CARBOXYLIC ACID AROMATIC AMIDES AS BRADYKININ B1 RECEPTOR ANTAGONISTS

Description

[0001] The present invention relates to carboxylic acid aromatic amides of general formula (I) as described and defined herein, to pharmacological compositions and combinations comprising said compounds and to the use of said compounds for manufacturing a pharmaceutical composition for the treatment or prophylaxis of a disease or disorder and for the treatment of pains, which are associated with such diseases, in particular of Bradykinin B1 receptor associated disorders which are related to inflammation or at least partially driven by neurogenic events like diseases related to chronic pain or frequent pain conditions like but not restricted to osteoarthritis, rheumatoid arthritis, gout, inflammatory bowel disease, and endometriosis and diseases related to Bradykinin B1 receptor activation and / or up-regulation in affected tissue like but not restricted to asthma, fibrosis in various tissues or diabetes as a sole agent or in combination with other active ingredients.BACKGROUND OF THE INVENTION

[0002] The present invention relates to chemical compounds that antagonize the effects of human Bradykinin B1 receptor (Gene Name BDKRB1, Gene ID 623).

[0003] The Bradykinin B1 receptor is a membrane-bound G-protein coupled receptor, which is linked to a second messenger system that triggers increase of intracellular calcium concentrations. The main signalling pathway is linked to Gq protein and phospholipase C (Leeb-Lundberg, L. M. et al. (2005), Pharmacol Rev 57(1): 27-77). Activation of Bradykinin B1 receptor has been shown to be pro-algesic, pro-fibrotic, and proinflammatory while Bradykinin B1 receptor antagonists had clear anti-inflammatory and analgesic effects in various animal models (Gougat, J. B. et al. (2004), J Pharmacol Exp Ther 309(2): 661-669; Dias, J. P. et al. (2007), Br J Pharmacol 152(2): 280-287; Schuelert, N. et al. (2015), Eur J Pain 19(1): 132-142). As consequence of Bradykinin B1 receptor activity increased gene expression and protein levels of proinflammatory cytokines like e.g. Il-6 and Il-8 that attract and activate inflammatory leucocytes, increase of PGE2 (Prostaglandin 2) levels and therefore activation of the inflammation related prostaglandin pathway, phosphorylation and upregulation of TRPV1 (Transient Receptor Potential Vanilloid 1) receptors which are important mediators of pain transduction and induction of neurogenic inflammation (neuropeptide release in inflamed tissue) were observed (Phagoo, S. B. et al. (1999). Mol Pharmacol 56(2): 325-333; Westermann, D. et al. (2009), Diabetes 58(6): 1373-1381; Walsh, D. A. et al. (2006), Curr Drug Targets 7(8): 1031-1042; Farkas S. et al. (2011), Drugs of the Future 36(4): 301-319). Bradykinin B1 receptor agonists are endogenously produced by the activated kallikrein-kinin system. This system consists of circulating kininogens, the ubiquitous expressed proteolytic enzymes kallikreins which are activated by tissue damage, and kinins which are formed by activated kallikreins out of kininogens (Review Fincham, C. I. et al. (2009), Expert Opin Ther Pat 19(7): 919-941). These kinins (e.g. bradykinin, kalidin, des-Arg9-bradykinin, des-Arg10-kalidin) are proinflammatory peptides that mediate vascular and pain responses to tissue injury, with functions in cardiovascular homeostasis, contraction or relaxation of smooth muscle, inflammation and nociception. They exert most of their effects by interacting with two classes of G-protein-coupled receptors called Bradykinin receptor 1 and 2. The classification of the kinin receptors was originally achieved by means of pharmacological studies originally carried out at the end of the 1970s. During the 1990s, the existence of Bradykinin B1 receptor and B2 receptors was further confirmed through cloning and genetic deletion studies (Menke, J. G. et al. (1994), J Biol Chem 269(34): 21583-21586). The past 30 years of research on the kinin system has indicated that both Bradykinin B1 receptor and B2 receptor are involved in pain and inflammation (Leeb-Lundberg, L. M. et al. (2005), Pharmacol Rev 57(1): 27-77; Marceau, F. (2005), Trends Pharmacol Sci 26(3): 116-118; Marceau, F. (2004), Nat Rev Drug Discov 3(10): 845-852; Chen, J. J. et al. (2007), Expert Opin Ther Targets 11 (1): 21 -35).

[0004] It has been demonstrated that the B2 receptor is widely expressed in a constitutive manner throughout most mammalian tissues. In contrast, the Bradykinin B1 receptor is not constitutively expressed to a great extent under normal conditions, but is up-regulated under various inflammatory conditions such as asthma, arthritis and osteoarthritis, sepsis and type-1 diabetes, as well as by some neuropathological diseases such as epilepsy, stroke and multiple sclerosis. Bradykinin B1 receptor up-regulation can be induced for example by Il-1beta (Phagoo, S. B.et al. (1999), Mol Pharmacol 56(2): 325-333) and Bradykinin B2 receptor activation (NF-kB activation leading to IL1b expression in fibroblasts) (Leeb-Lundberg, L. M. et al. (2005), Pharmacol Rev 57(1): 27-77).

[0005] Once upregulated, the Bradykinin B1 receptor is expressed on neurons, macrophages, neutrophils, fibroblasts, smooth muscle cells and the vascular endothelium (Fincham, C. I. et al. (2009), Expert Opin Ther Pat 19(7): 919-941). Recent findings suggest that the Bradykinin B1 receptor expressed in the peripheral and in the central nervous system is involved in processing of inflammatory pain (Schuelert, N. et al. (2015). Eur J Pain 19(1): 132-142).

[0006] In contrast to Bradykinin B2 receptor and many other GPCRs (G protein-coupled receptors), the Bradykinin B1 receptor does not show agonist induced internalization or relevant desensitization (Prado, G. N. et al. (2002), J Cell Physiol 193(3): 275-286; Eisenbarth, H. et al. (2004), Pain 110(1-2): 197-204). Activation of Bradykinin B1 receptor triggers auto-induction of the receptor. This might lead to an augmentation of the inflammatory or pain-inducing processes.

[0007] Therefore, Bradykinin B1 receptor has been suggested to have a pivotal role including but not limited to several chronic diseases involving diabetes, fibrosis, inflammation, neuroinflammation, neurodegeneration, inflammatory pain, and neuropathic pain (Campos, M. M. et al. (2006), Trends Pharmacol Sci 27(12): 646-651; Wang, P. H. et al. (2009), Int Immunopharmacol 9(6): 653-657; Passos, G. F. et al. (2013), Am J Pathol 182(5): 1740-1749; Gobeil, F. et al. (2014), Peptides 52: 82-89; Huart, A. (2015), Front Pharmacol 6: 8). The contribution of Bradykinin B1 receptor activation in inflammation and pain processes is supported by the demonstration that Bradykinin B1 receptor knockout mice have a largely decreased response to nociceptive and proinflammatory stimuli (Ferreira, J. et al. (2001), Neuropharmacology 41(8): 1006-1012; Ferreira, J. et al. (2005), J Neurosci 25(9): 2405-2412.). The therapeutic impact of Bradykinin B1 receptor blockage for inflammation related diseases is supported further by the pharmacological properties of Bradykinin B1 receptor antagonists shown in many inflammatory and neuropathic pain models (Gougat, J. B. et al. (2004), J Pharmacol Exp Ther 309(2): 661-669; Fox, A. et al. (2005), Br J Pharmacol 144(7): 889-899).

[0008] The fact that Bradykinin B1 receptor expression is induced under disease conditions clearly raises the possibility that therapeutic use of Bradykinin B1 receptor antagonists should be devoid of undesired adverse effects. This property supports the suitability of Bradykinin B1 receptor antagonists for treatment of benign diseases like endometriosis due the expected positive risk benefit ratio. The patient populations for nociceptive pain and neuropathic pain are large, and are driven by separate disease trends that necessitate pain relief. Chronic pain of moderate to severe intensity occurs in 19% of adult Europeans, seriously affecting the quality of their social and working lives (Breivik et al., Eur J Pain. 2006 May;10(4):287-333.). Unfortunately, current treatments for pain are only partially effective, and many cause life-style altering, debilitating, and / or dangerous side effects. For example, non-steroidal anti-inflammatory drugs (NSAIDS) such as aspirin, ibuprofen, and indomethacin are moderately effective against inflammatory pain but they are also renally toxic, and high doses tend to cause gastrointestinal irritation, ulceration, bleeding, confusion and increased cardiovascular risk. Notably, Vioxx was withdrawn from the market in 2004 due to a risk of myocardial infarction and stroke. Patients treated with opioids frequently experience confusion and constipation, and long-term opioid use is associated with tolerance and addiction. Local anaesthetics such as lidocaine and mexiletine simultaneously inhibit pain and cause loss of normal sensation. In addition, when used systemically, local anaesthetics are associated with adverse cardiovascular effects. Thus, there is currently an unmet need in the treatment of chronic pain in general.

[0009] Especially in gynaecological therapy field, endometriosis is the diseases associated with chronic pelvic pain severely affecting quality of life of the patients. Globally, approximately 11% of women aged 15-49 years are affected by endometriosis and additional 6% of women suffer from symptoms suggestive for endometriosis. Main symptoms of endometriosis are chronic or frequent pelvic pain, dyspareunia, dyschezia, dysuria and sub-or infertility. These symptoms severely impair quality of life of patients. Diagnosis of the disease involves a complete medical history, a physical examination and a laparoscopy. As an ultimate confirmation of endometriosis can only be made invasively and symptoms are often unspecific, the mean time from initial symptoms to diagnosis of endometriosis is about 7-10 years. Therefore, endometriosis is under-diagnosed and the number of affected women might be much higher than anticipated. Recently published EndoCost study demonstrated that cost of productivity loss of €6,298 per woman were double the healthcare cost of €3,113 per women, driven mainly by surgery and monitoring visit (Gao, X. et al. (2006), Fertil Steril 86(6): 1561-1572; Simoens S, et al. Hum Reprod (2012), 27(5):1292-9; De Graaff A, et al. (2013), Hum Reprod; 28(10): 2677-85).

[0010] Endometriosis is characterized by growth of endometrial tissue outside of the uterine cavity forming benign tumours (lesions) in the affected part of the body. Depending on lesion location and innervation severity of pain symptoms is observed. Up-regulation of various inflammation markers observed in the affected tissue and in the peritoneal tissue underline the inflammatory character of the disease (Stratton, P. et al. (2011), Hum Reprod Update 17(3): 327-346; Gao, X. et al. (2006), Fertil Steril 86(6): 1561-1572; Laux-Biehlmann et al. (2015), Trends Pharmacol Sci 36(5): 270-276).

[0011] The Bradykinin B1 receptor was identified in endometriosis lesion by immune-histological-chemical (IHC) staining (Yoshino et al. Journal of Reproductive Immunology 112 (2015) 121-140; www.proteinatlas.org) and analysis of mRNA expression of Bradykinin B1 receptor in affected tissue shows a positive correlation to pain severity reported by endometriosis patients. Data describing a role of Bradykinin B1 receptors in affecting the outcome of an endometriosis mouse model (Jingwei, C. et al. (2015), J Tradit Chin Med 35(2): 184-191) further support the concept to treat endometriosis with Bradykinin B1 receptor antagonists.

[0012] Suspected endometriosis is initially treated with non-steroidal anti-inflammatory drugs (NSAID) or combined oral contraceptives (COC) which are used off label. This procedure delays endometriosis diagnosis. Laparoscopy is the gold standard for endometriosis diagnosis which is performed when the initial treatment options fail. During laparoscopy, endometriotic lesions are ablated. However, this procedure is accompanied by a high recurrence rate. Approximately, 70% of treated patients have persistent symptoms that are not managed. Currently, there is no long-term medication available in COC / P (C ombined O ral C ontraceptives / P rogestin) non-responder endometriosis patients in which COCs and progestins failed. Treatment with Gonadotropin Releasing Hormone (GnRH) agonists, which are used as second line therapy (without proof of being superior versus first line) are only approved for short-term treatment (6 months). After GnRH agonist application, systemic estradiol levels are suppressed up to 90% leading to chemical castration with menopausal side effects like bone mass loss and hot flushes. Therefore, new and long-term treatment options with reduced side-effects and high efficacy for patients with COC / P non-responder endometriosis are urgently needed.

[0013] On this background the Bradykinin B1 receptor antagonists are of value for treatment of disorders which are related to inflammation or at least partially driven by neurogenic events like diseases related to chronic pain or frequent pain conditions like but not restricted to osteoarthritis (Kaufman, G. N. et al. (2011), Arthritis Res Ther 13(3): R76), rheumatoid arthritis (Cassim, B. et al. (2009), Rheumatology 48(5): 490-496), gout (Silva, C. R. et al. (2016), Ann Rheum Dis 75(1): 260-268), burn injuries and sunburn (Eisenbarth, H. et al. (2004), Pain 110(1-2): 197-204), inflammatory bowel disease, endometriosis (Yoshino et al. Journal of Reproductive Immunology 112 (2015) 121-140; Laux-Biehlmann et al. (2015), Trends Pharmacol Sci 36(5): 270-276; Jingwei, C. et al. (2015), J Tradit Chin Med 35(2): 184-191), pre-eclampsia (Moyes, A. J. et al. (2014), Hypertens Pregnancy 33(2): 177-190), diabetic neuropathy (Dias, J. P. et al. (2007), Br J Pharmacol 152(2): 280-287) including neuropathy related to diabetes type 1 and diabetes type 2, cardiac inflammation (Westermann, D. et al. (2009), Diabetes 58(6): 1373-1381), renal inflammation (Bascands, J. et al. (2009), Biochem Biophys Res Commun 386(2): 407-412), pancreatitis and diseases related to Bradykinin B1 receptor activation and / or up-regulation in affected tissue like but not restricted to asthma and cough (Bertram, C. M. et al. (2009), J Leukoc Biol 85(3): 544-552), atherosclerosis, diabetes (Dias, J. P. et al. (2012), J Cardiovasc Pharmacol 60(1): 61-69), adipositas including metabolic syndrome (Dias, J. P. et al. (2012), Diabetes Obes Metab 14(3): 244-253), diseases related to muscle atrophy including cachexia (Parreiras, E. S. L. T. et al. (2014), Clin Sci 127(3): 185-194) not limited to cancer cachexia, neuropathic pain (Luiz, A. P. et al. (2015), Neuroscience 300: 189-200), pruritus or itch (Hosogi, M. et al. (2006), Pain 126(1-3): 16-23), cancer (da Costa, P. L. et al. (2014), Cancer Lett 345(1): 27-38), neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) or Alzheimer's disease (Lacoste, et al. (2013) J Neuroinflammation 10: 57), fibrosis in cardiacs (Westermann, D. et al. (2009), Diabetes 58(6): 1373-1381), fibrosis in renal (Huart, A. et al. (2015), Front Pharmacol 6: 8) and fibrosis in lung tissues, overactive urinary bladder syndrome and cystitis (Forner, S. et al. (2012), Br J Pharmacol 167(8): 1737-1752 and Belichard, P. et al (1999), Br J Pharmacol 128(1):213-219), impaired or painful wound healing (Schremmer-Danninger, E. et al. (2004), Biol Chem 385(11): 1069-1076) and sepsis (Murugesan, P et al. (2016), J Infect Dis 213(4): 532-540).

[0014] Several new Bradykinin B1 receptor antagonists are known from prior art (Expert Opinion on Therapeutic Patents (2012), 22:12, 1443-1452). Various approaches for finding new Bradykinin B1 receptor antagonists are described, in particular peptidic structures and small molecules. Especially, arylsulfonamides and so-called cyclopropyl-carboxamides as the two main types of small molecules were investigated during the last decade.

[0015] WO2003 / 065789 (Merck) disclose bradykinin B1 receptor antagonists or inverse agonists of the following general formula which are useful in the treatment or prevention of symptoms such as pain and inflammation associated with the bradykinin B1 pathway.

[0016] Merck was developing the bradykinin B1 receptor antagonist MK-0686 (structure shown below) for the potential treatment of pain and inflammation. Several phase II trials in subjects with osteoarthritis and with post-herpetic neuralgia were initiated. Merck accounted that the compound has a suboptimal pharmacokinetic profile due to metabolic lability.

[0017] Jerini AG, now Shire Group, investigated active Bradykinin B1 receptor antagonists, for example (see WO2009 / 036996) which was reported to have in addition to its activity and acceptable penetration profile reasonable aqueous solubility and pharmacokinetic profile in rat, whereas its human metabolic stability was still poor (Schaudt M, Locardi E, Zischinsky G, et al., Bioorg Med Chem Lett 2010;20:1225-8). Jerini exchanged the cyclopropyl-carboxamide moiety to a semicarbazide or to a five-membered diamino-heterocyclic ring or even to hydroxyureas without any explanation.

[0018] Starting with arylsulfonamide compounds as Bradykinin B1 receptor antagonists, Boehringer Ingelheim reported about several cyclopropyl-carboxamides out of their further development compounds like of the following structure or related to that emerged with the highest binding affinity measured on human B1R-expressing CHO cells (Expert Opinion on Therapeutic Patents (2012), 22:12, 1443-1452).

[0019] In WO2012 / 059776 Gedeon Richter reported about cyclopropyl-carboxamides of the following formula wherein R 3< is selected from (1) -COOR; (2) -CN; (3) -CONR a< R b< ;

[0020] A majority of the compounds have a K i value below 20 nM on human recombinant Bradykinin receptors (expressed in CHO cells). Several indolyl compounds are disclosed and represented by the following compound: In WO2012 / 112567 (Georgetown University) small molecule inhibitors of ATP / GTP binding protein like 2 (AGBL2) of the formula are disclosed wherein Ar is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; L is absent or -(CHR 6< )-, wherein R 6< is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and R 1< , R 2< , R 3< , R 4< , and R 5< are each independently selected from hydrogen, halogen, hydroxyl, cyano, nitro, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted amino, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkoxyl, substituted or unsubstituted aryloxyl, substituted or unsubstituted carbonyl, or substituted or unsubstituted carboxyl. The compounds can be used in methods for treating or preventing cancer and neurologic disorders were described Aromatic Amides with carboxylic acid groups and cyclopropyl moiety are not specifically disclosed.

[0021] WO2012 / 103583 (Bionomics) discloses 1,2 -cyclopropyl-carboxamide compounds of formula (I) wherein R 4< is selected from optionally substituted heteroaryl, optionally substituted heterocyclyl, or optionally substituted aryl, and R 5< is selected from hydrogen or optionally substituted alkyl. Such compounds are useful in the positive modulation of the alpha 7 nicotinic acetylcholine receptor (alpha7nAChR). The disclosure of WO2012103583 also relates to the use of these compounds in the treatment or prevention of a broad range of diseases in which the positive modulation of alpha7nAChR is advantageous, including neurodegenerative and neuropsychiatric diseases and inflammatory diseases. 1,1-cyclopropyl-carboxamide compounds are not disclosed.

[0022] WO2007 / 087066 (Vertex) discloses novel compounds and pharmaceutically acceptable compositions thereof, which are useful as modulators of ATP-Binding Cassette ("ABC") transporters or fragments thereof, including Cystic Fibrosis Transmembrane Conductance Regulator ("CFTR"), having a benzamide core structure (I) wherein ring A is an optionally substituted cycloaliphatic or an optionally substituted heterocycloaliphatic where the atoms of ring A adjacent to C* are carbon atoms. R 4 is an optionally substituted aryl or an optionally substituted heteroaryl. R 1< is independently an optionally substituted C 1 -C 6 aliphatic, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted C 3 -C 10 membered cycloaliphatic or an optionally substituted 4 to 10 membered heterocycloaliphatic, carboxy, amido, amino, halo, or hydroxy, provided that at least one R 1< is an optionally substituted aryl or an optionally substituted heteroaryl and said R 1< is attached to the 3- or 4-position of the phenyl ring. The compounds of the present invention are not disclosed.

[0023] So, the state of the art described above does not describe the compounds of general formula (I) of the present invention as defined herein or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate, or a salt thereof, or a mixture of same, as described and defined herein, and as hereinafter referred to as "compounds of the present invention", or their pharmacological activity.SUMMARY of the INVENTION

[0024] The present invention covers compounds of general formula (I): in which R 1< represents phenyl, 5- or 6-membered heteroaryl, wherein said 5-membered heteroaryl contains 1, 2 or 3 heteroatoms or heteroatom-containing groups independently selected from the group consisting of S, N, NH, and O, and wherein said 6-membered heteroaryl contains 1 or 2 nitrogen atoms, or bicyclic 8- to 10-membered heteroaryl containing 1, 2 or 3 heteroatoms or heteroatom-containing groups independently selected from NH, N, O, S, SO and SO 2 , wherein said R 1< is optionally substituted at one or more carbon atoms with 1 to 3 substituents R 1a< which are the same or different, wherein R 1a< represents C 1 -C 5 -alkyl, C 3 -C 7 -cycloalkyl, -(C 1 -C 3 -alkyl)-(C 3 -C 7 -cycloalkyl), -OC 1 -C 5 -alkyl, -OC 3 -C 7 -cycloalkyl, NHR 4< , N(R 4< ) 2 , NH(C 3 -C 7 -cycloalkyl), halogen, CN, NHSO 2 R 4< , SO 2 R 4< , 5- to 7-membered lactam, or 4- to 7-membered heterocycloalkyl containing 1 or 2 heteroatoms or heteroatom-containing groups selected from NH, -NR 4< , N, O, S, SO and SO 2 , and wherein independently, if R 1< represents 5- membered heteroaryl or bicyclic 8- to 10-membered heteroaryl, each ring nitrogen atom, if present, of said R 1< is optionally substituted with a substituent R 1b< , wherein R 1b< represents C 1 -C 5 -alkyl, -(C 1 -C 3 -alkyl)-(C 3 -C 7 -cycloalkyl), C 3 -C 7 -cycloalkyl, SO 2 R 4< , or 4- to 7-membered heterocycloalkyl containing 1 or 2 heteroatoms or heteroatom-containing groups selected from NH, -NR 4< , N, O, S, SO and SO 2 , and if R 1a< represents C 1 -C 5 -alkyl, C 3 -C 7 -cycloalkyl, -(C 1 -C 3 -alkyl)-(C 3 -C 7 -cycloalkyl), -OC 1 -C 5 -alkyl or -OC 3 -C 7 -cycloalkyl and / or if R 1b< represents C 1 -C 5 -alkyl, -(C 1 -C 3 -alkyl)-(C 3 -C 7 -cycloalkyl) or C 3 -C 7 -cycloalkyl, said C 1 -C 5 -alkyl, C 3 -C 7 -cycloalkyl, -(C 1 -C 3 -alkyl)-(C 3 -C 7 -cycloalkyl), -OC 1 -C 5 -alkyl or -OC 3 -C 7 -cycloalkyl independently are optionally substituted with one or more substituents independently selected from the group consisting of methyl, ethyl, OH, OR 4< and F, and if R 1a< and / or R 1b< represent 4- to 7-membered heterocycloalkyl, each carbon atom of said 4- to 7-membered heterocycloalkyl is optionally substituted with one or more substituents independently selected from the group consisting of OH, OR 4< and F; R 2< represents • -(CH 2 ) p -(C 5 -C 7 -cycloalkyl), • -(CH 2 ) p -phenyl, • 5- or 6-membered heteroaryl wherein said 5-membered heteroaryl contains 1, 2 or 3 heteroatoms or heteroatom-containing groups independently selected from the group consisting of S, N, NH, and O, and wherein said 6-membered heteroaryl contains 1 or 2 N, or • bicyclic 8- to 10-membered heteroaryl, containing 1, 2 or 3 heteroatoms or heteroatom-containing groups independently selected from NH, N, O, S, SO and SO 2 , wherein said R 2< is optionally substituted at one or more carbon atoms with 1 to 3 substituents R 2a< which are the same or different wherein R 2a< represents C 1 -C 5 -alkyl, C 3 -C 7 -cycloalkyl, -(C 1 -C 3 -alkyl)-(C 3 -C 7 -cycloalkyl), -OC 1 -C 5 -alkyl, -OC 3 -C 7 -cycloalkyl, halogen, OH or CN, and wherein independently, if R 2< represents 5-membered heteroaryl or bicyclic 8- to 10-membered heteroaryl, each ring nitrogen atom, if present, of said R 2< is optionally substituted with a substituent R 2b< wherein R 2b< represents of C 1 -C 5 -alkyl, C 3 -C 7 -cycloalkyl or -(C 1 -C 3 -alkyl)-(C 3 -C 7 -cycloalkyl), and if R 2a< represents C 1 -C 5 -alkyl, C 3 -C 7 -cycloalkyl, -(C 1 -C 3 -alkyl)-(C 3 -C 7 -cycloalkyl), -OC 1 -C 5 -alkyl or -OC 3 -C 7 -cycloalkyl and / or if R 2b< represents C 1 -C 5 -alkyl, C 3 -C 7 -cycloalkyl or -(C 1 -C 3 -alkyl)-(C 3 -C 7 -cycloalkyl), said C 1 -C 5 -alkyl, C 3 -C 7 -cycloalkyl, -(C 1 -C 3 -alkyl)-(C 3 -C 7 -cycloalkyl), -OC 1 -C 5 -alkyl and -OC 3 -C 7 -cycloalkyl independently are optionally substituted with one or more substituents independently selected from the group consisting of OH, OR 4< , and 1 to 5 fluorine atoms; p0 or 1; R 3< represents H or F; R 4< represents C 1 -C 5 -alkyl, optionally substituted with 1 to 5 fluorine atoms; R 5< represents H, halogen, CN, C 1 -C 5 -alkyl, or -OC 1 -C 5 -alkyl wherein said C 1 -C 5 -alkyl and -OC 1 -C 5 -alkyl are optionally substituted with 1 to 5 fluorine atoms; and R 6< and R 7< represent H or C 1 -C 3 -alkyl, wherein said C 1 -C 3 -alkyl is optionally substituted with 1 to 5 fluorine atoms; or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate, or a salt thereof, or a mixture of the same.

[0025] The present invention further relates to pharmaceutical compositions and combinations comprising said compounds, to the use of said compounds for manufacturing a medicament for the treatment or prophylaxis of diseases or disorders and for the treatment of pains, which are associated with such diseases as well as for the treatment of inflammation, which are associated with such diseases; Furthermore, the present invention relates to pharmaceutical compositions and combinations comprising said compounds, to the use of said compounds for the treatment or prophylaxis of diseases or disorders and for the treatment of pains, which are associated with such diseases as well as for the treatment of inflammation, which are associated with such diseases.

[0026] It has now been found, and this constitutes the basis of the present invention, that said compounds of the present invention have surprising and advantageous properties.

[0027] In particular, said compounds of the present invention have surprisingly been found to effectively inhibit Bradykinin B1 receptor. Hence, the invention particularly relates to said compounds for use in the treatment or prophylaxis of following diseases or disorders: Pain and inflammation, in particular any one of visceral pain e.g. related to pancreatitis, interstitial cystitis, bladder pain syndrome, renal colic, or prostatitis, chronic pelvic pain, or pain related to infiltrating endometriosis; neuropathic pain such as post herpetic neuralgia, acute zoster pain, pain related to nerve injury, the dynias, including vulvodynia, phantom limb pain, pain related to root avulsions, pain related to radiculopathy, painful traumatic mononeuropathy, painful entrapment neuropathy, pain related to carpal tunnel syndrome, ulnar neuropathy, pain related to tarsal tunnel syndrome, painful diabetic neuropathy, painful polyneuropathy, trigeminal neuralgia, or pain related to familial amyloid polyneuropathy; central pain syndromes potentially caused by virtually any lesion at any level of the nervous system including but not limited to pain related to stroke, multiple sclerosis, and spinal cord injury; and postsurgical pain syndromes (including postmastectomy pain syndrome, postthoracotomy pain syndrome, stump pain), bone and joint pain (osteoarthritis), spine pain (including acute and chronic low back pain, neck pain, pain related to spinal stenosis), shoulder pain, repetitive motion pain, dental pain, pain related to sore throat, cancer pain, burn pain including sun-burn, myofascial pain (pain related to muscular injury, fibromyalgia) postoperative and perioperative pain (including but not limited to general surgery, orthopaedic, and gynaecological surgery); and acute and chronic pain, chronic pelvic pain, endometriosis associated pain, dysmenorrhea associated pain (primary and secondary), pain associated with uterine fibroids, vulvodynia associated pain, as well as pain associated with angina, or inflammatory pain of varied origins (including but not limited to pain associated with osteoarthritis, rheumatoid arthritis, rheumatic disease, tenosynovitis, gout, ankylosing spondylitis, and bursitis); and diseases selected from or related to any one of: gynaecological disorders and / or diseases, or effects and / or symptoms which negatively influence women health including endometriosis, uterine fibroids, pre-eclampsia, hormonal deficiency, spasms of the uterus, or heavy menstrual bleeding; the respiratory or excretion system including any of inflammatory hyperreactive airways, inflammatory events associated with airways disease like chronic obstructive pulmonary disease, asthma including allergic asthma (atopic or non-atopic) as well as exercise-induced bronchoconstriction, occupational asthma, viral or bacterial exacerbation of asthma, other non-allergic asthmas and wheezy-infant syndrome, chronic obstructive pulmonary disease including emphysema, adult respiratory distress syndrome, bronchitis, pneumonia, cough, lung injury, lung fibrosis, allergic rhinitis (seasonal and perennial), vasomotor rhinitis, angioedema (including hereditary angioedema and drug-induced angioedema including that caused by angiotensin converting enzyme (ACE) or ACE / neutral endopeptidase inhibitors like omepatrilat), pneumoconiosis, including aluminosis, anthracosis, asbestosis, chalicosis, ptilosis, siderosis, silicosis, tabacosis and byssinosis, bowel disease including Crohn's disease and ulcerative colitis, irritable bowel syndrome, pancreatitis, nephritis, cystitis (interstitial cystitis), bladder pain syndrome, kidney fibrosis, kidney failure, hyperactive bladder, and overactive bladder; dermatology including pruritus, itch, inflammatory skin disorders including psoriasis, eczema, and atopic dermatitis; affection of the joints or bones including rheumatoid arthritis, gout, osteoporosis, osteoarthritis, and ankylosing spondylitis; affection of the central and peripheral nervous system including neurodegenerative diseases including Parkinson's and Alzheimer's disease, amyotrophic lateral sclerosis (ALS), epilepsy, dementia, headache including cluster headache, migraine including prophylactic and acute use, stroke, closed head trauma, and multiple sclerosis; infection including HIV infection, and tuberculosis; trauma associated with oedema including cerebral oedema, burns, sunburns, and sprains or fracture; poisoning including aluminosis, anthracosis, asbestosis, chalicosis, ptilosis, siderosis, silicosis, tabacosis, and byssinosis uveitis; diabetes cluster or metabolism like diabetes type 1, diabetes type 2, diabetic vasculopathy, diabetic neuropathy, diabetic retinopathy, post capillary resistance or diabetic symptoms associated with insulitis (e.g. hyperglycaemia, diuresis, proteinuria and increased nitrite and kallikrein urinary excretion), diabetic macular oedema, metabolic syndrome, insulin resistance, obesity, fat or muscle metabolism; cachexia associated with or induced by any of cancer, AIDS, coeliac disease, chronic obstructive pulmonary disease, multiple sclerosis, rheumatoid arthritis, congestive heart failure, tuberculosis, familial amyloid polyneuropathy, mercury poisoning (acrodynia), and hormonal deficiency; cardio-vascular system including congestive heart failure, atherosclerosis, congestive heart failure, myocardial infarct, and heart fibrosis; and other conditions including primary peritonitis, secondary peritonitis, septic shock, sepsis, muscle atrophy, spasms of the gastrointestinal tract, benign prostatic hyperplasia, and liver diseases such as non-alcoholic and alcoholic fatty liver disease, non-alcoholic and alcoholic steatohepatitis, liver fibrosis, or liver cirrhosis.

[0028] Additionally, compounds of the present invention reduce the release of inflammation related cytokines like IL-6 and IL-8. Hence, the present invention also relates to a method for reducing inflammation related cytokine production, the method comprising the step of administering an effective amount of a compound of the present invention to a patient in need thereof. The invention also relates to the compounds of the invention as defined herein for use in the treatment of a disease associated with increased release of inflammation related cytokines, preferably associated with increased release of IL-6 and / or IL-8.FIGURE LEGENDS

[0029] Figure 1: Effect of Compound Example 3 on PCNA expression in lesions in rat 4 day endometriosis model Figure 2: Effect of Compound Example 3 on tumor necrosis factor (TNF) alpha in lesions in rat 4 day endometriosis model Figure 3: Effect of Compound Example 3 on interleukin 1 (IL-1) beta in lesions in rat 4 day endometriosis model Figure 4: Effect of Compound Example 3 on interleukin 6 (IL-6) in lesions in rat 4 day endometriosis model Figure 5: Effect of Compound Example 3 on interleukin 1 (IL-1) alpha in lesions in rat 15 day endometriosis model Figure 6: Effect of Compound Example 3 on interleukin 1 (IL-1) beta in lesions in rat 15 day endometriosis model Figure 7: Effect of Compound Example 3 on peroxidase signal reflecting neutrophil influx in mouse peritonitis model Figure 8: Effect of Compound Example 3 on thermal stimulation in STZ model (warm plate) Figure 9: Efficacy of Compound Example 3 on overactive bladder measured as number of micturitions / hour Figure 10: AUC during plateau phase of micturition 4 to 10 hours after transfer to metabolic cages Figure 11: Normalized bladder weight Figure 12: Intercontraction Interval Figure 13: Maximum Pressure of bladder contraction Figure 14: Influence of treatment with Compound Example 3 on arthritis severity in rat AIA model. Disease activity score (A) and joint thickness (B) were evaluated on the day of CFA injection (day 0) and daily onwards (A) or three times per week (B) after showing first symptoms (> day 8). Treatment with Compound Example 3 (60, 15 or 3 mg / kg QD) started with the induction of arthritis. Healthy control group (control) and AIA group (AIA) were treated with vehicle only. Data are shown as mean ±SD of n= 8 rats per group. ANOVA with Dunett's Test, *p < 0.05; **p < 0.01; ***p < 0.005; ****p < 0.001 compared with AIA group. Figure 15: Effect on hyperalgesia by Compound Example 3 treatment in rat AIA model. Grip strength was determined on the day of CFA injection (day 0) and 3 times weekly after showing first symptoms (> day 8). Treatment with Compound Example 3 (60, 15 or 3 mg / kg QD) started with the induction of arthritis. Healthy control group (control) and AIA group (AIA) were treated with vehicle only. Data are shown as mean ±SD of n= 8 rats per group. ANOVA with Dunett's Test, *p < 0.05; **p < 0.01; ***p < 0.005; ****p < 0.001 compared with AIA group. Figure 16: Schematic description of operation and treatments for CCI model. DETAILED DESCRIPTION of the INVENTION

[0030] The term "substituted" means that one or more hydrogen atoms on the designated atom or group are replaced with a selection from the indicated group, provided that the designated atom's normal valency under the existing circumstances is not exceeded. Combinations of substituents and / or variables are permissible.

