazolyl, or triazolyl. The above groups are unsubstituted or substituted as explicitly defined. The group —(CH2)p— is preferably absent, i.e. p represents the integer 0 and the group HET is directly bound to Ari. Particular examples of —(CH2)p-HET are especially the —(CH2)0-HET groups 1H-tetrazol-5-yl, 3-hydroxy-isoxazol-5-yl, 2-hydroxy-[1,3,4]oxadiazol-4-yl; further examples are 3-amino-isoxazol-5-yl, 2-amino-oxazol-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-hydroxy-ethyl)]-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, 1H-imidazol-4-yl, 5-methyl-1H-imidazol-4-yl, and 2,5-dimethyl-1H-imidazol-4-yl; as well as 1H-pyrazol-1-yl, 1H-pyrazol-3-yl, 3-methyl-pyrazol-1-yl, 1-methyl-1H-pyrazol-3-yl, 5-methyl-1H-pyrazol-3-yl, 3,5-dimethyl-pyrazol-1-yl, 4-carboxy-1H-pyrazol-3-yl, 1H-imidazol-2-yl, 3-methyl-3H-imidazol-4-yl, 2-methyl-1H-imidazol-4-yl, 1,5-dimethyl-1H-imidazol-2-yl, 1,2-dimethyl-1H-imidazol-4-yl, 1,5-dimethyl-1H-imidazol-4-yl, 2-cyclopropyl-1H-imidazol-4-yl, 2-cyclopropyl-1-methyl-1H-imidazol-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-methyl-thiazol-2-yl, 2-methyl-thiazol-4-yl, 2-amino-5-methyl-thiazol-4-yl, 4,5-dimethyl-thiazol-2-yl, 4-carboxy-thiazol-2-yl, 2-carboxy-thiazol-4-yl, 2-hydroxy-thiazol-4-yl, 2-amino-2-oxoethyl)thiazol-4-yl, isoxazol-3-yl, isoxazol-5-yl, 3-methyl-isoxazol-5-yl, 4-methyl-isoxazol-5-yl, 4-carboxy-3-methyl-isoxazol-5-yl, oxazol-5-yl, 2-methyl-oxazol-5-yl, 2-(2-carboxyethyl)-oxazol-5-yl, 2-(2-carboxyethyl)-4-methyl-oxazol-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-fluoro-pyridin-2-yl, pyrimidin-2-yl, 5-fluoro-pyrimidin-2-yl, 5-methoxy-pyrimidin-2-yl, 4-methoxy-pyrimidin-2-yl, 6-methoxy-pyrimidin-4-yl, 6-dimethylamino-pyrimidin-4-yl, pyrazin-2-yl, 6-methoxy-pyrazin-2-yl, 6-methoxy-pyridazin-3-yl, 3H-imidazol-4-yl, 3H-[1,2,3]triazol-4-yl, oxazol-2-yl, and 4,5-dimethyl-oxazol-2-yl. For avoidance of doubt, certain groups having tautomeric forms which may be considered predominantly aromatic (such as for example 3-hydroxy-isoxazolyl or 2-hydroxy-[1,3,4]oxadiazolyl groups) are defined herein as heteroaryl groups HET, even though their corresponding tautomeric form (3-oxo-2,3-dihydro-2H-isoxazolyl, respectively, 2-oxo-2,3-dihydro-3H-[1,3,4]oxadiazolyl) could also be considered as a non-aromatic group. Likewise, certain groups having tautomeric forms which may 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 for the substituent HET1, are defined herein as not being part of substituted heteroaryl groups as defined for HET, even though their corresponding tautomeric form (5-hydroxy-[1,2,4]oxadiazolyl, respectively, 5-mercapto-[1,2,4]oxadiazolyl), could also be considered as an heteroaryl group. It is understood that the corresponding tautomer is encompassed in the respective scope as defined.

The term “cyano” refers to a group —CN.

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

Examples of “—X2—NRN1RN2” groups as used for substituents of Ar1being phenyl or 5- or 6-membered heteroaryl are amino, methylamino, ethylamino, propylamino, amino-methyl, methylamino-methyl, isobutylamino-methyl, cyclopropylamino-methyl, cyclobutylamino-methyl, (2-methoxyethyl)amino-methyl, (2,2,2-trifluoro-ethyl)-amino; or —NH—CO—H, —N(C2H5)—CO—H, —NH—CO—C2H5, —NH—CO—CH2—CH2—OH, —NH—COO—CH3, —N(CH3)—COO—CH3; or pyrrolidin-1-yl, 2-oxo-pyrrolidin-1-yl, 1,1-dioxo-isothiazolidin-2-yl, morpholin-4-yl, azetidin-1-yl, or piperidin-1-yl; and 2-(dimethylamino)-ethoxy.

Examples of a group “—NH—CO—NRN5RN6” as used for substituents of the group Ar1are ureido (—NH—CO—NH2) and 3-ethylureido (—NH—CO—NH—C2H5).

Examples of a group “—(CH2)rCO—NRN3RN4wherein r represents the integer 0 or 1” as used for substituents of the group Ar1are preferably groups wherein r represents the integer 0 and at least one of RN3and RN4represents hydrogen (or less preferred, methyl). Particular examples of such group —CO—NRN3RN4are —CO—NH2, —CO—NH(CH3), —CO—N(CH3)2, —CO—NH(C2H5), —CO—NH—O-methyl, —CO—NH—O-ethyl, —CO—NH—O-isopropyl, —CO—NH—C2H4—OH, —CO—NH—O—C2H4—H, —CO—NH—C2H4—OCH3, —CO—NH—C2H4—N(CH3)2,and —CO—NH—O-benzyl. Further examples are —CO—NH-isopropyl and —CO—NH—OH, as well as —CO—N(CH3)2.

Examples of a group “—X1—CO—R1” as used for substituents of the group Ar1are especially the following groups:a) X1represents a direct bond; and RO1represents —OH; (i.e. —X1—CO—RO1represents —COOH); orb) X1represents a direct bond; and RO1represents —O—(C1-4)alkyl (especially ethoxy, or methoxy); (i.e. —X1—CO—RO1represents —CO—(C1-4)alkoxy (especially ethoxycarbonyl, methoxycarbonyl)); orc) X1represents a direct bond; and RO1represents —NH—SO2—RS3; wherein RS3represents (C1-4)alkyl; (C3-6)cycloalkyl wherein the (C3-6)cycloalkyl optionally contains a ring oxygen atom; (C3-6)cycloalkyl-(C1-3)alkylene wherein the (C3-6)cycloalkyl optionally contains a ring oxygen atom; (C1-3)fluoroalkyl; phenyl; or —NH2; (i.e. —X1—CO—RO1represents —CO—NH—SO2—RS3wherein RS3represents the above mentioned groups; notably methyl, ethyl, isopropyl, cyclopropyl, trifluoromethyl, amino; especially —X1—CO—RO1represents —CO—NH—SO2—CH3, —CO—NH—SO2—C(CH3)2, —CO—NH—SO2-cyclopropyl, —CO—NH—SO2-ethyl, or —CO—NH—SO2—NH2); ord) X1represents (C1-3)alkylene (especially —CH2—, —CH2—CH2—), —O—(C1-3)alkylene-* (especially —O—CH2—*, —O—CH(CH3)—*, —O—C(CH3)2—*, O—CH2—CH2*), —NH—(C1-3)alkylene-* (especially —NH—CH2*, —NH—CH(CH3)—*), —S—CH2—*, —CF2—, —CH═CH—, or —CH≡CH— [in a sub-embodiment X1represents especially —O—CH2—*, —NH—CH2—*, —S—CH2—*, or (C1-3)alkylene]; wherein the asterisks indicate the bond that is linked to the —CO—RO1group; and RO1represents —OH (i.e. —X1—CO—RO1represents —X1—COOH wherein X1represents the above mentioned groups; especially —X—CO—RO1represents —O—CH2—COOH or —NH—CH2—COOH; as well as —CH2—COOH, —CH2—CH2—COOH, —CH═CH—COOH, —CH≡CH—COOH, —O—CH2—CH2—COOH, —O—CH(CH3)—COOH, or —NH—CH(CH3)—COOH); ore) —X represents —NH—CO—* or —CO—; wherein the asterisk indicates the bond that is linked to the —CO—RO1group; and RO1represents —OH (i.e. —X—CO—RO1represents —X1—COOH wherein X1represents the above mentioned groups; especially —X—CO—RO1represents —NH—CO—COOH, —CO—COOH); orf) X1represents (C3-5)cycloalkylene; and RO1represents —OH; (i.e. —X—CO—RO1represents (C3-6)cycloalkyl which is mono-substituted with COOH; especially —X—CO—RO1represents 1-carboxy-cyclopropan-1-yl or 1-carboxy-cyclopentan-1-yl); org) X1represents a direct bond; and RO1represents —O—CH2—CO—RO4, wherein RO4represents hydroxy, or (C1-4)alkoxy, or —N[(C1-4)alkyl]2; especially —X1—CO—RO1represents —COO—CH2—COOH; or
wherein each of the groups a), b), c), d), e), f), and g) forms a particular sub-embodiment.

Compounds of Formula (I)/formula (II) containing a group “—X1—CO—RO1” wherein X1represents —CH═CH— may be in E- or Z-configuration. Preferably, such groups are in E-configuration.

Whenever a group Ar1is substituted with a substituent comprising a carboxylic acid group —COOH (such as in the substituents —(C0-3)alkylene-COORO2wherein RO2represents hydrogen; —(C0-3)alkylene-COORO3wherein RO3represents hydrogen; or in the substituents —X—CO—RO1wherein RO1represents —OH, especially in the —X1—CO—RO1groups a), d), e) and f) above) such carboxylic acid group may be present in form of a prodrug group. Such prodrugs are encompassed in the scope of the present invention. In certain instances, compounds comprising such carboxylic acid prodrug groups may as such exhibit biological activity on the EP2 and/or EP4 receptor, whereas in other instances, such compounds comprising such carboxylic acid prodrug groups require (e.g. enzymatic) cleavage of the prodrug to exhibit biological activity on the EP2 and/or EP4 receptor. 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. (Eds.) Prodrugs: Challenges and Rewards, Springer 2007, ISBN 978-O-387-49785-3).

Particular examples of prodrugs, for example suitable for —X1—COOH groups are:ester groups —X1—CO—O—P1wherein P1is for example (C1-4)alkyl; (C3-6)cycloalkyl wherein the (C3-6)cycloalkyl optionally contains a ring oxygen atom; (C3-6)cycloalkyl-(C1-3)alkyl wherein the (C3-6)cycloalkyl optionally contains a ring oxygen atom; (C1-3)fluoroalkyl; hydroxy-(C2-4)alkyl; or (C1-4)alkoxy-(C2-4)alkyl (especially P1is (C1-4)alkyl, in particular methyl or ethyl);groups —X1—CO—NH—SO2—RS3wherein RS3represents (C1-4)alkyl, (C3-6)cycloalkyl wherein the (C3-6)cycloalkyl optionally contains a ring oxygen atom; (C3-6)cycloalkyl-(C1-3)alkyl wherein the (C3-6)cycloalkyl optionally contains a ring oxygen atom; (C1-3)fluoroalkyl, —NH2; (especially RS3is (C1-4)alkyl, (C3-6)cycloalkyl; in particular methyl);groups —X1—CO—RO1wherein RO1represents —O—CH2—CO—RO4, wherein RO4represents hydroxy, or (C1-4)alkoxy, or —N[(C1-4)alkyl]2(especially —COO—CH2—COOH, —COO—CH2—CO—N(CH3)2);groups —X1—CO—RO1wherein RO1represents —O—CH2—O—CO—RO5, wherein RO5represents (C1-4)alkyl or (C1-4)alkoxy (especially —COO—CH2—O—CO—O-ethyl, —COO—CH2—O—CO-propyl);groups —X1—CO—RO1wherein RO1represents —O—CH2—CH2—N[(C1-4)alkyl]2(especially —COO—CH2—CH2—N(CH3)2); andgroups —X1—CO—RO1wherein RO1represents 5-methyl-2-oxo-[1,3]dioxol-4-yl)-methyloxy-.

Examples of “hydroxy-(C1-4)alkyl” groups as used for substituents of the group Ar1are hydroxymethyl and 1-hydroxy-ethyl.

An example of “dihydroxy-(C2-4)alkyl” groups as used for substituents of the group Ar is 1,2-dihydroxyethyl.

An example of “hydroxy-(C2-4)alkoxy” groups as used for substituents of the group Ar is 2-hydroxy-ethoxy.

An example of “(C1-4)alkoxy-(C2-4)alkoxy” groups as used for substituents of the group Ar is 2-methoxy-ethoxy.

Examples of a group “—SO2—RS1” as used for substituents of the group Ar are —SO2—CH3, —SO2—NH2, —SO2—NH—CH3.

Examples of a group “S—RS2” as used for substituents of the group Ar are methylsulfanyl, ethylsulfanyl, n-propylsulfanyl, isopropylsulfanyl, isobutylsulfanyl), cyclobutylsulfanyl, and (oxetan-3-yl)-sulfanyl.

An example of a “(C1-4)alkoxy-(C2-4)alkyl” group is 2-methoxyethyl.

An example of a “hydroxy-(C2-4)alkoxy” group is 2-hydroxy-ethoxy.

An example of a “hydroxy-(C2-4)alkyl” group is 2-hydroxy-ethyl.

An example of a “—CO—(C1-4)alkoxy” group as used for substituents of the group Ar is ethoxycarbonyl. Such groups may also be useful as produgs of the respective —COOH substituent.

Whenever the word “between” is used to describe a numerical range, it is to be understood that the end points of the indicated range are explicitly included in the range. For example: if a temperature range is described to be between 40° C. and 80° C., this means that the end points 40° C. and 80° C. are included in the range; or if a variable is defined as being an integer between 1 and 4, this means that the variable is the integer 1, 2, 3, or 4.

Unless used regarding temperatures, the term “about” placed before a numerical value “X” refers in the current application to an interval extending from X minus 10% of X to X plus 10% of X, and preferably to an interval extending from X minus 5% of X to X plus 5% of X. In the particular case of temperatures, the term “about” placed before a temperature “Y” refers in the current application to an interval extending from the temperature Y minus 10° C. to Y plus 10° C., and preferably to an interval extending from Y minus 5° C. to Y plus 5° C. Besides, the term “room temperature” as used herein refers to a temperature of about 25° C.