[0031] The term "optionally substituted" means that the number of substituents can be equal to or different from zero. Unless otherwise indicated, it is possible that optionally substituted groups are substituted with as many optional substituents as can be accommodated by replacing a hydrogen atom with a non-hydrogen substituent on any available carbon or nitrogen or sulfur atom. Commonly, it is possible for the number of optional substituents, when present, to be 1, 2, 3, 4 or 5, in particular 1, 2 or 3.

[0032] As used herein, the term "one or more", e.g. in the definition of the substituents of the compounds of general formula (I) of the present invention, means "one or a plurality up to the maximum possible amount", e.g. if the term refers to the carbon atoms of a C 7 -cycloalkyl, it relates to "1, 2, 3, 4, 5, 6 or 7". In particular, "one or more" means "1, 2, 3, 4 or 5, particularly 1, 2, 3 or 4, more particularly 1, 2 or 3, even more particularly 1 or 2".

[0033] When groups in the compounds according to the invention are substituted, it is possible for said groups to be mono-substituted or poly-substituted with substituent(s), unless otherwise specified. Within the scope of the present invention, the meanings of all groups, which occur repeatedly, are independent from one another. It is possible that groups in the compounds according to the invention are substituted with one, two or three identical or different substituents, particularly with one substituent.

[0034] The term "comprising" when used in the specification includes but is not restricted to "consisting of".

[0035] The terms as mentioned in the present text have preferably the following meanings: The term "halogen atom", "halogen", "halo-" or "Hal-" is to be understood as meaning a fluorine, chlorine, bromine or iodine atom, preferably a fluorine or a chlorine atom.

[0036] The term "C 1 -C 5 -alkyl" means a linear or branched, saturated, monovalent hydrocarbon group having 1, 2, 3, 4 or 5 carbon atoms, e.g. a methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, pentyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neo-pentyl or 1,1-dimethylpropyl group, or an isomer thereof.

[0037] The term "C 1 -C 3 -alkyl" means a linear or branched, saturated, monovalent hydrocarbon group having 1, 2 or 3 carbon atoms ("C 1 -C 3 -alkyl"), e.g. a methyl, ethyl, n-propyl or isopropyl group.

[0038] The term "-OC 1 -C 5 -alkyl" means a linear or branched, saturated, monovalent group which is attached through an oxygen atom, and in which the term "C 1 -C 5 -alkyl" is as defined supra, e.g. a methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy, tert-butoxy, pentyloxy or isopentyloxy, or an isomer thereof. The hyphen at the beginning of the group indicates the point of attachment of said OC 1 -C 5 -alkyl group to the rest of the molecule.

[0039] "C 3 -C 7 -cycloalkyl" is to be understood as meaning a saturated, monovalent, monocyclic or bicyclic hydrocarbon ring, which contains 3, 4, 5, 6 or 7 carbon atoms. Said C 3 -C 7 -cycloalkyl group is for example a monocyclic hydrocarbon ring, e.g. a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl group, or a bicyclic hydrocarbon ring, e.g. a bicyclo[2.2.1]heptanyl or bicyclo[3.2.0]heptanyl group. Particularly, said ring contains 3, 4 or 5 carbon atoms ("C 3 -C 5 -cycloalkyl") or 5, 6 or 7 carbon atoms ("C 5 -C 7 -cycloalkyl").

[0040] The term "bicyclic cycloalkyl" includes by definition spirocycloalkyl, bridged, and fused bicycloalkyl groups.

[0041] The term "spirocycloalkyl" means a saturated, monovalent bicyclic hydrocarbon group in which the two rings share one common ring carbon atom, and wherein said bicyclic hydrocarbon group contains 5, 6, or 7 carbon atoms, it being possible for said spirocycloalkyl group to be attached to the rest of the molecule via any one of the carbon atoms except the spiro carbon atom. Said spirocycloalkyl group is, for example, spiro[2.2]pentyl, spiro[2.3]hexyl or spiro[2.4]heptyl.

[0042] The term "fused bicycloalkyl" means a bicyclic, saturated hydrocarbon ring with 6 or 7 ring atoms in total, in which the two rings share two adjacent ring atoms.

[0043] Said fused cycloalkyl group is, for example, a bicyclo[3.1.0]hexanyl or bicyclo[3.2.0]heptanyl group.

[0044] The term "bridged bicycloalkyl" means a bicyclic, saturated hydrocarbon ring with 6 or 7 ring atoms in total, in which the two rings share two common ring atoms which are not adjacent.

[0045] Said bridged cycloalkyl group is, for example, bicyclo[2.1.1]hexanyl or bicyclo[2.2.1]heptanyl group.

[0046] The term "-(C 1 -C 3 -alkyl)-(C 3 -C 7 -cycloalkyl)" is to be understood as a C 3 -C 7 -cycloalkyl group as defined above which is attached through any carbon atom of said C 3 -C 7 -cycloalkyl group to any atom of the C 1 -C 3 -alkyl group as defined above. The hyphen at the beginning of the group indicates the point of attachment of said (C 1 -C 3 -alkyl)-(C 3 -C 7 -cycloalkyl) group to the rest of the molecule. Said (C 1 -C 3 -alkyl)-(C 3 -C 7 -cycloalkyl) groups are, for example, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, 2-cyclopropylethyl, 1-cyclopropylethyl, 2-cyclobutylethyl, 1-cyclobutylethyl, 2-cyclopentylethyl, 1-cyclopentylethyl, 2-cyclobutylpropyl, or 1-cyclobutylpropyl.

[0047] The term "-OC 3 -C 7 -cycloalkyl" means a saturated, monovalent, monocyclic group, which contains 3, 4, 5, 6 or 7 carbon atoms, in which the term "C 3 -C 7 -cycloalkyl" is defined supra, e.g. a cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, or cycloheptyloxy group.

[0048] The term "heterocycloalkyl" is to be understood as meaning a saturated, monovalent, monocyclic or bicyclic hydrocarbon ring with the number of ring atoms as specified in which one or two ring atoms of the hydrocarbon ring is / are replaced by one or two heteroatoms or heteroatom-containing groups independently selected from NH, -NR 4< , N, O, S, SO and SO 2 , wherein R 4< represents C 1 -C 5 -alkyl optionally substituted with 1 to 5 fluorine atoms.

[0049] 4- to 7-membered heterocycloalkyl in the context of the invention means a monocyclic or bicyclic, saturated heterocycle with 4, 5, 6 or 7 ring atoms in total, which contains one or two identical or different ring heteroatoms or heteroatom-containing groups from the series NH, -NR 4< , N, O, S, SO and SO 2 , wherein R 4< represents C 1 -C 5 -alkyl optionally substituted with 1 to 5 fluorine atoms. Said 4- to 7-membered heterocycloalkyl can be bound via a ring carbon or nitrogen atom to the rest of the molecule.

[0050] Said heterocycloalkyl can be connected to the rest of the molecule through a carbon or a nitrogen atom, if said nitrogen atom is present.

[0051] Examples for monocyclic heterocycloalkyl groups are azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrofuranyl, thiolanyl, 1,1-dioxidothiolanyl, 1,2-oxazolidinyl, 1,3-oxazolidinyl, 1,3-thiazolidinyl, piperidinyl, piperazinyl, tetrahydropyranyl, tetrahydrothiopyranyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,2-oxazinanyl, morpholinyl, thiomorpholinyl, 1,1-dioxidothio-morpholinyl, azepanyl, 1,4-diazepanyl, and 1,4-oxazepanyl.

[0052] Particularly, without being limited thereto, said heterocycloalkyl can be a 4-membered ring, such as an azetidinyl, oxetanyl or thietanyl, or a 5-membered ring, such as tetrahydrofuranyl, dioxolinyl, thiolanyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, 1,1-dioxidothiolanyl, 1,2-oxazolidinyl, 1,3-oxazolidinyl or 1,3-thiazolidinyl, or a 6-membered ring such as tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, 1,3-dioxanyl, 1,4-dioxanyl or 1,2-oxazinanyl, or a 7-membered ring, such as a azepanyl, 1,4-diazepanyl, or 1,4-oxazepanyl, for example.

[0053] The term "bicyclic heterocycloalkyl" includes by definition heterospirocycloalkyl, fused and bridged heterobicycloalkyl groups.

[0054] The term "heterospirocycloalkyl" means a bicyclic, saturated heterocycle with 6 or 7 ring atoms in total, in which the two rings share one common ring carbon atom, wherein the "heterospirocycloalkyl" contains one or two identical or different ring heteroatoms or heteroatom-containing groups from the series: NH, -NR 4< , N, O, S, SO and SO 2 , wherein R 4< represents C 1 -C 5 -alkyl optionally substituted with 1 to 5 fluorine atoms; it being possible for said heterospirocycloalkyl group to be attached to the rest of the molecule via any one of the carbon atoms, except the spiro carbon atom, or, if present, a nitrogen atom.

[0055] Said heterospirocycloalkyl group is, for example, azaspiro[2.3]hexyl, azaspiro[2.4]-heptanyl, azaspiro[3.3]heptyl, oxazaspiro[3.3]heptyl, thiazaspiro[3.3]heptyl, oxaspiro[3.3]heptyl, diazaspiro[3.3]heptyl or thiazaspiro[3.3]heptyl, or one of the further homologous scaffolds such as spiro[2.3]-, spiro[2.4]-, spiro[3.3]-.

[0056] The term "fused heterocycloalkyl" means a bicyclic, saturated heterocycle with 6 or 7 ring atoms in total, in which the two rings share two adjacent ring atoms, which "fused heterocycloalkyl" contains one or two identical or different ring heteroatoms or heteroatom-containing groups from the series: NH, -NR 4< , N, O, S, SO and SO 2 , wherein R 4< represents C 1 -C 5 -alkyl optionally substituted with 1 to 5 fluorine atoms; it being possible for said fused heterocycloalkyl group to be attached to the rest of the molecule via any one of the carbon atoms or, if present, a nitrogen atom.

[0057] Said fused heterocycloalkyl group is, for example, 3-azabicyclo[3.1.0]hexanyl or 3-azabicyclo[3.2.0]heptanyl.

[0058] The term "bridged heterocycloalkyl" means a bicyclic, saturated heterocycle with 6 or 7 ring atoms in total, in which the two rings share two common ring atoms which are not adjacent, which "bridged heterocycloalkyl" contains one or two identical or different ring heteroatoms or heteroatom-containing groups from the series: NH, - NR 4< , N, O, S, SO and SO 2 , wherein R 4< represents C 1 -C 5 -alkyl optionally substituted with 1 to 5 fluorine atoms; it being possible for said bridged heterocycloalkyl group to be attached to the rest of the molecule via any one of the carbon atoms, except the bridgehead carbon atoms, or, if present, a nitrogen atom.

[0059] Said bridged heterocycloalkyl group is, for example, azabicyclo[2.2.1]heptyl, oxazabicyclo[2.2.1]heptyl, thiazabicyclo[2.2.1]heptyl, or diazabicyclo[2.2.1]heptyl.

[0060] The term "5- to 7-membered lactam" means cyclic amides of amino carboxylic acids, having a 1-azacycloalkan-2-one structure, or analogues having unsaturation or heteroatoms replacing one or more carbon atoms of the ring having a ring size of 5, 6 or 7 ring system atoms. In particular said "5- to 7-membered lactam" means a γ-lactam (gamma-lactam), a δ-lactam (delta-lactam), and an ε-lactam (epsilon-lactam).

[0061] The term "heteroaryl" is understood as meaning a monovalent, monocyclic or bicyclic hydrocarbon ring system with at least one aromatic ring, and wherein at least one ring atom of the monovalent, monocyclic or bicyclic hydrocarbon ring system can be replaced by at least one heteroatom or heteroatom-containing group, like NH, N, O, S, SO, and SO 2 . The number of ring system atoms is as specified, e.g. a 5- or 6-membered heteroaryl.

[0062] "5- or 6-membered heteroaryl" is understood as meaning a monovalent, monocyclic heteroaryl having 5 or 6 ring atoms and wherein one, two or three ring atoms of a monovalent 5-membered hydrocarbon ring system is / are replaced by one, two or three heteroatoms or heteroatom-containing groups independently selected from S, N, NH and O; and wherein one or two ring atoms of a monovalent 6-membered hydrocarbon ring system is / are replaced by one or two nitrogen atoms.

[0063] The said 5-membered heteroaryl can be connected through a carbon or a nitrogen atom, if said nitrogen atom is present.

[0064] Said 5- or 6-membered heteroaryl group can be a 5-membered heteroaryl group, such as, for example, thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl or thiadiazolyl; or a 6-membered heteroaryl group, such as, for example, pyridinyl, pyridazinyl, pyrimidinyl or pyrazinyl.

[0065] In general, and unless otherwise mentioned, the term "heteroaryl" includes all possible isomeric forms thereof, e.g. tautomers and positional isomers with respect to the point of linkage to the rest of the molecule. Thus, to give some illustrative non-restricting examples, the term pyridinyl includes pyridin-2-yl, pyridin-3-yl, and pyridin-4-yl; or the term pyrimidinyl includes pyrimidin-2-yl, pyrimidin-4-yl and pyrimidin-5-yl; or the term pyrazolyl includes 1H-pyrazolyl; or the term imidazolyl includes 1H-imidazolyl and 4H-imidazolyl; the term thiophenyl includes 2-thiophenyl and 3-thiophenyl; or the term thiazolyl includes 1,3-thiazol-5-yl, 1,3-thiazol-4-yl and 1,3-thiazol-2-yl.

[0066] "Bicyclic 8- to 10-membered heteroaryl" is understood as meaning a bicyclic, monovalent, fused heteroaryl having 8, 9 or 10 ring atoms with at least one aromatic ring and wherein one, two or three ring atoms of a monovalent, 8- to 10-membered bicyclic hydrocarbon ring system is / are replaced by one, two or three heteroatoms or heteroatom-containing groups independently selected from NH, N, O, S, SO and SO 2 .

[0067] The said bicyclic 8- to 10-membered heteroaryl can be connected through a carbon or a nitrogen atom, if said nitrogen atom is present.

[0068] The term "bicyclic 8- to 10-membered heteroaryl" includes by definition fused and bridged heterobicycloalkyl groups.

[0069] Particularly, bicyclic heteroaryl is selected from for example, benzofuranyl, benzothienyl, benzothiazolyl, thienopyridinyl, thienopyrimidinyl, benzoxazolyl, benz-isoxazolyl, benzimidazolyl, benzotriazolyl, benzothiadiazolyl, indazolyl, indolyl, isoindolyl, etc. or for example, quinolinyl, quinazolinyl, isoquinolinyl, etc.; indolizinyl, or cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, etc.

[0070] The term "C 1 -C 3 " as used throughout this text is to be understood as meaning a group having a finite number of carbon atoms of 1 to 3, i.e. 1, 2, or 3 carbon atoms, e.g. in the context of the definition of "C 1 -C 3 -alkyl", it is to be understood as meaning an alkyl group having a finite number of carbon atoms of 1 to 3, i.e. 1, 2, or 3 carbon atoms. It is to be understood further that said term "C 1 -C 3 " is to be interpreted as any sub-range comprised therein, e.g. C 1 -C 2 , or C 2 -C 3 .

[0071] The term "C 1 -C 5 " as used throughout this text is to be understood as meaning a group having a finite number of carbon atoms of 1 to 5, i.e. 1, 2, 3, 4, or 5 carbon atoms, e.g. in the context of the definition of "C 1 -C 5 -alkyl", it is to be understood as meaning an alkyl group having a finite number of carbon atoms of 1 to 5, i.e. 1, 2, 3, 4, or 5 carbon atoms. It is to be understood further that said term "C 1 -C 5 " is to be interpreted as any sub-range comprised therein, e.g. C 1 -C 5 , C 2 -C 5 , C 3 -C 4 , C 2 -C 3 , C 2 -C 4 , or C 1 -C 4 .

[0072] The term "C 1 -C 3 " as used in the context of the definition "-OC 1 -C 3 -alkyl" is to be understood as meaning an alkyl group, having a finite number of carbon atoms of 1 to 3, i.e. 1, 2 or 3 carbon atoms.

[0073] Similarly, the mentioned above applies to "C 1 -C 4 -alkyl", "C 1 -C 3 -alkyl", "C 1 -C 3 -alkoxy", "C 1 -C 2 -alkyl" or "C 1 -C 2 -alkoxy".

[0074] Further, as used herein, the term "C 3 -C 7 ", as used throughout this text, is to be understood as meaning a group having a finite number of carbon atoms of 3 to 7, i.e. 3, 4, 5, 6 or 7 carbon atoms, e.g. in the context of the definition of "C 3 -C 7 -cycloalkyl", it is to be understood as meaning a cycloalkyl group having a finite number of carbon atoms of 3 to 7, i.e. 3, 4, 5, 6 or 7 carbon atoms. It is to be understood further that said term "C 3 -C 7 " is to be interpreted as any sub-range comprised therein, e.g. C 3 -C 6 , C 4 -C 5 , C 3 -C 5 , C 3 -C 4 , C 4 -C 6 , or C 5 -C 7 ; particularly C 3 -C 6 .

[0075] Furthermore, as used herein, the term "C 3 -C 5 ", as used in the present text, e.g. in the context of the definition of "C 3 -C 5 -cycloalkyl", means a cycloalkyl group having a finite number of carbon atoms of 3 to 5, i.e. 3, 4 or 5 carbon atoms.

[0076] When a range of values is given, said range encompasses each value and sub-range within said range.

[0077] For example: "C 1 -C 6 " encompasses C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 1 -C 6 , C 1 -C 5 , C 1 -C 4 , C 1 -C 3 , C 1 -C 2 , C 2 -C 6 , C 2 -C 5 , C 2 -C 4 , C 2 -C 3 , C 3 -C 6 , C 3 -C 5 , C 3 -C 4 , C 4 -C 6 , C 4 -C 5 , and C 5 -C 6 ; "C 2 -C 6 " encompasses C 2 , C 3 , C 4 , C 5 , C 6 , C 2 -C 6 , C 2 -C 5 , C 2 -C 4 , C 2 -C 3 , C 3 -C 6 , C 3 -C 5 , C 3 -C 4 , C 4 -C 6 , C 4 -C 5 , and C 5 -C 6 ; "C 3 -C 10 " encompasses C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 , C 3 -C 10 , C 3 -C 9 , C 3 -C 8 , C 3 -C 7 , C 3 -C 6 , C 3 -C 5 , C 3 -C 4 , C 4 -C 10 , C 4 -C 9 , C 4 -C 8 , C 4 -C 7 , C 4 -C 6 , C 4 -C 5 , C 5 -C 10 , C 5 -C 9 , C 5 -C 8 , C 5 -C 7 , C 5 -C 6 , C 6 -C 10 , C 6 -C 9 , C 6 -C 8 , C 6 -C 7 , C 7 -C 10 , C 7 -C 9 , C 7 -C 8 , C 8 -C 10 , C 8 -C 9 and C 9 -C 10 ; "C 3 -C 8 " encompasses C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 3 -C 8 , C 3 -C 7 , C 3 -C 6 , C 3 -C 5 , C 3 -C 4 , C 4 -C 8 , C 4 -C 7 , C 4 -C 6 , C 4 -C 5 , C 5 -C 8 , C 5 -C 7 , C 5 -C 6 , C 6 -C 8 , C 6 -C 7 and C 7 -C 8 ; "C 3 -C 6 " encompasses C 3 , C 4 , C 5 , C 6 , C 3 -C 6 , C 3 -C 5 , C 3 -C 4 , C 4 -C 6 , C 4 -C 5 , and C 5 -C 6 ; "C 4 -C 8 " encompasses C 4 , C 5 , C 6 , C 7 , C 8 , C 4 -C 8 , C 4 -C 7 , C 4 -C 6 , C 4 -C 5 , C 5 -C 8 , C 5 -C 7 , C 5 -C 6 , C 6 -C 8 , C 6 -C 7 and C 7 -C 8 ; "C 4 -C 7 " encompasses C 4 , C 5 , C 6 , C 7 , C 4 -C 7 , C 4 -C 6 , C 4 -C 5 , C 5 -C 7 , C 5 -C 6 and C 6 -C 7 ; "C 4 -C 6 " encompasses C 4 , C 5 , C 6 , C 4 -C 6 , C 4 -C 5 and C 5 -C 6 ; "C 5 -C 10 " encompasses C 5 , C 6 , C 7 , C 8 , C 9 , C 10 , C 5 -C 10 , C 5 -C 9 , C 5 -C 8 , C 5 -C 7 , C 5 -C 6 , C 6 -C 10 , C 6 -C 9 , C 6 -C 8 , C 6 -C 7 , C 7 -C 10 , C 7 -C 9 , C 7 -C 8 , C 8 -C 10 , C 8 -C 9 and C 9 -C 10 ; "C 6 -C 10 " encompasses C 6 , C 7 , C 8 , C 9 , C 10 , C 6 -C 10 , C 6 -C 9 , C 6 -C 8 , C 6 -C 7 , C 7 -C 10 , C 7 -C 9 , C 7 -C 8 , C 8 -C 10 , C 8 -C 9 and C 9 -C 10 .

[0078] As used herein, the term "leaving group" means an atom or a group of atoms that is displaced in a chemical reaction as stable species taking with it the bonding electrons. In particular, such a leaving group is selected from the group comprising: halide, in particular fluoride, chloride, bromide or iodide, (methylsulfonyl)oxy, [(trifluoromethyl)sulfonyl]oxy, [(nonafluorobutyl)sulfonyl]oxy, (phenylsulfonyl)oxy, [(4-methylphenyl)sulfonyl]oxy, [(4-bromophenyl)sulfonyl]oxy, [(4-nitrophenyl)-sulfonyl]oxy, [(2-nitrophenyl)sulfonyl]oxy, [(4-isopropylphenyl)sulfonyl]oxy, [(2,4,6-triisopropylphenyl)sulfonyl]oxy, [(2,4,6-trimethylphenyl)sulfonyl]oxy, [(4-tert-butylphenyt)sulfonyl]oxy and [(4-methoxyphenyl)sulfonyl]oxy.

[0079] It is possible for the compounds of general formula (I) to exist as isotopic variants. The invention therefore includes one or more isotopic variant(s) of the compounds of general formula (I), particularly deuterium-containing compounds of general formula (I).

[0080] The term "Isotopic variant" of a compound or a reagent is defined as a compound exhibiting an unnatural proportion of one or more of the isotopes that constitute such a compound.

[0081] The term "Isotopic variant of the compound of general formula (I)" is defined as a compound of general formula (I) exhibiting an unnatural proportion of one or more of the isotopes that constitute such a compound.

[0082] The expression "unnatural proportion" means a proportion of such isotope, which is higher than its natural abundance. The natural abundances of isotopes to be applied in this context are described in "Isotopic Compositions of the Elements 1997", Pure Appl. Chem., 70(1), 217-235, 1998, which is incorporated herein by reference.

[0083] Examples of such isotopes include stable and radioactive isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine and iodine, such as 2< H (deuterium), 3< H (tritium), 11< C, 13< C, 14< C, 15< N, 17< O, 18< O, 32< P, 33< P, 33< S, 34< S, 35< S, 36< S, 18< F, 36< Cl, 82< Br, 123< I, 124< I, 125< I, 129< I and 131< I, respectively.

[0084] With respect to the treatment and / or prophylaxis of the disorders specified herein the isotopic variant(s) of the compounds of general formula (I) preferably contain deuterium ("deuterium-containing compounds of general formula (I)"). Isotopic variants of the compounds of general formula (I) in which one or more radioactive isotopes, such as 3< H or 14< C, are incorporated are useful e.g. in drug and / or substrate tissue distribution studies. These isotopes are particularly preferred for the ease of their incorporation and detectability. Positron emitting isotopes such as 18< F or 11< C may be incorporated into a compound of general formula (I). These isotopic variants of the compounds of general formula (I) are useful for in vivo imaging applications. Deuterium-containing and 13< C-containing compounds of general formula (I) can be used in mass spectrometry analyses in the context of preclinical or clinical studies.

[0085] Isotopic variants of the compounds of general formula (I) can generally be prepared by methods known to a person skilled in the art, such as those described in the schemes and / or examples herein, by substituting a reagent for an isotopic variant of said reagent, preferably for a deuterium-containing reagent. Depending on the desired sites of deuteration, in some cases deuterium from D 2 O can be incorporated either directly into the compounds or into reagents that are useful for synthesizing such compounds. Deuterium gas is also a useful reagent for incorporating deuterium into molecules. Catalytic deuteration of olefinic bonds and acetylenic bonds is a rapid route for incorporation of deuterium. Metal catalysts (i.e. Pd, Pt, and Rh) in the presence of deuterium gas can be used to directly exchange deuterium for hydrogen in functional groups containing hydrocarbons. A variety of deuterated reagents and synthetic building blocks are commercially available from companies such as for example C / D / N Isotopes, Quebec, Canada; Cambridge Isotope Laboratories Inc., Andover, MA, USA; and CombiPhos Catalysts, Inc., Princeton, NJ, USA.

[0086] The term "deuterium-containing compound of general formula (I)" is defined as a compound of general formula (I), in which one or more hydrogen atom(s) is / are replaced by one or more deuterium atom(s) and in which the abundance of deuterium at each deuterated position of the compound of general formula (I) is higher than the natural abundance of deuterium, which is about 0.015%. Particularly, in a deuterium-containing compound of general formula (I) the abundance of deuterium at each deuterated position of the compound of general formula (I) is higher than 10%, 20%, 30%, 40%, 50%, 60%, 70% or 80%, preferably higher than 90%, 95%, 96% or 97%, even more preferably higher than 98% or 99% at said position(s). It is understood that the abundance of deuterium at each deuterated position is independent of the abundance of deuterium at other deuterated position(s).

[0087] The selective incorporation of one or more deuterium atom(s) into a compound of general formula (I) may alter the physicochemical properties (such as for example acidity [C. L. Perrin, et al., J. Am. Chem. Soc., 2007, 129, 4490], basicity [C. L. Perrin et al., J. Am. Chem. Soc., 2005, 127, 9641], lipophilicity [B. Testa et al., Int. J. Pharm., 1984, 19(3), 271] and / or the metabolic profile of the molecule and may result in changes in the ratio of parent compound to metabolites or in the amounts of metabolites formed. Such changes may result in certain therapeutic advantages and hence may be preferred in some circumstances. Reduced rates of metabolism and metabolic switching, where the ratio of metabolites is changed, have been reported (A. E. Mutlib et al., Toxicol. Appl. Pharmacol., 2000, 169, 102). These changes in the exposure to parent drug and metabolites can have important consequences with respect to the pharmacodynamics, tolerability and efficacy of a deuterium-containing compound of general formula (I). In some cases, deuterium substitution reduces or eliminates the formation of an undesired or toxic metabolite and enhances the formation of a desired metabolite (e.g. Nevirapine: A. M. Sharma et al., Chem. Res. Toxicol., 2013, 26, 410; Efavirenz: A. E. Mutlib et al., Toxicol. Appl. Pharmacol., 2000, 169, 102; both incorporated herein by reference). In other cases, the major effect of deuteration is to reduce the rate of systemic clearance. As a result, the biological half-life of the compound is increased. The potential clinical benefits would include the ability to maintain similar systemic exposure with decreased peak levels and increased trough levels. This could result in lower side effects and enhanced efficacy, depending on the particular compound's pharmacokinetic / pharmacodynamic relationship. ML-337 (C. J. Wenthur et al., J. Med. Chem., 2013, 56, 5208) and Odanacatib (K. Kassahun et al., WO2012 / 112363) are examples for this deuterium effect. Still other cases have been reported in which reduced rates of metabolism result in an increase in exposure of the drug without changing the rate of systemic clearance (e.g. Rofecoxib: F. Schneider et al., Arzneim. Forsch. / Drug. Res., 2006, 56, 295; Telaprevir: F. Maltais et al., J. Med. Chem., 2009, 52, 7993; incorporated herein by reference). Deuterated drugs showing this effect may have reduced dosing requirements (e.g. lower number of doses or lower dosage to achieve the desired effect) and / or may produce lower metabolite loads.

[0088] A compound of general formula (I) may have multiple potential sites of attack for metabolism. To optimize the above-described effects on physicochemical properties and metabolic profile, deuterium-containing compounds of general formula (I) having a certain pattern of one or more deuterium-hydrogen exchange(s) can be selected. Particularly, the deuterium atom(s) of deuterium-containing compound(s) of general formula (I) is / are attached to a carbon atom and / or is / are located at those positions of the compound of general formula (I), which are sites of attack for metabolizing enzymes such as e.g. cytochrome P 450 . Optical isomers can be obtained by resolution of the racemic mixtures according to conventional processes, for example, by the formation of diastereoisomeric salts using an optically active acid or base or formation of covalent diastereomers. Examples of appropriate acids are tartaric, diacetyltartaric, ditoluoyltartaric and camphorsulfonic acid. Mixtures of diastereoisomers can be separated into their individual diastereomers on the basis of their physical and / or chemical differences by methods known in the art, for example, by chromatography or fractional crystallisation. The optically active bases or acids are then liberated from the separated diastereomeric salts. A different process for separation of optical isomers involves the use of chiral chromatography (e.g., chiral HPLC columns), with or without conventional derivatisation, optimally chosen to maximise the separation of the enantiomers. Suitable chiral HPLC columns are manufactured by Daicel, e.g., Chiracel OD and Chiracel OJ among many others, all routinely selectable. Enzymatic separations, with or without derivatisation, are also useful. The optically active compounds of this invention can likewise be obtained by chiral syntheses utilizing optically active starting materials.

[0089] In order to limit different types of isomers from each other reference is made to IUPAC Rules Section E (Pure Appl Chem 45, 11-30, 1976).

[0090] Further, the compounds of the present invention may exist as tautomers.

[0091] The present invention includes all possible tautomers of the compounds of the present invention as single tautomers, or as any mixture of said tautomers, in any ratio.

[0092] The present invention also relates to useful forms of the compounds as disclosed herein, such as hydrates, solvates, and salts, in particular pharmaceutically acceptable salts.

[0093] Where the plural form of the word compounds, salts, polymorphs, hydrates, solvates and the like, is used herein, this is taken to mean also a single compound, salt, polymorph, isomer, hydrate, solvate or the like.

[0094] By "stable compound' or "stable structure" is meant a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.

[0095] The compounds of the present invention can exist as a hydrate, or as a solvate, wherein the compounds of the present invention contain polar solvents, in particular water, methanol or ethanol for example as structural element of the crystal lattice of the compounds. The amount of polar solvents, in particular water, may exist in a stoichiometric or non-stoichiometric ratio. In the case of stoichiometric solvates, e.g. a hydrate, hemi-, (semi-), mono-, sesqui-, di-, tri-, tetra-, penta- etc. solvates or hydrates, respectively, are possible. The present invention includes all such hydrates or solvates.

[0096] Further, the compounds of the present invention can exist in free form, e.g. as a free base, or as a free acid, or as a zwitterion, or can exist in the form of a salt. Said salt may be any salt, either an organic or inorganic addition salt, particularly any pharmaceutically acceptable organic or inorganic addition salt, customarily used in pharmacy.

[0097] The term "pharmaceutically acceptable salt" refers to a relatively non-toxic, inorganic or organic acid addition salt of a compound of the present invention. For example, see S. M. Berge, et al. "Pharmaceutical Salts," J. Pharm. Sci. 1977, 66, 1-19.

[0098] A suitable pharmaceutically acceptable salt of the compounds of the present invention may be, for example, an acid-addition salt of a compound of the present invention bearing a nitrogen atom, in a chain or in a ring, for example, which is sufficiently basic, such as an acid-addition salt with an inorganic acid, such as hydrochloric, hydrobromic, hydroiodic, sulfuric, bisulfuric, phosphoric, or nitric acid, for example, or with an organic acid, such as formic, acetic, acetoacetic, pyruvic, trifluoroacetic, propionic, butyric, hexanoic, heptanoic, undecanoic, lauric, benzoic, salicylic, 2-(4-hydroxybenzoyl)-benzoic, camphoric, cinnamic, cyclopentanepropionic, digluconic, 3-hydroxy-2-naphthoic, nicotinic, pamoic, pectinic, persulfuric, 3-phenylpropionic, picric, pivalic, 2-hydroxyethanesulfonate, itaconic, sulfamic, trifluoromethanesulfonic, dodecylsulfuric, ethansulfonic, benzenesulfonic, para-toluenesulfonic, methansulfonic, 2-naphthalenesulfonic, naphthalinedisulfonic, camphorsulfonic acid, citric, tartaric, stearic, lactic, oxalic, malonic, succinic, malic, adipic, alginic, maleic, fumaric, D-gluconic, mandelic, ascorbic, glucoheptanoic, glycerophosphoric, aspartic, sulfosalicylic, hemisulfuric, or thiocyanic acid, for example.

[0099] Further, another suitably pharmaceutically acceptable salt of a compound of the present invention which is sufficiently acidic, is an alkali metal salt, for example a sodium or potassium salt, an alkaline earth metal salt, for example a calcium or magnesium salt, an ammonium salt or a salt with an organic base which affords a physiologically acceptable cation, for example a salt with N-methyl-glucamine, dimethyl-glucamine, ethyl-glucamine, lysine, dicyclohexylamine, 1,6-hexadiamine, ethanolamine, glucosamine, sarcosine, serinol, tris-hydroxy-methyl-aminomethane, aminopropandiol, sovak-base, 1-amino-2,3,4-butantriol. Additionally, basic nitrogen containing groups may be quaternised with such agents as lower alkyl halides such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides; dialkyl sulfates like dimethyl, diethyl, and dibutyl sulfate; and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyl halides like benzyl and phenethyl bromides and others.

[0100] Those skilled in the art will further recognise that acid addition salts of the claimed compounds may be prepared by reaction of the compounds with the appropriate inorganic or organic acid via any of a number of known methods. Alternatively, alkali and alkaline earth metal salts of acidic compounds of the invention are prepared by reacting the compounds of the invention with the appropriate base via a variety of known methods.

[0101] The present invention includes all possible salts of the compounds of the present invention as single salts, or as any mixture of said salts, in any ratio.

[0102] Unless otherwise indicated, the compounds of the present invention are also referred to isomers, enantiomers, diastereomers, racemates, hydrates, solvates, a salt thereof, or a mixture of same.

[0103] As used herein, the term "in vivo hydrolysable ester" is understood as meaning an in vivo hydrolysable ester of a compound of the present invention containing a carboxy or hydroxy group, for example, a pharmaceutically acceptable ester that is hydrolysed in the human or animal body to produce the parent acid or alcohol. Suitable pharmaceutically acceptable esters for carboxy include for example alkyl, cycloalkyl and optionally substituted phenylalkyl, in particular benzyl esters, C 1 -C 6 alkoxymethyl esters, e.g. methoxymethyl, C 1 -C 6 alkanoyloxymethyl esters, e.g. pivaloyloxymethyl, phthalidyl esters, C 3 -C 8 cycloalkoxy-carbonyloxy-C 1 -C 6 alkyl esters, e.g. 1-cyclohexylcarbonyloxyethyl; 1,3-dioxolen-2-onylmethyl esters, e.g. 5-methyl-1,3-dioxolen-2-onylmethyl; and C 1 -C 6 -alkoxycarbonyloxyethyl esters, e.g. 1-methoxycarbonyloxyethyl, and may be formed at any carboxy group in the compounds of this invention. An in vivo hydrolysable ester of a compound of the present invention containing a hydroxy group includes inorganic esters such as phosphate esters and [alpha]-acyloxyalkyl ethers and related compounds which as a result of the in vivo hydrolysis of the ester breakdown to give the parent hydroxy group. Examples of [alpha]-acyloxyalkyl ethers include acetoxymethoxy and 2,2-dimethylpropionyloxymethoxy. A selection of in vivo hydrolysable ester forming groups for hydroxy include alkanoyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl, alkoxycarbonyl (to give alkyl carbonate esters), dialkylcarbamoyl and N-(dialkylaminoethyl)-N-alkylcarbamoyl (to give carbamates), dialkylaminoacetyl and carboxyacetyl. The present invention covers all such esters.

[0104] Furthermore, the present invention includes all possible crystalline forms, or polymorphs, of the compounds of the present invention, either as single polymorphs, or as a mixture of more than one polymorph, in any ratio.

[0105] In accordance with a first aspect, the present invention covers compounds of general formula (I) wherein R 1< represents phenyl, 5- or 6-membered heteroaryl wherein said 5-membered heteroaryl contains 1, 2 or 3 heteroatoms or heteroatom-containing groups independently selected from the group consisting of S, N, NH, and O and wherein said 6-membered heteroaryl contains 1 or 2 nitrogen atoms, or bicyclic 9- to 10-membered heteroaryl containing 1, 2 or 3 heteroatoms or heteroatom-containing groups independently selected from NH, N, O, S, SO and SO 2 , wherein R 1< is optionally substituted as defined in formula (I).

[0106] Also preferred are compounds of general formula (I), wherein R 1< represents phenyl, 5- or 6-membered heteroaryl wherein said 5-membered heteroaryl contains 1, 2 or 3 heteroatoms or heteroatom-containing groups independently selected from the group consisting of S, N, NH, and O and wherein said 6-membered heteroaryl contains 1 or 2 nitrogen atoms, or bicyclic 9- to 10-membered heteroaryl containing 1, 2 or 3 heteroatoms or heteroatom-containing groups independently selected from NH, N, O, S, SO and SO 2 , wherein said R 1< is optionally substituted at one or more carbon atoms with 1 or 2 substituents R 1a< which are the same or different wherein R 1a< represents C 1 -C 5 -alkyl, C 3 -C 7 -cycloalkyl, -(C 1 -C 3 -alkyl)-(C 3 -C 7 -cycloalkyl), -OC 1 -C 5 -alkyl,-OC 3 -C 7 -cycloalkyl, halogen or CN, and wherein independently, if R 1< represents 5- membered heteroaryl or bicyclic 9- or 10-membered heteroaryl, each ring nitrogen atom, if present, of said R 1< is optionally substituted with a substituent R 1b< wherein R 1b< represents C 1 -C 5 -alkyl, -(C 1 -C 3 -alkyl)-(C 3 -C 7 -cycloalkyl) or C 3 -C 7 -cycloalkyl, and if R 1a< represents C 1 -C 5 -alkyl, C 3 -C 7 -cycloalkyl, -(C 1 -C 3 -alkyl)-(C 3 -C 7 -cyclo-alkyl), -OC 1 -C 5 -alkyl or -OC 3 -C 7 -cycloalkyl and / or if R 1b< represents C 1 -C 5 -alkyl, -(C 1 -C 3 -alkyl)-(C 3 -C 7 -cycloalkyl) or C 3 -C 7 -cycloalkyl, said C 1 -C 5 -alkyl, C 3 -C 7 -cycloalkyl, -(C 1 -C 3 -alkyl)-(C 3 -C 7 -cycloalkyl), -OC 1 -C 5 -alkyl or -OC 3 -C 7 -cycloalkyl independently are optionally substituted with one or more substituents independently selected from the group consisting of methyl, OH, OR 4< and F; and R 4< has the same meaning as defined above in general formula (I).

[0107] Also preferred are compounds of general formula (I), wherein R 1< represents 6-membered heteroaryl, in particular pyridinyl, pyrimidinyl or pyrazinyl, wherein said R 1< is optionally substituted at one or more carbon atoms with 1 or 2 substituents R 1a< which are the same or different wherein R 1a< represents C 1 -C 5 -alkyl, C 3 -C 7 -cycloalkyl, -(C 1 -C 3 -alkyl)-(C 3 -C 7 -cycloalkyl),-OC 1 -C 5 -alkyl, -OC 3 -C 7 -cycloalkyl, halogen or CN, and wherein said C 1 -C 5 -alkyl, C 3 -C 7 -cycloalkyl, -(C 1 -C 3 -alkyl)-(C 3 -C 7 -cycloalkyl), -OC 1 -C 5 -alkyl and -OC 3 -C 7 -cycloalkyl independently are optionally substituted with one or more substituents independently selected from the group consisting of OH, OR 4< and F; and wherein R 4< has the same meaning as defined above in general formula (I).

[0108] Also preferred are compounds of general formula (I), wherein R 1< represents pyridinyl, in particular pyridin-3-yl, optionally substituted at one or more carbon atoms with 1 or 2 substituents R 1a< which are the same or different wherein R 1a< represents C 1 -C 5 -alkyl, C 3 -C 7 -cycloalkyl, -(C 1 -C 3 -alkyl)-(C 3 -C 7 -cycloalkyl), -OC 1 -C 5 -alkyl, -OC 3 -C 7 -cycloalkyl, halogen or CN, and wherein the substituent or at least one of said substituents R 1a< is preferably positioned para to the carbon atom which links the pyridinyl, in particular pyridin-3-yl, to the rest of the molecule, and wherein said C 1 -C 5 -alkyl, C 3 -C 7 -cycloalkyl, -(C 1 -C 3 -alkyl)-(C 3 -C 7 -cycloalkyl), -OC 1 -C 5 -alkyl and -OC 3 -C 7 -cycloalkyl independently are optionally substituted with one or more substituents independently selected from the group consisting of OH, OR 4< and F; and wherein R 4< has the same meaning as defined above in general formula (I).

[0109] Also preferred are compounds of general formula (I), wherein R 1< represents pyridinyl, in particular pyridin-3-yl, substituted at one or more carbon atoms with 1 or 2 substituents R 1a< which are the same or different wherein R 1a< represents methyl, ethyl, cyclobutyl, methoxy, ethoxy, trifluoromethyl, difluoromethyl, 1,1-difluoroethyl, 1,1-difluoropropyl or 2,2,2-trifluoroethyl, and wherein the substituent or at least one of said substituents R 1a< is preferably positioned para to the carbon atom which links the pyridinyl, in particular pyridin-3-yl, to the rest of the molecule.

[0110] Also preferred are compounds of general formula (I), wherein R 1< represents pyridinyl, in particular pyridin-2-yl, optionally substituted at one or more carbon atoms with 1 or 2 substituents R 1a< which are the same or different wherein R 1a< represents C 1 -C 5 -alkyl, C 3 -C 7 -cycloalkyl, -(C 1 -C 3 -alkyl)-(C 3 -C 7 -cycloalkyl), -OC 1 -C 5 -alkyl, -OC 3 -C 7 -cycloalkyl, halogen or CN, and wherein the substituent or at least one of said substituents R 1a< is preferably positioned para to the carbon atom which links the pyridinyl, in particular pyridin-2-yl, to the rest of the molecule, and wherein said C 1 -C 5 -alkyl, C 3 -C 7 -cycloalkyl, -(C 1 -C 3 -alkyl)-(C 3 -C 7 -cycloalkyl), -OC 1 -C 5 -alkyl and -OC 3 -C 7 -cycloalkyl independently are optionally substituted with one or more substituents independently selected from the group consisting of OH, OR 4< and F; and wherein R 4< has the same meaning as defined above in general formula (I).

[0111] Also preferred are compounds of general formula (I), wherein R 1< represents pyridinyl, in particular pyridin-2-yl, substituted at one or more carbon atoms with 1 or 2 substituents R 1a< which are the same or different wherein R 1a< represents methyl, ethyl, cyclobutyl, methoxy, ethoxy, trifluoromethyl, difluoromethyl, 1,1-difluoroethyl, 1,1-difluoropropyl or 2,2,2-trifluoroethyl, and wherein the substituent or at least one of said substituents R 1a< is preferably positioned para to the carbon atom which links the pyridinyl, in particular pyridin-2-yl, to the rest of the molecule.

[0112] Also preferred are compounds of general formula (I), wherein R 1< represents 5-membered heteroaryl wherein said 5-membered heteroaryl contains 1, 2 or 3 heteroatoms or heteroatom-containing groups independently selected from the group consisting of S, N, NH, and O, in particular pyrazolyl, thiazolyl, imidazolyl, or thiophenyl, wherein said R 1< is optionally substituted at one or more carbon atoms with 1 or 2 substituents R 1a< which are the same or different, wherein R 1a< represents C 1 -C 5 -alkyl, C 3 -C 7 -cycloalkyl, -(C 1 -C 3 -alkyl)-(C 3 -C 7 -cycloalkyl), -OC 1 -C 5 -alkyl, -OC 3 -C 7 -cycloalkyl, halogen, or CN, and wherein independently each ring nitrogen atom, if present, of said R 1< is optionally substituted with a substituent R 1b< , wherein R 1b< represents C 1 -C 5 -alkyl, -(C 1 -C 3 -alkyl)-(C 3 -C 7 -cycloalkyl), or C 3 -C 7 -cycloalkyl, and if R 1a< represents C 1 -C 5 -alkyl, C 3 -C 7 -cycloalkyl, -(C 1 -C 3 -alkyl)-(C 3 -C 7 -cycloalkyl), -OC 1 -C 5 -alkyl, or -OC 3 -C 7 -cycloalkyl, and / or if R 1b< represents C 1 -C 5 -alkyl, -(C 1 -C 3 -alkyl)-(C 3 -C 7 -cycloalkyl) or C 3 -C 7 -cycloalkyl, said C 1 -C 5 -alkyl, C 3 -C 7 -cycloalkyl, -(C 1 -C 3 -alkyl)-(C 3 -C 7 -cycloalkyl), -OC 1 -C 5 -alkyl, and -OC 3 -C 7 -cycloalkyl independently are optionally substituted with one or more substituents independently selected from the group consisting of methyl, ethyl, OH, OR 4< and F; and wherein R 4< has the same meaning as defined above in general formula (I).

[0113] Also preferred are compounds of general formula (I), wherein R 1< represents pyrazolyl, in particular pyrazol-4-yl, optionally substituted at one or more carbon atoms with 1 or 2 substituents R 1a< which are the same or different, wherein R 1a< represents C 1 -C 5 -alkyl, C 3 -C 7 -cycloalkyl, -(C 1 -C 3 -alkyl)-(C 3 -C 7 -cycloalkyl), -OC 1 -C 5 -alkyl, -OC 3 -C 7 -cycloalkyl, halogen, or CN, and wherein independently each ring nitrogen atom of said R 1< is optionally substituted with a substituent R 1b< ,wherein R 1b< represents C 1 -C 5 -alkyl, -(C 1 -C 3 -alkyl)-(C 3 -C 7 -cycloalkyl), or C 3 -C 7 -cycloalkyl, and if R 1a< represents C 1 -C 5 -alkyl, C 3 -C 7 -cycloalkyl, (C 1 -C 3 -alkyl)-(C 3 -C 7 -cycloalkyl), -OC 1 -C 5 -alkyl, or -OC 3 -C 7 -cycloalkyl, and / or if R 1b< represents C 1 -C 5 -alkyl, -(C 1 -C 3 -alkyl)-(C 3 -C 7 -cycloalkyl), or C 3 -C 7 -cycloalkyl, said C 1 -C 5 -alkyl, C 3 -C 7 -cycloalkyl, -(C 1 -C 3 -alkyl)-(C 3 -C 7 -cycloalkyl), -OC 1 -C 5 -alkyl and -OC 3 -C 7 -cycloalkyl independently are optionally substituted with one or more substituents independently selected from the group consisting of methyl, ethyl, OH, OR 4< and F; and wherein R 4< has the same meaning as defined above in general formula (I).

[0114] Also preferred are compounds of general formula (I), wherein R 1< represents pyrazol-4-yl substituted at the nitrogen atom at position 1 with a substituent R 1b< , wherein R 1b< represents C 1 -C 5 -alkyl, -(C 1 -C 3 -alkyl)-(C 3 -C 7 -cycloalkyl) or C 3 -C 7 -cycloalkyl, wherein said C 1 -C 5 -alkyl, C 3 -C 7 -cycloalkyl and -(C 1 -C 3 -alkyl)-(C 3 -C 7 -cycloalkyl) is optionally substituted with one or more substituents independently selected from the group consisting of methyl, ethyl, OH, OR 4< and F; and wherein R 4< has the same meaning as defined above in general formula (I).

[0115] Additionally preferred are compounds of general formula (I), wherein R 1< represents pyrazolyl, in particular pyrazol-4-yl, wherein said R 1< is optionally substituted with 1 or 2 R 1b< which are the same or different, wherein R 1a< represents C 1 -C 5 -alkyl, C 3 -C 7 -cycloalkyl and -(C 1 -C 3 -alkyl)-(C 3 -C 7 -cycloalkyl), and wherein one of said substituents R 1b< is attached to the pyrazolyl nitrogen atom at position 1, preferably attached to the pyrazol-4-yl nitrogen atom at position 1, and wherein said C 1 -C 5 -alkyl, C 3 -C 7 -cycloalkyl and -(C 1 -C 3 -alkyl)-(C 3 -C 7 -cycloalkyl) independently are optionally substituted with one or more substituents independently selected from the group consisting of methyl, ethyl, OH, OR 4< , and F; and wherein R 4< has the same meaning as defined above in general formula (I).

[0116] Additionally preferred are compounds of general formula (I), wherein R 1< represents pyrazol-4-yl substituted at the nitrogen atom at position 1 with C 3 -C 7 -cycloalkyl, wherein said C 3 -C 7 -cycloalkyl is optionally substituted with one or more substituents independently selected from the group consisting of methyl, ethyl, OH, OR 4< , and F; and wherein R 4< has the same meaning as defined above in general formula (I).

[0117] Additionally preferred are compounds of general formula (I), wherein R 1< represents pyrazol-4-yl substituted at the nitrogen atom at position 1 with C 3 -C 7 -cycloalkyl, wherein said C 3 -C 7 -cycloalkyl is optionally substituted with one or more substituents independently selected from the group consisting of methyl, OH, OR 4< , and F; and wherein R 4< has the same meaning as defined above in general formula (I).

[0118] Also preferred are compounds of general formula (I), wherein R 1< represents pyrazol-4-yl substituted at the nitrogen atom at position 1 with a substituent selected from the group consisting of methyl, ethyl, propyl, propan-2-yl, 2-methylpropyl, tertbutyl, butan-2-yl, cyclobutyl, 2,2-dimethyl-propyl, 3-methylbutan-2-yl, cyclopentyl, cyclohexyl, 1-cyclopropylmethyl, 1-cyclopropylethyl, 1-cyclobutylmethyl, 1-(1-methylcyclopropyl)methyl and 2,2,2-trifluoroethyl, in particular ethyl, propan-2-yl, 2-methylpropyl, butan-2-yl, cyclobutyl, cyclopentyl, 2,2-dimethylpropyl, 1-cyclopropylmethyl, 1-cyclopropylethyl, 1-(1-methylcyclopropyl)methyl, and 1-cyclobutylmethyl.

[0119] Particularly preferred are compounds of general formula (I), wherein R 1< represents pyrazol-4-yl, substituted at the nitrogen atom at position 1 with cyclobutyl.

[0120] Also preferred are compounds of general formula (I), wherein R 1< represents thiazolyl, in particular thiazol-5-yl, optionally substituted at one or more carbon atoms with 1 or 2 substituents R 1a< which are the same or different, wherein R 1a< represents C 1 -C 5 -alkyl, C 3 -C 7 -cycloalkyl, -(C 1 -C 3 -alkyl)-(C 3 -C 7 -cycloalkyl), -OC 1 -C 5 -alkyl, -OC 3 -C 7 -cycloalkyl, halogen, or CN, wherein said C 1 -C 5 -alkyl, C 3 -C 7 -cycloalkyl, -(C 1 -C 3 -alkyl)-(C 3 -C 7 -cycloalkyl), -OC 1 -C 5 -alkyl and -OC 3 -C 7 -cycloalkyl independently are optionally substituted with one or more substituents independently selected from the group consisting of methyl, ethyl, OH, OR 4< , and F; and wherein R 4< has the same meaning as defined above in general formula (I).

[0121] Also preferred are compounds of general formula (I), wherein R 1< represents thiazolyl, in particular thiazol-5-yl, optionally substituted at one or more carbon atoms with 1 or 2 substituents R 1a< which are the same or different, wherein R 1a< represents C 1 -C 5 -alkyl, C 3 -C 7 -cycloalkyl, -(C 1 -C 3 -alkyl)-(C 3 -C 7 -cycloalkyl), -OC 1 -C 5 -alkyl, -OC 3 -C 7 -cycloalkyl, halogen, or CN, wherein one of said substituents R 1a< is preferably positioned meta to the carbon atom which links the thiazolyl, in particular thiazol-5-yl, to the rest of the molecule, and wherein said C 1 -C 5 -alkyl, C 3 -C 7 -cycloalkyl, -(C 1 -C 3 -alkyl)-(C 3 -C 7 -cycloalkyl), -OC 1 -C 5 -alkyl and -OC 3 -C 7 -cycloalkyl independently are optionally substituted with one or more substituents independently selected from the group consisting of methyl, ethyl, OH, OR 4< ; and F; and wherein R 4< has the same meaning as defined above in general formula (I).

[0122] Also preferred are compounds of general formula (I), wherein R 1< represents thiazol-5-yl, optionally substituted at a carbon atom with a substituent R 1a< , wherein R 1a< represents C 1 -C 5 -alkyl, -(C 1 -C 3 -alkyl)-(C 3 -C 7 -cycloalkyl), or C 3 -C 7 -cycloalkyl, wherein said C 1 -C 5 -alkyl, C 3 -C 7 -cycloalkyl, or -(C 1 -C 3 -alkyl)-(C 3 -C 7 -cycloalkyl) is optionally substituted with one or more substituents independently selected from the group consisting of methyl, ethyl, OH, OR 4< , and F; and wherein R 4< has the same meaning as defined above in general formula (I).

[0123] Also preferred are compounds of general formula (I), wherein R 1< represents thiazol-5-yl, optionally substituted at a carbon atom with a substituent R 1a< , wherein R 1a< represents C 1 -C 5 -alkyl, -(C 1 -C 3 -alkyl)-(C 3 -C 7 -cycloalkyl), or C 3 -C 7 -cycloalkyl, wherein the said substituent R 1a< is preferably linked to the carbon atom at position 2 of thiazol-5-yl, and wherein said C 1 -C 5 -alkyl, C 3 -C 7 -cycloalkyl, or -(C 1 -C 3 -alkyl)-(C 3 -C 7 -cycloalkyl) is optionally substituted with one or more substituents independently selected from the group consisting of methyl, ethyl, OH, OR 4< , and F; and wherein R 4< has the same meaning as defined above in general formula (I).

[0124] Additionally preferred are compounds of general formula (I), wherein R 1< represents thiazol-5-yl substituted at the carbon atom at position 2 with C 3 -C 7 -cycloalkyl, wherein said C 3 -C 7 -cycloalkyl is optionally substituted with one or more substituents independently selected from the group consisting of methyl, ethyl, OH, OR 4< , and F, and wherein R 4< has the same meaning as defined above in general formula (I).

[0125] Additionally preferred are compounds of general formula (I), wherein R 1< represents thiazol-5-yl substituted at the carbon atom at position 2 with C 3 -C 7 -cycloalkyl, wherein said C 3 -C 7 -cycloalkyl is optionally substituted with one or more substituents independently selected from the group consisting of methyl, OH, OR 4< , and F, and wherein R 4< has the same meaning as defined above in general formula (I).

[0126] Also preferred are compounds of general formula (I), wherein R 1< represents thiazol-5-yl, substituted at the carbon atom at position 2 with a substituent selected from the group consisting of methyl, ethyl, propyl, propan-2-yl, 2-methylpropyl, tertbutyl, butan-2-yl, cyclopropyl, cyclobutyl, 2,2-dimethylpropyl, 3-methylbutan-2-yl, cyclopentyl, cyclohexyl, 1-cyclo-propylmethyl, 1-cyclopropylethyl, 1-cyclobutylmethyl, 1-(1-methyl-cyclopropyl)methyl and 2,2,2-trifluoroethyl, in particular ethyl, propan-2-yl, 2-methylpropyl, butan-2-yl, cyclobutyl, cyclopentyl, 2,2-dimethylpropyl, 1-cyclopropylmethyl, 1-cyclopropylethyl, 1-(1-methylcyclopropyl)methyl, and 1-cyclobutylmethyl.

[0127] Also preferred are compounds of general formula (I), wherein R 1< represents thiazolyl, in particular thiazol-2-yl, optionally substituted at one or more carbon atoms with 1 or 2 substituents R 1a< which are the same or different, wherein R 1a< represents C 1 -C 5 -alkyl, C 3 -C 7 -cycloalkyl, -(C 1 -C 3 -alkyl)-(C 3 -C 7 -cycloalkyl), -OC 1 -C 5 -alkyl, -OC 3 -C 7 -cycloalkyl, halogen or CN, wherein said C 1 -C 5 -alkyl, C 3 -C 7 -cycloalkyl, -(C 1 -C 3 -alkyl)-(C 3 -C 7 -cycloalkyl), -OC 1 -C 5 -alkyl, and -OC 3 -C 7 -cycloalkyl independently are optionally substituted with one or more substituents independently selected from the group consisting of methyl, ethyl, OH, OR 4< , and F; and R 4< has the same meaning as defined above in general formula (I).

[0128] Also preferred are compounds of general formula (I), wherein R 1< represents thiazol-2-yl optionally substituted at one or more carbon atoms with 1 or 2 substituents R 1a< which are the same or different, wherein R 1a< represents C 1 -C 5 -alkyl, C 3 -C 7 -cycloalkyl, -(C 1 -C 3 -alkyl)-(C 3 -C 7 -cycloalkyl), -OC 1 -C 5 -alkyl, -OC 3 -C 7 -cycloalkyl, halogen, or CN, wherein one of said substituents R 1a< is preferably linked to the carbon atom in the position 5 of thiazol-2-yl, and wherein said C 1 -C 5 -alkyl, C 3 -C 7 -cycloalkyl, -(C 1 -C 3 -alkyl)-(C 3 -C 7 -cycloalkyl), -OC 1 -C 5 -alkyl, and -OC 3 -C 7 -cycloalkyl independently are optionally substituted with one or more substituents independently selected from the group consisting of methyl, ethyl, OH, OR 4< , and F; and wherein R 4< has the same meaning as defined above in general formula (I).

[0129] Also preferred are compounds of general formula (I), wherein R 1< represents thiazol-2-yl, optionally substituted at a carbon atom with a substituent R 1a< , wherein R 1a< represents C 1 -C 5 -alkyl, -(C 1 -C 3 -alkyl)-(C 3 -C 7 -cycloalkyl) or C 3 -C 7 -cycloalkyl, wherein said C 1 -C 5 -alkyl, C 3 -C 7 -cycloalkyl, or -(C 1 -C 3 -alkyl)-(C 3 -C 7 -cycloalkyl) is optionally substituted with one or more substituents independently selected from the group consisting of methyl, ethyl, OH, OR 4< , and F; and wherein R 4< has the same meaning as defined above in general formula (I).

[0130] Also preferred are compounds of general formula (I), wherein R 1< represents thiazol-2-yl, optionally substituted at a carbon atom with a substituent R 1a< , wherein R 1a< represents C 1 -C 5 -alkyl, -(C 1 -C 3 -alkyl)-(C 3 -C 7 -cycloalkyl), or C 3 -C 7 -cycloalkyl, wherein the said substituent R 1a< is preferably linked to the carbon atom in the position 5 of thiazol-2-yl, and wherein said C 1 -C 5 -alkyl, C 3 -C 7 -cycloalkyl, or -(C 1 -C 3 -alkyl)-(C 3 -C 7 -cycloalkyl) is optionally substituted with one or more substituents independently selected from the group consisting of methyl, ethyl, OH, OR 4< , and F; and R 4< has the same meaning as defined above in general formula (I).

[0131] Additionally preferred are compounds of general formula (I), wherein R 1< represents thiazol-2-yl, substituted at the carbon atom in position 5 with C 3 -C 7 -cycloalkyl, wherein said C 3 -C 7 -cycloalkyl is optionally substituted with one or more substituents independently selected from the group consisting of methyl, ethyl, OH, OR 4< , and F; and wherein R 4< has the same meaning as defined above in general formula (I).

[0132] Additionally preferred are compounds of general formula (I), wherein R 1< represents thiazol-2-yl, substituted at the carbon atom in position 5 with C 3 -C 7 -cycloalkyl, wherein said C 3 -C 7 -cycloalkyl is optionally substituted with one or more substituents independently selected from the group consisting of methyl, OH, OR 4< , and F; and wherein R 4< has the same meaning as defined above in general formula (I).

[0133] Also preferred are compounds of general formula (I), wherein R 1< represents thiazol-2-yl, substituted at the carbon atom in position 5 with a substituent selected from the group consisting of methyl, ethyl, propyl, propan-2-yl, 2-methylpropyl, tertbutyl, butan-2-yl, cyclopropyl, cyclobutyl, 2,2-dimethylpropyl, 3-methylbutan-2-yl, cyclopentyl, cyclohexyl, 1-cyclo-propylmethyl, 1-cyclopropylethyl, 1-cyclobutylmethyl, 1-(1-methyl-cyclopropyl)methyl and 2,2,2-trifluoroethyl, in particular ethyl, propan-2-yl, 2-methylpropyl, butan-2-yl, cyclobutyl, cyclopentyl, 2,2-dimethylpropyl, 1-cyclopropylmethyl, 1-cyclopropylethyl, 1-(1-methylcyclopropyl)methyl, and 1-cyclobutylmethyl.

[0134] Also preferred are compounds of general formula (I), wherein R 1< represents a bicyclic 9-membered heteroaryl containing 1, 2, or 3 heteroatoms or heteroatom-containing groups independently selected from NH, N, O, S, SO, and SO 2 , in particular benzothiophenyl, wherein said R 1< is optionally substituted at one or more carbon atoms with 1 or 2 substituents R 1a< which are the same or different, wherein R 1a< represents C 1 -C 5 -alkyl, C 3 -C 7 -cycloalkyl, -(C 1 -C 3 -alkyl)-(C 3 -C 7 -cycloalkyl), -OC 1 -C 5 -alkyl,-OC 3 -C 7 -cycloalkyl, halogen, or CN, and wherein independently each ring nitrogen atom of said R 1< is optionally substituted with 1 substituent R 1b< , wherein R 1b< represents C 1 -C 5 -alkyl, -(C 1 -C 3 -alkyl)-(C 3 -C 7 -cycloalkyl), or C 3 -C 7 -cycloalkyl, and if R 1a< represents C 1 -C 5 -alkyl, C 3 -C 7 -cycloalkyl, -(C 1 -C 3 -alkyl)-(C 3 -C 7 -cyclo-alkyl), -OC 1 -C 5 -alkyl or -OC 3 -C 7 -cycloalkyl, and / or if R 1b< represents C 1 -C 5 -alkyl, -(C 1 -C 3 -alkyl)-(C 3 -C 7 -cycloalkyl), or C 3 -C 7 -cycloalkyl, said C 1 -C 5 -alkyl, C 3 -C 7 -cycloalkyl, -(C 1 -C 3 -alkyl)-(C 3 -C 7 -cycloalkyl), -OC 1 -C 5 -alkyl, and -OC 3 -C 7 -cycloalkyl independently are optionally substituted with one or more substituents independently selected from the group consisting of methyl, ethyl OH, OR 4< , and F; and wherein R 4< has the same meaning as defined above in general formula (I).

[0135] Additionally preferred are compounds of general formula (I), wherein R 1< represents phenyl, pyridinyl, pyrazolyl, thiazolyl, imidazolyl, thiophenyl, or benzothiophenyl, in particular pyridinyl, pyrazolyl, thiazolyl, or imidazolyl, wherein said R 1< is optionally substituted at one or more carbon atoms with 1 or 2 substituents R 1a< which are the same or different, wherein R 1a< represents C 1 -C 5 -alkyl, C 3 -C 7 -cycloalkyl, -(C 1 -C 3 -alkyl)-(C 3 -C 7 -cycloalkyl), -OC 1 -C 5 -alkyl, -OC 3 -C 7 -cycloalkyl, halogen or CN, and wherein independently, if R 1< represents pyrazolyl, thiazolyl, or imidazolyl, each ring nitrogen atom of said R 1< , is optionally substituted with a substituent R 1b< , wherein R 1b< represents C 1 -C 5 -alkyl, -(C 1 -C 3 -alkyl)-(C 3 -C 7 -cycloalkyl), or C 3 -C 7 -cycloalkyl, and if R 1a< represents C 1 -C 5 -alkyl, C 3 -C 7 -cycloalkyl, -(C 1 -C 3 -alkyl)-(C 3 -C 7 -cycloalkyl), -OC 1 -C 5 -alkyl or -OC 3 -C 7 -cycloalkyl, and / or if R 1b< represents C 1 -C 5 -alkyl, -(C 1 -C 3 -alkyl)-(C 3 -C 7 -cycloalkyl) or C 3 -C 7 -cycloalkyl, said C 1 -C 5 -alkyl, C 3 -C 7 -cycloalkyl, -(C 1 -C 3 -alkyl)-(C 3 -C 7 -cycloalkyl), -OC 1 -C 5 -alkyl and -OC 3 -C 7 -cycloalkyl independently are optionally substituted with one or more substituents independently selected from the group consisting of methyl, ethyl, OH, OR 4< and F; and wherein R 4< has the same meaning as defined above in general formula (I).

[0136] In accordance with a further aspect, the present invention covers compounds of general formula (I), wherein R 4< represents C 1 -C 5 -alkyl, in particular methyl, ethyl, propyl, or butyl optionally substituted with 1 to 3 fluorine atoms.

[0137] Also preferred are compounds of general formula (I), wherein R 4< represents methyl, difluoromethyl, or trifluoromethyl.

[0138] In accordance with a further aspect, the present invention covers compounds of general formula (I), wherein R 3< represents H.

[0139] In accordance with a further aspect, the present invention covers compounds of general formula (I), wherein R 5< represents H, F, Cl, or methyl, in particular H or F.

[0140] Particularly preferred are compounds of general formula (I), wherein R 5< represents H.

[0141] Also preferred are compounds of general formula (I), wherein R 5< represents F.

[0142] Particularly preferred are compounds of general formula (I), wherein R 3< represents H; and R 5< represents H.

[0143] Particularly preferred are compounds of general formula (I), wherein R 3< represents H; and R 5< represents F.

[0144] In accordance with a further aspect, the present invention covers compounds of general formula (I), wherein R 2< represents • -(CH 2 ) p -(C 5 -C 7 -cycloalkyl), • -(CH 2 ) p -phenyl, • 6-membered heteroaryl, containing 1 or 2 N, or • bicyclic 9- to 10-membered heteroaryl, containing 1, 2 or 3 heteroatoms or heteroatom-containing groups independently selected from NH, N, O, S, SO and SO 2 , wherein said R 2< is optionally substituted at one or more carbon atoms with 1 or 2 substituents R 2a< which are the same or different, wherein R 2a< represents C 1 -C 5 -alkyl, C 3 -C 7 -cycloalkyl, -(C 1 -C 3 -alkyl)-(C 3 -C 7 -cycloalkyl), -OC 1 -C 5 -alkyl, -OC 3 -C 7 -cycloalkyl, halogen, OH or CN, and wherein independently each nitrogen atom of said R 2< , if present, is optionally substituted with a substituent R 2b< wherein R 2b< represents C 1 -C 5 -alkyl, C 3 -C 7 -cycloalkyl or -(C 1 -C 3 -alkyl)-(C 3 -C 7 -cycloalkyl), and if R 2a< represents C 1 -C 5 -alkyl, C 3 -C 7 -cycloalkyl, -(C 1 -C 3 -alkyl)-(C 3 -C 7 -cycloalkyl), -OC 1 -C 5 -alkyl or -OC 3 -C 7 -cycloalkyl, and / or if R 2b< represents C 1 -C 5 -alkyl, -(C 1 -C 3 -alkyl)-(C 3 -C 7 -cycloalkyl) or C 3 -C 7 -cycloalkyl, said C 1 -C 5 -alkyl, C 3 -C 7 -cycloalkyl, -(C 1 -C 3 -alkyl)-(C 3 -C 7 -cycloalkyl), -OC 1 -C 5 -alkyl and -OC 3 -C 7 -cycloalkyl independently are optionally substituted with one or more substituents independently selected from the group consisting of OH, OR 4< and F; and wherein p and R 4< have the same meaning as defined in general formula (I).

[0145] A preferred embodiment of the present invention covers compounds of general formula (I), wherein R 2< represents • -(CH 2 ) p -(C 5 -C 7 -cycloalkyl), • -(CH 2 ) p -phenyl, or • 6-membered heteroaryl containing 1 or 2 N, wherein said R 2< is optionally substituted at one or more carbon atoms with 1 or 2 substituents R 2a< which are the same or different, wherein R 2a< represents C 1 -C 5 -alkyl,C 3 -C 7 -cycloalkyl, OC 1 -C 5 -alkyl, halogen or CN, wherein said C 1 -C 5 -alkyl, -OC 1 -C 5 -alkyl and C 3 -C 7 -cycloalkyl independently are optionally substituted with OH, OR 4< or 1 to 5 fluorine atoms, and wherein p and R 4< have the same meaning as defined in general formula (I).