Further embodiments of the invention are presented hereinafter:

9) Another embodiment relates to compounds according to embodiment 8), wherein Ar1represents

a phenyl group of the structure (Ar-I):

whereinRprepresents—X1—CO—RO1, whereinX1represents a direct bond, (C1-3)alkylene (especially —CH2—, —CH(CH3)—, —C(CH3)2—, —CH2—CH2—), —O—(C1-3)alkylene-* (especially —O—CH2*, —O—CH(CH3)*, —O—C(CH3)2—*, —O—CH2—CH2—*), —NH—(C1-3)alkylene-* (especially-NH—CH2*, —NH—CH(CH3)—*), —CH═CH—, —CH≡CH—, —NH—CO—*, or (C3-5)cycloalkylene; wherein the asterisks indicate the bond that is linked to the —CO—RO1group; andRO1represents—OH;—O—(C1-4)alkyl (especially ethoxy, methoxy);—NH—SO2—RS3wherein RS3represents (C1-4)alkyl, (C3-6)cycloalkyl wherein the (C3-6)cycloalkyl optionally contains a ring oxygen atom, (C3-6)cycloalkyl-(C1-3)alkylene wherein the (C3-6)cycloalkyl optionally contains a ring oxygen atom, (C1-3)fluoroalkyl, or —NH2;—O—CH2—CO—RO4, wherein RO4represents hydroxy, or (C1-4)alkoxy, or —N[(C1-4)alkyl]2;—O—CH2—O—CO—RO5, wherein RO5represents (C1-4)alkyl or (C1-4)alkoxy;—O—CH2—CH2—N[(C1-4)alkyl]2(especially —O—CH2—CH2—N(CH3)2); or(5-methyl-2-oxo-[1,3]dioxol-4-yl)-methyloxy-;[wherein in particular such group —X1—CO—RO1represents —OOH, —COO—CH3, —CO—O—C2H5, —O—CH2—COOH, —O—CH(CH3)—COOH, —O—C(CH3)2—COOH, —O—CH2—CH2—COOH, —NH—CH2—OOH, —NH—CH2—COO—CH3, —NH—CH(CH3)—COOH, —CO—NH—SO2—CH3, —CO—NH—SO2—C(CH3)2, —CO—NH—SO2-cyclopropyl, —CO—NH—SO2—C2H5, —CO—NH—SO2—NH2, —COO—CH2—OOH, —COO—CH2—CH2—N(CH3)2, —COO—CH2—CO—N(CH3)2, —COO—CH2—O—CO—O—C2H5, —CO—O—CH2—O—CO-propyl, (5-methyl-2-oxo-[1,3]dioxol-4-yl)-methyl-O—CO—, —CH2—COOH, —CH2—COO—CH3, —CH2—CO—O—C2H5, —CH2—CH2—COOH, —CH═CH—COOH, —CH≡CH—CO—O—C2H5, —NH—CO—COOH, 1-carboxy-cyclopropan-1-yl];

—NH—CO—NRN5RN6wherein RN5and RN6independently represent hydrogen or (C1-4)alkyl (wherein preferably at least one of RN5and RN6represents hydrogen; and wherein particular examples of such group —NH—CO—NRN5RN6are —NH—CO—NH2, —NH—CO—NH—C2H5);—(CH2)q-HET1, wherein q represents the integer 0, 1 or 2 (especially q is 0, i.e. HET1is linked to Ar1by a direct bond); and wherein HET1represents 5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl (encompassing its tautomeric form 5-hydroxy-[1,2,4]oxadiazol-3-yl), or 3-oxo-2,3-dihydro-[1,2,4]oxadiazol-5-yl (encompassing its tautomeric form 3-hydroxy-[1,2,4]oxadiazol-5-yl);—(CH2)p-HET, wherein p represents the integer 0 or 1 (especially p is 0, i.e. HET is linked to Ar1by a direct bond); and wherein HET represents a 5-membered heteroaryl (especially oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, imidazolyl, pyrazolyl, triazolyl, or tetrazolyl), wherein said 5-membered heteroaryl is unsubstituted, or mono- or di-substituted, wherein the substituents are independently selected from (C1-4)alkyl (especially methyl), (C1-4)alkoxy (especially methoxy), —COOH, hydroxy, hydroxy-(C1-3)alkyl (especially hydroxymethyl), (C3-5)cycloalkyl optionally containing one ring oxygen atom (especially cyclopropyl, oxetan-3-yl), or —NRN9RN10wherein RN9and RN10independently represent hydrogen, (C1-3)alkyl (especially methyl), or hydroxy-(C2-4)alkyl (especially 2-hydroxy-ethyl); (especially such group —(CH2)p-HET is 1H-tetrazol-5-yl, 3-hydroxy-isoxazol-5-yl, 2-hydroxy-[1,3,4]oxadiazol-4-yl, 3-amino-isoxazol-5-yl, 2-amino-oxazol-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-hydroxy-ethyl)]-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, 1H-imidazol-4-yl, 5-methyl-1H-imidazol-4-yl, 2,5-dimethyl-1H-imidazol-4-yl);Rm1representshydrogen;(C1-6)alkyl (especially methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl);(C1-4)alkoxy (especially methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy);(C1-3)fluoroalkyl (especially trifluoromethyl);(C1-3)fluoroalkoxy (especially difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy);halogen (especially fluoro or chloro);(C3-6)cycloalkyl (especially cyclopropyl);(C3-6)cycloalkyl-oxy (especially cyclopropyl-oxy, cyclobutyl-oxy, cyclopentyl-oxy);hydroxy;hydroxy-(C2-4)alkoxy (especially 2-hydroxy-ethoxy);—S—RS2wherein RS2represents (C1-4)alkyl (especially methyl, ethyl, n-propyl, isopropyl, isobutyl), or (C3-6)cycloalkyl optionally containing one ring oxygen atom (especially cyclobutyl, oxetan-3-yl); wherein in a sub-embodiment, Rm1especially is different from hydrogen;Rm2represents hydrogen, methyl, fluoro, or chloro; andRo1represents hydrogen; or, in case Rm2represents hydrogen, Ro1represents hydrogen or fluoro;or Ar1represents a 5-membered heteroaryl group of the structure (Ar-II):

whereinY represents CR8wherein R3represents especially hydrogen, or halogen (notably fluoro, chloro); or Y represents N;R7represents—X1—CO—RO1, whereinX1represents a direct bond, (C1-3)alkylene (especially —CH2—, —CH(CH3)—, —C(CH3)2—, —CH2—CH2—), —O—(C1-3)alkylene-* (especially —O—CH2—*, —O—CH(CH3)—*, —O—C(CH3)2—*, —O—CH2—CH2—*), —NH—(C1-3)alkylene* (especially —NH—CH2*, —NH—CH(CH3)—*), —CH═CH—, —CH≡CH—, —NH—CO—*, or (C3-5)cycloalkylene; wherein the asterisks indicate the bond that is linked to the —CO—RO1group; andRO1represents—OH;—O—(C1-4)alkyl (especially ethoxy, methoxy);—NH—SO2—RS3wherein RS3represents (C1-4)alkyl, (C3-6)cycloalkyl wherein the (C3-6)cycloalkyl optionally contains a ring oxygen atom, (C3-6)cycloalkyl-(C1-3)alkylene wherein the (C3-6)cycloalkyl optionally contains a ring oxygen atom, (C1-3)fluoroalkyl, or —NH2;—O—CH2—CO—R4, wherein RO4represents hydroxy, or (C1-4)alkoxy, or —N[(C1-4)alkyl]2;—O—CH2—O—CO—RO5, wherein RO5represents (C1-4)alkyl or (C1-4)alkoxy; or—O—CH2—CH2—N[(C1-4)alkyl]2(especially —O—CH2—CH2—N(CH3)2);(5-methyl-2-oxo-[1,3]dioxol-4-yl)-methyloxy-;[wherein in particular such group —X1—CO—RO1represents —COOH, —COO—CH3, —CO—O—C2H5, —O—CH2—COOH, —O—CH(CH3)—COOH, —O—C(CH3)2—COOH, —O—CH2—CH2—COOH, —NH—CH2—COOH, —NH—CH2—COO—CH3, —NH—CH(CH3)—COOH, —CO—NH—SO2—CH3, —CO—NH—SO2—C(CH3)2, —CO—NH—SO2-cyclopropyl, —CO—NH—SO2—C2H5, —CO—NH—SO2—NH2, —COO—CH2—COOH, —COO—CH2—CH2—N(CH3)2, —COO—CH2—CO—N(CH3)2, —COO—CH2—O—CO—O—C2H5, —COO—CH2—O—CO-propyl, (5-methyl-2-oxo-[1,3]dioxol-4-yl)-methyl-O—CO—, —CH2—COOH, —CH2—COO—CH3, —CH2—CO—O—C2H5, —CH2—CH2—COOH, —CH═CH—COOH, —CH≡CH—CO—O—C2H5, —NH—CO—COOH, 1-carboxy-cyclopropan-1-yl];—NH—CO—NRN5RN6wherein RN5and RN6independently represent hydrogen or (C1-4)alkyl (wherein preferably at least one of RN5and RN6represents hydrogen; and wherein particular examples of such group —NH—CO—NRN5RN6are —NH—CO—NH2, —NH—CO—NH—C2H5);—(CH2)q-HET1, wherein q represents the integer 0, 1 or 2 (especially q is 0, i.e. HET1is linked to Ar1by a direct bond); and wherein HET1represents 5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl (encompassing its tautomeric form 5-hydroxy-[1,2,4]oxadiazol-3-yl), or 3-oxo-2,3-dihydro-[1,2,4]oxadiazol-5-yl (encompassing its tautomeric form 3-hydroxy-[1,2,4]oxadiazol-5-yl);—(CH2)p-HET, wherein p represents the integer 0 or 1 (especially p is 0, i.e. HET is linked to Ar1by a direct bond); and wherein HET represents a 5-membered heteroaryl (especially oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, imidazolyl, pyrazolyl, triazolyl, or tetrazolyl), wherein said 5-membered heteroaryl is unsubstituted, or mono- or di-substituted, wherein the substituents are independently selected from (C1-4)alkyl (especially methyl), (C1-4)alkoxy (especially methoxy), —COOH, hydroxy, hydroxy-(C1-3)alkyl (especially hydroxymethyl), (C3-5)cycloalkyl optionally containing one ring oxygen atom (especially cyclopropyl, oxetan-3-yl), or —NRN9RN10wherein RN9and RN10independently represent hydrogen, (C1-3)alkyl (especially methyl), or hydroxy-(C2-4)alkyl (especially 2-hydroxy-ethyl); (especially such group —(CH2)p-HET is 1H-tetrazol-5-yl, 3-hydroxy-isoxazol-5-yl, 2-hydroxy-[1,3,4]oxadiazol-4-yl, 3-amino-isoxazol-5-yl, 2-amino-oxazol-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-hydroxy-ethyl)]-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, 1H-imidazol-4-yl, 5-methyl-1H-imidazol-4-yl, 2,5-dimethyl-1H-imidazol-4-yl);R6represents(C1-6)alkyl (especially methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl);(C1-4)alkoxy (especially methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy);(C1-3)fluoroalkyl (especially trifluoromethyl);(C1-3)fluoroalkoxy (especially difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy);halogen (especially fluoro or chloro);(C3-6)cycloalkyl (especially cyclopropyl);(C3-6)cycloalkyl-oxy (especially cyclopropyl-oxy, cyclobutyl-oxy, cyclopentyl-oxy);hydroxy-(C2-4)alkoxy (especially 2-hydroxy-ethoxy);—S—RS2wherein RS2represents (C1-4)alkyl (especially methyl, ethyl, n-propyl, isopropyl, isobutyl), or (C3-6)cycloalkyl optionally containing one ring oxygen atom (especially cyclobutyl, oxetan-3-yl);or Ar1represents 8- to 10-membered bicyclic heteroaryl (notably 9- or 10-membered bicyclic heteroaryl; especially indazolyl, benzoimidazolyl, indolyl, benzofuranyl, benzooxazolyl, quinoxalinyl, isoquinolinyl, or quinolinyl); wherein said 8- to 10-membered bicyclic heteroaryl independently is mono-substituted with —(C0-3)alkylene-COORO2wherein RO2represents hydrogen or (C1-4)alkyl (especially methyl) (wherein especially such group —(C0-3)alkylene-COORO2is —COOH); (especially such 8- to 10-membered bicyclic heteroaryl is 3-carboxy-1H-indol-6-yl, 4-carboxy-1H-indol-2-yl, 5-carboxy-1H-indol-2-yl, 6-carboxy-1H-indol-2-yl, 7-carboxy-1H-indol-2-yl, 5-(methoxycarbonyl)-1H-indol-2-yl, 6-(methoxycarbonyl)-1H-indol-2-yl), 6-carboxy-benzofuran-2-yl, 3-carboxy-benzofuran-6-yl, 2-carboxy-benzofuran-5-yl, or 2-carboxy-benzofuran-6-yl);
wherein in a sub-embodiment, Ar1especially is a phenyl group of the structure (Ar-I) (wherein in particular Rmespecially is different from hydrogen), or a 5-membered heteroaryl group of the structure (Ar-II), as defined herein above.
10) Another embodiment relates to compounds according to any one of embodiment 8) to 15), wherein Ar1representsa phenyl group of the structure (Ar-I):