[0146] A preferred embodiment of the present invention covers compounds of general formula (I), wherein R 2< represents -(CH 2 ) p -(C 5 -C 7 -cycloalkyl), optionally substituted at one or more carbon atoms with 1 or 2 substituents R 2a< which are the same or different, wherein R 2a< represents C 1 -C 5 -alkyl, C 3 -C 7 -cycloalkyl, OC 1 -C 5 -alkyl, halogen or CN, wherein said C 1 -C 5 -alkyl, -OC 1 -C 5 -alkyl and C 3 -C 7 -cycloalkyl independently are optionally substituted with OH, OR 4< or 1 to 5 fluorine atoms, and wherein p and R 4< have the same meaning as defined in general formula (I).

[0147] A preferred embodiment of the present invention covers compounds of general formula (I), wherein R 2< represents C 5 -C 7 -cycloalkyl, optionally substituted at one or more carbon atoms with 1 or 2 substituents R 2a< which are the same or different, wherein R 2a< represents C 1 -C 5 -alkyl, C 3 -C 7 -cycloalkyl, OC 1 -C 5 -alkyl, halogen or CN, wherein said C 1 -C 5 -alkyl, -OC 1 -C 5 -alkyl and C 3 -C 7 -cycloalkyl independently are optionally substituted with OH, OR 4< or 1 to 5 fluorine atoms, and wherein R 4< has the same meaning as defined in general formula (I).

[0148] A preferred embodiment of the present invention covers compounds of general formula (I), wherein R 2< represents -(CH 2 ) p -phenyl, optionally substituted at one or more carbon atoms with 1 or 2 substituents R 2a< which are the same or different wherein R 2a< represents C 1 -C 5 -alkyl, C 3 -C 7 -cycloalkyl, OC 1 -C 5 -alkyl, halogen or CN, wherein said C 1 -C 5 -alkyl, -OC 1 -C 5 -alkyl and C 3 -C 7 -cycloalkyl independently are optionally substituted with OH, OR 4< or 1 to 5 fluorine atoms, and p and R 4< have the same meaning as defined in general formula (I).

[0149] Also preferred are compounds of general formula (I), wherein R 2< represents phenyl optionally substituted with 1 or 2 substituents R 2a< which are the same or different wherein R 2a< represents C 1 -C 5 -alkyl, C 3 -C 7 -cycloalkyl, OC 1 -C 5 -alkyl, halogen or CN, wherein said C 1 -C 5 -alkyl,-OC 1 -C 5 -alkyl and C 3 -C 7 -cycloalkyl independently are optionally substituted with OH, OR 4< or 1 to 5 fluorine atoms, and R 4< has the same meaning as defined in general formula (I).

[0150] Also preferred are compounds of general formula (I), wherein R 2< represents phenyl optionally substituted with 1 or 2 substituents R 2a< which are the same or different wherein R 2a< represents C 1 -C 5 -alkyl, OC 1 -C 5 -alkyl, F or Cl, wherein said C 1 -C 5 -alkyl and -OC 1 -C 5 -alkyl independently are optionally substituted with OH, OR 4< or 1 to 5 fluorine atoms, and R 4< has the same meaning as defined in general formula (I).

[0151] Also preferred are compounds of general formula (I), wherein R 2< represents phenyl substituted with 1 or 2 substituents R 2a< which are the same or different wherein R 2a< represents C 1 -C 5 -alkyl, OC 1 -C 5 -alkyl, F or Cl, wherein if the substituent or at least one of said substituents is F, it is preferably positioned ortho to the carbon atom which links the phenyl to the rest of the molecule, and wherein said C 1 -C 5 -alkyl and -OC 1 -C 5 -alkyl independently are optionally substituted with 1 to 5 fluorine atoms.

[0152] Also preferred are compounds of general formula (I), wherein R 2< represents phenyl substituted with 1 or 2 substituents R 2a< which are the same or different wherein R 2a< represents C 1 -C 5 -alkyl, OC 1 -C 5 -alkyl, F or Cl, wherein if the substituent or at least one of said substituents is C 1 -C 5 -alkyl, -OC 1 -C 5 -alkyl or Cl, it is preferably positioned para to the carbon atom which links the phenyl to the rest of the molecule, and wherein said C 1 -C 5 -alkyl and -OC 1 -C 5 -alkyl independently are optionally substituted with 1 to 5 fluorine atoms.

[0153] Also preferred are compounds of general formula (I), wherein R 2< represents phenyl substituted with 2 substituents R 2a< which are the same or different wherein R 2a< represents C 1 -C 5 -alkyl, OC 1 -C 5 -alkyl, F or Cl, wherein if the substituent or at least one of said substituents is F, it is preferably positioned ortho to the carbon atom which links the phenyl to the rest of the molecule, and wherein if the substituent or at least one of said substituents is C 1 -C 5 -alkyl, -OC 1 -C 5 -alkyl or Cl, it is preferably positioned para to the carbon atom which links the phenyl to the rest of the molecule; and wherein said C 1 -C 5 -alkyl and -OC 1 -C 5 -alkyl independently are optionally substituted with 1 to 5 fluorine atoms.

[0154] Also preferred are compounds of general formula (I), wherein R 2< represents phenyl optionally substituted with 1 or 2 substituents R 2a< which are the same or different wherein R 2a< represents methyl, trifluoromethyl, trifluoromethoxy, F or Cl, wherein if the substituent or at least one of said substituents is F, it is preferably positioned ortho to the carbon atom which links the phenyl to the rest of the molecule, and wherein if the substituent or at least one of said substituents is methyl, trifluoromethyl, trifluoromethoxy or Cl, it is preferably positioned para to the carbon atom which links the phenyl to the rest of the molecule.

[0155] Also preferred are compounds of general formula (I), wherein R 2< represents 6-membered heteroaryl containing 1 or 2 N, in particular pyridinyl, wherein said R 2< is optionally substituted at one or more carbon atoms with 1 or 2 substituents R 2a< which are the same or different wherein R 2a< represents C 1 -C 5 -alkyl, OC 1 -C 5 -alkyl, C 3 -C 7 -cycloalkyl, halogen or CN, wherein said C 1 -C 5 -alkyl, -OC 1 -C 5 -alkyl and C 3 -C 7 -cycloalkyl independently are optionally substituted with OH, OR 4< or 1 to 5 fluorine atoms, and R 4< has the same meaning as defined in general formula (I).

[0156] Also preferred are compounds of general formula (I), wherein R 2< represents pyridinyl, in particular pyridin-2-yl, optionally substituted at one or more carbon atoms with 1 or 2 substituents R 2a< which are the same or different wherein R 2a< represents C 1 -C 5 -alkyl, OC 1 -C 5 -alkyl, F or Cl, wherein said C 1 -C 5 -alkyl and -OC 1 -C 5 -alkyl independently are optionally substituted with OH, OR 4< or 1 to 5 fluorine atoms, and R 4< has the same meaning as defined in general formula (I).

[0157] In accordance with a further aspect, the present invention covers compounds of general formula (I), wherein prepresents 0.

[0158] In accordance with a further aspect, the present invention covers compounds of general formula (I), wherein R 6< and R 7< represent H.

[0159] In accordance with a further aspect, the present invention covers compounds of general formula (I), wherein R 1< represents • phenyl, • 5- or 6-membered heteroaryl wherein said 5-membered heteroaryl contains 1, 2 or 3 heteroatoms or heteroatom-containing groups independently selected from the group consisting of S, N, NH, and O and wherein said 6-membered heteroaryl contains 1 or 2 nitrogen atoms, or • bicyclic 9- to 10-membered heteroaryl containing 1, 2 or 3 heteroatoms or heteroatom-containing groups independently selected from NH, N, O, S, SO and SO 2 , wherein said R 1< is optionally substituted at one or more carbon atoms with 1 to 3 substituents R 1a< which are the same or different wherein R 1a< represents C 1 -C 5 -alkyl, C 3 -C 7 -cycloalkyl, -(C 1 -C 3 -alkyl)-(C 3 -C 7 -cycloalkyl), -OC 1 -C 5 -alkyl,-OC 3 -C 7 -cycloalkyl, NHR 4< , N(R 4< ) 2 , NH(C 3 -C 7 -cycloalkyl), halogen, CN, NHSO 2 R 4< , SO 2 R 4< , 5- to 7-membered lactam or 4- to 7-membered heterocycloalkyl containing 1 or 2 heteroatoms or heteroatom-containing groups selected from NH, -NR 4< , N, O,S, SO and SO 2 , and wherein independently, if R 1< represents 5- membered heteroaryl or bicyclic 8- to 10-membered heteroaryl, each ring nitrogen atom, if present, of said R 1< is optionally substituted with a substituent R 1b< wherein R 1b< represents C 1 -C 5 -alkyl, -(C 1 -C 3 -alkyl)-(C 3 -C 7 -cycloalkyl), C 3 -C 7 -cycloalkyl, SO 2 R 4< or 4- to 7-membered heterocycloalkyl containing 1 or 2 heteroatoms or heteroatom-containing groups selected from NH, -NR 4< , N, O,S, SO and SO 2 , and if R 1a< represents C 1 -C 5 -alkyl, C 3 -C 7 -cycloalkyl, -(C 1 -C 3 -alkyl)-(C 3 -C 7 -cyclo-alkyl), -OC 1 -C 5 -alkyl or -OC 3 -C 7 -cycloalkyl and / or if R 1b< represents C 1 -C 5 -alkyl, -(C 1 -C 3 -alkyl)-(C 3 -C 7 -cycloalkyl) or C 3 -C 7 -cycloalkyl, said C 1 -C 5 -alkyl, C 3 -C 7 -cycloalkyl, -(C 1 -C 3 -alkyl)-(C 3 -C 7 -cycloalkyl), -OC 1 -C 5 -alkyl or -OC 3 -C 7 -cycloalkyl independently are optionally substituted with one or more substituents independently selected from the group consisting of methyl, ethyl, OH, OR 4< and F, and if R 1a< and / or R 1b< represent 4- to 7-membered heterocycloalkyl, each carbon atom of said 4- to 7-membered heterocycloalkyl is optionally substituted with one or more substituents independently selected from the group consisting of OH, OR 4< and F, R 3< represents H or F, in particular H, R 5< represents H, F, Cl or methyl, in particular H or F, and R 6< and R 7< represent H.

[0160] In accordance with a further aspect, the present invention covers compounds of general formula (I), wherein R 1< represents phenyl, 6-membered heteroaryl containing 1 or 2 N atoms, wherein said R 1< is optionally substituted at one or more carbon atoms with 1 or 2 substituents R 1a< which are the same or different wherein R 1a< represents C 1 -C 5 -alkyl, C 3 -C 7 -cycloalkyl, -(C 1 -C 3 -alkyl)-(C 3 -C 7 -cycloalkyl), -OC 1 -C 5 -alkyl, -OC 3 -C 7 -cycloalkyl, halogen or CN, wherein said C 1 -C 5 -alkyl, C 3 -C 7 -cycloalkyl, -(C 1 -C 3 -alkyl)-(C 3 -C 7 -cycloalkyl), -OC 1 -C 5 -alkyl and -OC 3 -C 7 -cycloalkyl independently are optionally substituted with one or more substituents independently selected from the group consisting of OH, OR 4< and F, R 3< represents H or F, in particular H, R 4< represents C 1 -C 5 -alkyl, optionally substituted with 1 to 5 fluorine atoms, R 5< represents H, F, Cl or methyl, in particular H or F, and R 6< and R 7< represent H.

[0161] In accordance with another aspect, the present invention covers compounds of general formula (I), wherein R 1< represents 5-membered heteroaryl wherein said 5-membered heteroaryl contains 1, 2 or 3 heteroatoms or heteroatom-containing groups independently selected from the group consisting of S, N, NH, and O,in particular pyrazolyl, thiazolyl, imidazolyl or thiophenyl, wherein said R 1< is optionally substituted at one or more carbon atoms with 1 or 2 substituents R 1a< which are the same or different wherein R 1a< represents C 1 -C 5 -alkyl, C 3 -C 7 -cycloalkyl, -(C 1 -C 3 -alkyl)-(C 3 -C 7 -cycloalkyl), -OC 1 -C 5 -alkyl, -OC 3 -C 7 -cycloalkyl, halogen or CN, and wherein independently each ring nitrogen atom, if present, of said R 1< is optionally substituted with a substituent R 1b< which are the same or different wherein R 1b< represents C 1 -C 5 -alkyl, -(C 1 -C 3 -alkyl)-(C 3 -C 7 -cycloalkyl) and C 3 -C 7 -cycloalkyl, if R 1a< represents C 1 -C 5 -alkyl, C 3 -C 7 -cycloalkyl, -(C 1 -C 3 -alkyl)-(C 3 -C 7 -cycloalkyl), -OC 1 -C 5 -alkyl or -OC 3 -C 7 -cycloalkyl and / or if R 1b< represents C 1 -C 5 -alkyl, -(C 1 -C 3 -alkyl)-(C 3 -C 7 -cycloalkyl) or C 3 -C 7 -cycloalkyl, said C 1 -C 5 -alkyl,C 3 -C 7 -cycloalkyl, -(C 1 -C 3 -alkyl)-(C 3 -C 7 -cycloalkyl), -OC 1 -C 5 -alkyl and -OC 3 -C 7 -cycloalkyl independently are optionally substituted with one or more substituents independently selected from the group consisting of methyl, ethyl, OH, OR 4< and F, R 3< represents H or F, in particular H, R 4< represents C 1 -C 5 -alkyl, optionally substituted with 1 to 5 fluorine atoms, R 5< represents H, F, Cl or methyl, in particular H or F, and R 6< and R 7< represent H.

[0162] In accordance with another aspect, the present invention covers compounds of general formula (I), wherein R 1< represents pyridinyl, in particular pyridin-3-yl, optionally substituted at one or more carbon atoms with 1 or 2 substituents R 1a< which are the same or different wherein R 1a< represents C 1 -C 5 -alkyl, C 3 -C 7 -cycloalkyl, -(C 1 -C 3 -alkyl)-(C 3 -C 7 -cycloalkyl), -OC 1 -C 5 -alkyl, -OC 3 -C 7 -cycloalkyl, halogen or CN, and wherein one of said substituents is preferably positioned wherein one of said substituents R 1a< is preferably positioned para to the carbon atom which links the pyridinyl, in particular pyridin-3-yl, to the rest of the molecule, and wherein said C 1 -C 5 -alkyl, C 3 -C 7 -cycloalkyl, -(C 1 -C 3 -alkyl)-(C 3 -C 7 -cycloalkyl), -OC 1 -C 5 -alkyl and -OC 3 -C 7 -cycloalkyl independently are optionally substituted with one or more substituents independently selected from the group consisting of methyl, ethyl, OH, OR 4< and F, R 3< represents H or F, in particular H, R 4< represents C 1 -C 5 -alkyl, optionally substituted with 1 to 5 fluorine atoms, R 5< represents H, F, Cl or methyl, in particular H or F, and R 6< and R 7< represent H.

[0163] In accordance with another aspect, the present invention covers compounds of general formula (I), wherein R 1< represents pyridinyl, in particular pyridin-3-yl, substituted at one or more carbon atoms with 1 or 2 substituents R 1a< which are the same or different wherein R 1a< represents methyl, ethyl, methoxy, ethoxy, cyclobutyl, trifluoromethyl, difluoromethyl, 1,1-difluoroethyl, 1,1-difluoropropyl or 2,2,2-trifluoroethyl, and wherein the substituent or at least one of said substituents is preferably positioned para to the carbon atom which links the pyridinyl, in particular pyridin-3-yl, to the rest of the molecule, and R 3< represents H or F, in particular H, R 5< represents H, F, Cl or methyl, in particular H or F, and R 6< and R 7< represent H.

[0164] In accordance with another aspect, the present invention covers compounds of general formula (I), wherein R 1< represents pyridinyl, in particular pyridin-2-yl, optionally substituted at one or more carbon atoms with 1 or 2 substituents R 1a< which are the same or different wherein R 1a< represents C 1 -C 5 -alkyl, C 3 -C 7 -cycloalkyl, -(C 1 -C 3 -alkyl)-(C 3 -C 7 -cycloalkyl), -OC 1 -C 5 -alkyl, -OC 3 -C 7 -cycloalkyl, halogen or CN, and wherein one of said substituents R 1a< is preferably positioned para to the carbon atom which links the pyridinyl, in particular pyridin-2-yl, to the rest of the molecule, and wherein said C 1 -C 5 -alkyl, C 3 -C 7 -cycloalkyl, -(C 1 -C 3 -alkyl)-(C 3 -C 7 -cycloalkyl), -OC 1 -C 5 -alkyl and -OC 3 -C 7 -cycloalkyl independently are optionally substituted with one or more substituents independently selected from the group consisting of methyl, ethyl, OH, OR 4< and F, R 3< represents H or F, in particular H, R 4< represents C 1 -C 5 -alkyl,optionally substituted with 1 to 5 fluorine atoms, R 5< represents H, F, Cl or methyl, in particular H or F, and R 6< and R 7< represent H.

[0165] In accordance with another aspect, the present invention covers compounds of general formula (I), wherein R 1< represents pyridinyl, in particular pyridin-2-yl, substituted at one or more carbon atoms with 1 or 2 substituents R 1a< which are the same or different wherein R 1a< represents methyl, ethyl, methoxy, ethoxy, cyclobutyl, trifluoromethyl, difluoromethyl, 1,1-difluoroethyl, 1,1-difluoropropyl or 2,2,2-trifluoroethyl, and wherein the substituent or at least one of said substituents is preferably positioned para to the carbon atom which links the pyridinyl, in particular pyridin-2-yl, to the rest of the molecule, and R 3< represents H or F, in particular H, R 5< represents H, F, Cl or methyl, in particular H or F, and R 6< and R 7< represent H.

[0166] In accordance with another aspect, the present invention covers compounds of general formula (I), wherein R 1< represents pyrazolyl, in particular pyrazol-4-yl, optionally substituted at one or more carbon atoms with 1 or 2 substituents R 1a< which are the same or different wherein R 1a< represents C 1 -C 5 -alkyl, C 3 -C 7 -cycloalkyl, -(C 1 -C 3 -alkyl)-(C 3 -C 7 -cycloalkyl), -OC 1 -C 5 -alkyl,-OC 3 -C 7 -cycloalkyl, halogen or CN, and wherein independently each nitrogen atom of said R 1< is optionally substituted with a substituent R 1b< wherein R 1b< represents C 1 -C 5 -alkyl, -(C 1 -C 3 -alkyl)-(C 3 -C 7 -cycloalkyl) and C 3 -C 7 -cycloalkyl, and if R 1a< represents C 1 -C 5 -alkyl, C 3 -C 7 -cycloalkyl, -(C 1 -C 3 -alkyl)-(C 3 -C 7 -cycloalkyl), -OC 1 -C 5 -alkyl or -OC 3 -C 7 -cycloalkyl and / or if R 1b< represents C 1 -C 5 -alkyl, -(C 1 -C 3 -alkyl)-(C 3 -C 7 -cycloalkyl) or C 3 -C 7 -cycloalkyl, said C 1 -C 5 -alkyl, C 3 -C 7 -cycloalkyl, -(C 1 -C 3 -alkyl)-(C 3 -C 7 -cycloalkyl), -OC 1 -C 5 -alkyl and -OC 3 -C 7 -cycloalkyl independently are optionally substituted with one or more substituents independently selected from the group consisting of methyl, OH, OR 4< and F, R 3< represents H or F, in particular H, R 4< represents C 1 -C 5 -alkyl, optionally substituted with 1 to 5 fluorine atoms, R 5< represents H, F, Cl or methyl, in particular H or F, and R 6< and R 7< represent H.

[0167] A preferred embodiment of the present invention covers compounds of general formula (I), wherein R 1< represents pyrazolyl, in particular pyrazol-4-yl, optionally substituted at one or more carbon atoms with 1 or 2 substituents R 1a< which are the same or different wherein R 1a< represents C 1 -C 5 -alkyl, C 3 -C 7 -cycloalkyl, -(C 1 -C 3 -alkyl)-(C 3 -C 7 -cycloalkyl), -OC 1 -C 5 -alkyl,-OC 3 -C 7 -cycloalkyl, halogen or CN, and wherein independently each nitrogen atom of said R 1< is optionally substituted with a substituent R 1b< which are the same or different wherein R 1b< represents C 1 -C 5 -alkyl, -(C 1 -C 3 -alkyl)-(C 3 -C 7 -cycloalkyl) or C 3 -C 7 -cyclo-alkyl, and if R 1a< represents C 1 -C 5 -alkyl, C 3 -C 7 -cycloalkyl, -(C 1 -C 3 -alkyl)-(C 3 -C 7 -cyclo-alkyl), -OC 1 -C 5 -alkyl or -OC 3 -C 7 -cycloalkyl and / or if R 1b< represents C 1 -C 5 -alkyl, -(C 1 -C 3 -alkyl)-(C 3 -C 7 -cycloalkyl) or C 3 -C 7 -cycloalkyl, said C 1 -C 5 -alkyl, C 3 -C 7 -cycloalkyl, -(C 1 -C 3 -alkyl)-(C 3 -C 7 -cycloalkyl), -OC 1 -C 5 -alkyl and -OC 3 -C 7 -cycloalkyl independently are optionally substituted with one or more substituents independently selected from the group consisting of methyl, OH, OR 4< and F, R 3< represents H or F, in particular H, R 4< represents C 1 -C 5 -alkyl, optionally substituted with 1 to 5 fluorine atoms, R 5< represents H, F, Cl or methyl, in particular H or F, and R 6< and R 7< represent H.

[0168] A preferred embodiment of the present invention covers compounds of general formula (I), wherein R 1< represents pyrazol-4-yl, optionally substituted at a nitrogen atom with 1 substituent R 1b< selected from the group consisting of C 1 -C 5 -alkyl, -(C 1 -C 3 -alkyl)-(C 3 -C 7 -cycloalkyl) and C 3 -C 7 -cycloalkyl, wherein independently said C 1 -C 5 -alkyl, C 3 -C 7 -cycloalkyl and -(C 1 -C 3 -alkyl)-(C 3 -C 7 -cycloalkyl) are optionally substituted with one or more substituents independently selected from the group consisting of methyl, OH, OR 4< and F, R 3< represents H or F, in particular H, R 4< represents C 1 -C 5 -alkyl, optionally substituted with 1 to 5 fluorine atoms, R 5< represents H, F, Cl or methyl, in particular H or F, and R 6< and R 7< represent H.

[0169] A preferred embodiment of the present invention covers compounds of general formula (I), wherein R 1< represents pyrazol-4-yl substituted at a nitrogen atom with a substituent R 1b< selected from the group consisting of methyl, ethyl, propyl, propan-2-yl, 2-methylpropyl, cyclopropyl, tertbutyl, butan-2-yl, cyclobutyl, 2,2-dimethyl-propyl, 3-methylbutan-2-yl, cyclopentyl, cyclohexyl, 1-cyclopropylmethyl, 1-cyclopropylethyl, 1-cyclobutylmethyl, 1-(1-methylcyclopropyl)methyl and 2,2,2-trifluoroethyl, in particular ethyl, propan-2-yl, 2-methylpropyl, butan-2-yl, cyclobutyl, cyclopentyl, 2,2-dimethylpropyl, 1-cyclopropylmethyl, 1-cyclopropylethyl, 1-(1-methylcyclopropyl)methyl and 1-cyclobutylmethyl, R 3< represents H or F, in particular H, R 5< represents H, F, Cl or methyl, in particular H or F, and R 6< and R 7< represent H.

[0170] In accordance with another aspect, the present invention covers compounds of general formula (I), wherein R 1< represents thiazolyl, in particular thiazol-5-yl, optionally substituted at one or more carbon atoms with 1 or 2 substituents R 1a< which are the same or different wherein R 1a< represents C 1 -C 5 -alkyl, C 3 -C 7 -cycloalkyl, -(C 1 -C 3 -alkyl)-(C 3 -C 7 -cycloalkyl), -OC 1 -C 5 -alkyl, -OC 3 -C 7 -cycloalkyl, halogen or CN, wherein said C 1 -C 5 -alkyl,C 3 -C 7 -cycloalkyl, -(C 1 -C 3 -alkyl)-(C 3 -C 7 -cycloalkyl), -OC 1 -C 5 -alkyl and -OC 3 -C 7 -cycloalkyl independently are optionally substituted with one or more substituents independently selected from the group consisting of methyl, OH, OR 4< and F, R 3< represents H or F, in particular H, R 4< represents C 1 -C 5 -alkyl,optionally substituted with 1 to 5 fluorine atoms, R 5< represents H, F, Cl or methyl, in particular H or F, and R 6< and R 7< represent H.

[0171] A preferred embodiment of the present invention covers compounds of general formula (I), wherein R 1< represents thiazolyl, in particular thiazol-5-yl, substituted at one or more carbon atoms with 1 or 2 substituents R 1a< which are the same or different wherein R 1a< represents C 1 -C 5 -alkyl, C 3 -C 7 -cycloalkyl, -(C 1 -C 3 -alkyl)-(C 3 -C 7 -cycloalkyl), -OC 1 -C 5 -alkyl, -OC 3 -C 7 -cycloalkyl, halogen or CN, wherein one of said substituents R 1a< is preferably positioned meta to the carbon atom which links the thiazolyl, in particular thiazol-5-yl, to the rest of the molecule, and wherein said C 1 -C 5 -alkyl, C 3 -C 7 -cycloalkyl, -(C 1 -C 3 -alkyl)-(C 3 -C 7 -cycloalkyl), -OC 1 -C 5 -alkyl and -OC 3 -C 7 -cycloalkyl independently are optionally substituted with one or more substituents independently selected from the group consisting of methyl, OH, OR 4< and F, R 3< represents H or F, in particular H, R 4< represents C 1 -C 5 -alkyl, optionally substituted with 1 to 5 fluorine atoms, R 5< represents H, F, Cl or methyl, in particular H or F, and R 6< and R 7< represent H.

[0172] A preferred embodiment of the present invention covers compounds of general formula (I), wherein R 1< represents thiazol-5-yl, optionally substituted at a carbon atom with a substituent R 1a< wherein R 1a< represents C 1 -C 5 -alkyl, -(C 1 -C 3 -alkyl)-(C 3 -C 7 -cyclo-alkyl) or C 3 -C 7 -cycloalkyl, wherein the said substituent R 1a< is preferably attached to the carbon atom at position 2 of thiazol-5-yl, and wherein said C 1 -C 5 -alkyl, C 3 -C 7 -cycloalkyl and -(C 1 -C 3 -alkyl)-(C 3 -C 7 -cycloalkyl) independently are optionally substituted with one or more substituents independently selected from the group consisting of methyl, OH, OR 4< and F, R 3< represents H or F, in particular H, R 4< represents C 1 -C 5 -alkyl,optionally substituted with 1 to 5 fluorine atoms, R 5< represents H, F, Cl or methyl, in particular H or F, and R 6< and R 7< represent H.

[0173] A preferred embodiment of the present invention covers compounds of general formula (I), wherein R 1< represents thiazol-5-yl substituted at the carbon atom at position 2 with C 3 -C 7 -cycloalkyl, wherein said C 3 -C 7 -cycloalkyl is optionally substituted with one or more substituents independently selected from the group consisting of methyl, OH, OR 4< and F, R 3< represents H or F, in particular H, R 4< represents C 1 -C 5 -alkyl, optionally substituted with 1 to 5 fluorine atoms, R 5< represents H, F, Cl or methyl, in particular H or F, and R 6< and R 7< represent H.

[0174] A preferred embodiment of the present invention covers compounds of general formula (I), wherein R 1< represents thiazol-5-yl, substituted at the carbon atom at position 2 with a substituent selected from the group consisting of methyl, ethyl, propyl, propan-2-yl, 2-methylpropyl, cyclopropyl, tertbutyl, butan-2-yl, cyclobutyl, 2,2-dimethylpropyl, 3-methylbutan-2-yl, cyclopentyl, cyclohexyl, 1-cyclo-propylmethyl, 1-cyclopropylethyl, 1-cyclobutylmethyl, 1-(1-methyl-cyclopropyl)methyl and 2,2,2-trifluoroethyl, in particular ethyl, propan-2-yl, cyclopropyl, 2-methylpropyl, butan-2-yl, cyclobutyl, cyclopentyl, 2,2-dimethylpropyl, 1-cyclopropylmethyl, 1-cyclopropylethyl, 1-(1-methyl-cyclopropyl)methyl and 1-cyclobutylmethyl, R 3< represents H or F, in particular H, R 5< represents H, F, Cl or methyl, in particular H or F, and R 6< and R 7< represent H.

[0175] In accordance with another aspect, the present invention covers compounds of general formula (I), wherein R 1< represents thiazol-2-yl, optionally substituted at a carbon atom with a substituent R 1a< wherein R 1a< represents C 1 -C 5 -alkyl, -(C 1 -C 3 -alkyl)-(C 3 -C 7 -cyclo-alkyl) or C 3 -C 7 -cycloalkyl, wherein said substituent R 1a< is preferably attached to the carbon atom in the position 5 of thiazol-2-yl, and wherein said C 1 -C 5 -alkyl, C 3 -C 7 -cycloalkyl and -(C 1 -C 3 -alkyl)-(C 3 -C 7 -cycloalkyl) independently are optionally substituted with one or more substituents independently selected from the group consisting of methyl, OH, OR 4< and F, R 3< represents H or F, in particular H, R 4< represents C 1 -C 5 -alkyl,optionally substituted with 1 to 5 fluorine atoms, R 5< represents H, F, Cl or methyl, in particular H or F, and R 6< and R 7< represent H.

[0176] A preferred embodiment of the present invention covers compounds of general formula (I), wherein R 1< represents thiazol-2-yl substituted at the carbon atom in position 5 with C 3 -C 7 -cycloalkyl, and wherein said C 3 -C 7 -cycloalkyl is optionally substituted with one or more substituents independently selected from the group consisting of methyl, OH, OR 4< and F, R 3< represents H or F, in particular H, R 4< represents C 1 -C 5 -alkyl,optionally substituted with 1 to 5 fluorine atoms, R 5< represents H, F, Cl or methyl, in particular H or F, and R 6< and R 7< represent H.

[0177] A preferred embodiment of the present invention covers compounds of general formula (I), wherein R 1< represents thiazol-2-yl substituted at the carbon atom in position 5 with a substituent selected from the group consisting of methyl, ethyl, propyl, propan-2-yl, cyclopropyl, 2-methylpropyl, tertbutyl, butan-2-yl, cyclobutyl, 2,2-dimethylpropyl, 3-methylbutan-2-yl, cyclopentyl, cyclohexyl, 1-cyclo-propylmethyl, 1-cyclopropylethyl, 1-cyclobutylmethyl, 1-(1-methyl-cyclopropyl)methyl and 2,2,2-trifluoroethyl, in particular ethyl, propan-2-yl, cyclopropyl, 2-methylpropyl, butan-2-yl, cyclobutyl, cyclopentyl, 2,2-dimethylpropyl, 1-cyclopropylmethyl, 1-cyclopropylethyl, 1-(1-methyl-cyclopropyl)methyl and 1-cyclobutylmethyl, R 3< represents H or F, in particular H, R 5< represents H, F, Cl or methyl, in particular H or F, and R 6< and R 7< represent H.

[0178] In accordance with a further aspect, the present invention covers compounds of general formula (I), wherein R 2< represents • C 5 -C 7 -cycloalkyl, • phenyl, or • 6-membered heteroaryl containing 1 or 2 N, in particular pyridin-2-yl, wherein said R 2< is optionally substituted at one or more carbon atoms with 1 or 2 substituents R 2a< which are the same or different wherein R 2a< represents C 1 -C 5 -alkyl,C 3 -C 7 -cycloalkyl, OC 1 -C 5 -alkyl, halogen or CN, wherein said C 1 -C 5 -alkyl, -OC 1 -C 5 -alkyl and C 3 -C 7 -cycloalkyl independently are optionally substituted with OH, OR 4< or 1 to 5 fluorine atoms, R 3< represents H or F, in particular H, R 4< represents C 1 -C 5 -alkyl, optionally substituted with 1 to 5 fluorine atoms, R 5< represents H, F, Cl or methyl, in particular H or F, and R 6< and R 7< represent H.

[0179] A preferred embodiment of the invention relates to compounds of general formula (I), wherein R 2< represents phenyl optionally substituted at one or more carbon atoms with 1 or 2 substituents R 2a< which are the same or different wherein R 2a< represents C 1 -C 5 -alkyl, C 3 -C 7 -cycloalkyl, OC 1 -C 5 -alkyl, F and Cl, wherein said C 1 -C 5 -alkyl, -OC 1 -C 5 -alkyl or C 3 -C 7 -cycloalkyl are optionally substituted with 1 to 5 fluorine atoms, R 3< represents H or F, in particular H, R 5< represents H, F, Cl or methyl, in particular H or F, and R 6< and R 7< represent H.

[0180] A preferred embodiment of the invention relates to compounds of general formula (I), wherein R 2< represents phenyl substituted with 1 or 2 substituents R 2a< which are the same or different wherein R 2a< represents C 1 -C 5 -alkyl, OC 1 -C 5 -alkyl, F or Cl, and wherein if the substituent or at least one of said substituents is F, it is preferably positioned ortho to the carbon atom which links the phenyl to the rest of the molecule, and wherein said C 1 -C 5 -alkyl and -OC 1 -C 5 -alkyl independently are optionally substituted with 1 to 5 fluorine atoms, R 3< represents H or F, in particular H, R 5< represents H, F, Cl or methyl, in particular H or F, and R 6< and R 7< represent H.

[0181] A preferred embodiment of the invention relates to compounds of general formula (I), wherein R 2< represents phenyl substituted with 1 or 2 substituents R 2a< which are the same or different wherein R 2a< represents C 1 -C 5 -alkyl, OC 1 -C 5 -alkyl, F or Cl, and wherein if the substituent or at least one of said substituents is C 1 -C 5 -alkyl, -OC 1 -C 5 -alkyl or Cl, it is preferably positioned para to the carbon atom which links the phenyl to the rest of the molecule, and wherein said C 1 -C 5 -alkyl and -OC 1 -C 5 -alkyl independently are optionally substituted with 1 to 5 fluorine atoms, R 3< represents H or F, in particular H, R 5< represents H, F, Cl or methyl, in particular H or F, and R 6< and R 7< represent H.