whereinRprepresents—X1—CO—RO1, whereinX1represents a direct bond, (C1-3)alkylene (especially —CH2—, —CH(CH3)—, —C(CH3)2—, —CH2—CH2—), —O—(C1-3)alkylene-* (especially —O—CH2—*, —O—CH(CH3)—*, —O—C(CH3)2—*, —O—CH2—CH2-*), —NH—(C1-3)alkylene* (especially —NH—CH2*, —NH—CH(CH3)—*), —CH═CH—, —NH—CO—*, or (C3-5)cycloalkylene; wherein the asterisks indicate the bond that is linked to the —CO—RO1group; andRO1represents—OH;—O—(C1-4)alkyl (especially ethoxy, methoxy);—NH—SO2—RS3wherein RS3represents (C1-4)alkyl, (C3-6)cycloalkyl wherein the (C3-6)cycloalkyl optionally contains a ring oxygen atom, (C3-6)cycloalkyl-(C1-3)alkylene wherein the (C3-6)cycloalkyl optionally contains a ring oxygen atom, (C1-3)fluoroalkyl, or —NH2;[wherein in particular such group —X—CO—RO1represents —COOH, —COO—CH3, —CO—O—C2H5, —O—CH2—COOH, —O—CH(CH3)—COOH, —O—C(CH3)2—COOH, —O—CH2—CH2—COOH, —NH—CH2—COOH, —NH—CH2—COO—CH3, —NH—CH(CH3)—COOH, —CO—NH—SO2—CH3, —CO—NH—SO2—C(CH3)2, —CO—NH—SO2-cyclopropyl, —CO—NH—SO2—C2H5, —CO—NH—SO2—NH2, —CH2—COOH, —CH2—COO—CH3, —CH2—CO—O—C2H5, —CH2—CH2—COOH, —CH═CH—COOH, —NH—CO—COOH, 1-carboxy-cyclopropan-1-yl];HET1, wherein HET1represents 5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl (encompassing its tautomeric form 5-hydroxy-[1,2,4]oxadiazol-3-yl), or 3-oxo-2,3-dihydro-[1,2,4]oxadiazol-5-yl (encompassing its tautomeric form 3-hydroxy-[1,2,4]oxadiazol-5-yl);HET, wherein HET represents a 5-membered heteroaryl selected from oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, imidazolyl, pyrazolyl, triazolyl, or tetrazolyl; in particular isoxazolyl and tetrazolyl, wherein said 5-membered heteroaryl is unsubstituted, or mono-substituted, wherein the substituent is independently selected from (C1-4)alkyl (especially methyl), (C1-4)alkoxy (especially methoxy), —COOH, hydroxy, hydroxy-(C1-3)alkyl (especially hydroxymethyl), (C3-5)cycloalkyl optionally containing one ring oxygen atom (especially cyclopropyl, oxetan-3-yl), or —NRN9RN10wherein RN9and RN10independently represent hydrogen, (C1-3)alkyl (especially methyl), or hydroxy-(C2-4)alkyl (especially 2-hydroxy-ethyl); [in particular HET is unsubstituted or mono-substituted with hydroxy; especially HET is 1H-tetrazol-5-yl, 3-hydroxy-isoxazol-5-yl, or 2-hydroxy-[1,3,4]oxadiazol-4-yl];Rm1representshydrogen;(C1-6)alkyl (especially methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl);(C1-4)alkoxy (especially methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy);(C1-3)fluoroalkyl (especially trifluoromethyl);(C1-3)fluoroalkoxy (especially difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy);halogen (especially fluoro or chloro);(C3-6)cycloalkyl (especially cyclopropyl);(C3-6)cycloalkyl-oxy (especially cyclopropyl-oxy, cyclobutyl-oxy, cyclopentyl-oxy);hydroxy;hydroxy-(C2-4)alkoxy (especially 2-hydroxy-ethoxy);—S—RS2wherein RS2represents (C1-4)alkyl (especially methyl, ethyl, n-propyl, isopropyl, isobutyl), or (C3-6)cycloalkyl optionally containing one ring oxygen atom (especially cyclobutyl, oxetan-3-yl); wherein in a sub-embodiment, Rm1especially is different from hydrogen;Rm2represents hydrogen, methyl, fluoro, or chloro; andRo1represents hydrogen;or Ar1represents a 5-membered heteroaryl group of the structure (Ar-II):

whereinY represents CH or N;R7represents—X1—CO—RO1, whereinX1represents a direct bond, (C1-3)alkylene (especially —CH2—, —CH(CH3)—, —C(CH3)2—, —CH2—CH2—), —O—(C1-3)alkylene-* (especially —O—CH2—*, —O—CH(CH3)—*, —O—C(CH3)2—*, —O—CH2—CH2—*), —NH—(C1-3)alkylene* (especially —NH—CH2*, —NH—CH(CH3)—*), —S—CH2*, —CF2—, —CH═CH—, —CH≡CH—, —NH—CO—*, —CO—, or (C3-5)cycloalkylene; wherein the asterisks indicate the bond that is linked to the —CO—RO1group; andRO1represents—OH;—O—(C1-4)alkyl (especially ethoxy, methoxy);—NH—SO2—RS3wherein RS3represents (C1-4)alkyl, (C3-6)cycloalkyl wherein the (C3-6)cycloalkyl optionally contains a ring oxygen atom, (C3-6)cycloalkyl-(C1-3)alkylene wherein the (C3-6)cycloalkyl optionally contains a ring oxygen atom, (C1-3)fluoroalkyl, or —NH2;[wherein in particular such group —X1—CO—RO1represents —OOH, —COO—CH3, —CO—O—C2H5, —O—CH2—COOH, —O—CH(CH3)—COOH, —O—C(CH3)2—COOH, —O—CH2—CH2—OOH, —NH—CH2—OOH, —NH—CH2—COO—CH3, —NH—CH(CH3)—COOH, —CO—NH—SO2—CH3, —CO—NH—SO2—C(CH3)2, —CO—NH—SO2-cyclopropyl, —CO—NH—SO2—C2H5, —CO—NH—SO2—NH2, —CH2—OOH, —CH2—COO—CH3, —CH2—CO—O—C2H5, —CH2—CH2—COOH, —CH═CH—COOH, —NH—CO—OOH, 1-carboxy-cyclopropan-1-yl];HET1, wherein HET1represents 5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl (encompassing its tautomeric form 5-hydroxy-[1,2,4]oxadiazol-3-yl), or 3-oxo-2,3-dihydro-[1,2,4]oxadiazol-5-yl (encompassing its tautomeric form 3-hydroxy-[1,2,4]oxadiazol-5-yl);HET, wherein HET represents a 5-membered heteroaryl selected from oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, imidazolyl, pyrazolyl, triazolyl, or tetrazolyl; in particular isoxazolyl and tetrazolyl, wherein said 5-membered heteroaryl is unsubstituted, or mono-substituted, wherein the substituent is independently selected from (C1-4)alkyl (especially methyl), (C1-4)alkoxy (especially methoxy), —COOH, hydroxy, hydroxy-(C1-3)alkyl (especially hydroxymethyl), (C3-5)cycloalkyl optionally containing one ring oxygen atom (especially cyclopropyl, oxetan-3-yl), or —NRN9RN10wherein RN9and RN10independently represent hydrogen, (C1-3)alkyl (especially methyl), or hydroxy-(C2-4)alkyl (especially 2-hydroxy-ethyl) [in particular HET is unsubstituted or mono-substituted with hydroxy; especially HET is 1H-tetrazol-5-yl, 3-hydroxy-isoxazol-5-yl, or 2-hydroxy-[1,3,4]oxadiazol-4-yl];R6represents(C1-6)alkyl (especially methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl);(C1-4)alkoxy (especially methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy);(C1-3)fluoroalkyl (especially trifluoromethyl);(C1-3)fluoroalkoxy (especially difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy);halogen (especially fluoro or chloro);hydroxy;(C3-6)cycloalkyl (especially cyclopropyl);(C3-6)cycloalkyl-oxy (especially cyclopropyl-oxy, cyclobutyl-oxy, cyclopentyl-oxy);hydroxy-(C2-4)alkoxy (especially 2-hydroxy-ethoxy);—S—RS2wherein RS2represents (C1-4)alkyl (especially methyl, ethyl, n-propyl, isopropyl, isobutyl), or (C3-6)cycloalkyl optionally containing one ring oxygen atom (especially cyclobutyl, oxetan-3-yl);or Ar1represents 8- to 10-membered bicyclic heteroaryl selected from indazolyl, benzoimidazolyl, indolyl, benzofuranyl, benzooxazolyl, quinoxalinyl, isoquinolinyl, and quinolinyl; wherein said 8- to 10-membered bicyclic heteroaryl independently is mono-substituted with —(C0-3)alkylene-COORO2wherein RO2represents hydrogen or (C1-4)alkyl (especially methyl) (wherein especially such group —(C0-3)alkylene-COORO2is —COOH); (especially such 8- to 10-membered bicyclic heteroaryl is 3-carboxy-1H-indol-6-yl, 4-carboxy-1H-indol-2-yl, 5-carboxy-1H-indol-2-yl, 6-carboxy-1H-indol-2-yl, 7-carboxy-1H-indol-2-yl, 5-(methoxycarbonyl)-1H-indol-2-yl, 6-(methoxycarbonyl)-1H-indol-2-yl), 6-carboxy-benzofuran-2-yl, 3-carboxy-benzofuran-6-yl, 2-carboxy-benzofuran-5-yl, or 2-carboxy-benzofuran-6-yl);
wherein in a sub-embodiment, Ar1especially is a phenyl group of the structure (Ar-I) (wherein in particular Rm1especially is different from hydrogen), or a 5-membered heteroaryl group of the structure (Ar-II), as defined herein above.
11) Another embodiment relates to compounds according to embodiment 8), wherein Ar1represents a group selected from:
A)


or, in addition, Ar1represents a group selected from:
B)


wherein each of the groups A) and B) forms a particular sub-embodiment;
wherein in a further sub-embodiment, Ar1especially is a phenyl group (in particular a di-substituted phenyl group), or a thiophenyl group, or a thiazolyl group, as defined in groups A) and/or B) herein above.
12) Another embodiment relates to compounds according to embodiment 8), wherein
a) Ar1represents a phenyl group selected from:


b) or Ar1represents a thiophenyl group selected from:


c) or Ar1represents a thiazolyl group selected from:

or Ar1represents 9- or 10-membered bicyclic heteroaryl selected from

or Ar1represents a group selected from:


wherein in a sub-embodiment, Ar1especially is a phenyl group (in particular a di-substituted phenyl group), or a thiophenyl group, or a thiazolyl group, as defined herein above.
13) Another embodiment relates to compounds according to embodiment 8), wherein
(i) Ar1represents a phenyl group selected from:a)

b)

c)

d)


(ii) or Ar1represents a thiophenyl group selected from:a)

b)

c)

d)

e)


(iii) or Ar1represents a thiazolyl group selected from:a)

b)


(iv) or Ar represents 9- or 10-membered bicyclic heteroaryl selected froma)

b)


(v) or Ar1represents a group selected from:


wherein in a sub-embodiment, Ar1especially is a phenyl group (in particular a di-substituted phenyl group), or a thiophenyl group, or a thiazolyl group, as defined herein above.
14) Another embodiment relates to compounds according to embodiment 8), wherein Ar1represents a group selected from
A)


or, in addition, Ar1represents a group selected from
B)


wherein each of the groups A) and B) forms a particular sub-embodiment.
15) Another embodiment relates to compounds of formula (II) according to any one of embodiments 8) to 13), wherein X represents S.
16) Another embodiment relates to compounds of formula (II) according to any one of embodiments 8) to 13), wherein X represents 0.
17) A second embodiment relates to compounds of formula (II) according to any one of embodiments 8) to 15), wherein R2represents hydrogen.
18) Another embodiment relates to compounds of formula (II) according to any one of embodiments 8) to 16), wherein R2represents (C1-4)alkyl (especially methyl, ethyl), halogen (especially chloro, bromo), or cyano.
19) Another embodiment relates to compounds of formula (II) according to any one of embodiments 8) to 16), wherein R2represents (C1-4)alkyl (especially methyl, ethyl).
20) Another embodiment relates to compounds of formula (II) according to any one of embodiments 8) to 15), wherein R2represents (C1-4)alkyl (especially methyl, ethyl), or cyano.
21) Another embodiment relates to compounds of formula (II) according to any one of embodiments 8) to 15), wherein R2represents cyano.
22) Another embodiment relates to compounds according to any one of embodiments 8) to 21), wherein in the fragment


(R1)nrepresents one, two or three substituents (i.e. said fragment is, in addition to R2, substituted with one, two or three R1), wherein said substituents R1are independently selected from (C1-3)alkyl (especially methyl), (C1-3)alkoxy (especially methoxy), halogen (especially fluoro, or chloro), (C1-3)fluoroalkyl (especially trifuoromethyl), (C1-3)fluoroalkoxy (especially trifluoromethoxy), or cyano.
23) Another embodiment relates to compounds according to any one of embodiments 8) to 21), wherein in the fragment


(R1)nrepresents one, two or three substituents (i.e. said fragment is, in addition to R2, substituted with one, two or three R1), wherein said substituents R1are independently selected from (C1-3)alkyl (especially methyl), (C1-3)alkoxy (especially methoxy), or halogen (especially fluoro, or chloro).
24) Another embodiment relates to compounds according to any one of embodiments 8) to 16), wherein the fragment


representsa benzothiophene selected from:

or, in addition, said fragment may represent the benzothiophene:

or a benzofurane selected from:


25) Another embodiment relates to compounds according to any one of embodiments 8) to 16), wherein the fragment


represents a benzothiophene selected from


(especially


26) The invention, thus, relates to compounds of the formula (I) as defined in embodiment 1) for use according to embodiment 1), or to such compounds further limited by the characteristics of any one of embodiments 2) to 25), under consideration of their respective dependencies; to pharmaceutically acceptable salts thereof; and to the use of such compounds according to embodiment 1), and as further described herein below. For avoidance of any doubt, especially the following embodiments relating to the compounds of formula (I) are thus possible and intended and herewith specifically disclosed in individualized form:
1, 9+1, 13+1, 14+1, 15+1, 15+9+1, 15+13+1, 15+14+1, 20+15+1, 20+15+9+1, 20+15+13+1, 20+15+14+1, 24+1, 24+9+1, 24+13+1, 24+15+1, 24+15+9+1, 24+15+13+1, 24+15+14+1, 24+20+15+1, 24+20+15+9+1, 24+20+15+13+1, 24+20+15+14+1, 25+1, 25+9+1, 25+14+1, 25+15+1, 25+15+9+1, 25+15+13+1, 25+15+14+1, 25+20+15+1, 25+20+15+9+1, 25+20+15+13+1, 25+20+15+14+1.

In the list above the numbers refer to the embodiments according to their numbering provided hereinabove whereas “+” indicates the dependency from another embodiment. The different individualized embodiments are separated by commas. In other words, “25+15+14+1” for example refers to embodiment 25) depending on embodiment 15), depending on embodiment 14), depending on embodiment 1), i.e. embodiment “25+15+14+8” corresponds to the compounds of formula (I) as defined in embodiment 1) for use according to embodiment 1), further limited by all the structural features of the embodiments 14), 15), and 25).

27) The invention, thus, further relates to compounds of the formula (II) as defined in embodiment 8), or to such compounds further limited by the characteristics of any one of embodiments 9) to 25), under consideration of their respective dependencies; to pharmaceutically acceptable salts thereof; and to the use of such compounds as medicaments especially in the prevention/prophylaxis or treatment of diseases which respond to the blockage of the EP2 receptors and/or the EP4 receptors as described herein below. For avoidance of any doubt, especially the following embodiments relating to the compounds of formula (II) are thus possible and intended and herewith specifically disclosed in individualized form:
8, 9+8, 10+8, 12+8, 13+8, 14+8, 15+8, 15+9+8, 15+10+8, 15+12+8, 15+13+8, 15+14+8, 18+15+8, 18+15+9+8, 18+15+10+8, 18+15+12+8, 18+15+13+8, 18+15+14+8, 20+15+8, 20+15+9+8, 20+15+10+8, 20+15+12+8, 20+15+13+8, 20+15+14+8, 22+8, 22+10+8, 22+15+8, 22+15+9+8, 22+15+10+8, 22+15+12+8, 22+15+13+8, 22+15+14+8, 22+18+15+8, 22+18+15+9+8, 22+18+15+10+8, 22+18+15+12+8, 22+18+15+13+8, 22+18+15+14+8, 24+8, 24+13+8, 24+15+8, 24+15+9+8, 24+15+10+8, 24+15+12+8, 24+15+13+8, 24+15+14+8, 24+20+15+8, 24+20+15+9+8, 24+20+15+10+8, 24+20+15+12+8, 24+20+15+13+8, 24+20+15+14+8, 25+8, 25+14+8, 25+15+8, 25+15+9+8, 25+15+10+8, 25+15+12+8, 25+15+13+8, 25+15+14+8, 25+20+15+8, 25+20+15+9+8, 25+20+15+10+8, 25+20+15+12+8, 25+20+15+13+8, 25+20+15+14+8.

In the list above the numbers refer to the embodiments according to their numbering provided hereinabove whereas “+” indicates the dependency from another embodiment. The different individualized embodiments are separated by commas. In other words, “25+15+14+8” for example refers to embodiment 25) depending on embodiment 15), depending on embodiment 14), depending on embodiment 8), i.e. embodiment “25+15+14+8” corresponds to the compounds of formula (II) according to embodiment 8) further limited by all the features of the embodiments 14), 15), and 25).

28) Another embodiment relates to compounds of formula (II) according to embodiment 8), which are selected from the following compounds:

5-{6-[2-(5-Chloro-7-methoxy-2-methyl-benzofuran-3-yl)-ethylamino]-pyrimidin-4-yl}-3-methyl-thiophene-2-carboxylic acid;4-{6-[2-(2-Cyano-5-fluoro-7-methyl-benzo[b]thiophen-3-yl)-ethylamino]-pyrimidin-4-yl}-2-methylsulfanyl-benzoic acid;4-{6-[2-(2-Cyano-7-methoxy-benzo[b]thiophen-3-yl)-ethylamino]-pyrimidin-4-yl}-2-methylsulfanyl-benzoic acid;3-Ethoxy-5-{6-[2-(4-fluoro-2,7-dimethyl-benzo[b]thiophen-3-yl)-ethylamino]-pyrimidin-4-yl}-thiophene-2-carboxylic acid;5-{6-[2-(2-Cyano-5-fluoro-7-methyl-benzo[b]thiophen-3-yl)-ethylamino]-pyrimidin-4-yl}-3-ethoxy-thiophene-2-carboxylic acid;5-{6-[2-(2-Cyano-7-methoxy-benzo[b]thiophen-3-yl)-ethylamino]-pyrimidin-4-yl}-3-ethoxy-thiophene-2-carboxylic acid;3-Ethoxy-5-{6-[2-(4-fluoro-7-methoxy-2-methyl-benzo[b]thiophen-3-yl)-ethylamino]-pyrimidin-4-yl}-thiophene-2-carboxylic acid;5-{6-[2-(4-Chloro-2,7-dimethyl-benzo[b]thiophen-3-yl)-ethylamino]-pyrimidin-4-yl}-3-ethoxy-thiophene-2-carboxylic acid;5-{6-[2-(4-Chloro-7-methoxy-2-methyl-benzo[b]thiophen-3-yl)-ethylamino]-pyrimidin-4-yl}-3-ethoxy-thiophene-2-carboxylic acid;5-{6-[2-(4,5-Difluoro-7-methoxy-2-methyl-benzofuran-3-yl)-ethylamino]-pyrimidin-4-yl}-3-ethoxy-thiophene-2-carboxylic acid;3-Ethoxy-5-{6-[2-(5-fluoro-2,7-dimethyl-benzo[b]thiophen-3-yl)-ethylamino]-pyrimidin-4-yl}-thiophene-2-carboxylic acid;5-[6-(2-Benzo[b]thiophen-3-yl}-ethylamino)-pyrimidin-4-yl]-3-ethoxy-thiophene-2-carboxylic acid;3-Ethoxy-5-{6-[2-(4-fluoro-7-methoxy-2-methyl-benzofuran-3-yl)-ethylamino]-pyrimidin-4-yl}-thiophene-2-carboxylic acid;5-{6-[2-(7-Chloro-2-methyl-benzofuran-3-yl)-ethylamino]-pyrimidin-4-yl}-3-ethoxy-thiophene-2-carboxylic acid;5-{6-[2-(2,7-Dimethyl-benzo[b]thiophen-3-yl)-ethylamino]-pyrimidin-4-yl}-3-ethoxy-thiophene-2-carboxylic acid;3-Ethoxy-5-{6-[2-(5-fluoro-2,7-dimethyl-benzofuran-3-yl)-ethylamino]-pyrimidin-4-yl}-thiophene-2-carboxylic acid;5-{6-[2-(5-Chloro-7-methoxy-2-methyl-benzofuran-3-yl)-ethylamino]-pyrimidin-4-yl}-3-ethoxy-thiophene-2-carboxylic acid;5-{6-[2-(5-Fluoro-2,7-dimethyl-benzo[b]thiophen-3-yl)-ethylamino]-pyrimidin-4-yl}-3-(2-hydroxy-ethoxy)-thiophene-2-carboxylic acid;5-{6-[2-(5-Fluoro-2,7-dimethyl-benzo[b]thiophen-3-yl)-ethylamino]-pyrimidin-4-yl}-3-trifluoromethyl-thiophene-2-carboxylic acid;4-{6-[2-(2-Cyano-5-fluoro-7-methyl-benzo[b]thiophen-3-yl)-ethylamino]-pyrimidin-4-yl}-2-ethoxy-benzoic acid;4-{6-[2-(2-Cyano-7-methoxy-benzo[b]thiophen-3-yl)-ethylamino]-pyrimidin-4-yl}-2-ethoxy-benzoic acid;6-{6-[2-(2,7-Dimethyl-benzo[b]thiophen-3-yl)-ethylamino]-pyrimidin-4-yl}-benzofuran-2-carboxylic acid;5-{6-[2-(2,7-Dimethyl-benzo[b]thiophen-3-yl)-ethylamino]-pyrimidin-4-yl}-benzofuran-2-carboxylic acid;5-(4-{6-[2-(5-Fluoro-2,7-dimethyl-benzo[b]thiophen-3-yl)-ethylamino]-pyrimidin-4-yl}-phenyl)-[1,2,4]oxadiazol-3(2H)-one [tautomeric form: 5-(4-(6-((2-(5-fluoro-2,7-dimethyl benzo[b]thiophen-3-yl)ethyl)amino)pyrimidin-4-yl)phenyl)-[1,2,4]oxadiazol-3-ol];2-{6-[2-(5-Fluoro-2,7-dimethyl-benzo[b]thiophen-3-yl)-ethylamino]-pyrimidin-4-yl}-1H-indole-4-carboxylic acid;(E)-3-(3-Ethoxy-5-{6-[2-(5-fluoro-2,7-dimethyl-benzo[b]thiophen-3-yl)-ethylamino]-pyrimidin-4-yl}-thiophen-2-yl)-acrylic acid;(4-{6-[2-(2-Cyano-5-fluoro-7-methyl-benzo[b]thiophen-3-yl)-ethylamino]-pyrimidin-4-yl}-2-ethoxy-phenyl)-acetic acid;2-Difluoromethoxy-4-{6-[2-(5-fluoro-2,7-dimethyl-benzo[b]thiophen-3-yl)-ethylamino]-pyrimidin-4-yl}-benzoic acid;(2-Ethoxy-4-{6-[2-(4-fluoro-7-methoxy-2-methyl-benzo[b]thiophen-3-yl)-ethylamino]-pyrimidin-4-yl}-phenoxy)-acetic acid;(2-Ethoxy-4-{6-[2-(4-fluoro-2,7-dimethyl-benzo[b]thiophen-3-yl)-ethylamino]-pyrimidin-4-yl}-phenoxy)-acetic acid;(2-Ethoxy-4-{6-[2-(5-fluoro-2,7-dimethyl-benzo[b]thiophen-3-yl)-ethylamino]-pyrimidin-4-yl}-phenylamino)-acetic acid;N-(3-Ethoxy-5-{6-[2-(5-fluoro-2,7-dimethyl-benzo[b]thiophen-3-yl)-ethylamino]-pyrimidin-4-yl}-thiophene-2-carbonyl)-methanesulfonamide;{6-[4-Ethoxy-5-(1H-tetrazol-5-yl)-thiophen-2-yl]-pyrimidin-4-yl}-[2-(5-fluoro-2,7-dimethyl-benzo[b]thiophen-3-yl)-ethyl]-amine;3-(3-Ethoxy-5-{6-[2-(5-fluoro-2,7-dimethyl-benzo[b]thiophen-3-yl)-ethylamino]-pyrimidin-4-yl}-thiophen-2-yl)-[1,2,4]oxadiazol-5(4H)-one [tautomeric form: 3-(3-ethoxy-5-(6-((2-(5-fluoro-2,7-dimethylbenzo[b]thiophen-3-yl)ethyl)amino)pyrimidin-4-yl)thiophen-2-yl)-[1,2,4]oxadiazol-5-ol];4-Ethoxy-2-{6-[2-(5-fluoro-2,7-dimethyl-benzo[b]thiophen-3-yl)-ethylamino]-pyrimidin-4-yl}-thiazole-5-carboxylic acid; and3-(4-Ethoxy-2-{6-[2-(5-fluoro-2,7-dimethyl-benzo[b]thiophen-3-yl)-ethylamino]-pyrimidin-4-yl}-thiazol-5-yl)-[1,2,4]oxadiazol-5(4H)-one [tautomeric form: 3-(4-ethoxy-2-(6-((2-(5-fluoro-2,7-dimethylbenzo[b]thiophen-3-yl)ethyl)amino)pyrimidin-4-yl)thiazol-5-yl)-[1,2,4]oxadiazol-5-ol].
29) In addition to the compounds listed in embodiment 28), further compounds of formula (II) according to embodiment 8), are selected from the following compounds:5-{6-[2-(5-Fluoro-2,7-dimethyl-benzofuran-3-yl)-ethylamino]-pyrimidin-4-yl}-3-methyl-thiophene-2-carboxylic acid;5-{6-[2-(2,7-Dimethyl-benzo[b]thiophen-3-yl)-ethylamino]-pyrimidin-4-yl}-3-methyl-thiophene-2-carboxylic acid;5-{6-[2-(5-Chloro-2,7-dimethyl-benzofuran-3-yl)-ethylamino]-pyrimidin-4-yl}-3-methyl-thiophene-2-carboxylic acid;3-Methyl-5-{6-[2-(2-methyl-benzofuran-3-yl)-ethylamino]-pyrimidin-4-yl}-thiophene-2-carboxylic acid;4-{6-[2-(2,7-Dimethyl-benzo[b]thiophen-3-yl)-ethylamino]-pyrimidin-4-yl}-benzoic acid;4-{6-[2-(4-Chloro-7-methoxy-2-methyl-benzo[b]thiophen-3-yl)-ethylamino]-pyrimidin-4-yl}-2-hydroxy-benzoic acid;4-{6-[2-(5-Fluoro-2,7-dimethyl-benzo[b]thiophen-3-yl)-ethylamino]-pyrimidin-4-yl}-2-hydroxy-benzoic acid;4-{6-[2-(2,7-Dimethyl-benzo[b]thiophen-3-yl)-ethylamino]-pyrimidin-4-yl}-2-methylsulfanyl-benzoic acid;4-{6-[2-(4-Chloro-7-methoxy-2-methyl-benzo[b]thiophen-3-yl)-ethylamino]-pyrimidin-4-yl}-2-methylsulfanyl-benzoic acid;4-{6-[2-(5-Fluoro-2,7-dimethyl-benzofuran-3-yl)-ethylamino]-pyrimidin-4-yl}-2-methylsulfanyl-benzoic acid;4-{6-[2-(5-Fluoro-2,7-dimethyl-benzo[b]thiophen-3-yl)-ethylamino]-pyrimidin-4-yl}-2-methylsulfanyl-benzoic acid;4-{6-[2-(2-Methyl-benzofuran-3-yl)-ethylamino]-pyrimidin-4-yl}-2-methylsulfanyl-benzoic acid;4-{6-[2-(4-Chloro-2,7-dimethyl-benzo[b]thiophen-3-yl)-ethylamino]-pyrimidin-4-yl}-2-methylsulfanyl-benzoic acid;4-{6-[2-(4,7-Dichloro-2-methyl-benzo[b]thiophen-3-yl)-ethylamino]-pyrimidin-4-yl}-2-methylsulfanyl-benzoic acid;4-{6-[2-(6-Fluoro-2,7-dimethyl-benzo[b]thiophen-3-yl)-ethylamino]-pyrimidin-4-yl}-2-methylsulfanyl-benzoic acid;4-{6-[2-(7-Chloro-5-fluoro-2-methyl-benzo[b]thiophen-3-yl)-ethylamino]-pyrimidin-4-yl}-2-methylsulfanyl-benzoic acid;4-{6-[2-(2-Methyl-benzo[b]thiophen-3-yl)-ethylamino]-pyrimidin-4-yl}-2-methylsulfanyl-benzoic acid;3-Ethoxy-5-{6-[2-(2-ethyl-5-fluoro-7-methyl-benzofuran-3-yl)-ethylamino]-pyrimidin-4-yl}-thiophene-2-carboxyli acid;4-{6-[2-(4-Chloro-7-methoxy-2-methyl-benzo[b]thiophen-3-yl)-ethylamino]-pyrimidin-4-yl}-2-methoxy-benzoic acid;4-{6-[2-(2,7-Dimethyl-benzo[b]thiophen-3-yl)-ethylamino]-pyrimidin-4-yl}-2-ethylsulfanyl-benzoic acid;2-Ethylsulfanyl-4-{6-[2-(2-methyl-benzo[b]thiophen-3-yl)-ethylamino]-pyrimidin-4-yl}-benzoic acid;2-Ethylsulfanyl-4-{6-[2-(2-methyl-benzofuran-3-yl)-ethylamino]-pyrimidin-4-yl}-benzoic acid;4-{6-[2-(5-Fluoro-2,7-dimethyl-benzo[b]thiophen-3-yl)-ethylamino]-pyrimidin-4-yl}-2-propyl-benzoic acid;4-{6-[2-(2,7-Dimethyl-benzo[b]thiophen-3-yl)-ethylamino]-pyrimidin-4-yl}-2-fluoro-6-methylsulfanyl-benzoic acid;2-Chloro-4-{6-[2-(2,7-dimethyl-benzo[b]thiophen-3-yl)-ethylamino]-pyrimidin-4-yl}-6-methylsulfanyl-benzoic acid;(3-Ethoxy-5-{6-[2-(5-fluoro-2,7-dimethyl-benzo[b]thiophen-3-yl)-ethylamino]-pyrimidin-4-yl}-thiophen-2-yl)-acetic acid;2-Ethoxy-4-{6-[2-(4-fluoro-7-methoxy-2-methyl-benzo[b]thiophen-3-yl)-ethylamino]-pyrimidin-4-yl}-benzoic acid;2-Ethoxy-4-{6-[2-(5-fluoro-2,7-dimethyl-benzo[b]thiophen-3-yl)-ethylamino]-pyrimidin-4-yl}-benzoic acid;4-{6-[2-(4-Chloro-7-methoxy-2-methyl-benzo[b]thiophen-3-yl)-ethylamino]-pyrimidin-4-yl}-2-ethoxy-benzoic acid;4-{6-[2-(2-Bromo-5-fluoro-7-methyl-benzo[b]thiophen-3-yl)-ethylamino]-pyrimidin-4-yl}-2-ethoxy-benzoic acid;4-{6-[2-(2-Chloro-5-fluoro-7-methyl-benzo[b]thiophen-3-yl)-ethylamino]-pyrimidin-4-yl}-2-ethoxy-benzoic acid;4-{6-[2-(2,7-Dimethyl-benzo[b]thiophen-3-yl)-ethylamino]-pyrimidin-4-yl}-2-ethoxy-benzoic acid;2-Ethoxy-4-{6-[2-(4-fluoro-2,7-dimethyl-benzo[b]thiophen-3-yl)-ethylamino]-pyrimidin-4-yl}-benzoic acid;2-Ethoxy-4-{6-[2-(6-fluoro-2,7-dimethyl-benzo[b]thiophen-3-yl)-ethylamino]-pyrimidin-4-yl}-benzoic acid;4-{6-[2-(4,7-Dichloro-2-methyl-benzo[b]thiophen-3-yl)-ethylamino]-pyrimidin-4-yl}-2-ethoxy-benzoic acid;4-{6-[2-(5-Chloro-2,7-dimethyl-benzofuran-3-yl)-ethylamino]-pyrimidin-4-yl}-2-ethoxy-benzoic acid;4-{6-[2-(7-Chloro-5-fluoro-2-methyl-benzo[b]thiophen-3-yl)-ethylamino]-pyrimidin-4-yl}-2-ethoxy-benzoic acid;4-{6-[2-(7-Chloro-2-methyl-benzofuran-3-yl)-ethylamino]-pyrimidin-4-yl}-2-ethoxy-benzoic acid;2-Ethoxy-4-{6-[2-(5-fluoro-2,7-dimethyl-benzofuran-3-yl)-ethylamino]-pyrimidin-4-yl}-benzoic acid;4-{6-[2-(5-Chloro-7-methoxy-2-methyl-benzofuran-3-yl)-ethylamino]-pyrimidin-4-yl}-2-ethoxy-benzoic acid;4-{6-[2-(5,7-Dichloro-2-methyl-benzofuran-3-yl)-ethylamino]-pyrimidin-4-yl}-2-ethoxy-benzoic acid;2-Ethoxy-4-{6-[2-(2-methyl-benzo[b]thiophen-3-yl)-ethylamino]-pyrimidin-4-yl}-benzoic acid;2-Ethoxy-4-{6-[2-(2-methyl-benzofuran-3-yl)-ethylamino]-pyrimidin-4-yl}-benzoic acid;4-{6-[2-(2-chloro-benzo[b]thiophen-3-yl)-ethylamino]-pyrimidin-4-yl}-2-ethoxy-benzoic acid;2-{6-[2-(5-Fluoro-2,7-dimethyl-benzo[b]thiophen-3-yl)-ethylamino]-pyrimidin-4-yl}-1H-indole-6-carboxylic acid;4-{6-[2-(5-Chloro-7-methoxy-2-methyl-benzofuran-3-yl)-ethylamino]-pyrimidin-4-yl}-2-cyclopropoxy-benzoic acid;2-Cyclopropoxy-4-{6-[2-(4-fluoro-7-methoxy-2-methyl-benzo[b]thiophen-3-yl)-ethylamino]-pyrimidin-4-yl}-benzoic acid;2-Cyclopropoxy-4-{6-[2-(4,5-difluoro-7-methoxy-2-methyl-benzofuran-3-yl)-ethylamino]-pyrimidin-4-yl}-benzoic acid;4-{6-[2-(5-fluoro-2,7-dimethyl-benzo[b]thiophen-3-yl)-ethylamino]-pyrimidin-4-yl}-2-(2-hydroxy-ethoxy)-benzoic acid;4-{6-[2-(2,7-Dimethyl-benzo[b]thiophen-3-yl)-ethylamino]-pyrimidin-4-yl}-2-propylsulfanyl-benzoic acid;4-{6-[2-(2-Methyl-benzo[b]thiophen-3-yl)-ethylamino]-pyrimidin-4-yl}-2-propylsulfanyl-benzoic acid;4-{6-[2-(2-Methyl-benzofuran-3-yl)-ethylamino]-pyrimidin-4-yl}-2-propylsulfanyl-benzoic acid;4-{6-[2-(2,7-Dimethyl-benzo[b]thiophen-3-yl)-ethylamino]-pyrimidin-4-yl}-2-isopropylsulfanyl-benzoic acid;2-Isopropylsulfanyl-4-{6-[2-(2-methyl-benzo[b]thiophen-3-yl)-ethylamino]-pyrimidin-4-yl}-benzoic acid;2-Isopropylsulfanyl-4-{6-[2-(2-methyl-benzofuran-3-yl)-ethylamino]-pyrimidin-4-yl}-benzoic acid;2-Fluoro-4-{6-[2-(5-fluoro-2,7-dimethyl-benzo[b]thiophen-3-yl)-ethylamino]-pyrimidin-4-yl}-6-propyl-benzoic acid;4-{6-[2-(5-Fluoro-2,7-dimethyl-benzo[b]thiophen-3-yl)-ethylamino]-pyrimidin-4-yl}-2-isobutyl-benzoic acid;4-{6-[2-(4-Chloro-7-methoxy-2-methyl-benzo[b]thiophen-3-yl)-ethylamino]-pyrimidin-4-yl}-2-isopropoxy-benzoic acid;4-{6-[2-(6-Fluoro-2,7-dimethyl-benzo[b]thiophen-3-yl)-ethylamino]-pyrimidin-4-yl}-2-propoxy-benzoic acid;4-{6-[2-(5-Fluoro-2,7-dimethyl-benzo[b]thiophen-3-yl)-ethylamino]-pyrimidin-4-yl}-2-propoxy-benzoic