[0182] A preferred embodiment of the invention relates to compounds of general formula (I), wherein R 2< represents phenyl substituted with 1 or 2 substituents R 2a< which are the same or different wherein R 2a< represents C 1 -C 5 -alkyl, OC 1 -C 5 -alkyl, F or Cl, and wherein if the substituent or at least one of said substituents is F, it is preferably positioned ortho to the carbon atom which links the phenyl to the rest of the molecule, and wherein if the substituent or at least one of said substituents is C 1 -C 5 -alkyl, -OC 1 -C 5 -alkyl or Cl, it is preferably positioned para to the carbon atom which links the phenyl to the rest of the molecule, and wherein said C 1 -C 5 -alkyl and -OC 1 -C 5 -alkyl independently are optionally substituted with 1 to 5 fluorine atoms, R 3< represents H or F, in particular H, R 5< represents H, F, Cl or methyl, in particular H or F, and R 6< and R 7< represent H.

[0183] A preferred embodiment of the invention relates to compounds of general formula (I), wherein R 2< represents phenyl substituted with 1 or 2 substituents R 2a< which are the same or different wherein R 2a< represents methyl, trifluoromethyl, trifluoromethoxy, F or Cl, and wherein if the substituent or at least one of said substituents is F, it is preferably positioned ortho to the carbon atom which links the phenyl to the rest of the molecule, and wherein if the substituent or at least one of said substituents is methyl, trifluoromethyl, trifluoromethoxy or Cl, it is preferably positioned para to the carbon atom which links the phenyl to the rest of the molecule, and R 3< represents H or F, in particular H, R 5< represents H, F, Cl or methyl, in particular H or F, and R 6< and R 7< represent H.

[0184] In accordance with a further aspect, the present invention covers compounds of general formula (I), wherein R 1< represents pyridinyl, in particular pyridin-3-yl, optionally substituted as defined in general formula (I) and, R 2< represents phenyl or pyridin-2-yl, in particular phenyl, wherein R 2< is optionally substituted as defined in general formula (I), R 3< represents H or F, in particular H, R 5< represents H, F, Cl or methyl, in particular H or F, and R 6< and R 7< represent H.

[0185] A preferred embodiment of the present invention covers compounds of general formula (I), wherein R 1< represents pyridinyl, in particular pyridin-3-yl, optionally substituted at one or more carbon atoms with 1 or 2 substituents R 1a< which are the same or different wherein R 1a< represents C 1 -C 5 -alkyl, C 3 -C 7 -cycloalkyl, -(C 1 -C 3 -alkyl)-(C 3 -C 7 -cycloalkyl), -OC 1 -C 5 -alkyl,-OC 3 -C 7 -cycloalkyl, halogen or CN, wherein the substituent or at least one of said substituents is preferably positioned para to the carbon atom which links the pyridinyl, in particular pyridin-3-yl, to the rest of the molecule, and wherein said C 1 -C 5 -alkyl, C 3 -C 7 -cycloalkyl, -(C 1 -C 3 -alkyl)-(C 3 -C 7 -cycloalkyl), -OC 1 -C 5 -alkyl and -OC 3 -C 7 -cycloalkyl independently are optionally substituted with one or more substituents independently selected from the group consisting of OH, OR 4< and F, R 2< represents phenyl optionally substituted with 1 or 2 substituents R 2a< which are the same or different wherein R 2a< represents C 1 -C 5 -alkyl, OC 1 -C 5 -alkyl, F or Cl, and wherein said C 1 -C 5 -alkyl and -OC 1 -C 5 -alkyl independently are optionally substituted with 1 to 5 fluorine atoms, R 3< represents H or F, in particular H, R 4< represents C 1 -C 5 -alkyl, optionally substituted with 1 to 5 fluorine atoms, R 5< represents H, F, Cl or methyl, in particular H or F, and R 6< and R 7< represent H.

[0186] A preferred embodiment of the present invention covers compounds of general formula (I), wherein R 1< represents pyridinyl, in particular pyridin-3-yl, optionally substituted at one or more carbon atoms with 1 or 2 substituents R 1a< which are the same or different wherein R 1a< represents C 1 -C 5 -alkyl, C 3 -C 7 -cycloalkyl, -(C 1 -C 3 -alkyl)-(C 3 -C 7 -cycloalkyl), -OC 1 -C 5 -alkyl,-OC 3 -C 7 -cycloalkyl, halogen or CN, wherein the substituent or at least one of said substituents is preferably positioned para to the carbon atom which links the pyridinyl, in particular pyridin-3-yl, to the rest of the molecule, and wherein said C 1 -C 5 -alkyl, C 3 -C 7 -cycloalkyl, -(C 1 -C 3 -alkyl)-(C 3 -C 7 -cycloalkyl), -OC 1 -C 5 -alkyl and -OC 3 -C 7 -cycloalkyl independently are optionally substituted with one or more substituents independently selected from the group consisting of OH, OR 4< and F, R 2< represents phenyl substituted with 1 or 2 substituents R 2a< which are the same or different wherein R 2a< represents C 1 -C 5 -alkyl, OC 1 -C 5 -alkyl, F or Cl, and wherein if the substituent or at least one of said substituents is F, it is preferably positioned ortho to the carbon atom which links the phenyl to the rest of the molecule, and wherein said C 1 -C 5 -alkyl and -OC 1 -C 5 -alkyl independently are optionally substituted with 1 to 5 fluorine atoms, R 3< represents H or F, in particular H, R 4< represents C 1 -C 5 -alkyl, optionally substituted with 1 to 5 fluorine atoms, R 5< represents H, F, Cl or methyl, in particular H or F, and R 6< and R 7< represent H.

[0187] A preferred embodiment of the present invention covers compounds of general formula (I), wherein R 1< represents pyridinyl, in particular pyridin-3-yl, optionally substituted at one or more carbon atoms with 1 or 2 substituents R 1a< which are the same or different wherein R 1a< represents C 1 -C 5 -alkyl, C 3 -C 7 -cycloalkyl, -(C 1 -C 3 -alkyl)-(C 3 -C 7 -cycloalkyl), -OC 1 -C 5 -alkyl, -OC 3 -C 7 -cycloalkyl, halogen or CN, wherein the substituent or at least one of said substituents is preferably positioned para to the carbon atom which links the pyridinyl, in particular pyridin-3-yl, to the rest of the molecule; and wherein said C 1 -C 5 -alkyl,C 3 -C 7 -cycloalkyl, -(C 1 -C 3 -alkyl)-(C 3 -C 7 -cycloalkyl), -OC 1 -C 5 -alkyl and -OC 3 -C 7 -cycloalkyl independently are optionally substituted with one or more substituents independently selected from the group consisting of OH, OR 4< and F, R 2< represents phenyl substituted with 1 or 2 substituents R 2a< which are the same or different wherein R 2a< represents C 1 -C 5 -alkyl, OC 1 -C 5 -alkyl, F or Cl, wherein if the substituent or at least one of said substituents is C 1 -C 5 -alkyl, -OC 1 -C 5 -alkyl or Cl, it is preferably positioned para to the carbon atom which links the phenyl to the rest of the molecule, and wherein said C 1 -C 5 -alkyl and -OC 1 -C 5 -alkyl independently are optionally substituted with 1 to 5 fluorine atoms, R 3< represents H or F, in particular H, R 4< represents C 1 -C 5 -alkyl, optionally substituted with 1 to 5 fluorine atoms, R 5< represents H, F, Cl or methyl, in particular H or F, and R 6< and R 7< represent H.

[0188] A preferred embodiment of the present invention covers compounds of general formula (I), wherein R 1< represents pyridinyl, in particular pyridin-3-yl, optionally substituted at one or more carbon atoms with 1 or 2 substituents R 1a< which are the same or different wherein R 1a< represents C 1 -C 5 -alkyl, C 3 -C 7 -cycloalkyl, -(C 1 -C 3 -alkyl)-(C 3 -C 7 -cycloalkyl), -OC 1 -C 5 -alkyl, -OC 3 -C 7 -cycloalkyl, halogen or CN, wherein one of said substituents is preferably positioned para to the carbon atom which links the pyridinyl, in particular pyridin-3-yl, to the rest of the molecule, and wherein said C 1 -C 5 -alkyl, C 3 -C 7 -cycloalkyl, -(C 1 -C 3 -alkyl)-(C 3 -C 7 -cycloalkyl), -OC 1 -C 5 -alkyl and -OC 3 -C 7 -cycloalkyl independently are optionally substituted with one or more substituents independently selected from the group consisting of OH, OR 4< and F, R 2< represents phenyl substituted with 2 substituents R 2a< which are the same or different wherein R 2a< represents C 1 -C 5 -alkyl, OC 1 -C 5 -alkyl, F and Cl, and wherein if the substituent or at least one of said substituents is F, it is preferably positioned ortho to the carbon atom which links the phenyl to the rest of the molecule, and wherein if the substituent or at least one of said substituents is C 1 -C 5 -alkyl, -OC 1 -C 5 -alkyl or Cl, it is preferably positioned para to the carbon atom which links the phenyl to the rest of the molecule, and wherein said C 1 -C 5 -alkyl and -OC 1 -C 5 -alkyl independently are optionally substituted with 1 to 5 fluorine atoms, R 3< represents H or F, in particular H, R 4< represents C 1 -C 5 -alkyl, optionally substituted with 1 to 5 fluorine atoms, R 5< represents H, F, Cl or methyl, in particular H or F, and R 6< and R 7< represent H.

[0189] A preferred embodiment of the present invention covers compounds of general formula (I), wherein R 1< represents pyridinyl, in particular pyridin-3-yl, substituted at one or more carbon atoms with 1 or 2 substituents R 1a< which are the same or different wherein R 1a< represents methyl, ethyl, methoxy, ethoxy, cyclobutyl, trifluoromethyl, difluoromethyl, 1,1-difluoroethyl, 1,1-difluoropropyl or 2,2,2-trifluoroethyl, and wherein the substituent or at least one of said substituents is preferably positioned para to the carbon atom which links the pyridinyl, in particular pyridin-3-yl, to the rest of the molecule, and R 2< represents phenyl substituted with 1 or 2 substituents R 1a< which are the same or different wherein R 1a< represents methyl, trifluoromethyl, trifluoromethoxy, F or Cl, and wherein if the substituent or at least one of said substituents is F, it is preferably positioned ortho to the carbon atom which links the phenyl to the rest of the molecule, and wherein if the substituent or at least one of said substituents is methyl, trifluoromethyl, trifluoromethoxy or Cl, it is preferably positioned para to the carbon atom which links the phenyl to the rest of the molecule, and R 3< represents H or F, in particular H, R 5< represents H, F, Cl or methyl, in particular H or F, and R 6< and R 7< represent H.

[0190] In accordance with a further aspect, the present invention covers compounds of general formula (I), wherein R 1< represents pyridinyl, in particular pyridin-2-yl, optionally substituted as defined in general formula (I), R 2< represents phenyl or pyridin-2-yl, in particular phenyl, optionally substituted as defined in general formula (I), R 3< represents H or F, in particular H, R 5< represents H, F, Cl or methyl, in particular H or F, and R 6< and R 7< represent H.

[0191] A preferred embodiment of the present invention covers compounds of general formula (I), wherein R 1< represents pyridinyl, in particular pyridin-2-yl, optionally substituted at one or more carbon atoms with 1 or 2 substituents R 1a< which are the same or different wherein R 1a< represents C 1 -C 5 -alkyl, C 3 -C 7 -cycloalkyl, -(C 1 -C 3 -alkyl)-(C 3 -C 7 -cycloalkyl), -OC 1 -C 5 -alkyl,-OC 3 -C 7 -cycloalkyl, halogen or CN, wherein the substituent or at least one of said substituents is preferably positioned para to the carbon atom which links the pyridinyl, in particular pyridin-2-yl, to the rest of the molecule, and wherein said C 1 -C 5 -alkyl, C 3 -C 7 -cycloalkyl, -(C 1 -C 3 -alkyl)-(C 3 -C 7 -cycloalkyl), -OC 1 -C 5 -alkyl and -OC 3 -C 7 -cycloalkyl independently are optionally substituted with one or more substituents independently selected from the group consisting of OH, OR 4< and F, R 2< represents phenyl substituted with 1 or 2 substituents R 2a< which are the same or different wherein R 2a< represents C 1 -C 5 -alkyl, OC 1 -C 5 -alkyl, F or Cl, wherein if the substituent or at least one of said substituents is C 1 -C 5 -alkyl, -OC 1 -C 5 -alkyl or Cl, it is preferably positioned para to the carbon atom which links the phenyl to the rest of the molecule, and wherein said C 1 -C 5 -alkyl and -OC 1 -C 5 -alkyl independently are optionally substituted with 1 to 5 fluorine atoms, R 3< represents H or F, in particular H, R 4< represents C 1 -C 5 -alkyl,optionally substituted with 1 to 5 fluorine atoms, R 5< represents H, F, Cl or methyl, in particular H or F, and R 6< and R 7< represent H.

[0192] A preferred embodiment of the present invention covers compounds of general formula (I), wherein R 1< represents pyridinyl, in particular pyridin-2-yl, optionally substituted at one or more carbon atoms with 1 or 2 substituents R 1a< which are the same or different wherein R 1a< represents C 1 -C 5 -alkyl, C 3 -C 7 -cycloalkyl, -(C 1 -C 3 -alkyl)-(C 3 -C 7 -cycloalkyl), -OC 1 -C 5 -alkyl, -OC 3 -C 7 -cycloalkyl, halogen or CN, wherein one of said substituents is preferably positioned para to the carbon atom which links the pyridinyl, in particular pyridin-2-yl, to the rest of the molecule, and wherein said C 1 -C 5 -alkyl, C 3 -C 7 -cycloalkyl, -(C 1 -C 3 -alkyl)-(C 3 -C 7 -cycloalkyl), -OC 1 -C 5 -alkyl and -OC 3 -C 7 -cycloalkyl independently are optionally substituted with one or more substituents independently selected from the group consisting of OH, OR 4< and F, R 2< represents phenyl substituted with 2 substituents R 2a< which are the same or different wherein R 2a< represents C 1 -C 5 -alkyl, OC 1 -C 5 -alkyl, F and Cl, and wherein if the substituent or at least one of said substituents is F, it is preferably positioned ortho to the carbon atom which links the phenyl to the rest of the molecule, and wherein if the substituent or at least one of said substituents is C 1 -C 5 -alkyl, -OC 1 -C 5 -alkyl or Cl, it is preferably positioned para to the carbon atom which links the phenyl to the rest of the molecule, and wherein said C 1 -C 5 -alkyl and -OC 1 -C 5 -alkyl independently are optionally substituted with 1 to 5 fluorine atoms, R 3< represents H or F, in particular H, R 4< represents C 1 -C 5 -alkyl,optionally substituted with 1 to 5 fluorine atoms, R 5< represents H, F, Cl or methyl, in particular H or F, and R 6< and R 7< represent H.

[0193] A preferred embodiment of the present invention covers compounds of general formula (I), wherein R 1< represents pyridinyl, in particular pyridin-2-yl, substituted at one or more carbon atoms with 1 or 2 substituents R 1a< which are the same or different wherein R 1a< represents methyl, ethyl, methoxy, ethoxy, cyclobutyl, trifluoromethyl, difluoromethyl, 1,1-difluoroethyl, 1,1-difluoropropyl or 2,2,2-trifluoroethyl, and wherein the substituent or at least one of said substituents is preferably positioned para to the carbon atom which links the pyridinyl, in particular pyridin-2-yl, to the rest of the molecule, and R 2< represents phenyl substituted with 1 or 2 substituents R 1a< which are the same or different wherein R 1a< represents methyl, trifluoromethyl, trifluoromethoxy, F or Cl, and wherein if the substituent or at least one of said substituents is F, it is preferably positioned ortho to the carbon atom which links the phenyl to the rest of the molecule, and wherein if the substituent or at least one of said substituents is methyl, trifluoromethyl, trifluoromethoxy or Cl, it is preferably positioned para to the carbon atom which links the phenyl to the rest of the molecule, and R 3< represents H or F, in particular H, R 5< represents H, F, Cl or methyl, in particular H or F, and R 6< and R 7< represent H.

[0194] A preferred embodiment of the present invention covers compounds of general formula (I), wherein R 1< represents 5-membered heteroaryl containing 1, 2 or 3 heteroatoms or heteroatom-containing groups independently selected from the group consisting of S, N, NH, and O,in particular pyrazolyl, thiazolyl, imidazolyl or thiophenyl, wherein R 1< is optionally substituted as defined in general formula (I) and, R 2< represents phenyl optionally substituted with 1 or 2 substituents R 2a< which are the same or different wherein R 2a< represents C 1 -C 5 -alkyl, OC 1 -C 5 -alkyl, F or Cl, and wherein said C 1 -C 5 -alkyl and -OC 1 -C 5 -alkyl are optionally substituted with 1 to 5 fluorine atoms, R 3< represents H or F, in particular H, R 5< represents H, F, Cl or methyl, in particular H or F, and R 6< and R 7< represent H.

[0195] A preferred embodiment of the present invention covers compounds of general formula (I), wherein R 1< represents 5-membered heteroaryl containing 1, 2 or 3 heteroatoms or heteroatom-containing groups independently selected from the group consisting of S, N, NH, and O,in particular pyrazolyl, thiazolyl, imidazolyl or thiophenyl, wherein R 1< is optionally substituted as defined in general formula (I) and, R 2< represents phenyl substituted with 1 or 2 substituents R 2a< which are the same or different wherein R 2a< represents C 1 -C 5 -alkyl, OC 1 -C 5 -alkyl, F or Cl, and wherein if the substituent or at least one of said substituents is F, it is preferably positioned ortho to the carbon atom which links the phenyl to the rest of the molecule, and wherein said C 1 -C 5 -alkyl and -OC 1 -C 5 -alkyl independently are optionally substituted with 1 to 5 fluorine atoms, R 3< represents H or F, in particular H, R 5< represents H, F, Cl or methyl, in particular H or F, and R 6< and R 7< represent H.

[0196] A preferred embodiment of the present invention covers compounds of general formula (I), wherein R 1< represents 5-membered heteroaryl containing 1, 2 or 3 heteroatoms or heteroatom-containing groups independently selected from the group consisting of S, N, NH, and O, in particular pyrazolyl, thiazolyl, imidazolyl or thiophenyl, wherein R 1< is optionally substituted as defined in general formula (I) and, R 2< represents phenyl substituted with 1 or 2 substituents R 2a< which are the same or different wherein R 2a< represents C 1 -C 5 -alkyl, OC 1 -C 5 -alkyl, F or Cl, wherein if the substituent or at least one of said substituents is C 1 -C 5 -alkyl, -OC 1 -C 5 -alkyl or Cl, it is preferably positioned para to the carbon atom which links the phenyl to the rest of the molecule, and wherein said C 1 -C 5 -alkyl and -OC 1 -C 5 -alkyl independently are optionally substituted with 1 to 5 fluorine atoms, R 3< represents H or F, in particular H, R 5< represents H, F, Cl or methyl, in particular H or F, and R 6< and R 7< represent H.

[0197] A preferred embodiment of the present invention covers compounds of general formula (I), wherein R 1< represents 5-membered heteroaryl containing 1, 2 or 3 heteroatoms or heteroatom-containing groups independently selected from the group consisting of S, N, NH, and O, in particular pyrazolyl, thiazolyl, imidazolyl or thiophenyl, wherein R 1< is optionally substituted as defined in general formula (I) and, R 2< represents phenyl substituted with 2 substituents R 2a< which are the same or different wherein R 2a< representsC 1 -C 5 -alkyl, OC 1 -C 5 -alkyl, F or Cl, and wherein if the substituent or at least one of said substituents is F, it is preferably positioned ortho to the carbon atom which links the phenyl to the rest of the molecule, and wherein if the substituent or at least one of said substituents is C 1 -C 5 -alkyl, -OC 1 -C 5 -alkyl or Cl, it is preferably positioned para to the carbon atom which links the phenyl to the rest of the molecule, and wherein said C 1 -C 5 -alkyl and -OC 1 -C 5 -alkyl independently are optionally substituted with 1 to 5 fluorine atoms, R 3< represents H or F, in particular H, R 5< represents H, F, Cl or methyl, in particular H or F, and R 6< and R 7< represent H.

[0198] A preferred embodiment of the present invention covers compounds of general formula (I), wherein R 1< represents 5-membered heteroaryl containing 1, 2 or 3 heteroatoms or heteroatom-containing groups independently selected from the group consisting of S, N, NH, and O, in particular pyrazolyl, thiazolyl, imidazolyl or thiophenyl, wherein R 1< is optionally substituted as defined in general formula (I) and, R 2< represents phenyl substituted with 1 or 2 substituents R 2a< which are the same or different wherein R 2a< represents methyl, trifluoromethyl, trifluoromethoxy, F or Cl, and wherein if the substituent or at least one of said substituents is F, it is preferably positioned ortho to the carbon atom which links the phenyl to the rest of the molecule, and wherein if the substituent or at least one of said substituents is methyl, trifluoromethyl, trifluoromethoxy or Cl, it is preferably positioned para to the carbon atom which links the phenyl to the rest of the molecule, and R 3< represents H or F, in particular H, R 5< represents H, F, Cl or methyl, in particular H or F, and R 6< and R 7< represent H.

[0199] A preferred embodiment of the present invention covers compounds of general formula (I), wherein R 1< represents pyrazolyl, in particular pyrazol-4-yl, substituted at one or more carbon atoms with 1 or 2 substituents R 1a< which are the same or different wherein R 1a< represents C 1 -C 5 -alkyl, C 3 -C 7 -cycloalkyl, -(C 1 -C 3 -alkyl)-(C 3 -C 7 -cycloalkyl), -OC 1 -C 5 -alkyl, -OC 3 -C 7 -cycloalkyl, halogen or CN, and wherein independently each nitrogen atom of said R 1< is optionally substituted with a substituent R 1b< which are the same or different wherein R 1b< represents C 1 -C 5 -alkyl, -(C 1 -C 3 -alkyl)-(C 3 -C 7 -cycloalkyl) or C 3 -C 7 -cyclo-alkyl, and if R 1a< represents C 1 -C 5 -alkyl, C 3 -C 7 -cycloalkyl, -(C 1- C 3 -alkyl)-(C 3 -cyclo-alkyl), -OC 1 -C 5 -alkyl or -OC 3 -C 7 -cycloalkyl and / or if R 1b< represents C 1 -C 5 -alkyl, -(C 1 -C 3 -alkyl)-(C 3 -C 7 -cycloalkyl) or C 3 -C 7 -cycloalkyl, said C 1 -C 5 -alkyl, C 3 -C 7 -cycloalkyl, -(C 1 -C 3 -alkyl)-(C 3 -C 7 -cycloalkyl), -OC 1 -C 5 -alkyl and OC 3 -C 7 -cycloalkyl independently are optionally substituted with one or more substituents independently selected from the group consisting of methyl, OH, OR 4< and F, and R 2< represents phenyl optionally substituted with 1 or 2 substituents R 2a< which are the same or different wherein R 2a< represents C 1 -C 5 -alkyl, OC 1 -C 5 -alkyl, F or Cl, and wherein said C 1 -C 5 -alkyl and -OC 1 -C 5 -alkyl independently are optionally substituted with 1 to 5 fluorine atoms, R 3< represents H or F, in particular H, R 4< represents C 1 -C 5 -alkyl, optionally substituted with 1 to 5 fluorine atoms, R 5< represents H, F, Cl or methyl, in particular H or F, and R 6< and R 7< represent H.

[0200] A preferred embodiment of the present invention covers compounds of general formula (I), wherein R 1< represents pyrazolyl, in particular pyrazol-4-yl, optionally substituted at one or more carbon atoms with 1 or 2 substituents R 1a< which are the same or different wherein R 1a< represents C 1 -C 5 -alkyl, C 3 -C 7 -cycloalkyl, -(C 1 -C 3 -alkyl)-(C 3 -C 7 -cycloalkyl), -OC 1 -C 5 -alkyl, -OC 3 -C 7 -cycloalkyl, halogen or CN, and wherein independently each nitrogen atom of said R 1< is optionally substituted with a substituent R 1b< which are the same or different wherein R 1b< represents C 1 -C 5 -alkyl, -(C 1 -C 3 -alkyl)-(C 3 -C 7 -cycloalkyl) or C 3 -C 7 -cycloalkyl, and if R 1a< represents C 1 -C 5 -alkyl, C 3 -C 7 -cycloalkyl, -(C 1- C 3 -alkyl)-(C 3 -C 7 -cyclo-alkyl), -OC 1 -C 5 -alkyl or -OC 3 -C 7 -cycloalkyl and / or if R 1b< represents C 1 -C 5 -alkyl, -(C 1 -C 3 -alkyl)-(C 3 -C 7 -cycloalkyl) or C 3 -C 7 -cycloalkyl, said C 1 -C 5 -alkyl, C 3 -C 7 -cycloalkyl, -(C 1 -C 3 -alkyl)-(C 3 -C 7 -cycloalkyl), -OC 1 -C 5 -alkyl and OC 3 -C 7 -cycloalkyl independently are optionally substituted with one or more substituents independently selected from the group consisting of methyl, OH, OR 4< and F, and R 2< represents phenyl substituted with 1 or 2 substituents R 2a< which are the same or different wherein R 2a< C 1 -C 5 -alkyl, OC 1 -C 5 -alkyl, F or Cl, and wherein if the substituent or at least one of said substituents is F, it is preferably positioned ortho to the carbon atom which links the phenyl to the rest of the molecule, and wherein said C 1 -C 5 -alkyl and -OC 1 -C 5 -alkyl independently are optionally substituted with 1 to 5 fluorine atoms, R 3< represents H or F, in particular H, R 4< represents C 1 -C 5 -alkyl, optionally substituted with 1 to 5 fluorine atoms, R 5< represents H, F, Cl or methyl, in particular H or F, and R 6< and R 7< represent H.

[0201] A preferred embodiment of the present invention covers compounds of general formula (I), wherein R 1< represents pyrazolyl, in particular pyrazol-4-yl, optionally substituted at one or more carbon atoms with 1 or 2 substituents R 1a< which are the same or different wherein R 1a< represents C 1 -C 5 -alkyl, C 3 -C 7 -cycloalkyl, -(C 1 -C 3 -alkyl)-(C 3 -C 7 -cycloalkyl), -OC 1 -C 5 -alkyl, -OC 3 -C 7 -cycloalkyl, halogen or CN, and wherein independently each nitrogen atom of said R 1< is optionally substituted with a substituent R 1b< which are the same or different wherein R 1b< represents C 1 -C 5 -alkyl, -(C 1 -C 3 -alkyl)-(C 3 -C 7 -cycloalkyl) or C 3 -C 7 -cycloalkyl, if R 1a< represents C 1 -C 5 -alkyl, C 3 -C 7 -cycloalkyl, -(C 1 -C 3 -alkyl)-(C 3 -C 7 -cycloalkyl), -OC 1 -C 5 -alkyl or -OC 3 -C 7 -cycloalkyl and / or if R 1b< represents C 1 -C 5 -alkyl, -(C 1 -C 3 -alkyl)-(C 3 -C 7 -cycloalkyl) or C 3 -C 7 -cycloalkyl, said C 1 -C 5 -alkyl, C 3 -C 7 -cycloalkyl, -(C 1 -C 3 -alkyl)-(C 3 -C 7 -cycloalkyl), -OC 1 -C 5 -alkyl and OC 3 -C 7 -cycloalkyl independently are optionally substituted with one or more substituents independently selected from the group consisting of methyl, OH, OR 4< and F, and R 2< represents phenyl substituted with 1 or 2 substituents R 2a< which are the same or different wherein R 2a< represents C 1 -C 5 -alkyl, OC 1 -C 5 -alkyl, F or Cl, wherein if the substituent or at least one of said substituents is C 1 -C 5 -alkyl, -OC 1 -C 5 -alkyl or Cl, it is preferably positioned para to the carbon atom which links the phenyl to the rest of the molecule, and wherein said C 1 -C 5 -alkyl and -OC 1 -C 5 -alkyl independently are optionally substituted with 1 to 5 fluorine atoms, R 3< represents H or F, in particular H, R 4< represents C 1 -C 5 -alkyl, optionally substituted with 1 to 5 fluorine atoms, R 5< represents H, F, Cl or methyl, in particular H or F, and R 6< and R 7< represent H.

[0202] A preferred embodiment of the present invention covers compounds of general formula (I), wherein R 1< represents pyrazolyl, in particular pyrazol-4-yl, optionally substituted at one or more carbon atoms with 1 or 2 substituents R 1a< which are the same or different wherein R 1a< represents C 1 -C 5 -alkyl, C 3 -C 7 -cycloalkyl, -(C 1 -C 3 -alkyl)-(C 3 -C 7 -cycloalkyl), -OC 1 -C 5 -alkyl, -OC 3 -C 7 -cycloalkyl, halogen or CN, and wherein independently each nitrogen atom of said R 1< is optionally substituted with a substituent R 1b< which are the same or different wherein R 1b< represents C 1 -C 5 -alkyl, -(C 1 -C 3 -alkyl)-(C 3 -C 7 -cycloalkyl) or C 3 -C 7 -cycloalkyl, if R 1a< represents C 1 -C 5 -alkyl, C 3 -C 7 -cycloalkyl, (C 1 -C 3 -alkyl)-(C 3 -C 7 -cycloalkyl), -OC 1 -C 5 -alkyl or -OC 3 -C 7 -cycloalkyl and / or if R 1b< represents C 1 -C 5 -alkyl, -(C 1 -C 3 -alkyl)-(C 3 -C 7 -cycloalkyl) or C 3 -C 7 -cycloalkyl, said C 1 -C 5 -alkyl, C 3 -C 7 -cycloalkyl, -(C 1 -C 3 -alkyl)-(C 3 -C 7 -cycloalkyl), -OC 1 -C 5 -alkyl and OC 3 -C 7 -cycloalkyl independently are optionally substituted with one or more substituents independently selected from the group consisting of methyl, OH, OR 4< and F, and R 2< represents phenyl substituted with 2 substituents R 2a< which are the same or different wherein R 2a< represents C 1 -C 5 -alkyl, OC 1 -C 5 -alkyl, F or Cl, and wherein if the substituent or at least one of said substituents is F, it is preferably positioned ortho to the carbon atom which links the phenyl to the rest of the molecule, and wherein if the substituent or at least one of said substituents is C 1 -C 5 -alkyl, -OC 1 -C 5 -alkyl or Cl, it is preferably positioned para to the carbon atom which links the phenyl to the rest of the molecule, and wherein said C 1 -C 5 -alkyl and -OC 1 -C 5 -alkyl independently are optionally substituted with 1 to 5 fluorine atoms, R 3< represents H or F, in particular H, R 4< represents C 1 -C 5 -alkyl, optionally substituted with 1 to 5 fluorine atoms, R 5< represents H, F, Cl or methyl, in particular H or F, and R 6< and R 7< represent H.

[0203] A preferred embodiment of the present invention covers compounds of general formula (I), wherein R 1< represents pyrazolyl, in particular pyrazol-4-yl, optionally substituted at one or more carbon atoms with 1 or 2 substituents R 1a< which are the same or different wherein R 1a< represents C 1 -C 5 -alkyl, C 3 -C 7 -cycloalkyl, -(C 1 -C 3 -alkyl)-(C 3 -C 7 -cycloalkyl), -OC 1 -C 5 -alkyl, -OC 3 -C 7 -cycloalkyl, halogen or CN, and wherein independently each nitrogen atom of said R 1< is optionally substituted with a substituent R 1b< which are the same or different wherein R 1b< represents C 1 -C 5 -alkyl, -(C 1 -C 3 -alkyl)-(C 3 -C 7 -cycloalkyl) or C 3 -C 7 -cycloalkyl, if R 1a< represents C 1 -C 5 -alkyl, C 3 -C 7 -cycloalkyl, (C 1 -C 3 -alkyl)-(C 3 -C 7 -cycloalkyl), -OC 1 -C 5 -alkyl or -OC 3 -C 7 -cycloalkyl and / or if R 1b< represents C 1 -C 5 -alkyl, -(C 1 -C 3 -alkyl)-(C 3 -C 7 -cycloalkyl) or C 3 -C 7 -cycloalkyl, said C 1 -C 5 -alkyl, C 3 -C 7 -cycloalkyl, -(C 1 -C 3 -alkyl)-(C 3 -C 7 -cycloalkyl), -OC 1 -C 5 -alkyl and OC 3 -C 7 -cycloalkyl independently are optionally substituted with one or more substituents independently selected from the group consisting of methyl, OH, OR 4< and F, and R 2< represents phenyl substituted with 1 or 2 substituents R 2a< which are the same or different wherein R 2a< represents methyl, trifluoromethyl, trifluoromethoxy, F or Cl, and wherein if the substituent or at least if one of said substituents is F, it is preferably positioned ortho to the carbon atom which links the phenyl to the rest of the molecule, and wherein if the substituent or at least one of said substituents is methyl, trifluoromethyl, trifluoromethoxy or Cl, it is preferably positioned para to the carbon atom which links the phenyl to the rest of the molecule, R 3< represents H or F, in particular H, R 4< represents C 1 -C 5 -alkyl, optionally substituted with 1 to 5 fluorine atoms, R 5< represents H, F, Cl or methyl, in particular H or F, and R 6< and R 7< represent H.

[0204] A preferred embodiment of the present invention covers compounds of general formula (I), wherein R 1< represents pyrazol-4-yl optionally substituted at a nitrogen atom with a substituent R 1b< selected from the group consisting of C 1 -C 5 -alkyl, -(C 1 -C 3 -alkyl)-(C 3 -C 7 -cycloalkyl) and C 3 -C 7 -cycloalkyl, wherein said C 1 -C 5 -alkyl, C 3 -C 7 -cycloalkyl and -(C 1 -C 3 -alkyl)-(C 3 -C 7 -cycloalkyl) independently are optionally substituted with one or more substituents independently selected from the group consisting of methyl, OH, OR 4< and F, R 2< represents phenyl substituted with 1 or 2 substituents R 2a< which are the same or different wherein R 2a< represents methyl, trifluoromethyl, trifluoromethoxy, F or Cl, and wherein if the substituent or at least one of said substituents is F, it is preferably positioned ortho to the carbon atom which links the phenyl to the rest of the molecule, and wherein if the substituent or at least one of said substituents is methyl, trifluoromethyl, trifluoromethoxy or Cl, it is preferably positioned para to the carbon atom which links the phenyl to the rest of the molecule, and R 3< represents H or F, in particular H, R 4< represents C 1 -C 5 -alkyl, optionally substituted with 1 to 5 fluorine atoms, R 5< represents H, F, Cl or methyl, in particular H or F, and R 6< and R 7< represent H.