acid;4-{6-[2-(4-Chloro-7-methoxy-2-methyl-benzo[b]thiophen-3-yl)-ethylamino]-pyrimidin-4-yl}-2-propoxy-benzoic acid;4-{6-[2-(4,7-Dichloro-2-methyl-benzo[b]thiophen-3-yl)-ethylamino]-pyrimidin-4-yl}-2-propoxy-benzoic acid;(4-{6-[2-(2,7-Dimethyl-benzo[b]thiophen-3-yl)-ethylamino]-pyrimidin-4-yl}-2-ethoxy-phenyl)-acetic acid;4-{6-[2-(4-Chloro-7-methoxy-2-methyl-benzo[b]thiophen-3-yl)-ethylamino]-pyrimidin-4-yl}-2-difluoromethoxy-benzoic acid;(4-{6-[2-(7-Chloro-2-methyl-benzofuran-3-yl)-ethylamino]-pyrimidin-4-yl}-2-ethoxy-phenoxy)-acetic acid;(4-{6-[2-(2,7-Dimethyl-benzo[b]thiophen-3-yl)-ethylamino]-pyrimidin-4-yl}-2-ethoxy-phenoxy)-acetic acid;2-Cyclobutylsulfanyl-4-{6-[2-(2-methyl-benzofuran-3-yl)-ethylamino]-pyrimidin-4-yl}-benzoic acid;2-Cyclobutylsulfanyl-4-{6-[2-(2,7-dimethyl-benzo[b]thiophen-3-yl)-ethylamino]-pyrimidin-4-yl}-benzoic acid;4-{6-[2-(2,7-Dimethyl-benzo[b]thiophen-3-yl)-ethylamino]-pyrimidin-4-yl}-2-(oxetan-3-ylsulfanyl)-benzoic acid;4-{6-[2-(5-Chloro-7-methoxy-2-methyl-benzofuran-3-yl)-ethylamino]-pyrimidin-4-yl}-2-cyclobutoxy-benzoic acid;2-Cyclobutoxy-4-{6-[2-(4-fluoro-7-methoxy-2-methyl-benzo[b]thiophen-3-yl)-ethylamino]-pyrimidin-4-yl}-benzoic acid;4-{6-[2-(4-Chloro-7-methoxy-2-methyl-benzo[b]thiophen-3-yl)-ethylamino]-pyrimidin-4-yl}-2-cyclobutoxy-benzoic acid;2-Cyclobutoxy-4-{6-[2-(4-fluoro-2,7-dimethyl-benzo[b]thiophen-3-yl)-ethylamino]-pyrimidin-4-yl}-benzoic acid;4-{6-[2-(7-Chloro-2-methyl-benzofuran-3-yl)-ethylamino]-pyrimidin-4-yl}-2-cyclobutoxy-benzoic acid;2-Cyclobutoxy-4-{6-[2-(5-fluoro-2,7-dimethyl-benzo[b]thiophen-3-yl)-ethylamino]-pyrimidin-4-yl}-benzoic acid;2-Cyclobutoxy-4-{6-[2-(5-fluoro-2,7-dimethyl-benzofuran-3-yl)-ethylamino]-pyrimidin-4-yl}-benzoic acid;{6-[3-Ethoxy-4-(1H-tetrazol-5-yl)-phenyl]-pyrimidin-4-yl}-[2-(5-fluoro-2,7-dimethyl-benzo[b]thiophen-3-yl)-ethyl]-amine;3-(2-Ethoxy-4-{6-[2-(5-fluoro-2,7-dimethyl-benzo[b]thiophen-3-yl)-ethylamino]-pyrimidin-4-yl}-phenoxy)-propionic acid;2-Butoxy-6-fluoro-4-{6-[2-(5-fluoro-2,7-dimethyl-benzo[b]thiophen-3-yl)-ethylamino]-pyrimidin-4-yl}-benzoic acid;N-(2-Ethoxy-4-{6-[2-(5-fluoro-2,7-dimethyl-benzo[b]thiophen-3-yl)-ethylamino]-pyrimidin-4-yl}-phenyl)-oxalamic acid;2-Cyclobutoxy-3-fluoro-4-{6-[2-(4-fluoro-7-methoxy-2-methyl-benzo[b]thiophen-3-yl)-ethylamino]-pyrimidin-4-yl}-benzoic acid;2-Cyclobutoxy-4-{6-[2-(4,5-difluoro-7-methoxy-2-methyl-benzofuran-3-yl)-ethylamino]-pyrimidin-4-yl}-6-fluoro-benzoic acid;4-{6-[2-(5-Chloro-7-methoxy-2-methyl-benzofuran-3-yl)-ethylamino]-pyrimidin-4-yl}-2-cyclobutoxy-6-fluoro-benzoic acid;2-Cyclopentyloxy-4-{6-[2-(5-fluoro-2,7-dimethyl-benzo[b]thiophen-3-yl)-ethylamino]-pyrimidin-4-yl}-benzoic acid;2-Cyclopentyloxy-4-{6-[2-(5-fluoro-2,7-dimethyl-benzofuran-3-yl)-ethylamino]-pyrimidin-4-yl}-benzoic acid;3-(2-Ethoxy-4-{6-[2-(5-fluoro-2,7-dimethyl-benzo[b]thiophen-3-yl)-ethylamino]-pyrimidin-4-yl}-phenyl)-[1,2,4]oxadiazol-5(4H)-one [tautomeric form: 3-(2-ethoxy-4-(6-((2-(5-fluoro-2,7-dimethylbenzo[b]thiophen-3-yl)ethyl)amino)pyrimidin-4-yl)phenyl)-[1,2,4]oxadiazol-5-ol];3-Ethoxy-5-(6-((2-(5-fluoro-2,7-dimethylbenzo[b]thiophen-3-yl)ethyl)amino)pyrimidin-4-yl)-N-sulfamoylthiophene-2-carboxamide;4-Ethyl-2-{6-[2-(5-fluoro-2,7-dimethyl-benzo[b]thiophen-3-yl)-ethylamino]-pyrimidin-4-yl}-thiazole-5-carboxylic acid; and3-(4-Ethyl-2-{6-[2-(5-fluoro-2,7-dimethyl-benzo[b]thiophen-3-yl)-ethylamino]-pyrimidin-4-yl}-thiazol-5-yl)-[1,2,4]oxadiazol-5(4H)-one [tautomeric form: 3-(4-ethyl-2-(6-((2-(5-fluoro-2,7-dimethylbenzo[b]thiophen-3-yl)ethyl)amino)pyrimidin-4-yl)thiazol-5-yl)-[1,2,4]oxadiazol-5-ol].
30) Another embodiment relates to compounds of formula (I) as defined in embodiment 1) for use according to embodiment 1) which are selected from the compounds according to embodiments 28) and/or 29).
31) In addition to the compounds listed in embodiments 28) and 29), further compounds of formula (II) according to embodiment 8), are selected from the following compounds:(4-{6-[2-(2-Cyano-5-fluoro-7-methyl-benzo[b]thiophen-3-yl)-ethylamino]-pyrimidin-4-yl}-2-ethoxy-6-fluoro-phenyl)-acetic acid;4-{6-[2-(2-Cyano-5-fluoro-7-methyl-benzo[b]thiophen-3-yl)-ethylamino]-pyrimidin-4-yl}-2-propyl-benzoic acid;(4-{6-[2-(2-Cyano-5-fluoro-7-methyl-benzo[b]thiophen-3-yl)-ethylamino]-pyrimidin-4-yl}-2-methoxy-phenyl)-acetic acid;(4-{6-[2-(2-Cyano-5-fluoro-7-methyl-benzo[b]thiophen-3-yl)-ethylamino]-pyrimidin-4-yl}-2-propoxy-phenyl)-acetic acid;(4-{6-[2-(2-Cyano-5-fluoro-7-methyl-benzo[b]thiophen-3-yl)-ethylamino]-pyrimidin-4-yl}-2-propyl-phenyl)-acetic acid;(4-{6-[2-(2-Cyano-5-fluoro-7-methyl-benzo[b]thiophen-3-yl)-ethylamino]-pyrimidin-4-yl}-2-isopropoxy-phenyl)-acetic acid;4-{6-[2-(2-Cyano-5-fluoro-7-methyl-benzo[b]thiophen-3-yl)-ethylamino]-pyrimidin-4-yl}-2-isopropoxy-benzoic acid;3-(4-{6-[2-(2-Cyano-5-fluoro-7-methyl-benzo[b]thiophen-3-yl)-ethylamino]-pyrimidin-4-yl}-2-ethoxy-phenoxy)-propionic acid;2-Ethylsulfanyl-4-{6-[2-(5-fluoro-2,7-dimethyl-benzo[b]thiophen-3-yl)-ethylamino]-pyrimidin-4-yl}-benzoic acid;3-(4-{6-[2-(5-Fluoro-2,7-dimethyl-benzo[b]thiophen-3-yl)-ethylamino]-pyrimidin-4-yl}-phenyl)-4-hydroxy-cyclobut-3-ene-1,2-dione;(4-{6-[2-(5-Fluoro-2,7-dimethyl-benzo[b]thiophen-3-yl)-ethylamino]-pyrimidin-4-yl}-2-isobutyl-phenyl)-acetic acid;(2-Ethyl-4-{6-[2-(5-fluoro-2,7-dimethyl-benzo[b]thiophen-3-yl)-ethylamino]-pyrimidin-4-yl}-phenyl)-acetic acid;(2-Ethoxy-4-{6-[2-(5-fluoro-2,7-dimethyl-benzo[b]thiophen-3-yl)-ethylamino]-pyrimidin-4-yl}-phenyl)-oxo-acetic acid;(4-{6-[2-(5-Fluoro-2,7-dimethyl-benzo[b]thiophen-3-yl)-ethylamino]-pyrimidin-4-yl}-2-propoxy-phenyl)-acetic acid;N-(2-Ethoxy-4-{6-[2-(5-fluoro-2,7-dimethyl-benzo[b]thiophen-3-yl)-ethylamino]-pyrimidin-4-yl}-phenyl)-formamide;(2-Ethyl-4-{6-[2-(5-fluoro-2,7-dimethyl-benzo[b]thiophen-3-yl)-ethylamino]-pyrimidin-4-yl}-6-methyl-phenyl)-acetic acid;2-Cyclopropoxy-4-{6-[2-(5-fluoro-2,7-dimethyl-benzo[b]thiophen-3-yl)-ethylamino]-pyrimidin-4-yl}-benzoic acid;(2-Cyclopropoxy-4-{6-[2-(5-fluoro-2,7-dimethyl-benzo[b]thiophen-3-yl)-ethylamino]-pyrimidin-4-yl}-phenyl)-acetic acid;(3-Ethyl-5-{6-[2-(5-fluoro-2,7-dimethyl-benzo[b]thiophen-3-yl)-ethylamino]-pyrimidin-4-yl}-thiophen-2-yl)-acetic acid;(2-Chloro-4-{6-[2-(5-fluoro-2,7-dimethyl-benzo[b]thiophen-3-yl)-ethylamino]-pyrimidin-4-yl}-6-methyl-phenyl)-acetic acid;5-(2-Ethoxy-4-{6-[2-(5-fluoro-2,7-dimethyl-benzo[b]thiophen-3-yl)-ethylamino]-pyrimidin-4-yl}-phenyl)-isoxazol-3-ol[tautomeric form: 5-(2-ethoxy-4-(6-((2-(5-fluoro-2,7-dimethylbenzo[b]thiophen-3-yl)ethyl)amino)pyrimidin-4-yl)phenyl)isoxazol-3(2H)-one];1-(2-Ethoxy-4-{6-[2-(5-fluoro-2,7-dimethyl-benzo[b]thiophen-3-yl)-ethylamino]-pyrimidin-4-yl}-phenyl)-cyclopropanecarboxylic acid; and1-(4-{6-[2-(5-Fluoro-2,7-dimethyl-benzo[b]thiophen-3-yl)-ethylamino]-pyrimidin-4-yl}-2-propyl-phenyl)-cyclopropanecarboxylic acid.
32) In addition to the compounds listed in embodiments 28), 29), and 31), further compounds of formula (II) according to embodiment 8), are selected from the following compounds:4-{6-[2-(2,7-Dimethyl-benzo[b]thiophen-3-yl)-ethylamino]-pyrimidin-4-yl}-2-isobutylsulfanyl-benzoic acid;4-{6-[2-(2-Cyano-benzo[b]thiophen-3-yl)-ethylamino]-pyrimidin-4-yl}-2-methylsulfanyl-benzoic acid;(4-{6-[2-(2-Cyano-benzo[b]thiophen-3-yl)-ethylamino]-pyrimidin-4-yl}-2-ethoxy-phenyl)-acetic acid;3-(4-{6-[2-(5-Fluoro-2,7-dimethyl-benzo[b]thiophen-3-yl)-ethylamino]-pyrimidin-4-yl}-phenyl)-[1,2,4]oxadiazol-(4H)-one [tautomeric form: 3-(4-{6-[2-(5-Fluoro-2,7-dimethyl-benzo[b]thiophen-3-yl)-ethylamino]-pyrimidin-4-yl}-phenyl)-[1,2,4]oxadiazol-5-ol];4-{6-[2-(5-Fluoro-2,7-dimethyl-benzo[b]thiophen-3-yl)-ethylamino]-pyrimidin-4-yl}-benzamide;[2-(5-Fluoro-2,7-dimethyl-benzo[b]thiophen-3-yl)-ethyl]-[6-(1H-indol-5-yl)-pyrimidin-4-yl]-amine;4-{6-[2-(5-Fluoro-2,7-dimethyl-benzo[b]thiophen-3-yl)-ethylamino]-pyrimidin-4-yl}-2-isobutoxy-benzoic acid;(4-{6-[2-(5-Fluoro-2,7-dimethyl-benzo[b]thiophen-3-yl)-ethylamino]-pyrimidin-4-yl}-2-propyl-phenyl)-acetic acid;(4-{6-[2-(5-Fluoro-2,7-dimethyl-benzo[b]thiophen-3-yl)-ethylamino]-pyrimidin-4-yl}-2-trifluoromethoxy-phenyl)-acetic acid;N-(4-{6-[2-(5-Fluoro-2,7-dimethyl-benzo[b]thiophen-3-yl)-ethylamino]-pyrimidin-4-yl}-phenyl)-formamide;(4-{6-[2-(5-Fluoro-2,7-dimethyl-benzo[b]thiophen-3-yl)-ethylamino]-pyrimidin-4-yl}-2-isopropoxy-phenyl)-acetic acid;2-Ethyl-4-{6-[2-(5-fluoro-2,7-dimethyl-benzo[b]thiophen-3-yl)-ethylamino]-pyrimidin-4-yl}-benzoic acid;5-(4-{6-[2-(5-Fluoro-2,7-dimethyl-benzo[b]thiophen-3-yl)-ethylamino]-pyrimidin-4-yl}-2-methoxy-phenyl)-isoxazol-3-ol [tautomeric form: 5-(4-(6-((2-(5-fluoro-2,7-dimethylbenzo[b]thiophen-3-yl)ethyl)amino)pyrimidin-4-yl)-2-methoxyphenyl)isoxazol-3(2H)-one];5-{6-[2-(5-Fluoro-2,7-dimethyl-benzo[b]thiophen-3-yl)-ethylamino]-pyrimidin-4-yl}-2-methyl-1H-pyrrole-3-carboxylic acid;4-{6-[2-(5-Fluoro-2,7-dimethyl-benzo[b]thiophen-3-yl)-ethylamino]-pyrimidin-4-yl}-2-propyl-benzamide;4-{6-[2-(5-Fluoro-2,7-dimethyl-benzo[b]thiophen-3-yl)-ethylamino]-pyrimidin-4-yl}-N-(2-hydroxy-2-methyl-propyl)-2-propyl-benzamide;4-{6-[2-(5-Fluoro-2,7-dimethyl-benzo[b]thiophen-3-yl)-ethylamino]-pyrimidin-4-yl}-N-(2-methoxy-ethyl)-2-propyl-benzamide;4-{6-[2-(5-Fluoro-2,7-dimethyl-benzo[b]thiophen-3-yl)-ethylamino]-pyrimidin-4-yl}-N-(2-hydroxy-ethyl)-2-propyl-benzamide;4-{6-[2-(5-Fluoro-2,7-dimethyl-benzo[b]thiophen-3-yl)-ethylamino]-pyrimidin-4-yl}-N-methyl-2-propyl-benzamide;2-Ethoxy-4-{6-[2-(5-fluoro-2,7-dimethyl-benzo[b]thiophen-3-yl)-ethylamino]-pyrimidin-4-yl}-N-(2-hydroxy-ethyl)-benzamide;2-Ethoxy-4-{6-[2-(5-fluoro-2,7-dimethyl-benzo[b]thiophen-3-yl)-ethylamino]-pyrimidin-4-yl}-N-methyl-benzamide;2-Ethoxy-4-{6-[2-(5-fluoro-2.7-dimethyl-benzo[b]thiophen-3-yl)-ethylamino]-pyrimidin-4-yl}-benzamide:(2-Ethoxy-3-fluoro-4-{6-[2-(5-fluoro-2,7-dimethyl-benzo[b]thiophen-3-yl)-ethylamino]-pyrimidin-4-yl}-phenyl)-acetic acid;(5-{6-[2-(5-Fluoro-2,7-dimethyl-benzo[b]thiophen-3-yl)-ethylamino]-pyrimidin-4-yl}-3-propyl-thiophen-2-yl)-acetic acid;(3-Difluoromethoxy-5-{6-[2-(5-fluoro-2,7-dimethyl-benzo[b]thiophen-3-yl)-ethylamino]-pyrimidin-4-yl}-thiophen-2-yl)-acetic acid;2-{6-[2-(5-Fluoro-2,7-dimethyl-benzo[b]thiophen-3-yl)-ethylamino]-pyrimidin-4-yl}-1H-indole-7-carboxylic acid;2-{6-[2-(5-Fluoro-2,7-dimethyl-benzo[b]thiophen-3-yl)-ethylamino]-pyrimidin-4-yl}-benzo[b]thiophene-7-carboxylic acid; and3-(4-{6-[2-(5-Fluoro-2,7-dimethyl-benzo[b]thiophen-3-yl)-ethylamino]-pyrimidin-4-yl}-2-methoxy-phenyl)-propionic acid.
33) In addition to the compounds listed in embodiments 28), 29), 31) and 32), a further compound of formula (II) according to embodiment 8) is:(4-{6-[2-(2-Cyano-7-methoxy-benzo[b]thiophen-3-yl)-ethylamino]-pyrimidin-4-yl}-2-ethoxy-phenyl)-acetic acid.
34) Another embodiment relates to compounds of formula (I) as defined in embodiment 1) for use according to embodiment 1) which are selected from the compounds according to embodiments 31 to 33); as well as the following compounds:3-Ethoxy-5-{6-[2-(5-fluoro-2,7-dimethyl-benzo[b]thiophen-3-yl)-ethylamino]-pyrimidin-4-yl}-1H-pyrrole-2-carboxylic acid;1-Ethyl-4-{6-[2-(5-fluoro-2,7-dimethyl-benzo[b]thiophen-3-yl)-ethylamino]-pyrimidin-4-yl}-1H-pyrrole-2-carboxylic acid; and4-{6-[2-(5-Fluoro-2,7-dimethyl-benzo[b]thiophen-3-yl)-ethylamino]-pyrimidin-4-yl}-1-propyl-1H-pyrrole-2-carboxylic acid.

The compounds of formula (I)/formula (II) according to embodiments 1) to 34) and their pharmaceutically acceptable salts can be used as medicaments, e.g. in the form of pharmaceutical compositions for enteral (such especially oral e.g. in form of a tablet or a capsule) or parenteral administration (including topical application or inhalation).

The production of the pharmaceutical compositions can be effected in a manner which will be familiar to any person skilled in the art (see for example Remington,The Science and Practice of Pharmacy,21st Edition (2005), Part 5, “Pharmaceutical Manufacturing” [published by Lippincott Williams & Wilkins]) by bringing the described compounds of formula (I)/formula (II) or their pharmaceutically acceptable salts, optionally in combination with other therapeutically valuable substances, into a galenical administration form together with suitable, non-toxic, inert, therapeutically compatible solid or liquid carrier materials and, if desired, usual pharmaceutical adjuvants.

The present invention also relates to a method for the prevention/prophylaxis or treatment of a disease or disorder mentioned herein comprising administering to a subject a pharmaceutically active amount of a compound of formula (I)/formula (II) according to embodiments 1) to 34).

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

Whenever the word “between” is used to describe a numerical range, it is to be understood that the end points of the indicated range are explicitly included in the range. For example: if a temperature range is described to be between 40° C. and 80° C., this means that the end points 40° C. and 80° C. are included in the range; or if a variable is defined as being an integer between 1 and 4, this means that the variable is the integer 1, 2, 3, or 4.

Unless used regarding temperatures, the term “about” placed before a numerical value “X” refers in the current application to an interval extending from X minus 10% of X to X plus 10% of X, and preferably to an interval extending from X minus 5% of X to X plus 5% of X. In the particular case of temperatures, the term “about” placed before a temperature “Y” refers in the current application to an interval extending from the temperature Y minus 10° C. to Y plus 10° C., and preferably to an interval extending from Y minus 5° C. to Y plus 5° C.

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

The compounds of formula (I)/formula (II) according to embodiments 1) to 34) are useful for the prevention/prophylaxis or treatment of disorders relating to the EP2 and/or EP4 receptors.

Certain compounds of formula (I)/formula (II) according to embodiments 1) to 34) exhibit their biological activity as modulators of the prostaglandin 2 receptors EP2 and/or EP4 in a biological environment, (i.e. in the presence of one or more enzymes capable of breaking a covalent bond linked to a carbonyl group such as an amidase, an esterase or any suitable equivalent thereof capable of removing a prodrug group from a carboxylic acid group.

Diseases or disorders relating to the EP2 and/or EP4 receptors are especiallycancer (notably melanoma including metastatic melanoma; lung cancer including non-small cell lung cancer; bladder cancer including urinary bladder cancer, urothelial cell carcinoma; renal carcinomas including renal cell carcinoma, metastatic renal cell carcinoma, metastatic renal clear cell carcinoma; gastro-intestinal cancers including colorectal cancer, metastatic colorectal cancer, familial adenomatous polyposis (FAP), oesophageal cancer, gastric cancer, gallbladder cancer, cholangiocarcinoma, hepatocellular carcinoma, and pancreatic cancer such as pancreatic adenocarcinoma or pancreatic ductal carcinoma; endometrial cancer; ovarian cancer; cervical cancer; neuroblastoma; prostate cancer including castrate-resistant prostate cancer; brain tumors including brain metastases, malignant gliomas, glioblastoma multiforme, medulloblastoma, meningiomas; breast cancer including triple negative breast carcinoma; oral tumors; nasopharyngeal tumors; 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; lymphoma including Burkitt's lymphoma, Hodgkin's lymphoma, MALT lymphoma; multiple myelomas; and virally induced tumors; especially melanoma; lung cancer; bladder cancer; renal carcinomas; gastro-intestinal cancers; endometrial cancer; ovarian cancer; cervical cancer; and neuroblastoma);
as well as further diseases or disorders relating to the EP2 and/or EP4 receptors such as:pain (notably inflammatory pain and painful menstruation);endometriosis;autosomal dominant polycystic kidney disease;acute ischemic syndromes in atherosclerotic patients;pneumonia; andneurodegenerative diseases including amyotrophic lateral sclerosis, stroke; Parkinson disease, Alzheimer's disease and HIV associated dementia;and EP2 and/or EP4 antagonists may further be used to control female fertility.

Further diseases or disorders relating to the EP2 and/or EP4 receptors are autoimmune disorders such as especially multiple sclerosis, rheumatoid arthritis and osteoarthritis; and osteoporosis.

The compounds of formula (I)/formula (II) according to any one of embodiments 1) to 34) are in particular useful as therapeutic agents for the prevention/prophylaxis or treatment of a cancer. They can be used as single therapeutic agents or in combination with one or more chemotherapy agents and/or radiotherapy and/or targeted therapy. Such combined treatment may be effected simultaneously, separately, or over a period of time.

The invention, thus, also relates to pharmaceutical compositions comprising a pharmaceutically acceptable carrier material, and:a compound of formula (I)/formula (II) according to any one of embodiments 1) to 34);and one or more cytotoxic chemotherapy agents.

The invention, thus, further relates to a kit comprisinga pharmaceutical composition, said composition comprising a pharmaceutically acceptable carrier material, and:a compound of formula (I)/formula (II) according to anyone of embodiments 1) to 34);and instructions how to use said pharmaceutical composition for the prevention/prophylaxis or the treatment of a cancer, in combination with chemotherapy and/or radiotherapy and/or targeted therapy. The terms “radiotherapy” or “radiation therapy” or “radiation oncology”, refer to the medical use of ionizing radiation in the prevention/prophylaxis (adjuvant therapy) and/or treatment of cancer; including external and internal radiotherapy.

The term “targeted therapy” refers to the prevention/prophylaxis (adjuvant therapy) and/or treatment of cancer with one or more anti-neoplastic agents such as small molecules or antibodies which act on specific types of cancer cells or stromal cells. Some 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 (immunotherapies); or inhibit angiogenesis, the growth and formation of new blood vessels in the tumor; or deliver toxic substances directly to cancer cells and kill them. An example of a targeted therapy which is in particular suitable to be combined with the compounds of the present invention is immunotherapy, especially immunotherapy targeting the programmed cell death receptor 1 (PD-1 receptor) or its ligand PD-L1 (Zelenay et al., 2015, Cell 162, 1-14; Yongkui Li et al., Oncoimmunology 2016, 5(2):e1074374).

When used in combination with the compounds of formula (I)/formula (II), the term “targeted therapy” especially refers to agents such as:a) Epidermal growth factor receptor (EGFR) inhibitors or blocking antibodies (for example Gefitinib, Erlotinib, Afatinib, Icotinib, Lapatinib, Panitumumab, Zalutumumab, Nimotuzumab, Matuzumab and Cetuximab);b) RAS/RAF/MEK pathway inhibitors (for example Vemurafenib, Sorafenib, Dabrafenib,GDC-0879, PLX-4720, LGX818, RG7304, Trametinib (GSK1120212), Cobimetinib (GDC-0973/XL518), Binimetinib (MEK162, ARRY-162), Selumetinib (AZD6244));c) Aromatase inhibitors (for example Exemestane, Letrozole, Anastrozole, Vorozole, Formestane, Fadrozole);d) Angiogenesis inhibitors, especially VEGF signalling inhibitors such as Bevacuzimab (Avastin), Ramucirumab, Sorafenib or Axitinib;e) Immune Checkpoint inhibitors (for example: anti-PD1 antibodies such as Pembrolizumab (Lambrolizumab, MK-3475), Nivolumab, Pidilizumab (CT-011), AMP-514/MED10680, PDR001, SHR-1210; REGN2810, BGBA317; fusion proteins targeting PD-1 such as AMP-224; small molecule anti-PD1 agents such as for example compounds disclosed in WO2015/033299, WO2015/044900 and WO2015/034820; anti-PD1L antibodies, such as BMS-936559, atezolizumab (MPDL3280A, RG7446), MED14736, avelumab (MSB0010718C), durvalumab (MED14736); anti-PDL2 antibodies, such as AMP224; anti-CTLA-4 antibodies, such as ipilimumab, tremilmumab; anti-Lymphocyte-activation 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) Vaccination approaches (for example dendritic cell vaccination, peptide or protein vaccination (for example with gp100 peptide or MAGE-A3 peptide);g) Re-introduction of patient derived or allogenic (non-self) cancer cells genetically modified to secrete immunomodulatory factors such as granulocyte monocyte colony stimulating factor (GMCSF) gene-transfected tumor cell vaccine (GVAX) or Fms-related tyrosine kinase 3 (Flt-3) ligand gene-transfected tumor cell vaccine (FVAX),or Toll like receptor enhanced GM-CSF tumor based vaccine (TEGVAX);h) T-cell based adoptive immunotherapies, including chimeric antigen receptor (CAR) engineered T-cells (for example CTL019);i) Cytokine or immunocytokine based therapy (for example Interferon alpha, interferon beta, interferon gamma, interleukin 2, interleukin 15);j) Toll-like receptor (TLR) agonists (for example resiquimod, imiquimod, glucopyranosyl lipid A, CpG oligodesoxynucleotides);k) Thalidomide analogues (for example Lenalidomide, Pomalidomide);l) Indoleamin-2,3-Dioxgenase (IDO) and/or Tryptophane-2,3-Dioxygenase (TDO) inhibitors (for example RG6078/NLG919/GDC-0919; Indoximod/1MT (1-methyltryptophan), INCB024360/Epacadostat, PF-06840003 (EOS200271), F001287);m) Activators of T-cell co-stimulatory receptors (for example anti-OX40/CD134 (Tumor necrosis factor receptor superfamily, member 4, such as RG7888 (MOXR0916), 9B12; MED6469, GSK3174998, MED0562), anti OX40-Ligand/CD252; anti-glucocorticoid-induced TNFR family related gene (GITR) (such as TRX518, MED11873, MK-4166, BMS-986156), anti-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) Molecules binding a tumor specific antigen as well as a T-cell surface marker such as bispecific antibodies (for example RG7802 targeting CEA and CD3) or antibody fragments, antibody mimetic proteins such as designed ankyrin repeat proteins (DARPINS), bispecific T-cell engager (BITE, for example AMG103, AMG330);o) Antibodies or small molecular weight inhibitors targeting colony-stimulating factor-1 receptor (CSF-1R) (for example Emactuzumab (RG7155), Cabiralizumab (FPA-008), PLX3397);p) Agents targeting immune cell check points on natural killer cells such as antibodies against Killer-cell immunoglobulin-like receptors (KIR) for example Lirilumab (IPH2102/BMS-986015);q) Agents targeting the Adenosine receptors or the ectonucleases CD39 and CD73 that convert ATP to Adenosine, such as MEDI9447 (anti-CD73 antibody), PBF-509; CPI-444 (Adenosine A2a receptor antagonist).

When used in combination with the compounds of formula (I)/formula (II), immune checkpoint inhibitors such as those listed under d), and especially those targeting the programmed cell death receptor 1 (PD-1 receptor) or its ligand PD-L1 are preferred.

The term “chemotherapy” refers to the treatment of cancer with one or more cytotoxic anti-neoplastic agents (“cytotoxic chemotherapy agents”). Chemotherapy is often used in conjunction with other cancer treatments, such as radiation therapy or surgery. The term especially refers to conventional cytotoxic chemotherapeutic agents which act by killing cells that divide rapidly, one of the main properties of most cancer cells. Chemotherapy may use one drug at a time (single-agent chemotherapy) or several drugs at once (combination chemotherapy or polychemotherapy). Chemotherapy using drugs that convert to cytotoxic activity only upon light exposure is called photochemotherapy or photodynamic therapy.

The term “cytotoxic chemotherapy agent” or “chemotherapy agent” as used herein refers to an active anti-neoplastic agent inducing apoptosis or necrotic cell death. When used in combination with the compounds of formula (I)/formula (II), the term especially refers to conventional cytotoxic chemotherapy agents such as:a) alkylating agents (for example mechlorethamine, chlorambucil, cyclophosphamide, ifosfamide, streptozocin, carmustine, lomustine, melphalan, dacarbazine, temozolomide, fotemustine, thiotepa or altretamine; especially cyclophosphamide, carmustine, melphalan, dacarbazine, or temozolomide);b) platinum drugs (especially cisplatin, carboplatin or oxaliplatin);c) antimetabolite drugs (for example 5-fluorouracil, folic acid/leucovorin, capecitabine, 6-mercaptopurine, methotrexate, gemcitabine, cytarabine, fludarabine or pemetrexed; especially 5-fluorouracil, folic acid/leucovorin, capecitabine, methotrexate, gemcitabine or pemetrexed);d) anti-tumor antibiotics (for example daunorubicin, doxorubicin, epirubicin, idarubicin, actinomycin-D, bleomycin, mitomycin-C or mitoxantrone; especially doxorubicin);e) mitotic inhibitors (for example paclitaxel, docetaxel, ixabepilone, vinblastine, vincristine, vinorelbine, vindesine or estramustine; especially paclitaxel, docetaxel, ixabepilone or, vincristine); orf) topoisomerase inhibitors (for example etoposide, teniposide, topotecan, irinotecan, diflomotecan or elomotecan; especially etoposide or irinotecan).

When used in combination with the compounds of formula (I)/formula (II), preferred cytotoxic chemotherapy agents are the above-mentioned alkylating agents (notably fotemustine, cyclophosphamide, ifosfamide, carmustine, dacarbazine and prodrugs thereof such as especially temozolomide or pharmaceutically acceptable salts of these compounds; in particular temozolomide); mitotic inhibitors (notably paclitaxel, docetaxel, ixabepilone; or pharmaceutically acceptable salts of these compounds; in particular paclitaxel); platinum drugs (notably cisplatin, oxaliplatin and carboplatin); as well etoposide and gemcitabine.

Chemotherapy may be given with a curative intent or it may aim to prolong life or to palliate symptoms.Combined modality chemotherapy is the use of drugs with other cancer treatments, such as radiation therapy or surgery.Induction chemotherapy is the first line treatment of cancer with a chemotherapeutic drug. This type of chemotherapy is used for curative intent.Consolidation chemotherapy is the given after remission in order to prolong the overall disease free time and improve overall survival. The drug that is administered is the same as the drug that achieved remission.Intensification chemotherapy is identical to consolidation chemotherapy but a different drug than the induction chemotherapy is used.Combination chemotherapy involves treating a patient with a number of different drugs simultaneously. The drugs differ in their mechanism and side effects. The biggest advantage is minimising the chances of resistance developing to any one agent. Also, the drugs can often be used at lower doses, reducing toxicity.Neoadjuvant chemotherapy is given prior to a local treatment such as surgery, and is designed to shrink the primary tumor. It is also given to cancers with a high risk of micrometastatic disease.Adjuvant chemotherapy is given after a local treatment (radiotherapy or surgery). It can be used when there is little evidence of cancer present, but there is risk of recurrence. It is also useful in killing any cancerous cells that have spread to other parts of the body. These micrometastases can be treated with adjuvant chemotherapy and can reduce relapse rates caused by these disseminated cells.Maintenance chemotherapy is a repeated low-dose treatment to prolong remission.Salvage chemotherapy or palliative chemotherapy is given without curative intent, but simply to decrease tumor load and increase life expectancy. For these regimens, a better toxicity profile is generally expected.