[0205] A preferred embodiment of the present invention covers compounds of general formula (I), wherein R 1< represents pyrazol-4-yl substituted at a nitrogen atom with a substituent R 1b< selected from the group consisting of methyl, ethyl, propyl, propan-2-yl, cyclopropyl, 2-methylpropyl, tertbutyl, butan-2-yl, cyclobutyl, 2,2-dimethyl-propyl, 3-methylbutan-2-yl, cyclopentyl, cyclohexyl, 1-cyclopropylmethyl, 1-cyclopropylethyl, 1-cyclobutylmethyl, 1-(1-methylcyclopropyl)methyl and 2,2,2-trifluoroethyl, in particular ethyl, propan-2-yl, 2-methylpropyl, butan-2-yl, cyclobutyl, cyclopentyl, 2,2-dimethylpropyl, 1-cyclopropylmethyl, 1-cyclopropylethyl, 1-(1-methylcyclopropyl)methyl or 1-cyclobutylmethyl, R 2< represents phenyl substituted with 1 or 2 substituents R 2a< which are the same or different wherein R 2a< represents methyl, trifluoromethyl, trifluoromethoxy, F or Cl, and wherein if the substituent or at least one of said substituents is F, it is preferably positioned ortho to the carbon atom which links the phenyl to the rest of the molecule, and wherein if the substituent or at least one of said substituents is methyl, trifluoromethyl, trifluoromethoxy or Cl, it is preferably positioned para to the carbon atom which links the phenyl to the rest of the molecule, and R 3< represents H or F, in particular H, R 5< represents H, F, Cl or methyl, in particular H or F, and R 6< and R 7< represent H.

[0206] A preferred embodiment of the present invention covers compounds of general formula (I), wherein R 1< represents pyrazol-4-yl substituted at the nitrogen atom at position 1 with a substituent R 1b< selected from the group consisting of methyl, ethyl, propyl, propan-2-yl, cyclopropyl, 2-methylpropyl, tertbutyl, butan-2-yl, cyclobutyl, 2,2-dimethylpropyl, 3-methylbutan-2-yl, cyclopentyl, cyclohexyl, 1-cyclo-propylmethyl, 1-cyclopropylethyl, 1-cyclobutylmethyl, 1-(1-methyl-cyclopropyl)methyl and 2,2,2-trifluoroethyl, in particular ethyl, propan-2-yl, 2-methylpropyl, butan-2-yl, cyclobutyl, cyclopentyl, 2,2-dimethylpropyl, 1-cyclopropylmethyl, 1-cyclopropylethyl, 1-(1-methylcyclopropyl)methyl or 1-cyclobutylmethyl, R 2< represents phenyl substituted with 1 or 2 substituents R 2a< which are the same or different wherein R 2a< represents methyl, trifluoromethyl, trifluoromethoxy, F or Cl, and wherein if the substituent or at least one of said substituents is F, it is preferably positioned ortho to the carbon atom which links the phenyl to the rest of the molecule, and wherein if the substituent or at least one of said substituents is methyl, trifluoromethyl, trifluoromethoxy or Cl, it is preferably positioned para to the carbon atom which links the phenyl to the rest of the molecule, and R 3< represents H, R 5< represents H, and R 6< and R 7< represent H.

[0207] A preferred embodiment of the present invention covers compounds of general formula (I), wherein R 1< represents pyrazol-4-yl substituted at the nitrogen atom at position 1 with a substituent R 1b< selected from the group consisting of methyl, ethyl, propyl, propan-2-yl, cyclopropyl, 2-methylpropyl, tertbutyl, butan-2-yl, cyclobutyl, 2,2-dimethylpropyl, 3-methylbutan-2-yl, cyclopentyl, cyclohexyl, 1-cyclo-propylmethyl, 1-cyclopropylethyl, 1-cyclobutylmethyl, 1-(1-methyl-cyclopropyl)methyl and 2,2,2-trifluoroethyl, in particular ethyl, propan-2-yl, 2-methylpropyl, butan-2-yl, cyclobutyl, cyclopentyl, 2,2-dimethylpropyl, 1-cyclopropylmethyl, 1-cyclopropylethyl, 1-(1-methylcyclopropyl)methyl or 1-cyclobutylmethyl, R 2< represents phenyl substituted with 1 or 2 substituents R 2a< which are the same or different wherein R 2a< represents methyl, trifluoromethyl, trifluoromethoxy, F or Cl, and wherein if the substituent or at least one of said substituents is F, it is preferably positioned ortho to the carbon atom which links the phenyl to the rest of the molecule, and wherein if the substituent or at least one of said substituents is methyl, trifluoromethyl, trifluoromethoxy or Cl, it is preferably positioned para to the carbon atom which links the phenyl to the rest of the molecule, and R 3< represents H, R 5< represents F, and R 6< and R 7< represent H.

[0208] A preferred embodiment of the present invention covers compounds of general formula (I), wherein R 1< represents pyrazol-4-yl substituted at a nitrogen atom with a substituent R 1b< selected from the group consisting of C 1 -C 5 -alkyl, -(C 1 -C 3 -alkyl)-(C 3 -C 7 cycloalkyl) and C 3 -C 7 -cycloalkyl, wherein said C 1 -C 5 -alkyl, C 3 -C 7 -cycloalkyl and -(C 1 -C 3 -alkyl)-(C 3 -C 7 -cycloalkyl) independently are optionally substituted with one or more substituents independently selected from the group consisting of OH, OR 4< and F, R 2< represents C 5 -C 7 -cycloalkyl optionally substituted with 1 or 2 substituents R 2a< which are the same or different wherein R 2a< represents C 1 -C 5 -alkyl, OC 1 -C 5 -alkyl, F or Cl, and wherein said C 1 -C 5 -alkyl and -OC 1 -C 5 -alkyl independently are optionally substituted with 1 to 5 fluorine atoms, R 3< represents H or F, in particular H, R 4< represents C 1 -C 5 -alkyl, optionally substituted with 1 to 5 fluorine atoms, R 5< represents H, F, Cl or methyl, in particular H or F, and R 6< and R 7< represent H.

[0209] In accordance with another aspect, the present invention covers compounds of general formula (I), wherein R 1< represents thiazolyl, in particular thiazol-5-yl, optionally substituted at one or more carbon atoms with 1 or 2 substituents R 1a< which are the same or different wherein R 1a< represents C 1 -C 5 -alkyl, C 3 -C 7 -cycloalkyl, -(C 1 -C 3 -alkyl)-(C 3 -C 7 -cycloalkyl), -OC 1 -C 5 -alkyl, -OC 3 -C 7 -cycloalkyl, halogen or CN, wherein said C 1 -C 5 -alkyl, C 3 -C 7 -cycloalkyl, -(C 1 -C 3 -alkyl)-(C 3 -C 7 -cycloalkyl), -OC 1 -C 5 -alkyl and -OC 3 -C 7 -cycloalkyl independently are optionally substituted with one or more substituents independently selected from the group consisting of methyl, OH, OR 4< and F, R 2< represents phenyl optionally substituted with 1 or 2 substituents R 2a< which are the same or different wherein R 2a< represents C 1 -C 5 -alkyl, OC 1 -C 5 -alkyl, F or Cl, and wherein said C 1 -C 5 -alkyl and -OC 1 -C 5 -alkyl independently are optionally substituted with 1 to 5 fluorine atoms, R 3< represents H or F, in particular H, R 4< represents C 1 -C 5 -alkyl, optionally substituted with 1 to 5 fluorine atoms, R 5< represents H, F, Cl or methyl, in particular H or F, and R 6< and R 7< represent H.

[0210] A preferred embodiment of the present invention covers compounds of general formula (I), wherein R 1< represents thiazolyl, in particular thiazol-5-yl, optionally substituted at one or more carbon atoms with 1 or 2 substituents R 1a< which are the same or different wherein R 1a< represents C 1 -C 5 -alkyl, C 3 -C 7 -cycloalkyl, -(C 1 -C 3 -alkyl)-(C 3 -C 7 -cycloalkyl), -OC 1 -C 5 -alkyl, -OC 3 -C 7 -cycloalkyl, halogen or CN, wherein the substituent or at least one of said substituents is preferably positioned meta to the carbon atom which links the thiazolyl, in particular thiazol-5-yl, to the rest of the molecule; and wherein said C 1 -C 5 -alkyl, C 3 -C 7 -cycloalkyl, -(C 1 -C 3 -alkyl)-(C 3 -Cycloalkyl), -OC 1 -C 5 -alkyl and -OC 3 -C 7 -cycloalkyl independently are optionally substituted with one or more substituents independently selected from the group consisting of methyl, OH, OR 4< and F, and R 2< represents phenyl substituted with 1 or 2 substituents R 2a< which are the same or different wherein R 2a< represents C 1 -C 5 -alkyl, OC 1 -C 5 -alkyl, F or Cl, and wherein if the substituent or at least one of said substituents is F, it is preferably positioned ortho to the carbon atom which links the phenyl to the rest of the molecule, and wherein said C 1 -C 5 -alkyl and -OC 1 -C 5 -alkyl independently are optionally substituted with 1 to 5 fluorine atoms, R 3< represents H or F, in particular H, R 4< represents C 1 -C 5 -alkyl, optionally substituted with 1 to 5 fluorine atoms, R 5< represents H, F, Cl or methyl, in particular H or F, and R 6< and R 7< represent H.

[0211] A preferred embodiment of the present invention covers compounds of general formula (I), wherein R 1< represents thiazol-5-yl, wherein said R 1< is substituted at a carbon atom with a substituent R 1a< selected from the group consisting of C 1 -C 5 -alkyl, -(C 1 -C 3 -alkyl)-(C 3 -C 7 -cycloalkyl) and C 3 -C 7 -cycloalkyl, wherein said substituent R 1a< is preferably attached to the carbon atom at position 2 of thiazol-5-yl; and wherein said C 1 -C 5 -alkyl, C 3 -C 7 -cycloalkyl and -(C 1 -C 3 -alkyl)-(C 3 -C 7 -cycloalkyl) independently are optionally substituted with one or more substituents independently selected from the group consisting of methyl, OH, OR 4< and F, R 2< represents phenyl substituted with 1 or 2 substituents R 2a< which are the same or different wherein R 2a< represents C 1 -C 5 -alkyl, OC 1 -C 5 -alkyl, F or Cl, wherein if the substituent or at least one of said substituents is C 1 -C 5 -alkyl, -OC 1 -C 5 -alkyl or Cl, it is preferably positioned para to the carbon atom which links the phenyl to the rest of the molecule, and wherein said C 1 -C 5 -alkyl and -OC 1 -C 5 -alkyl independently are optionally substituted with 1 to 5 fluorine atoms, R 3< represents H or F, in particular H, R 4< represents C 1 -C 5 -alkyl, optionally substituted with 1 to 5 fluorine atoms, R 5< represents H, F, Cl or methyl, in particular H or F, and R 6< and R 7< represent H.

[0212] A preferred embodiment of the present invention covers compounds of general formula (I), wherein R 1< represents thiazol-5-yl substituted at the carbon atom at position 2 with C 3 -C 7 -cycloalkyl, wherein said C 3 -C 7 -cycloalkyl independently is optionally substituted with one or more substituents independently selected from the group consisting of methyl, OH, OR 4< and F, R 2< represents phenyl substituted with 1 or 2 substituents R 2a< which are the same or different wherein R 2a< represents methyl, trifluoromethyl, trifluoromethoxy, F or Cl, and wherein if the substituent or at least one of said substituents is F, it is preferably positioned ortho to the carbon atom which links the phenyl to the rest of the molecule, and wherein if the substituent or at least one of said substituents is methyl, trifluoromethyl, trifluoromethoxy or Cl, it is preferably positioned para to the carbon atom which links the phenyl to the rest of the molecule, and R 3< represents H or F, in particular H, R 4< represents C 1 -C 5 -alkyl, optionally substituted with 1 to 5 fluorine atoms, R 5< represents H, F, Cl or methyl, in particular H or F, and R 6< and R 7< represent H.

[0213] A preferred embodiment of the present invention covers compounds of general formula (I), wherein R 1< represents thiazol-5-yl, optionally substituted at the carbon atom at position 2 with a substituent R 1a< selected from the group consisting of methyl, ethyl, propyl, propan-2-yl, cyclopropyl, 2-methylpropyl, tertbutyl, butan-2-yl, cyclobutyl, 2,2-dimethylpropyl, 3-methylbutan-2-yl, cyclopentyl, cyclohexyl, 1-cyclopropylmethyl, 1-cyclopropylethyl, 1-cyclobutylmethyl, 1-(1-methyl-cyclopropyl)methyl and 2,2,2-trifluoroethyl, in particular ethyl, propan-2-yl, cyclopropyl, 2-methylpropyl, butan-2-yl, cyclobutyl, 2,2-dimethylpropyl, cyclopentyl, 1-cyclopropylmethyl, 1-cyclopropylethyl, 1-(1-methylcyclo-propyl)methyl and 1-cyclobutylmethyl, R 2< represents phenyl substituted with 1 or 2 substituents R 2a< which are the same or different wherein R 2a< represents methyl, trifluoromethyl, trifluoromethoxy, F or Cl, and wherein if the substituent or at least one of said substituents is F, it is preferably positioned ortho to the carbon atom which links the phenyl to the rest of the molecule, and wherein if the substituent or at least one of said substituents is methyl, trifluoromethyl, trifluoromethoxy or Cl, it is preferably positioned para to the carbon atom which links the phenyl to the rest of the molecule, R 3< represents H or F, in particular H, R 5< represents H, F, Cl or methyl, in particular H or F, and R 6< and R 7< represent H.

[0214] A preferred embodiment of the present invention covers compounds of general formula (I), wherein R 1< represents thiazol-5-yl, optionally substituted at the carbon atom at position 2 with a substituent R 1a< selected from the group consisting of methyl, ethyl, propyl, propan-2-yl, cyclopropyl, 2-methylpropyl, tertbutyl, butan-2-yl, cyclobutyl, 2,2-dimethylpropyl, 3-methylbutan-2-yl, cyclopentyl, cyclohexyl, 1-cyclopropylmethyl, 1-cyclopropylethyl, 1-cyclobutylmethyl, 1-(1-methyl-cyclopropyl)methyl and 2,2,2-trifluoroethyl, in particular ethyl, propan-2-yl, cyclopropyl, 2-methylpropyl, butan-2-yl, cyclobutyl, 2,2-dimethylpropyl, cyclopentyl, 1-cyclopropylmethyl, 1-cyclopropylethyl, 1-(1-methylcyclo-propyl)methyl and 1-cyclobutylmethyl, R 2< represents phenyl substituted with 1 or 2 substituents R 2a< which are the same or different wherein R 2a< represents methyl, trifluoromethyl, trifluoromethoxy, F or Cl, and wherein if the substituent or at least one of said substituents is F, it is preferably positioned ortho to the carbon atom which links the phenyl to the rest of the molecule, and wherein if the substituent or at least one of said substituents is methyl, trifluoromethyl, trifluoromethoxy or Cl, it is preferably positioned para to the carbon atom which links the phenyl to the rest of the molecule, R 3< represents H, R 5< represents H, and R 6< and R 7< represent H.

[0215] A preferred embodiment of the present invention covers compounds of general formula (I), wherein R 1< represents thiazol-5-yl, optionally substituted at the carbon atom at position 2 with a substituent R 1a< selected from the group consisting of methyl, ethyl, propyl, propan-2-yl, cyclopropyl, 2-methylpropyl, tertbutyl, butan-2-yl, cyclobutyl, 2,2-dimethylpropyl, 3-methylbutan-2-yl, cyclopentyl, cyclohexyl, 1-cyclopropylmethyl, 1-cyclopropylethyl, 1-cyclobutylmethyl, 1-(1-methylcyclopropyl)methyl and 2,2,2-trifluoroethyl, in particular ethyl, propan-2-yl, cyclopropyl, 2-methylpropyl, butan-2-yl, cyclobutyl, 2,2-dimethylpropyl, cyclopentyl, 1-cyclopropylmethyl, 1-cyclopropylethyl, 1-(1-methylcyclopropyl)methyl and 1-cyclobutylmethyl, R 2< represents phenyl substituted with 1 or 2 substituents R 2a< which are the same or different wherein R 2a< represents methyl, trifluoromethyl, trifluoromethoxy, F or Cl, and wherein if the substituent or at least one of said substituents is F, it is preferably positioned ortho to the carbon atom which links the phenyl to the rest of the molecule, and wherein if the substituent or at least one of said substituents is methyl, trifluoromethyl, trifluoromethoxy or Cl, it is preferably positioned para to the carbon atom which links the phenyl to the rest of the molecule, R 3< represents H, R 5< represents F, and R 6< and R 7< represent H.

[0216] In accordance with another aspect, the present invention covers compounds of general formula (I), wherein R 1< represents thiazolyl, in particular thiazol-2-yl, optionally substituted at one or more carbon atoms with 1 or 2 substituents R 1a< which are the same or different wherein R 1a< represents C 1 -C 5 -alkyl, C 3 -C 7 -cycloalkyl, -(C 1 -C 3 -alkyl)-(C 3 -C 7 -cycloalkyl), -OC 1 -C 5 -alkyl, -OC 3 -C 7 -cycloalkyl, halogen or CN, wherein said C 1 -C 5 -alkyl, C 3 -C 7 -cycloalkyl, -(C 1 -C 3 -alkyl)-(C 3 -C 7 -cycloalkyl), -OC 1 -C 5 -alkyl and -OC 3 -C 7 -cycloalkyl independently are optionally substituted with one or more substituents independently selected from the group consisting of methyl, OH, OR 4< and F, R 2< represents phenyl optionally substituted with 1 or 2 substituents R 2a< which are the same or different wherein R 2a< represents C 1 -C 5 -alkyl, OC 1 -C 5 -alkyl, F or Cl, and wherein said C 1 -C 5 -alkyl and -OC 1 -C 5 -alkyl independently are optionally substituted with 1 to 5 fluorine atoms, R 3< represents H or F, in particular H, R 4< represents C 1 -C 5 -alkyl, optionally substituted with 1 to 5 fluorine atoms, R 5< represents H, F, Cl or methyl, in particular H or F, and R 6< and R 7< represent H.

[0217] A preferred embodiment of the present invention covers compounds of general formula (I), wherein R 1< represents thiazol-2-yl substituted at a carbon atom with a substituent R 1a< selected from the group consisting of C 1 -C 5 -alkyl, -(C 1 -C 3 -alkyl)-(C 3 -C 7 -cycloalkyl) and C 3 -C 7 -cycloalkyl, wherein said substituent R 1a< is preferably attached to the carbon atom in the position 5 of thiazol-2-yl; and wherein said C 1 -C 5 -alkyl, C 3 -C 7 -cycloalkyl and -(C 1 -C 3 -alkyl)-(C 3 -C 7 -cycloalkyl) independently are optionally substituted with one or more substituents independently selected from the group consisting of methyl, OH, OR 4< and F, R 2< represents phenyl substituted with 1 or 2 substituents R 2a< which are the same or different wherein R 2a< represents C 1 -C 5 -alkyl, OC 1 -C 5 -alkyl, F or Cl, wherein if the substituent or at least one of said substituents is C 1 -C 5 -alkyl, -OC 1 -C 5 -alkyl or Cl, it is preferably positioned para to the carbon atom which links the phenyl to the rest of the molecule, and wherein said C 1 -C 5 -alkyl and -OC 1 -C 5 -alkyl independently are optionally substituted with 1 to 5 fluorine atoms, R 3< represents H or F, in particular H, R 4< represents C 1 -C 5 -alkyl, optionally substituted with 1 to 5 fluorine atoms, R 5< represents H, F, Cl or methyl, in particular H or F, and R 6< and R 7< represent H.

[0218] A preferred embodiment of the present invention covers compounds of general formula (I), wherein R 1< represents thiazol-2-yl substituted at the carbon atom in position 5 with C 3 -C 7 -cycloalkyl, wherein said C 3 -C 7 -cycloalkyl independently is optionally substituted with one or more substituents independently selected from the group consisting of methyl, OH, OR 4< and F, R 2< represents phenyl substituted with 1 or 2 substituents R 2a< which are the same or different wherein R 2a< represents methyl, trifluoromethyl, trifluoromethoxy, F or Cl, and wherein if the substituent or at least one of said substituents is F, it is preferably positioned ortho to the carbon atom which links the phenyl to the rest of the molecule, and wherein if the substituent or at least one of said substituents is methyl, trifluoromethyl, trifluoromethoxy or Cl, it is preferably positioned para to the carbon atom which links the phenyl to the rest of the molecule, and R 3< represents H or F, in particular H, R 4< represents C 1 -C 5 -alkyl, optionally substituted with 1 to 5 fluorine atoms, R 5< represents H, F, Cl or methyl, in particular H or F, and R 6< and R 7< represent H.

[0219] A preferred embodiment of the present invention covers compounds of general formula (I), wherein R 1< represents thiazol-2-yl, optionally substituted at the carbon atom in position 5 with a substituent R 1a< selected from the group consisting of methyl, ethyl, propyl, propan-2-yl, cyclopropyl, 2-methylpropyl, tertbutyl, butan-2-yl, cyclobutyl, 2,2-dimethylpropyl, 3-methylbutan-2-yl, cyclopentyl, cyclohexyl, 1-cyclopropylmethyl, 1-cyclopropylethyl, 1-cyclobutylmethyl, 1-(1-methyl-cyclopropyl)methyl and 2,2,2-trifluoroethyl, in particular ethyl, propan-2-yl, cyclopropyl, 2-methylpropyl, butan-2-yl, cyclobutyl, 2,2-dimethylpropyl, cyclopentyl, 1-cyclopropylmethyl, 1-cyclopropylethyl, 1-(1-methylcyclopropyl)methyl and 1-cyclobutylmethyl, R 2< represents phenyl substituted with 1 or 2 substituents R 2a< which are the same or different wherein R 2a< represents methyl, trifluoromethyl, trifluoromethoxy, F or Cl, and wherein if the substituent or at least one of said substituents is F, it is preferably positioned ortho to the carbon atom which links the phenyl to the rest of the molecule, and wherein if the substituent or at least one of said substituents is methyl, trifluoromethyl, trifluoromethoxy or Cl, it is preferably positioned para to the carbon atom which links the phenyl to the rest of the molecule, R 3< represents H or F, in particular H, R 5< represents H, F, Cl or methyl, in particular H or F, and R 6< and R 7< represent H.

[0220] A preferred embodiment of the present invention covers compounds of general formula (I), wherein R 1< represents thiazol-2-yl, optionally substituted at the carbon atom in position 5 with a substituent R 1a< selected from the group consisting of methyl, ethyl, propyl, propan-2-yl, cyclopropyl, 2-methylpropyl, tertbutyl, butan-2-yl, cyclobutyl, 2,2-dimethylpropyl, 3-methylbutan-2-yl, cyclopentyl, cyclohexyl, 1-cyclopropylmethyl, 1-cyclopropylethyl, 1-cyclobutylmethyl, 1-(1-methyl-cyclopropyl)methyl and 2,2,2-trifluoroethyl, in particular ethyl, propan-2-yl, cyclopropyl, 2-methylpropyl, butan-2-yl, cyclobutyl, 2,2-dimethylpropyl, cyclopentyl, 1-cyclopropylmethyl, 1-cyclopropylethyl, 1-(1-methylcyclo-propyl)methyl and 1-cyclobutylmethyl, R 2< represents phenyl substituted with 1 or 2 substituents R 2a< which are the same or different wherein R 2a< represents methyl, trifluoromethyl, trifluoromethoxy, F or Cl, and wherein if the substituent or at least one of said substituents is F, it is preferably positioned ortho to the carbon atom which links the phenyl to the rest of the molecule, and wherein if the substituent or at least one of said substituents is methyl, trifluoromethyl, trifluoromethoxy or Cl, it is preferably positioned para to the carbon atom which links the phenyl to the rest of the molecule, R 3< represents H, R 5< represents H, and R 6< and R 7< represent H.

[0221] A preferred embodiment of the present invention covers compounds of general formula (I), wherein R 1< represents thiazol-2-yl, optionally substituted at the carbon atom in position 5 with a substituent R 1a< selected from the group consisting of methyl, ethyl, propyl, propan-2-yl, cyclopropyl, 2-methylpropyl, tertbutyl, butan-2-yl, cyclobutyl, 2,2-dimethylpropyl, 3-methylbutan-2-yl, cyclopentyl, cyclohexyl, 1-cyclopropylmethyl, 1-cyclopropylethyl, 1-cyclobutylmethyl, 1-(1-methyl-cyclopropyl)methyl and 2,2,2-trifluoroethyl, in particular ethyl, propan-2-yl, cyclopropyl, 2-methylpropyl, butan-2-yl, cyclobutyl, 2,2-dimethylpropyl, cyclopentyl, 1-cyclopropylmethyl, 1-cyclopropylethyl, 1-(1-methylcyclo-propyl)methyl and 1-cyclobutylmethyl, R 2< represents phenyl substituted with 1 or 2 substituents R 2a< which are the same or different wherein R 2a< represents methyl, trifluoromethyl, trifluoromethoxy, F or Cl, and wherein if the substituent or at least one of said substituents is F, it is preferably positioned ortho to the carbon atom which links the phenyl to the rest of the molecule, and wherein if the substituent or at least one of said substituents is methyl, trifluoromethyl, trifluoromethoxy or Cl, it is preferably positioned para to the carbon atom which links the phenyl to the rest of the molecule, R 3< represents H, R 5< represents F, and R 6< and R 7< represent H.

[0222] Preferred compounds are, namely 2-(1-benzothiophen-2-yl)-5-[({1-[2-fluoro-4-(trifluoromethyl)phenyl]cyclopropyl}carbonyl)amino]benzoic acid 2-[6-(1,1-difluoropropyl)pyridin-3-yl]-5-[({1-[2-fluoro-4-(trifluoromethyl)phenyl]cyclopropyl}carbonyl)amino]benzoic acid 2-(1-cyclobutyl-1H-pyrazol-4-yl)-5-[({1-[2-fluoro-4-(trifluoromethyl)phenyl]cyclopropyl}carbonyl)amino]benzoic acid 2-(6-ethoxypyridin-3-yl)-5-[({1-[2-fluoro-4-(trifluoromethyl)phenyl]cyclopropyl}carbonyl)amino]benzoic acid 2-(6-ethoxypyridin-3-yl)-5-[({1-[2-fluoro-4-(trifluoromethoxy)phenyl]cyclopropyl}carbonyl)amino]benzoic acid 2-(1-cyclobutyl-1H-pyrazol-4-yl)-3-fluoro-5-({[1-(2-fluoro-4-methylphenyl)cyclopropyl]carbonyl}amino)benzoic acid 2-[6-(1,1-difluoropropyl)pyridin-3-yl]-5-[({1-[2-fluoro-4-(trifluoromethoxy)phenyl]cyclopropyl}carbonyl)amino]benzoic acid 3-fluoro-5-[({1-[2-fluoro-4-(trifluoromethyl)phenyl]cyclopropyl}carbonyl)amino]-2-[6-(trifluoromethyl)pyridin-3-yl]benzoic acid 5-[({1-[2-fluoro-4-(trifluoromethyl)phenyl]cyclopropyl}carbonyl)amino]-2-[1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl]benzoic acid 5-({[1-(4-chlorophenyl)cyclopropyl]carbonyl}amino)-2-(1-cyclobutyl-1H-pyrazol-4-yl)-3-fluorobenzoic acid 2-(1-cyclobutyl-1H-pyrazol-4-yl)-3-fluoro-5-[({1-[4-(trifluoromethyl)phenyl]cyclopropyl}carbonyl)amino]benzoic acid 2-(1-cyclobutyl-1H-pyrazol-4-yl)-3-fluoro-5-[({1-[4-(trifluoromethoxy)phenyl]cyclopropyl}carbonyl)amino]benzoic acid 2-(1-cyclobutyl-1H-pyrazol-4-yl)-5-({[1-(3,4-difluorophenyl)cyclopropyl]carbonyl}amino)-3-fluorobenzoic acid 2-(1-cyclobutyl-1H-pyrazol-4-yl)-3-fluoro-5-[({1-[3-fluoro-4-(trifluoromethyl)phenyl]cyclopropyl}carbonyl)amino]benzoic acid 2-(1-cyclobutyl-1H-pyrazol-4-yl)-5-({[1-(2,4-difluorophenyl)cyclopropyl]carbonyl}amino)-3-fluorobenzoic acid 5-({[1-(4-chloro-2-fluorophenyl)cyclopropyl]carbonyl}amino)-2-(1-cyclobutyl-1H-pyrazol-4-yl)-3-fluorobenzoic acid 2-(1-cyclobutyl-1H-pyrazol-4-yl)-3-fluoro-5-[({1-[2-fluoro-4-(trifluoromethyl)phenyl]cyclopropyl}carbonyl)amino]benzoic acid 2-(1-cyclobutyt-1H-pyrazol-4-yt)-3-fluoro-5-[(fl-[2-fluoro-4-(trifluoromethoxy)phenyl]cyclopropyl}carbonyl)amino]benzoic acid 2-(1-cyclobutyt-1H-pyrazol-4-yt)-3-fluoro-5-(1[1-(5-fluoropyridin-2-yl)cyclopropyl]carbonyl}amino)benzoic acid 2-(1-cyclobutyl-3-fluoro-1H-pyrazol-4-yl)-5-[({1-[2-fluoro-4-(trifluoromethyl)phenyl]cyclopropyl}carbonyl)amino]benzoic acid 5-({[1-(4-chloro-3-fluorophenyl)cyclopropyl]carbonyl}amino)-2-(1-cyclobutyl-1H-pyrazol-4-yl)benzoic acid 2-(1-cyclobutyl-1H-pyrazol-4-yl)-5-[({1-[2-fluoro-4-(trifluoromethoxy)phenyl]cyclopropyl}carbonyl)amino]benzoic acid 5-({[1-(4-chloro-2-fluorophenyl)cyclopropyl]carbonyl}amino)-2-(1-cyclobutyl-1H-pyrazol-4-yl)benzoic acid 5-({[1-(5-chloro-2-fluorophenyl)cyclopropyl]carbonyl}amino)-2-(1-cyclobutyl-1H-pyrazol-4-yl)benzoic acid 2-(1-ethyl-1H-pyrazol-4-yl)-5-[({1-[2-fluoro-4-(trifluoromethyl)phenyl]cyclopropyl}carbonyl)amino]benzoic acid 2-(1-ethyl-1H-pyrazol-4-yl)-5-[({1-[2-fluoro-4-(trifluoromethoxy)phenyl]cyclopropyl}carbonyl)amino]benzoic acid 5-[({1-[2-fluoro-4-(trifluoromethyl)phenyl]cyclopropyl}carbonyl)amino]-2-[1-(propan-2-yl)-1H-pyrazol-4-yl]benzoic acid 5-[({1-[2-fluoro-4-(trifluoromethoxy)phenyl]cyclopropyl}carbonyl)amino]-2-[1-(propan-2-yl)-1H-pyrazol-4-yl]benzoic acid 2-(1-tert-butyl-1H-pyrazol-4-yl)-5-[({1-[2-fluoro-4-(trifluoromethyl)phenyl]cyclopropyl}carbonyl)amino]benzoic acid 2-(1-tert-butyl-1H-pyrazol-4-yl)-5-[({1-[2-fluoro-4-(trifluoromethoxy)phenyl]cyclopropyl}carbonyl)amino]benzoic acid 5-[({1-[2-fluoro-4-(trifluoromethyl)phenyl]cyclopropyl}carbonyl)amino]-2-[1-(2-methylpropyl)-1H-pyrazol-4-yl]benzoic acid 5-[({1-[2-fluoro-4-(trifluoromethoxy)phenyl]cyclopropyl}carbonyl)amino]-2-[1-(2-methylpropyl)-1H-pyrazol-4-yl]benzoic acid 2-[1-(2,2-dimethylpropyl)-1H-pyrazol-4-yl]-5-[({1-[2-fluoro-4-(trifluoromethyl)phenyl]cyclopropyl}carbonyl)amino]benzoic acid 2-[1-(2,2-dimethylpropyl)-1H-pyrazol-4-yl]-5-[({1-[2-fluoro-4-(trifluoromethoxy)phenyl]cyclopropyl}carbonyl)amino]benzoic acid 3-fluoro-5-(1[1-(2-fluoro-4-methylphenyt)cyclopropyt]carbonyl}amino)-2-[1-(propan-2-yl)-1H-pyrazol-4-yl]benzoic acid 3-fluoro-5-[({1-[2-fluoro-4-(trifluoromethyl)phenyl]cyclopropyl}carbonyl)amino]-2-[1-(propan-2-yl)-1H-pyrazol-4-yl]benzoic acid 3-fluoro-5-[({1-[2-fluoro-4-(trifluoromethoxy)phenyl]cyclopropyl}carbonyl)amino]-2-[1-(propan-2-yl)-1H-pyrazol-4-yl]benzoic acid 2-(4-tert-butyt-1H-imidazol-1-yt)-3-fluoro-5-[({1-[2-fluoro-4-(trifluoromethyl)phenyl]cyclopropyl}carbonyl)amino]benzoic acid 2-(4-tert-butyt-1H-imidazol-1-yl)-3-fluoro-5-[({1-[2-fluoro-4-(trifluoromethoxy)phenyl]cyclopropyl}carbonyl)amino]benzoic acid 3-fluoro-5-[({1-[2-fluoro-4-(trifluoromethyl)phenyl]cyclopropyl}carbonyl)amino]-2-[1-(2-methylpropyl)-1H-pyrazol-4-yl]benzoic acid 2-[6-(difluoromethyl)pyridin-3-yl]-3-fluoro-5-[({1-[2-fluoro-4-(trifluoromethyl)phenyl]cyclopropyl}carbonyl)amino]benzoic acid 2-[6-(difluoromethyl)pyridin-3-yl]-3-fluoro-5-[({1-[2-fluoro-4-(trifluoromethoxy)phenyl]cyclopropyl}carbonyl)amino]benzoic acid 2-[6-(1,1-difluoropropyl)pyridin-3-yl]-3-fluoro-5-[({1-[2-fluoro-4-(trifluoromethyl)phenyl]cyclopropyl}carbonyl)amino]benzoic acid 2-[6-(1,1-difluoropropyt)pyridin-3-yt]-3-fluoro-5-[({1-[2-fluoro-4-(trifluoromethoxy)phenyl]cyclopropyl}carbonyl)amino]benzoic acid 3-chloro-2-(1-cyclobutyl-1H-pyrazol-4-yl)-5-[({1-[2-fluoro-4-(trifluoromethyl)phenyl]cyclopropyl}carbonyl)amino]benzoic acid 3-chloro-2-(1-cyclobutyl-1H-pyrazol-4-yl)-5-[({1-[2-fluoro-4-(trifluoromethoxy)phenyl]cyclopropyl}carbonyl)amino]benzoic acid 3-chloro-2-[6-(1,1-difluoropropyl)pyridin-3-yl]-5-[({1-[2-fluoro-4-(trifluoromethyl)phenyl]cyclopropyl}carbonyl)amino]benzoic acid 3-chloro-2-[6-(1,1-difluoropropyl)pyridin-3-yl]-5-[({1-[2-fluoro-4-(trifluoromethoxy)phenyl]cyclopropyl}carbonyl)amino]benzoic acid 2-(1-cyclobutyl-1H-pyrazol-4-yl)-5-[({1-[2-fluoro-4-(trifluoromethyl)phenyl]cyclopropyl}carbonyl)amino]-3-methylbenzoic acid 2-(1-cyclobutyl-1H-pyrazol-4-yl)-5-[({1-[2-fluoro-4-(trifluoromethoxy)phenyl]cyclopropyl}carbonyl)amino]-3-methylbenzoic acid 2-[1-(cyclobutylmethyl)-1H-pyrazol-4-yl]-5-[({1-[2-fluoro-4-(trifluoromethyl)phenyl]cyclopropyl}carbonyl)amino]benzoic acid 2-[1-(cyclobutylmethyl)-1H-pyrazol-4-yl]-5-[({1-[2-fluoro-4-(trifluoromethoxy)phenyl]cyclopropyl}carbonyl)amino]benzoic acid 2-(1-cyclopentyl-1H-pyrazol-4-yl)-5-[({1-[2-fluoro-4-(trifluoromethyl)phenyl]cyclopropyl}carbonyl)amino]benzoic acid 2-(1-cyclohexyl-1H-pyrazol-4-yl)-5-[({1-[2-fluoro-4-(trifluoromethyl)phenyl]cyclopropyl}carbonyl)amino]benzoic acid 2-(1-cyclohexyl-1H-pyrazol-4-yl)-5-[({1-[2-fluoro-4-(trifluoromethoxy)phenyl]cyclopropyl}carbonyl)amino]benzoic acid 2-[1-(cyclopropylmethyl)-1H-pyrazol-4-yl]-3-fluoro-5-[({1-[2-fluoro-4-(trifluoromethyl)phenyl]cyclopropyl}carbonyl)amino]benzoic acid 2-[1-(cyclopropylmethyl)-1H-pyrazol-4-yl]-3-fluoro-5-[({1-[2-fluoro-4-(trifluoromethoxy)phenyl]cyclopropyl}carbonyl)amino]benzoic acid 3-fluoro-5-[({1-[2-fluoro-4-(trifluoromethyl)phenyl]cyclopropyl}carbonyl)amino]-2-(6-methylpyridin-3-yl)benzoic acid 2-{1-[(2S)-butan-2-yl]-1H-pyrazol-4-yl}-5-[({1-[2-fluoro-4-(trifluoromethyl)phenyl]cyclopropyl}carbonyl)amino]benzoic acid 2-{1-[(2R)-butan-2-yl]-1H-pyrazol-4-yl}-5-[({1-[2-fluoro-4-(trifluoromethoxy)phenyl]cyclopropyl}carbonyl)amino]benzoic acid 2-{1-[(2S)-butan-2-yl]-1H-pyrazol-4-yl}-3-fluoro-5-[({1-[2-fluoro-4-(trifluoromethyl)phenyl]cyclopropyl}carbonyl)amino]benzoic acid 2-{1-[(2R)-butan-2-yl]-1H-pyrazol-4-yl}-3-fluoro-5-[({1-[2-fluoro-4-(trifluoromethyl)phenyl]cyclopropyl}carbonyl)amino]benzoic acid 2-(1-ethyl-1H-pyrazol-4-yl)-3-fluoro-5-[({1-[2-fluoro-4-(trifluoromethyl)phenyl]cyclopropyl}carbonyl)amino]benzoic acid 2-(1-ethyl-1H-pyrazol-4-yl)-3-fluoro-5-[({1-[2-fluoro-4-(trifluoromethoxy)phenyl]cyclopropyl}carbonyl)amino]benzoic acid 5-({[1-(4-chloro-2-fluorophenyl)cyclopropyl]carbonyl}amino)-3-fluoro-2-[1-(propan-2-yl)-1H-pyrazol-4-yl]benzoic acid 5-([[l-(4-chloro-2-fluorophenyt)cyclopropyt]carbonyt}amino)-2-(2-cyclobutyt-1,3-thiazol-5-yl)benzoic acid 2-(2-cyclobutyl-1,3-thiazol-5-yl)-5-({[1-(2-fluoro-4-methylphenyl)cyclopropyl]carbonyl}amino)benzoic acid 2-(2-cyclobutyl-1,3-thiazol-5-yl)-5-[({1-[2-fluoro-4-(trifluoromethyl)phenyl]cyclopropyl}carbonyl)amino]benzoic acid 2-(2-cyclobutyl-1,3-thiazol-5-yl)-5-[({1-[2-fluoro-4-(trifluoromethoxy)phenyl]cyclopropyl}carbonyl)amino]benzoic acid 5-[({1-[2-fluoro-4-(trifluoromethyl)phenyl]cyclopropyl}carbonyl)amino]-2{1-[(1-methylcyclopropyl)methyl]-1H-pyrazol-4-yl}benzoic acid 5-[({1-[2-fluoro-4-(trifluoromethoxy)phenyl]cyclopropyl}carbonyl)amino]-2-{1-[(1-methylcyclopropyl)methyl]-1H-pyrazol-4-yl}benzoic acid 2-{1-[(1S)-1-cyclopropylethyl]-1H-pyrazol-4-yl}-5-[({1-[2-fluoro-4-(trifluoromethyl)phenyl]cyclopropyl}carbonyl)amino]benzoic acid 2-(6-ethylpyridin-3-yt)-5-[({1-[2-fluoro-4-(trifluoromethyl)phenyl]cyclopropyl}carbonyl)amino]benzoic acid 2-(6-ethylpyridin-3-yl)-5-[({1-[2-fluoro-4-(trifluoromethoxy)phenyl]cyclopropyl}carbonyl)amino]benzoic acid 2-(6-ethylpyridin-3-yt)-3-fluoro-5-[({1-[2-fluoro-4-(trifluoromethyl)phenyl]cyclopropyl}carbonyl)amino]benzoic acid 3-fluoro-5-[({1-[2-fluoro-4-(trifluoromethoxy)phenyl]cyclopropyl}carbonyl)amino]-2-(1-methyl-1H-indazol-6-yl)benzoic acid 2-(2-cyclopentyl-1,3-thiazol-5-yl)-5-[({1-[2-fluoro-4-(trifluoromethyl)phenyl]cyclopropyl}carbonyl)amino]benzoic acid 2-(2-cyclobutyl-1,3-thiazol-5-yl)-3-fluoro-5-[({1-[2-fluoro-4-(trifluoromethyl)phenyl]cyclopropyl}carbonyl)amino]benzoic acid 3-fluoro-5-[({1-[2-fluoro-4-(trifluoromethyl)phenyl]cyclopropyl}carbonyl)amino]-2-[1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl]benzoic acid or an isomer, enantiomer, diastereomer, tautomer, racemate, hydrate, solvate, or a salt thereof, or a mixture of same.