“Simultaneously”, when referring to an administration type, means in the present application that the administration type concerned consists in the administration of two or more active ingredients and/or treatments at approximately the same time; wherein it is understood that a simultaneous administration will lead to exposure of the subject to the two or more active ingredients and/or treatments at the same time. When administered simultaneously, said two or more active ingredients may be administered in a fixed dose combination, or in an equivalent non-fixed dose combination (e.g. by using two or more different pharmaceutical compositions to be administered by the same route of administration at approximately the same time), or by a non-fixed dose combination using two or more different routes of administration; wherein said administration leads to essentially simultaneous exposure of the subject to the two or more active ingredients and/or treatments. For example, when used in combination with chemotherapy and/or suitable targeted therapy, the present EP2/EP4 antagonists would possibly be used “simultaneously”.

“Fixed dose combination”, when referring to an administration type, means in the present application that the administration type concerned consists in the administration of one single pharmaceutical composition comprising the two or more active ingredients.

“Separately”, when referring to an administration type, means in the present application that the administration type concerned consists in the administration of two or more active ingredients and/or treatments at different points in time; wherein it is understood that a separate administration will lead to a treatment phase (e.g. at least 1 hour, notably at least 6 hours, especially at least 12 hours) where the subject is exposed to the two or more active ingredients and/or treatments at the same time; but a separate administration may also lead to a treatment phase where for a certain period of time (e.g. at least 12 hours, especially at least one day) the subject is exposed to only one of the two or more active ingredients and/or treatments. Separate administration especially refers to situations wherein at least one of the active ingredients and/or treatments is given with a periodicity substantially different from daily (such as once or twice daily) administration (e.g. wherein one active ingredient and/or treatment is given e.g. once or twice a day, and another is given e.g. every other day, or once a week or at even longer distances). For example, when used in combination with radiotherapy, the present EP2/EP4 antagonists would possibly be used “separately”.

By administration “over a period of time” is meant in the present application the subsequent administration of two or more active ingredients and/or treatments at different times. The term in particular refers to an administration method according to which the entire administration of one of the active ingredients and/or treatments is completed before the administration of the other/the others begins. In this way it is possible to administer one of the active ingredients and/or treatments for several months before administering the other active ingredient(s) and/or treatment(s).

Administration “over a period of time” also encompasses situations wherein the compound of formula (I)/formula (II) would be used in a treatment that starts after termination of an initial chemotherapeutic (for example an induction chemotherapy) and/or radiotherapeutic treatment and/or targeted therapy treatment, wherein optionally said treatment would be in combination with a further/an ongoing chemotherapeutic and/or radiotherapeutic treatment and/or targeted therapy treatment (for example in combination with a consolidation chemotherapy, an intensification chemotherapy, an adjuvant chemotherapy, or a maintenance chemotherapy; or radiotherapeutic equivalents thereof); wherein such further/ongoing chemotherapeutic and/or radiotherapeutic treatment and/or targeted therapy treatment would be simultaneously, separately, or over a period of time in the sense of “not given with the same periodicity”.

The compounds of formula (I)/formula (II) as defined in embodiments 1) to 34) are also useful in a method of modulating an immune response in a subject having a tumor, comprising the administration of an effective amount of the compound of formula (I)/formula (II) [wherein notably said administration of said effective amount results in the pharmacologically active blockage of the EP2 receptors, or of the EP4 receptors, or of both the EP2 and the EP4 receptors]; wherein said effective amount reactivates the immune system in the tumor of said subject; wherein especially said effective amount:counteracts the polarization of tumor-associated macrophages towards tumor-promoting M2 macrophages; and/ordown-regulates the activation, expansion and/or the effector function of immunosuppressive cells that have accumulated in a tumor (especially of regulatory T cells (Tregs) and/or myeloid derived suppressor cells (MDSC)); and/orup-regulates 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 (leading to the induction of tumor cell apoptosis and/or restrained tumorigenesis); and/ordirectly or indirectly counteracts the suppressed activation, IL-2 responsiveness and expansion of cytotoxic T-cells (thereby decreasing local immunsuppression).

The compounds of formula (I)/formula (II) as defined in embodiments 1) to 34) are also useful in a method of diminishing tumor growth and/or reducing tumor size in a subject having a tumor, comprising the administration of an effective amount of the compound of formula (I)/formula (II) [wherein notably said administration of said effective amount results in the pharmacologically active blockage of the EP2 receptors, or of the EP4 receptors, or of both the EP2 and the EP4 receptors]; wherein said effective amount down-regulates tumor angiogenesis (especially by decreasing endothelial cell motility and/or survival, and/or by decreasing the expression of VEGF (vascular endothelial growth factor)); and/or wherein said effective amount diminishes tumor cell survival and/or induces tumor cell apoptosis (especially via inhibition of P3K/AKT and MAPK signalling).

The compounds of formula (I)/formula (II) as defined in embodiments 1) to 34) are also useful in a method of modulating an immune response in a subject having a tumor, comprising the administration of an effective amount of the compound of formula (I)/formula (II) [wherein notably said administration of said effective amount results in the pharmacologically active blockage of the EP2 receptors, or of the EP4 receptors, or of both the EP2 and the EP4 receptors]; wherein said effective amount reactivates the immune system in the tumor of said subject; wherein said effective amount activates the cytotoxicity and cytokine production of natural killer cells and/or cytotoxic T-cells.

Besides, any preferences and (sub-)embodiments indicated for the compounds of formula (II) (whether for the compounds themselves, salts thereof, compositions containing the compounds or salts thereof, or uses of the compounds or salts thereof, etc.) apply mutatis mutandis to compounds of formula (I).

Preparation of compounds of formula (I): The compounds of formula (I)/formula (II) can be prepared by well-known literature methods, by the methods given below, by the methods given in the experimental part below or by analogous methods. Optimum reaction conditions may vary with the particular reactants or solvents used, but such conditions can be determined by a person skilled in the art by routine optimisation procedures. In some cases the order of carrying out the following reaction schemes, and/or reaction steps, may be varied to facilitate the reaction or to avoid unwanted reaction products. In the general sequence of reactions outlined below, the generic groups R1, R2, R3, R4a, R4b, R5a, R5band Ar1are as defined for formula (I). Other abbreviations used herein are explicitly defined, or are as defined in the experimental section. In some instances the generic groups R1, R2, R3, R4a, R4b, R5a, R5band Ar1might be incompatible with the assembly illustrated in the schemes below and so 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”, T. W. Greene, P. G. M. Wuts, Wiley-Interscience, 1999). For the purposes of this discussion, it will be assumed that such protecting groups as necessary are in place. In some cases the final product may be further modified, for example, by manipulation of substituents to give a new final product. These manipulations may include, but are not limited to, reduction, oxidation, alkylation, acylation, hydrolysis and transition-metal catalysed cross-coupling reactions which are commonly known to those skilled in the art. The compounds obtained may also be converted into salts, especially pharmaceutically acceptable salts, in a manner known per se.

Compounds of formula (I)/formula (II) of the present invention can be prepared according to the general sequence of reactions outlined below.

A general synthetic route allowing the preparation of compounds of formula (I) is presented in scheme 1. Thus, precursors A3 can be obtained by nucleophilic aromatic substitutions between primary amines A1 and pyrimidine halides A2 (wherein X is a chlorine, a bromine or an iodine), in the presence of a base such as TEA, DIPEA or K2CO3, in a solvent such as isopropanol, butanol, DMF or THF, at RT or at elevated temperatures. Compounds of formula (I) can be produced via Suzuki cross-coupling reactions of the pyrimidine halides A3 with boronic acids or boronate esters A4. Typical Suzuki cross-coupling reactions may be carried out in the presence of a base such as K2CO3, Cs2CO3, Na2CO3, K3PO4, or CsF and a catalyst such as Pd(PPh3)4, Pd(dppf)Cl2or Pd(OAc)2, in a solvent like ethanol, THF, water, or mixtures thereof, typically at elevated temperatures. Boronic acids or boronate esters A4 can be obtained from commercial sources, or synthesized by methods described in the literature, or by methods known by a person skilled in the art. A boronic acid derivative can be formed by the Miyaura borylation reaction, by cross-coupling of 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)Cl2. Alternatively, a boronic acid derivative can be formed by a lithiation/borylation sequence, typically at low temperatures, using butyllithium or lithium diisopropylamide as the base, and tri-isopropylborate or isopropoxyboronic acid pinacol ester, in a solvent such as diethyl ether or THF. In a variant, compounds of formula (I) can be prepared via nucleophilic aromatic substitutions between primary amines A1 and substituted pyrimidine halides A5, wherein X is a chlorine, a bromine or an iodine (scheme 1).



Alternatively, compounds of formula (I) can be synthesized by reacting a compound of formula A1 with a compound of formula A5 wherein X represents OH, in presence of a coupling agent such as (benzotriazol-1-yloxy)-tris(dimethylamino)-phosphonium hexafluorophosphate (BOP), (benzotriazol-1-yl}-oxy)-tripyrrolidino-phosphonium hexafluorophosphate (PyBOP) or hexachlorocyclotriphosphazene, in 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.

Substituted benzothiophenes corresponding to compounds of formula (I) (with R2representing CN) can be prepared according to the synthetic route described in scheme 2. Ortho-fluorobenzonitriles or ortho-chlorobenzonitriles B1 can undergo aromatic nucleophilic substitutions by treatment with methyl 2-mercaptoacetate in the presence of a base (K2CO3/DMF), and benzothiophenes B2 can be obtained after a subsequent ring closure. The related 3-bromobenzothiophenes B3 can be obtained via deaminative bromination (tert-butyl nitrite/copper(II) bromide/MeCN), and alkaline hydrolysis of the ester functionality in B3 followed by coupling of the corresponding acid chlorides with ammonium hydroxide can provide primary amides B4. A dehydration of the primary amide moiety in B4 (cyanuric chloride//DMF) can furnish the benzo[b]thiophene-2-carbonitrile derivatives B5. A subsequent Suzuki-Miyaura aminoethylation [Pd(OAc)2/RuPhos/Cs2CO3/toluene/H2O] of bromobenzothiophenes B5 using Boc-protected potassium-aminoethyltrifluoroborates B6 can furnish derivatives B7 that can be converted to primary amines B8 after Boc-deprotection under acidic conditions. Finally, target products B9 corresponding to compounds of formula (I) can be obtained from B8 with the preparations described in scheme 1.



Substituted benzothiophenes corresponding to compounds of formula (I) (with R2representing Me) can be prepared according to the synthetic route described in scheme 3. This multi-step synthesis started with the preparation of 2-methylbenzothiophenes C3 via a thio-Claisen rearrangement. Thus, S-alkylation of thiophenols C1 by treatment with 2,3-dichloropropene in the presence of potassium carbonate can introduce the required 2-chloropropene moiety in derivatives C2. A subsequent thio-Claisen rearrangement in refluxing N,N-diethylaniline can convert the S-alkylated derivatives C2 into the target 2-methylbenzothiophenes C3. The aldehyde functionality can be introduced at the unsubstituted 3-position via selective formylation of the thiophene ring under mild conditions (dichloromethyl methyl ether/tin(IV) chloride) affording compounds C4. The β-aminoethyl side-chain in C5 can result from the reduction (lithium aluminum hydride/THF/heating) of the corresponding nitroalkenes that can be prepared from aldehydes C4 via Henry reaction (nitromethane/butylamine/acetic acid/heating). Finally, target products C6 corresponding to compounds of formula (I) can be obtained according to the sequences described in scheme 1.



Substituted benzothiophenes corresponding to compounds of formula (I) (with R2representing C1 or Br) can be prepared according to the sequence of reactions described in scheme 2. This multi-step synthesis started with the preparation of 2-unsubstituted benzothiophenes D6 as precursors for the planned halogenation at position-2. Thus, S-alkylation of thiophenols D1 (methyl bromoacetate/potassium carbonate) followed by alkaline hydrolysis of the ester functionality can provide the 2-(phenylthio)acetic acid derivatives D2. Conversion of the carboxylic acids D2 into the corresponding acid chlorides, and subsequent Friedel-Crafts acylation (aluminum chloride/DCM) can deliver benzo[b]thiophen-3(2H)-ones D3. The substituted benzothiophenes D4 can be obtained via Wittig olefination of D3 [(carbethoxymethylene)triphenylphosphorane/toluene/reflux], and the protected β-aminoethyl side-chain in D6 can result from the reduction of the ester functionality in D4 followed by reaction of the resulting primary alcohols D5 with phthalimide under Mitsunobu conditions (diethyl azodicarboxylate/triphenylphosphine/THF). A subsequent regioselective chlorination (N-chlorosuccinimide/DMF/heating) or bromination (N-bromosuccinimide/DMF/heating) of the unsubstituted 2-position of the thiophene ring in D6 can deliver the corresponding derivatives D7, and primary amines D8 can be obtained after cleavage of the phthalimide moiety (hydrazine hydrate/MeOH/heating). Finally, target products D9 corresponding to compounds of formula (I) can be obtained from D8 with the sequence of reactions described in scheme 1.



Substituted benzofurans corresponding to compounds of formula (I) [with R2representing (C1-4)alkyl] can be prepared according to the synthetic route shown in scheme 5. Ortho-hydroxybenzaldehydes E1 can be converted to the corresponding carboxylic acids E2 via O-alkylation with the appropriate electrophile followed by saponification of the ester functionality. Subsequent heating of the produced carboxylic acids E2 with sodium acetate in acetic anhydride can deliver the substituted benzofurans E3. The aldehyde functionality in E4 can be introduced at the unsubstituted 3-position of benzofurans E3 via regioselective formylation of the furan ring under mild conditions (dichloromethyl methyl ether/tin(IV) chloride). The β-aminoethyl side-chain in E5 can result from the reduction of the corresponding nitroalkenes that can be prepared from aldehydes E4 via Henry reaction (nitromethane/butylamine/acetic acid). Finally, target products E6 corresponding to compounds of formula (I) can be obtained with the sequence of reactions described in scheme 1.



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