[0223] It is to be understood that the present invention relates also to any combination of the preferred embodiments described above.

[0224] As mentioned above, compounds of the present invention effectively inhibit Bradykinin B1 receptor and may therefore be used for the treatment or prophylaxis of diseases that are related to pain and to inflammation.

[0225] Additionally, compounds of the present invention reduce the release of inflammation related cytokines like IL-6 and IL-8.Pharmaceutical compositions of the compounds of the invention

[0226] It is possible for the compounds according to the invention to have systemic and / or local activity. For this purpose, they can be administered in a suitable manner, such as, for example, via the oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, vaginal, dermal, transdermal, conjunctival, otic route or as an implant or stent.

[0227] For these administration routes, it is possible for the compounds according to the invention to be administered in suitable administration forms.

[0228] For oral administration, it is possible to formulate the compounds according to the invention to dosage forms known in the art that deliver the compounds of the invention rapidly and / or in a modified manner, such as, for example, tablets (uncoated or coated tablets, for example with enteric or controlled release coatings that dissolve with a delay or are insoluble), orally-disintegrating tablets, films / wafers, films / lyophylisates, capsules (for example hard or soft gelatine capsules), sugar-coated tablets, granules, pellets, powders, emulsions, suspensions, aerosols or solutions. It is possible to incorporate the compounds according to the invention in crystalline and / or amorphised and / or dissolved form into said dosage forms.

[0229] Parenteral administration can be effected with avoidance of an absorption step (for example intravenous, intraarterial, intracardial, intraspinal or intralumbal) or with inclusion of absorption (for example intramuscular, subcutaneous, intracutaneous, percutaneous or intraperitoneal). Administration forms which are suitable for parenteral administration are, inter alia, preparations for injection and infusion in the form of solutions, suspensions, emulsions, lyophylisates or sterile powders.

[0230] Examples which are suitable for other administration routes are pharmaceutical forms for inhalation [inter alia powder inhalers, nebulizers], nasal drops, nasal solutions, nasal sprays; tablets / films / wafers / capsules for lingual, sublingual or buccal administration; suppositories; eye drops, eye ointments, eye baths, ocular inserts, ear drops, ear sprays, ear powders, ear-rinses, ear tampons; vaginal capsules, aqueous suspensions (lotions, mixturae agitandae), lipophilic suspensions, emulsions, ointments, creams, transdermal therapeutic systems (such as, for example, patches), milk, pastes, foams, dusting powders, implants or stents.

[0231] The compounds according to the invention can be incorporated into the stated administration forms. This can be effected in a manner known per se by mixing with pharmaceutically suitable excipients. Pharmaceutically suitable excipients include, inter alia, fillers and carriers (for example cellulose, microcrystalline cellulose (such as, for example, Avicel ®< ), lactose, mannitol, starch, calcium phosphate (such as, for example, Di-Cafos ®< )), ointment bases (for example petroleum jelly, paraffins, triglycerides, waxes, wool wax, wool wax alcohols, lanolin, hydrophilic ointment, polyethylene glycols), bases for suppositories (for example polyethylene glycols, cacao butter, hard fat), solvents (for example water, ethanol, isopropanol, glycerol, propylene glycol, medium chain-length triglycerides fatty oils, liquid polyethylene glycols, paraffins), surfactants, emulsifiers, dispersants or wetters (for example sodium dodecyl sulfate), lecithin, phospholipids, fatty alcohols (such as, for example, Lanette ®< ), sorbitan fatty acid esters (such as, for example, Span ®< ), polyoxyethylene sorbitan fatty acid esters (such as, for example, Tween ®< ), polyoxyethylene fatty acid glycerides (such as, for example, Cremophor ®< ), polyoxethylene fatty acid esters, polyoxyethylene fatty alcohol ethers, glycerol fatty acid esters, poloxamers (such as, for example, Pluronic ®< ), buffers, acids and bases (for example phosphates, carbonates, citric acid, acetic acid, hydrochloric acid, sodium hydroxide solution, ammonium carbonate, trometamol, triethanolamine), isotonicity agents (for example glucose, sodium chloride), adsorbents (for example highly-disperse silicas), viscosity-increasing agents, gel formers, thickeners and / or binders (for example polyvinylpyrrolidone, methylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, carboxymethylcellulose-sodium, starch, carbomers, polyacrylic acids (such as, for example, Carbopol ®< ); alginates, gelatine), disintegrants (for example modified starch, carboxymethylcellulose-sodium, sodium starch glycolate (such as, for example, Explotab ®< ), cross- linked polyvinylpyrrolidone, croscarmellose-sodium (such as, for example, AcDiSol ®< )), flow regulators, lubricants, glidants and mould release agents (for example magnesium stearate, stearic acid, talc, highly-disperse silicas (such as, for example, Aerosil ®< )), coating materials (for example sugar, shellac) and film formers for films or diffusion membranes which dissolve rapidly or in a modified manner (for example polyvinylpyrrolidones (such as, for example, Kollidon ®< ), polyvinyl alcohol, hydroxypropylmethylcellulose, hydroxypropylcellulose, ethylcellulose, hydroxypropylmethylcellulose phthalate, cellulose acetate, cellulose acetate phthalate, polyacrylates, polymethacrylates such as, for example, Eudragit ®< )), capsule materials (for example gelatine, hydroxypropylmethylcellulose), synthetic polymers (for example polylactides, polyglycolides, polyacrylates, polymethacrylates (such as, for example, Eudragit ®< ), polyvinylpyrrolidones (such as, for example, Kollidon ®< ), polyvinyl alcohols, polyvinyl acetates, polyethylene oxides, polyethylene glycols and their copolymers and blockcopolymers), plasticizers (for example polyethylene glycols, propylene glycol, glycerol, triacetine, triacetyl citrate, dibutyl phthalate), penetration enhancers, stabilisers (for example antioxidants such as, for example, ascorbic acid, ascorbyl palmitate, sodium ascorbate, butylhydroxyanisole, butylhydroxytoluene, propyl gallate), preservatives (for example parabens, sorbic acid, thiomersal, benzalkonium chloride, chlorhexidine acetate, sodium benzoate), colourants (for example inorganic pigments such as, for example, iron oxides, titanium dioxide), flavourings, sweeteners, flavour- and / or odour-masking agents.

[0232] The present invention furthermore relates to a pharmaceutical composition which comprise at least one compound according to the invention, conventionally together with one or more pharmaceutically suitable excipient(s), and to their use according to the present invention.Combination therapies

[0233] The term "combination" in the present invention is used as known to persons skilled in the art and may be present as a fixed combination, a non-fixed combination or kit-of-parts.

[0234] A "fixed combination" in the present invention is used as known to persons skilled in the art and is defined as a combination wherein the said first active ingredient and the said second active ingredient are present together in one unit dosage or in a single entity. One example of a "fixed combination" is a pharmaceutical composition wherein the said first active ingredient and the said second active ingredient are present in admixture for simultaneous administration, such as in a formulation. Another example of a "fixed combination" is a pharmaceutical combination wherein the said first active ingredient and the said second active ingredient are present in one unit without being in admixture.

[0235] A non-fixed combination or "kit-of-parts" in the present invention is used as known to persons skilled in the art and is defined as a combination wherein the said first active ingredient and the said second active ingredient are present in more than one unit. One example of a non-fixed combination or kit-of-parts is a combination wherein the said first active ingredient and the said second active ingredient are present separately. The components of the non-fixed combination or kit-of-parts may be administered separately, sequentially, simultaneously, concurrently or chronologically staggered.

[0236] The compounds of this invention can be administered as the sole pharmaceutical agent or in combination with one or more other pharmaceutical agents where the combination causes no unacceptable adverse effects. The present invention relates also to such combinations.

[0237] For example, the compounds of this invention can be combined with known hormonal therapeutical agents.

[0238] In particular, the compounds of the present invention can be administered in combination or as comedication with hormonal contraceptives. Hormonal contraceptives are for example Combined Oral Contraceptives (COCs) or Progestin-Only-Pills (POPs) or hormone-containing devices.

[0239] COCs include but are not limited to birth control pills or a birth control method that includes a combination of an estrogen (estradiol) and a progestogen (progestin). The estrogenic part is in most of the COCs ethinyl estradiol. Some COCs contain estradiol or estradiol valerate.

[0240] Said COCs contain the progestins norethynodrel, norethindrone, norethindrone acetate, ethynodiol acetate, norgestrel, levonorgestrel, norgestimate, desogestrel, gestodene, drospirenone, dienogest, or nomegestrol acetate.

[0241] Birth control pills include for example but are not limited to Yasmin, Yaz, both containing ethinyl estradiol and drospirenone; Microgynon or Miranova containing levonorgestrel and ethinyl estradiol; Marvelon containing ethinyl estradiol and desogestrel; Valette containing ethinyl estradiol and dienogest; Belara and Enriqa containing ethinyl estradiol and chlormadinonacetate; Qlaira containing estradiol valerate and dienogest as active ingredients; and Zoely containing estradiol and normegestrol.

[0242] POPs are contraceptive pills that contain only synthetic progestogens (progestins) and do not contain estrogen. They are colloquially known as mini pills.

[0243] POPs include but are not limited to Cerazette containing desogestrel; and Micronor containing norethindrone.

[0244] Other Progeston-Only forms are intrauterine devices (IUDs), for example Mirena containing levonorgestrel or injectables, for example Depo-Provera containing medroxyprogesterone acetate, or implants, for example Implanon containing etonogestrel.

[0245] Other hormone-containing devices with contraceptive effect which are suitable for a combination with the compounds of the present invention are vaginal rings like Nuvaring containing ethinyl estradiol and etonogestrel, or transdermal systems like contraceptive patches, for example Ortho-Evra containing ethinyl estradiol and norelgestromin or Apleek (Lisvy) containing ethinyl estradiol and gestodene.

[0246] A preferred embodiment of the present invention is the administration of a compound of general formula (I) in combination with a COC or a POP or other Progestin-Only forms, as well as in combination with vaginal rings or contraceptive patches as mentioned above.

[0247] Furthermore, the compounds of the present invention can be combined with therapeutic agents or active ingredients, that are already approved or that are still under development for the treatment and / or prophylaxis of diseases which are related to or mediated by the Bradykinin B1 receptor.

[0248] For the treatment and / or prophylaxis of urinary tract diseases, the compounds of the present invention can be administered in combination or as co-medication with any substance that can be applied as therapeutic agent in the following indications: Urinary tract disease states associated with the bladder outlet obstruction; urinary incontinence conditions such as reduced bladder capacity, increased frequency of micturition, urge incontinence, stress incontinence, or bladder hyperreactivity; benign prostatic hypertrophy; prostatic hyperplasia; prostatitis; detrusor hyperreflexia; overactive bladder and symptoms related to overactive bladder wherein said symptoms are in particular increased urinary frequency, nocturia, urinary urgency or urge incontinence; pelvic hypersensitivity; urethritis; prostatitis; prostatodynia; cystitis, in particular interstitial cystitis; bladder pain syndrome;idiopathic bladder hypersensitivity.

[0249] For the treatment and / or prophylaxis of overactive bladder and symptoms related to overactive bladder, the compounds of the present invention can be administered in combination or as co-medication in addition to behavioural therapy like diet, lifestyle or bladder training with anticholinergics like oxybutynin, tolterodine, propiverine, solifenacin, darifenacin, trospium, fesoterdine; β-3 agonists like mirabegron; neurotoxins like onabutolinumtoxin A; or antidepressants like imipramine, duloxetine.

[0250] For the treatment and / or prophylaxis of interstitial cystitis and / or bladder pain syndrome, the compounds of the present invention can be administered in combination or as co-medication in addition to behavioural therapy like diet, lifestyle or bladder training with pentosans like elmiron; antidepressants like amitriptyline, imipramine; or antihistamines like loratadine.

[0251] For the treatment and / or prophylaxis of gynaecological diseases, the compounds of the present invention can be administered in combination or as co-medication with any substance that can be applied as therapeutic agent in the following indications: dysmenorrhea, including primary and secondary; dyspareunia; endometriosis; endometriosis-associated pain; endometriosis-associated symptoms, such as and in particular dysmenorrhea, dyspareunia, dysuria, or dyschezia.

[0252] For the treatment and / or prophylaxis of dysmenorrhea, including primary and secondary; dyspareunia; endometriosis and endometriosis-associated pain, the compounds of the present invention can be administered in in combination with ovulation inhibiting treatment, in particular COCs as mentioned above or contraceptive patches like Ortho-Evra or Apleek (Lisvy); or with progestogenes like dienogest (Visanne); or with GnRH analogous, in particular GnRH agonists and antagonists, for example leuprorelin, nafarelin, goserelin, cetrorelix, abarelix, ganirelix, degarelix; or with androgens: danazol.

[0253] For the treatment and / or prophylaxis of diseases, which are associated with pain, or pain syndromes, the compounds of the present invention can be administered in combination or as co-medication with any substance that can be applied as therapeutic agent in the following indications: pain-associated diseases or disorders like hyperalgesia, allodynia, functional bowel disorders (such as irritable bowel syndrome) and arthritis (such as osteoarthritis, rheumatoid arthritis and ankylosing spondylitis), burning mouth syndrome, burns, migraine or cluster headache, nerve injury, traumatic nerve injury, post-traumatic injuries (including fractures and sport injuries), neuritis, neuralgia, poisoning, ischemic injury, interstitial cystitis, bladder pain syndrome, viral, trigeminal neuralgia, small fiber neuropathy, diabetic neuropathy, chronic arthritis and related neuralgias, HIV and HIV treatment-induced neuropathy.

[0254] The compounds of the present invention can be combined with other pharmacological agents and compounds that are intended to treat inflammatory diseases, inflammatory pain or general pain conditions.

[0255] In addition to well-known medicaments which are already approved and on the market, the compounds of the present invention can be administered in combination with inhibitors of the P2X purinoceptor family (P2X3, P2X4), with inhibitors of IRAK4 and with antagonists of the prostanoid EP4 receptor.

[0256] In particular, the compounds of the present invention can be administered in combination with pharmacological endometriosis agents, intended to treat inflammatory diseases, inflammatory pain or general pain conditions and / or interfering with endometriotic proliferation and endometriosis associated symptoms, namely with inhibitors of Aldo-keto-reductase1C3 (AKR1C3) and with functional blocking antibodies of the prolactin receptor.

[0257] The compounds of the present invention can be combined with other pharmacological agents and compounds that are intended for the treatment, prevention or management of cancer.

[0258] In particular, the compounds of the present invention can be administered in combination with 1311-chTNT, abarelix, abiraterone, aclarubicin, ado-trastuzumab emtansine, afatinib, aflibercept, aldesleukin, alemtuzumab, Alendronic acid, alitretinoin, altretamine, amifostine, aminoglutethimide, Hexyl aminolevulinate,amrubicin, amsacrine, anastrozole, ancestim, anethole dithiolethione, angiotensin II, antithrombin III, aprepitant, arcitumomab, arglabin, arsenic trioxide, asparaginase, axitinib, azacitidine, basiliximab, belotecan, bendamustine, belinostat, bevacizumab, bexarotene, bicalutamide, bisantrene, bleomycin, bortezomib, buserelin, bosutinib, brentuximab vedotin, busulfan, cabazitaxel, cabozantinib, calcium folinate, calcium levofolinate, capecitabine, capromab, carboplatin, carfilzomib, carmofur, carmustine, catumaxomab, celecoxib, celmoleukin, ceritinib, cetuximab, chlorambucil, chlormadinone, chlormethine, cidofovir, cinacalcet, cisplatin, cladribine, clodronic acid, clofarabine, copanlisib , crisantaspase, cyclophosphamide, cyproterone, cytarabine, dacarbazine, dactinomycin, darbepoetin alfa, dabrafenib, dasatinib, daunorubicin, decitabine, degarelix, denileukin diftitox, denosumab, depreotide, deslorelin, dexrazoxane, dibrospidium chloride, dianhydrogalactitol, diclofenac, docetaxel, dolasetron, doxifluridine, doxorubicin, doxorubicin + estrone, dronabinol, eculizumab, edrecolomab, elliptinium acetate, eltrombopag, endostatin, enocitabine, enzalutamide, epirubicin, epitiostanol, epoetin alfa, epoetin beta, epoetin zeta, eptaplatin, eribulin, erlotinib, esomeprazole, estradiol, estramustine, etoposide, everolimus, exemestane, fadrozole, fentanyl, filgrastim, fluoxymesterone, floxuridine, fludarabine, fluorouracil, flutamide, folinic acid, formestane, fosaprepitant, fotemustine, fulvestrant, gadobutrol, gadoteridol, gadoteric acid meglumine, gadoversetamide, gadoxetic acid, gallium nitrate, ganirelix, gefitinib, gemcitabine, gemtuzumab, Glucarpidase, glutoxim, GM-CSF, goserelin, granisetron, granulocyte colony stimulating factor, histamine dihydrochloride, histrelin, hydroxycarbamide, I-125 seeds, lansoprazole, ibandronic acid, ibritumomab tiuxetan, ibrutinib, idarubicin, ifosfamide, imatinib, imiquimod, improsulfan, indisetron, incadronic acid, ingenol mebutate, interferon alfa, interferon beta, interferon gamma, iobitridol, iobenguane (1231), iomeprol, ipilimumab, irinotecan, Itraconazole, ixabepilone, lanreotide, lapatinib, lasocholine, lenalidomide, lenograstim, lentinan, letrozole, leuprorelin, levamisole, levonorgestrel, levothyroxine sodium, lisuride, lobaplatin, lomustine, lonidamine, masoprocol, medroxyprogesterone, megestrol, melarsoprol, melphalan, mepitiostane, mercaptopurine, mesna, methadone, methotrexate, methoxsalen, methylaminolevulinate, methylprednisolone, methyltestosterone, metirosine, mifamurtide, miltefosine, miriplatin, mitobronitol, mitoguazone, mitolactol, mitomycin, mitotane, mitoxantrone, mogamulizumab, molgramostim, mopidamol, morphine hydrochloride, morphine sulfate, nabilone, nabiximols, nafarelin, naloxone + pentazocine, naltrexone, nartograstim, nedaplatin, nelarabine, neridronic acid, nivolumabpentetreotide, nilotinib, nilutamide, nimorazole, nimotuzumab, nimustine, nitracrine, nivolumab, obinutuzumab, octreotide, ofatumumab, omacetaxine mepesuccinate, omeprazole, ondansetron, oprelvekin, orgotein, orilotimod, oxaliplatin, oxycodone, oxymetholone, ozogamicine, p53 gene therapy, paclitaxel, palifermin, palladium-103 seed, palonosetron, pamidronic acid, panitumumab, pantoprazole, pazopanib, pegaspargase, PEG-epoetin beta (methoxy PEG-epoetin beta), pembrolizumab, pegfilgrastim, peginterferon alfa-2b, pemetrexed, pentazocine, pentostatin, peplomycin, Perflubutane, perfosfamide, Pertuzumab, picibanil, pilocarpine, pirarubicin, pixantrone, plerixafor, plicamycin, poliglusam, polyestradiol phosphate, polyvinylpyrrolidone + sodium hyaluronate, polysaccharide-K, pomalidomide, ponatinib, porfimer sodium, pralatrexate, prednimustine, prednisone, procarbazine, procodazole, propranolol, quinagolide, rabeprazole, racotumomab, radium-223 chloride, radotinib, raloxifene, raltitrexed, ramosetron, ramucirumab, ranimustine, rasburicase, razoxane, refametinib , regorafenib, risedronic acid, rhenium-186 etidronate, rituximab, romidepsin, romiplostim, romurtide, roniciclib , samarium (153Sm) lexidronam, sargramostim, satumomab, secretin, sipuleucel-T, sizofiran, sobuzoxane, sodium glycididazole, sorafenib, stanozolol, streptozocin, sunitinib, talaporfin, tamibarotene, tamoxifen, tapentadol, tasonermin, teceleukin, technetium (99mTc) nofetumomab merpentan, 99mTc-HYNIC-[Tyr3]-octreotide, tegafur, tegafur + gimeracil + oteracil, temoporfin, temozolomide, temsirolimus, teniposide, testosterone, tetrofosmin, thalidomide, thiotepa, thymalfasin, thyrotropin alfa, tioguanine, tocilizumab, topotecan, toremifene, tositumomab, trabectedin, tramadol, trastuzumab, trastuzumab emtansine, treosulfan, tretinoin, trifluridine + tipiracil, trilostane, triptorelin, trametinib, trofosfamide, thrombopoietin, tryptophan, ubenimex, valatinib , valrubicin, vandetanib, vapreotide, vemurafenib, vinblastine, vincristine, vindesine, vinflunine, vinorelbine, vismodegib, vorinostat, vorozole, yttrium-90 glass microspheres, zinostatin, zinostatin stimalamer, zoledronic acid, or zorubicin.

[0259] Furthermore, the compounds of the present invention can be combined with active ingredients, which are well known for the treatment of cancer-related pain and chronic pain. Such combinations include, but are not limited to step II opiods like codeine phosphate, dextropropoxyphene, dihydro-codeine,Tramadol), step III opiods like morphine, fentanyl, buprenorphine, oxymorphone, oxycodone and hydromorphone; and other medications used for the treatment of cancer pain like steroids as Dexamethasone and methylprednisolone; bisphosphonates like Etidronate, Clodronate, Alendronate, Risedronate, and Zoledronate; tricyclic antidepressants like Amitriptyline, Clomipramine, Desipramine, Imipramine and Doxepin; class I antiarrhythmics like mexiletine and lidocaine; anticonvulsants like carbamazepine, Gabapentin, oxcarbazepine, phenytoin, pregabalin, topiramate, alprazolam, diazepam, flurazepam, pentobarbital and phenobarbital.

[0260] In addition to those mentioned above, the inventive Bradykinin B1 inhibitors can also be combined with any of the following active ingredients: active ingredients for Alzheimer's therapy, for example acetylcholinesterase inhibitors (e.g. donepezil, rivastigmine, galantamine, tacrine), NMDA (N-methyl-D-aspartate) receptor antagonists (e.g. memantine); L-DOPA / carbidopa (L-3,4-dihydroxyphenylalanine), COMT (catechol-O-methyltransferase) inhibitors (e.g. entacapone), dopamine agonists (e.g. ropinrole, pramipexole, bromocriptine), MAO-B (monoaminooxidase-B) inhibitors (e.g. selegiline), anticholinergics (e.g. trihexyphenidyl) and NMDA antagonists (e.g. amantadine) for treatment of Parkinson's; beta-interferon (IFN-beta) (e.g. IFN beta-1b, IFN beta-1a Avonex ®< and Betaferon ®< ), glatiramer acetate, immunoglobulins, natalizumab, fingolimod and immunosuppressants such as mitoxantrone, azathioprine and cyclophosphamide for treatment of multiple sclerosis; substances for treatment of pulmonary disorders, for example beta-2-sympathomimetics (e.g. salbutamol), anticholinergics (e.g. glycopyrronium), methylxanthines (e.g. theophylline), leukotriene receptor antagonists (e.g. montelukast), PDE-4 (phosphodiesterase type 4) inhibitors (e.g. roflumilast), methotrexate, IgE antibodies, azathioprine and cyclophosphamide, cortisol-containing preparations; substances for treatment of osteoarthritis such as non-steroidal anti-inflammatory substances (NSAIDs). In addition to the two therapies mentioned, methotrexate and biologics for B-cell and T-cell therapy (e.g. rituximab, abatacept) should be mentioned for rheumatoid disorders such as rheumatoid arthritis and juvenile idiopathic arthritis. Neurotrophic substances such as acetylcholinesterase inhibitors (e.g. donepezil), MAO (monoaminooxidase) inhibitors (e.g. selegiline), interferons und anticonvulsives (e.g. gabapentin); active ingredients for treatment of cardiovascular disorders such as beta-blockers (e.g. metoprolol), ACE inhibitors (e.g. benazepril), diuretics (e.g. hydrochlorothiazide), calcium channel blockers (e.g. nifedipine), statins (e.g. simvastatin); anti-diabetic drugs, for example metformin and glibenclamide, sulphonylureas (e.g. tolbutamide) and insulin therapy for treatment of diabetes and metabolic syndrome. Active ingredients such as mesalazine, sulfasalazine, azathioprine, 6-mercaptopurine or methotrexate, probiotic bacteria (Mutaflor, VSL#3 ®< , Lactobacillus GG, Lactobacillus plantarum, L. acidophilus, L. casei, Bifidobacterium infantis 35624, Enterococcus fecium SF68, Bifidobacterium longum, Escherichia coli Nissle 1917), antibiotics, for example ciprofloxacin and metronidazole, anti-diarrhoea drugs, for example loperamide, or laxatives (bisacodyl) for treatment of chronic-inflammatory bowel disorders. Immunosuppressants such as glucocorticoids and non-steroidale anti-inflammatory substances (NSAIDs), cortisone, chloroquine, cyclosporine, azathioprine, belimumab, rituximab, cyclophosphamide for treatment of lupus erythematosus. By way of example but not exclusively, calcineurin inhibitors (e.g. tacrolimus and ciclosporin), cell division inhibitors (e.g. azathioprine, mycophenolate mofetil, mycophenolic acid, everolimus or sirolimus), rapamycin, basiliximab, daclizumab, anti-CD3 antibodies, anti-T-lymphocyte globulin / antilymphocyte globulin for organ transplants, Vitamin D3 analogues, for example calcipotriol, tacalcitol or calcitriol, salicylic acid, urea, ciclosporine, methotrexate, or efalizumab for dermatological disorders.Methods of treating

[0261] The present invention relates to a method for using the compounds of the present invention and compositions thereof, to inhibit the Bradykinin B1 receptor.

[0262] The present invention relates to a method for using the compounds of the present invention and compositions thereof, to treat mammalian disorders and diseases which include but are not limited to:

[0263] Diseases related to pain and inflammation, in particular selected from the group consisting of visceral pain e.g. related to pancreatitis, interstitial cystitis, bladder pain syndrome, renal colic, or prostatitis, chronic pelvic pain, or pain related to infiltrating endometriosis; neuropathic pain such as post herpetic neuralgia, acute zoster pain, pain related to nerve injury, the dynias, including vulvodynia, phantom limb pain, pain related to root avulsions, pain related to radiculopathy, painful traumatic mononeuropathy, painful entrapment neuropathy, pain related to carpal tunnel syndrome, ulnar neuropathy, pain related to tarsal tunnel syndrome, painful diabetic neuropathy, painful polyneuropathy, trigeminal neuralgia, or pain related to familial amyloid polyneuropathy; central pain syndromes potentially caused by virtually any lesion at any level of the nervous system including but not limited to pain related to stroke, multiple sclerosis, and spinal cord injury; postsurgical pain syndromes (including postmastectomy pain syndrome, postthoracotomy pain syndrome, stump pain), bone and joint pain (osteoarthritis), spine pain (including acute and chronic low back pain, neck pain, pain related to spinal stenosis), shoulder pain, repetitive motion pain, dental pain, pain related to sore throat, cancer pain, burn pain including sun-burn, myofascial pain (pain related to muscular injury, fibromyalgia) postoperative, and perioperative pain (including but not limited to general surgery, orthopaedic, and gynaecological surgery); and acute and chronic pain, chronic pelvic pain, endometriosis associated pain, dysmenorrhea associated pain (primary and secondary), pain associated with uterine fibroids, vulvodynia associated pain, as well as pain associated with angina, or inflammatory pain of varied origins (including but not limited to pain associated with osteoarthritis, rheumatoid arthritis, rheumatic disease, tenosynovitis, gout, ankylosing spondylitis, and bursitis); and diseases like or related to a disease selected from related to the group consisting of: gynaecological disorders and / or diseases, or effects and / or symptoms which negatively influence women health including endometriosis, uterine fibroids, pre-eclampsia, hormonal deficiency, spasms of the uterus, or heavy menstrual bleeding; the respiratory or excretion system including any of inflammatory hyperreactive airways, inflammatory events associated with airways disease like chronic obstructive pulmonary disease, asthma including allergic asthma (atopic or non-atopic) as well as exercise-induced bronchoconstriction, occupational asthma, viral or bacterial exacerbation of asthma, other non-allergic asthmas and wheezy-infant syndrome, chronic obstructive pulmonary disease including emphysema, adult respiratory distress syndrome, bronchitis, pneumonia, cough, lung injury, lung fibrosis, allergic rhinitis (seasonal and perennial), vasomotor rhinitis, angioedema (including hereditary angioedema and drug-induced angioedema including that caused by angiotensin converting enzyme (ACE) or ACE / neutral endopeptidase inhibitors like omepatrilat), pneumoconiosis, including aluminosis, anthracosis, asbestosis, chalicosis, ptilosis, siderosis, silicosis, tabacosis and byssinosis, bowel disease including Crohn's disease and ulcerative colitis, irritable bowel syndrome, pancreatitis, nephritis, cystitis (interstitial cystitis), bladder pain syndrome, kidney fibrosis, kidney failure, hyperactive bladder, and overactive bladder; dermatology including pruritus, itch, inflammatory skin disorders including psoriasis, eczema, and atopic dermatitis; affection of the joints or bones including rheumatoid arthritis, gout, osteoporosis, osteoarthritis, and ankylosing spondylitis; affection of the central and peripheral nervous system including neurodegenerative diseases including Parkinson's and Alzheimer's disease, amyotrophic lateral sclerosis (ALS), epilepsy, dementia, headache including cluster headache, migraine including prophylactic and acute use, stroke, closed head trauma, and multiple sclerosis; infection including HIV infection, and tuberculosis; trauma associated with oedema including cerebral oedema, burns, sunburns, and sprains or fracture; poisoning including aluminosis, anthracosis, asbestosis, chalicosis, ptilosis, siderosis, silicosis, tabacosis, and byssinosis uveitis; diabetes cluster or metabolism like diabetes type 1, diabetes type 2, diabetic vasculopathy, diabetic neuropathy, diabetic retinopathy, post capillary resistance or diabetic symptoms associated with insulitis (e.g. hyperglycaemia, diuresis, proteinuria and increased nitrite and kallikrein urinary excretion), diabetic macular oedema, metabolic syndrome, insulin resistance, obesity, or fat or muscle metabolism; cachexia associated with or induced by any of cancer, AIDS, coeliac disease, chronic obstructive pulmonary disease, multiple sclerosis, rheumatoid arthritis, congestive heart failure, tuberculosis, familial amyloid polyneuropathy, mercury poisoning (acrodynia), and hormonal deficiency; cardio-vascular system including congestive heart failure, atherosclerosis, congestive heart failure, myocardial infarct, and heart fibrosis; and other conditions including primary peritonitis, secondary peritonitis,, septic shock, sepsis, muscle atrophy, spasms of the gastrointestinal tract, benign prostatic hyperplasia, and liver diseases such as non-alcoholic and alcoholic fatty liver disease, non-alcoholic and alcoholic steatohepatitis, liver fibrosis, or liver cirrhosis.

[0264] A preferred embodiment of the present invention relates to a method for using the compounds of the present invention and compositions thereof, to treat a gynaecological disease, preferably dysmenorrhea, dyspareunia or endometriosis, endometriosis-associated pain, or other endometriosis-associated symptoms, wherein said symptoms include dysmenorrhea, dyspareunia, dysuria, or dyschezia. Additionally the present invention relates to a method for using the compounds of the present invention and compositions thereof, to treat osteoarthritis, rheumatoid arthritis, gout, neuropathic pain, asthma, cough, lung injury, lung fibrosis, pneumonia, kidney fibrosis, kidney failure pruritus, irritable bowel disease, overactive urinary bladder, diabetes type 1, diabetes type 2, diabetic neuropathy, diabetic retinopathy, diabetic macular oedema, metabolic syndrome, obesity, heart fibrosis, cachexia, muscle atrophy, Alzheimer's disease, bladder pain syndrome and interstitial cystitis.

[0265] These disorders have been well characterized in humans, but also exist with a similar etiology in other mammals, and can be treated by administering pharmaceutical compositions of the present invention.

[0266] The term "treating" or "treatment" as stated throughout this document is used conventionally, e.g., the management or care of a subject for the purpose of combating, alleviating, reducing, relieving, improving the condition of, etc., of a disease or disorder, such as a gynaecological disease.Dose and administration

[0267] Based upon standard laboratory techniques known to evaluate compounds useful for the treatment of disorders and / or diseases which are mediated by Bradykinin B1 receptor, by standard toxicity tests and by standard pharmacological assays for the determination of treatment of the conditions identified above in mammals, and by comparison of these results with the results of known medicaments that are used to treat these conditions, the effective dosage of the compounds of this invention can readily be determined for treatment of each desired indication. The amount of the active ingredient to be administered in the treatment of one of these conditions can vary widely according to such considerations as the particular compound and dosage unit employed the mode of administration, the period of treatment, the age and sex of the patient treated, and the nature and extent of the condition treated.

[0268] The total amount of the active ingredient to be administered will generally range from about 0.001 mg / kg to about 200 mg / kg body weight per day, preferably from about 0.01 mg / kg to about 20 mg / kg body weight per day. A preferred administration of the compound of the present invention includes but is not limited to 0.1 mg / kg to about 10 mg / kg body weight per day. Clinically useful dosing schedules will range from one to three times a day dosing to once every four weeks dosing. In addition, "drug holidays" in which a patient is not dosed with a drug for a certain period of time, may be beneficial to the overall balance between pharmacological effect and tolerability. A unit dosage may contain from about 0.5 mg to about 1500 mg of active ingredient, and can be administered one or more times per day or less than once a day. A preferred oral unit dosage for administration of the compounds of the present invention includes but is not limited to 0.1 mg / kg to about 10 mg / kg body weight one to three times a day to once a week. The average daily dosage for administration by injection, including intravenous, intramuscular, subcutaneous and parenteral injections, and use of infusion techniques will preferably be from 0.01 to 200 mg / kg of total body weight. The average daily rectal dosage regimen will preferably be from 0.01 to 200 mg / kg of total body weight. The average daily vaginal dosage regimen will preferably be from 0.01 to 200 mg / kg of total body weight. The average daily topical dosage regimen will preferably be from 0.1 to 200 mg administered between one to four times daily. The transdermal concentration will preferably be that required to maintain a daily dose of from 0.01 to 200 mg / kg of total body weight. The average daily inhalation dosage regimen will preferably be from 0.01 to 100 mg / kg of total body weight.

[0269] Of course the specific initial and continuing dosage regimen for each patient will vary according to the nature and severity of the condition as determined by the attending diagnostician, the activity of the specific compound employed, the age and general condition of the patient, time of administration, route of administration, rate of excretion of the drug, drug combinations, and the like. The desired mode of treatment and number of doses of a compound of the present invention or a pharmaceutically acceptable salt or ester or composition thereof can be ascertained by those skilled in the art using conventional treatment tests.

[0270] Preferably, the diseases treated with said method are gynaecological disorders, more preferably dysmenorrhea, dyspareunia or endometriosis, endometriosis-associated pain, or other endometriosis-associated symptoms, wherein said symptoms include dysmenorrhea, dyspareunia, dysuria, or dyschezia. Further diseases which can be treated with said method are osteoarthritis, rheumatoid arthritis, gout, neuropathic pain, asthma, cough, lung injury, lung fibrosis, pneumonia, kidney fibrosis, kidney failure pruritus, irritable bowel disease, overactive urinary bladder, diabetes type 1, diabetes type 2, diabetic neuropathy, diabetic retinopathy, diabetic macular oedema, metabolic syndrome, obesity, heart fibrosis, cachexia, muscle atrophy, Alzheimer's disease, bladder pain syndrome and interstitial cystitis.

[0271] Preferably, the method of treating the diseases mentioned above is not limited to the treatment of said disease but also includes the treatment of pain related to or associated with said diseases.

[0272] The compounds of the present invention can be used in particular in therapy and prevention, i.e. prophylaxis, of genitourinary, gastrointestinal, respiratory or pain-related disease, condition or disorder.

[0273] Methods of testing for a particular pharmacological or pharmaceutical property are well known to persons skilled in the art.

[0274] The example testing experiments described herein serve to illustrate the present invention and the invention is not limited to the examples given.Synthesis of compounds of general formula (I) of the present invention

[0275] Compounds of general formula (I) with the meaning of R 1< , R 2< , R 3< , R 5< , R 6< and R 7< as defined in general formula (I), can be synthesised according to various general procedures.

[0276] Scheme 1 depicts the synthesis starting from synthons of the formula (II), wherein Hal stands for Cl, Br or I, Br being preferred; and wherein ALK stands for C 1 -C 5 -alkyl, methyl, ethyl and propyl being preferred). The aryl halides of the general formula (II) can be cross-coupled with boronic acids of the general formula (III) or alternatively with their respective pinacol esters to yield compounds of general formula (IV) by Pd-mediated reactions (Suzuki coupling) known to those skilled in the art. A suitable solvent (for example N,N-dimethylformamide, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane and optionally water) is used and a base (such as triethylamine, potassium carbonate, caesium carbonate) and a catalyst-ligand mixture, for example of palladium(II) acetate / triphenylphosphine, tetrakis-(triphenylphosphine)palladium(0), bis(triphenylphosphine)palladium(II) dichloride, bis(diphenylphosphino)ferrocenedichloropalladium (II) is utilised at temperatures between 20 °C and 120 °C, preferred at 100 °C.

[0277] Aromatic amines of general formula (IV) may react with carboxylic acids of general formula (V) by methods known to those skilled in the art to give the amide compounds of general formula (VI). The reaction is mediated by activating a carboxylic acid of general formula (V) with reagents such as dicyclohexylcarbodiimide (DCC), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI), N-hydroxybenzotriazole (HOBT), N-[(dimethylamino)-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yloxy)methyliden]-N-methylmethanaminium hexafluorophosphate (HATU) or propylphosphonic anhydride (T3P). For example, the reaction with HATU takes place in an inert solvent, such as N,N-dimethylformamide, dichloromethane or dimethyl sulfoxide in the presence of the appropriate aniline of general formula (IV) and a tertiary amine (such as triethylamine or diisopropylethylamine) at temperatures between -30 °C and +60 °C.

[0278] It is also possible to convert a carboxylic acid of the general formula (V) into the corresponding carboxylic acid chloride with an inorganic acid chloride (such as phosphorus pentachloride, phosphorus trichloride or thionyl chloride) and then into the amide compounds of general formula (VI), in pyridine or a solvent (such as dichloromethane, or N,N-dimethylformamide), in the presence of the appropriate amine formula (IV) and a tertiary amine (for example triethylamine) at temperatures between -30 °C and +60 °C. The ester moiety of compounds of general formula (VI) are then converted to the final target compounds of general formula (I) by ester group saponification in a solvent (such as tetrahydrofuran, methanol or N,N-dimethylformamide) using an appropriate base (for example aqueous lithium hydroxide or aqueous sodium hydroxide) at temperatures between 0 °C and +80 °C. Alternatively, the ester compounds of general formula (VI) can be converted to the final target compounds of general formula (I) by ester group saponification using an appropriate inorganic acid (for example hydrochloric acid or sulfuric acid) at temperatures between 0 °C and +80 °C, usually at circa +60 °C.

[0279] Aryl halides of the general formula (II) are either commercially available or can be synthesised by those skilled in the art from the corresponding carboxylic acid compound. For example, by reacting the corresponding carboxylic acid with an alcohol (such as methanol, ethanol or propanol) in inorganic acid (for example hydrochloric acid or sulfuric acid) at temperatures between 0 °C and 100 °C.

[0280] The starting materials of the general formula (II) are either commercially available or can be synthesized via methods known to those skilled in the art from appropriate precursors. For example, the amino group may be obtained by reduction of the corresponding nitro group with hydrogen in the presence of a palladium catalyst in solvents like ethanol, ethyl acetate or mixtures thereof. Alternatively, the nitro group may be reduced using iron powder in solvents like methanol or ethanol in the presence of acid (such as hydrochloric or acetic acid). The nitro group may be introduced by classical methods like treatment with nitric acid / sulphuric acid or potassium nitrate / sulphuric acid (with appropriate concentration and volume ratio) at temperatures between 0 °C and 25 °C. The sequence of reaction steps (nitro reduction, Suzuki reaction, amide formation, nitrile hydrolysis) may be changed as appropriate.

[0281] The carboxylic acids of the general formula (V) are either commercially available or can be synthesized via methods known to those skilled in the art from appropriate precursors. For example, arylcyclopropanecarboxylic acids may be prepared from the corresponding arylacetonitrile by cyclopropanation with 1-bromo-2-chloroethane (1.5 eq) in aqueous base (such as sodium hydroxide solution) in the presence of benzyltriethylammonium chloride (0.02 eq.) and subsequent acidic or basic hydrolysis of the nitrile with e.g. lithium hydroxide in water or concentrated hydrochloric acid at temperatures between 20 °C and 100 °C.

[0282] Scheme 2 depicts the synthesis starting from synthons of the formula (VII), wherein Hal stands for Cl, Br or I, Br being preferred. The aryl halides of the general formula (VII) can be cross-coupled with boronic acids of the general formula (III) or alternatively with their respective pinacol esters to yield compounds of general formula (VIII) by Pd-mediated reactions (Suzuki coupling) known to those skilled in the art. A suitable solvent (for example N,N-dimethylformamide, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane and optionally water) is used and a base (such as potassium carbonate or caesium carbonate) and a catalyst-ligand mixture, for example of palladium(II) acetate / triphenylphosphine, tetrakis(triphenylphosphine)palladium(0), bis(triphenylphosphine)-palladium(II) dichloride, bis(diphenylphosphino)ferrocenedichloropalladium (II) is utilised at temperatures between 20 °C and 120 °C, preferred at 100 °C. The nitro group of a compound of general formula (VIII) is then reduced to the corresponding aniline of general formula (IX) by reaction under a hydrogen atmosphere in the presence of a palladium catalyst (for example 5-10% palladium on carbon) in an appropriate solvent (for example ethanol or ethyl acetate) at temperatures between 0 °C and 100 °C. In analogy to the procedures described for Scheme 1, amide coupling gives compounds of the general formula (X). The nitrile moiety of formula (X) is hydrolysed to carboxylic acid of general formula (I) by reaction with either an inorganic base (for example aqueous lithium hydroxide or aqueous sodium hydroxide) or an inorganic acid (for example hydrochloric acid or sulfuric acid) optionally in an inert solvent (such as tetrahydrofuran, 1,4-dioxane or N,N-dimethylformamide) at temperatures between 10 °C and 100 °C.

[0283] Scheme 3 shows an alternative approach in which the sequence of reaction steps is changed and the nitrile moiety of general formula (IX) is transformed into an ester group in two steps (wherein ALK stands for methyl, ethyl or propyl) and later revealed as the carboxylic acid group. Starting from synthons of general formula (IX), first the nitrile is converted into the carboxylic acid of general formula (XI) and then reacted with a suitable alcohol (such as methanol, ethanol or propanol) in inorganic acid (for example hydrochloric acid or sulfuric acid) at temperatures between 0 °C and 100 °C to form ester compounds of general formula (IV). In analogy to the procedures described for Scheme 1, amide coupling gives compounds of the general formula (VI), followed by ester group saponification to yield the target compounds of general formula (I).

[0284] Scheme 4 shows an alternative approach to synthesis of compounds of general formula (I) where R 1< is an N-linked optionally substituted 5-membered heteroaryl group, for example pyrazolyl or imidazolyl, or alternatively R 1< is an N-linked optionally substituted bicyclic 8- to 10-membered heteroaryl group, for example indole. Starting from synthons of the general formula (VII) (wherein Hal stands for F, Cl or Br) the aryl halide can first be substituted by a nucleophile of general formula (XIV) to yield a compound of general formula (VIII). The substitution takes place in a dipolar aprotic solvent such as acetonitrile, dimethylsulfoxide or N,N-dimethylformamide and in the presence of an appropriate base (for example potassium carbonate or sodium hydride) at temperatures between 20 °C and 100 °C, preferably at 60 °C. In analogy to the procedures described for Scheme 2, nitro group reduction followed by amide formation gives compounds of general formula (X) that are subsequently converted to the final targets of general formula (I) by nitrile group hydrolysis.

[0285] In Scheme 4 general formula (XIV) represents R 1< -H wherein R 1< is an optionally substituted 5-membered heteroaryl group linked through a ring nitrogen atom to the hydrogen atom, or R 1< is an optionally substituted bicyclic 8- to 10-membered heteroaryl linked through a ring nitrogen atom to the hydrogen atom.

[0286] Scheme 5 shows an alternative approach to synthesis compounds of general formula (I) where R 1< is an N-linked optionally substituted 5-membered heteroaryl group, for example pyrazolyl or imidazolyl, or alternatively R 1< is an N-linked optionally substituted bicyclic 8- to 10-membered heteroaryl group, for example indole. Starting from synthons of the general formula (XII) (wherein Hal stands for F, Cl or Br; and wherein ALK stands for methyl, ethyl or propyl), the aryl halide can first be substituted by a nucleophile of general formula (XIV) to yield a compound of general formula (XIII). The substitution takes place in a dipolar aprotic solvent such as acetonitrile, dimethylsulfoxide or N,N-dimethylformamide and in the presence of an appropriate base (for example potassium carbonate or sodium hydride) at temperatures between 20 °C and 100 °C, preferably at 60 °C. In analogy to the procedures described for Scheme 2, nitro reduction gives compounds of general formula (IV), followed by amide coupling gives compounds of the general formula (VI), followed by ester group saponification to yield the target compounds of general formula (I).

[0287] In Scheme 5 general formula (XIV) represents R 1< -H wherein R 1< is an optionally substituted 5-membered heteroaryl group linked through a ring nitrogen atom to the hydrogen atom, or R 1< is an optionally substituted bicyclic 8- to 10-membered heteroaryl linked through a ring nitrogen atom to the hydrogen atom.

[0288] Scheme 6 depicts the synthesis starting from synthons of the formula (XV), wherein Hal stands for Br or I, Br being preferred. The aryl halides of the general formula (XV) can be cross-coupled with boronic acids of the general formula (III) or alternatively with their respective pinacol esters to yield compounds of general formula (XVI) by Pd-mediated reactions (Suzuki coupling) known to those skilled in the art. A suitable solvent (for example N,N-dimethylformamide, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane and optionally water) is used and a base (such as triethylamine, potassium carbonate, caesium carbonate) and a catalyst-ligand mixture, for example of palladium(II) acetate / triphenylphosphine, tetrakis-(triphenylphosphine)palladium(0), bis(triphenylphosphine)-palladium(II) dichloride, bis(diphenylphosphino)ferrocenedichloropalladium (II) is utilised at temperatures between 20 °C and 120 °C, preferred at 100 °C. The chloro group of a compound of general formula (XVI) is converted to a nitrile group to yield compounds of general formula (IX), by Pd-mediated cyanation reactions with potassium ferrocyanide known to those skilled in the art. A suitable solvent mixture (for example 1,4-dioxane or tetrahydrofuran and optionally water) is used and a base (such as potassium acetate) and a catalyst-ligand mixture (for example tris[dibenzylideneacetone]dipalladium / dicyclohexyl[2',4',6'-tri(propan-2-yl)biphenyl-2-yl]phosphane) is utilised at temperatures between 20 °C and 120 °C, usually 100 °C. In analogy to the procedures described for Scheme 3, the nitrile moiety of general formula (IX) is converted into the carboxylic acid of general formula (XI) and then reacted with a suitable alcohol (such as methanol, ethanol or propanol; wherein ALK stands for methyl, ethyl or propyl) in inorganic acid (for example hydrochloric acid or sulfuric acid) at temperatures between 0 °C and 100 °C to form ester compounds of general formula (IV). In analogy to the procedures described for Scheme 1, amide coupling gives compounds of the general formula (VI), followed by ester group saponification to yield the target compounds of general formula (I). The sequence of reaction steps (nitrile hydrolysis, amide formation) may be changed as appropriate. In analogy with Scheme 2, final compounds of general formula (I) can be accessed directly via nitrile group hydrolysis carried out as a final transformation.

[0289] Scheme 7 shows an alternative approach to synthesis of compounds of general formula (I) with the meaning of R 1< , R 2< , X and R 3< as defined in general formula (I). The aryl group of general formula (XVII) can be nitrated by reaction with a mixture of nitric acid and sulfuric acid at temperatures between -20 °C and +20 °C, preferred below +10 °C. The carboxylic acid group of a compound of general formula (XVIII) is reacted with a suitable alcohol (such as methanol, ethanol or propanol; wherein ALK stands for methyl, ethyl or propyl) in inorganic acid (for example hydrochloric acid or sulfuric acid) at temperatures between 0 °C and 100 °C to form ester compounds of general formula (XIX). The hydroxy group of a compound of general formula (XIX) is converted to a triflate group to yield compounds of general formula (XX), by reaction with trifluoromethanesulfonic anhydride in base (for example triethylamine) and an inert solvent (such as dichloromethane) at temperatures between -20 °C and + 40 °C, usually at 0 °C. The aryl triflates of the general formula (XX) can be cross-coupled with boronic acids of general formula (III) or alternatively with their respective pinacol esters to yield compounds of general formula (XIII), by Pd-mediated reactions (Suzuki coupling) known to those skilled in the art. A suitable solvent (for example N,N-dimethylformamide, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane and optionally water) is used and a base (such as triethylamine, potassium carbonate, caesium carbonate) and a catalyst-ligand mixture, for example of palladium(II) acetate / triphenylphosphine, tetrakis(triphenylphosphine)palladium(0), bis(triphenylphosphine)-palladium(II) dichloride, bis(diphenylphosphino)ferrocene-dichloropalladium (II) is utilised at temperatures between 20 °C and 120 °C, preferred at 100 °C. In analogy to the procedures described for Scheme 2, nitro group reduction followed by amide formation gives compounds of general formula (VI) that are subsequently converted to the final targets of general formula (I) by ester group hydrolysis as detailed in Scheme 1.

[0290] Scheme 8 shows an alternative approach to synthesis of compounds of general formula (I). Starting from synthons of general formula (XXI), the aniline can first be protected using a combination of two equivalents of a strong base (such as nBuLi) and 1,2-bis(chlorodimethylsilyl)ethane. The intermediate obtained can then be lithiated in situ using nBuLi and then quenched with an alkylchloroformate (such as ethylchloroformate). Subsequent treatment with an inorganic aqueous acid (such as hydrochloric acid) gives compounds of general formula (XXII) wherein ALK stands for methyl, ethyl or propyl. In analogy to the procedures described for Scheme 1, Suzuki coupling followed by amide coupling gives compounds of the general formula (VI). Subsequent ester group saponification yields the target compounds of general formula (I).

[0291] Scheme 9 shows an alternative approach to synthesis of compounds of general formula (I) in which the sequence of reaction steps is changed in comparison to Scheme 1, wherein Hal stands for Cl, Br or I, Br being preferred; and wherein ALK stands for methyl, ethyl or propyl. Starting from synthons of the general formula (II), the aromatic amine may react with carboxylic acids of general formula (V) by methods known to those skilled in the art to give the amide compounds of general formula (XXIII). The reaction is mediated by activating a carboxylic acid of general formula (V) with reagents such as dicyclohexylcarbodiimide (DCC), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI), N-hydroxybenzotriazole (HOBT), N-[(di-methylamino)-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yloxy)methyliden]-N-methyl-methanaminium hexafluorophosphate (HATU) or propylphosphonic anhydride (T3P). For example, the reaction with T3P takes place in an inert solvent, such as N,N-dimethylformamide or dichloromethane in the presence of the appropriate aniline general formula (II) and a tertiary amine (such as triethylamine or diisopropylethylamine) at temperatures between -30 °C and +60 °C.

[0292] The aryl halides of the general formula (XXIII) can be cross-coupled with boronic acids of the general formula (III) or alternatively with their respective pinacol esters to yield compounds of general formula (VI) by Pd-mediated reactions (Suzuki coupling) known to those skilled in the art. A suitable solvent (for example N,N-dimethylformamide, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane and optionally water) is used and a base (such as potassium carbonate or caesium carbonate) and a catalyst-ligand mixture, for example of palladium(II) acetate / triphenylphosphine, tetrakis(triphenylphosphine)palladium(0), bis(triphenylphosphine)palladium(II) dichloride, bis(diphenylphosphino)ferrocenedichloro-palladium (II) is utilised at temperatures between 20 °C and 120 °C, preferred at 100 °C. In analogy to the procedures described for Scheme 1, ester group saponification of an intermediate compound of general formula (VI) yields the target compounds of general formula (I).

[0293] Scheme 10 shows an alternative approach to synthesis of compounds of general formula (I). Alkylation of 2-acetylbutyrolactones of general formula (XXIV) can be achieved with an alkylating agent of general formula (XXV) wherein X stands for Cl, Br or I, Br being preferred in the presence of a base (such as potassium carbonate or sodium carbonate) in an apolar solvent (such as acetonitrile or tetrahydrofuran) at a temperature between 20 °C and 60 °C. Subsequent rearrangement of compounds of general formula (XXVI) to give cyclopropanes of general formula (XXVII) can be achieved via reaction with lithium iodide in a polar solvent (such as dimethylformamide or 1-methyl-2-pyrrolidinone) at temperatures between 100 °C and 200 °C. Carboxylic acids of general formula (V) can then be formed via reaction of compounds of general formula (XXVII) with bromine or iodine in the presence of a sodium hydroxide in a solvent (such as tetrahydrofuran or 1,4-dioxane) at temperatures between 0 °C to 20 °C. In analogy to the procedures described for Scheme 1, amide coupling gives compounds of the general formula (VI). Subsequent ester group saponification yields the target compounds of general formula (I).

[0294] Scheme 11 shows an alternative approach to synthesis of compounds of general formula (I). Starting from synthons of the general formula (XII) (wherein Hal stands for Cl, Br or I; and wherein ALK stands for methyl, ethyl or propyl) the aryl halide can first be converted to a stannane of general formula (XXVIII) via reaction with hexabutyldistannane in the presence of a palladium catalyst (such as tetrakis-(triphenylphosphine)palladium(0), bis(triphenylphosphine)-palladium(II) dichloride) in a suitable solvent (for example N,N-dimethylformamide, tetrahydrofuran, 1,4-dioxane or 1,2-dimethoxyethane) at temperatures between 20 °C and 120 °C, preferred at 100 °C. The aryl stannane of the general formula (XXVIII) can then be cross-coupled with aryl halides of the general formula (XXIX), with the meaning of R 1< as defined in general formula (I), by Pd-mediated reactions (Stille coupling) known to those skilled in the art. A suitable solvent (for example N,N-dimethylformamide, tetrahydrofuran, 1,4-dioxane or 1,2-dimethoxyethane) is used with a catalyst-ligand mixture, for example of palladium(II) acetate / triphenylphosphine, tetrakis(triphenylphosphine)palladium(0), bis(triphenylphosphine)-palladium(II) dichloride, bis(diphenylphosphino)ferrocenedichloropalladium (II) is utilised at temperatures between 20 °C and 120 °C, preferred at 100 °C. In analogy to the procedures described for Scheme 1, nitro reduction gives compounds of general formula (IV), followed by amide coupling gives compounds of the general formula (VI), followed by ester group saponification to yield the target compounds of general formula (I). Experimental Section

[0295] The example testing experiments described herein serve to illustrate the present invention and the invention is not limited to the examples given.

[0296] The following table lists the abbreviations used in this paragraph, and in the examples section. Abbreviation Meaning Cs 2 CO 3 Cesium carbonateCu(I)ClCopper(I) chlorideca.circaDCE1,2-DichloroethaneDCMDichloromethaneDIADDiisopropyl azodicarboxylateDIPEAN-Ethyl-N-isopropylpropan-2-amineDMAPN,N-Dimethylpyridin-4-amineDME1,2-DimethoxyethaneDMFN,N-DimethylformamideDMSODimethyl sulfoxideDPDesired productEEEthyl acetatehHourHATUN-[(Dimethylamino)(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yloxy)methylene]-N-methylmethanaminium hexafluorophosphateHBrHydrogen bromideHClHydrochloric acidhexn-HexaneHPLCHigh performance liquid chromatographyHNO 3 Nitric acidH 2 SO 4 Sulfuric acidIntIntermediateIPCIn process checkK 2 CO 3 Potassium carbonateLC-MSliquid chromatography - mass spectrometryLCMSliquid chromatography - mass spectrometryLiOHLithium hydroxideMMolarµWMicrowaveMeCNAcetonitrileMeOHMethanolMgSO 4 Magnesium sulfateminMinute(s)NNormalNa 2 CO 3 Sodium carbonateNaHSodium hydrideNaHCO 3 Sodium bicarbonateNalSodium iodideNaOHSodium hydroxideNa 2 SO 4 Sodium sulfateNH 4 ClAmmonium chlorideNMRnuclear magnetic resonance spectroscopyPdCl 2 (PPh 3 ) 2 Bis(triphenylphosphine)palladium(II) dichloridePd(dppf)Cl 2 [1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II)Pd(dppf)Cl 2 ·CH 2 Cl 2 1,1'-Bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complexPPh 3 Triphenylphosphineppmparts per millionPyPyridineRTRoom temperaturertRetention timeRtRetention timesat.SaturatedSEM2-(trimethylsi lyl)ethoxymethylSMStarting materialSTABSodium triacetoxyborohydrideHSnBu 3 Tributyltin hydrideTMS-azideAzidotrimethylsilaneTMS-N 3 AzidotrimethylsilaneT3PPropylphosphonic anhydrideTBABTetra-N-butylammonium bromideTBAITetra-N-butylammonium iodideTBMEtert-Butyl methyl etherTEATriethylamineTFATrifluoroacetic acid(Tf) 2 OTrifluoromethanesulfonic anhydrideTfO-TrifluoromethanesulfonateTHFTetrahydrofuran Analysis methods Analytical LCMS methods

[0297] Method 1: Instrument: Waters Acquity Platform ZQ4000; column: Waters BEHC 18, 50 mm × 2.1 mm, 1.7µ; eluent A: water / 0.05% formic acid, eluent B: acetonitrile / 0.05% formic acid; gradient: 0.0 min 98% A → 0.2 min: 98% A → 1.7 min: 10% A → 1.9 min: 10% A → 2 min: 98% A → 2.5 min: 98% A; flow: 1.3 ml / min; column temperature: 60°C; UV-detection: 200-400 nm.

[0298] Method 2: Instrument: Waters Acquity LCT; column: Phenomenex Kinetex C18, 50 mm × 2.1 mm, 2.6µ; eluent A: water / 0.05% formic acid, eluent B: acetonitrile / 0.05% formic acid; gradient: 0.0 min 98% A → 0.2 min: 98% A → 1.7 min: 10% A → 1.9 min: 10% A → 2 min: 98% A → 2.5 min: 98% A; flow: 1.3 ml / min; column temperature: 60°C; UV-detection: 200-400 nm.

[0299] Method 3: Instrument: Waters Acquity UPLCMS SingleQuad; Column: Acquity UPLC BEH C18 1.7 µm, 50×2.1mm; eluent A: water + 0.1 vol % formic acid (99%), eluent B: acetonitrile; gradient: 0-1.6 min 1-99% B, 1.6-2.0 min 99% B; flow 0.8 ml / min; temperature: 60 °C; DAD scan: 210-400 nm.

[0300] Method 4: Instrument: Waters Acquity UPLCMS SingleQuad; Column: Acquity UPLC BEH C18 1.7 µm, 50×2.1mm; eluent A: water + 0.2 vol % aqueous ammonia (32%), eluent B: acetonitrile; gradient: 0-1.6 min 1-99% B, 1.6-2.0 min 99% B; flow 0.8 ml / min; temperature: 60 °C; DAD scan: 210-400 nm.LC-MS, Analytical Method A: Routine high throughput analysis

[0301] Column: Kinetex Core-Shell C18, 2.1 × 50 mm, 5µm; Eluent A: Water + 0.1% Formic acid, Eluent B: Acetonitrile + 0.1% Formic acid; Gradient 0.00 mins 95% A → 1.20 mins 100% B → 1.30 mins 100% B → 1.31 mins 95% A; column temperature: 40 °C; flow rate 1.2 ml / min; injection volume: 3 µl; UV-detection range: 210-420 nm.LC-MS, Analytical Method B: Routine high throughput analysis

[0302] Column: Waters Atlantis dC18, 2.1 × 50 mm, 3µm; Eluent A: Water + 0.1% Formic acid, Eluent B: Acetonitrile + 0.1% Formic acid; Gradient 0.00 mins 95% A → 2.5 mins 100% B → 2.7 mins 100% B → 2.71 mins 5% A → 3.5 mins 5% A; column temperature: 40 °C; flow rate 1.0 ml / min; injection volume: 3 µl; UV-detection range: 210-420 nm.LC-MS, Analytical Method C: Routine high throughput analysis at high pH

[0303] Column: Phenomenex Gemini-NX C18, 2.0 × 50 mm, 3 µm; Eluent A: 2 mM ammonium bicarbonate, buffered to pH10, Eluent B: Acetonitrile; Gradient 0.00 mins 99% A → 1.80 mins 100% B → 2.10 mins 100% B → 2.30 mins 99% A → 3.50 mins 99% A; column temperature: 40 °C; flow rate 1.0 ml / min; injection volume: 3 µl; UV-detection range: 210-420 nm.LC-MS, Analytical Method D:

[0304] Column: Waters Atlantis dC18, 2.1 × 100 mm, 3 µm; Eluent A: Water + 0.1% Formic acid, Eluent B: Acetonitrile + 0.1% Formic acid; Gradient 0.00 mins 95% A → 5.00 mins 100% B → 5.40 mins 100% B → 5.42 mins 95% A → 7.00 mins 95% A; column temperature: 40 °C; flow rate 0.6 ml / min; injection volume: 3 µl; UV-detection range: 210-420 nm.LC-MS, Analytical Method E: High pH

[0305] Column: Phenomenex Gemini -NX C18, 2.0 ×100 mm, 3 µm; Eluent A: 2 mM ammonium bicarbonate, buffered to pH10, Eluent B: Acetonitrile; Gradient 0.00 mins 95% A → 5.50 mins 100% B → 5.90 mins 100% B → 5.92 mins 95% A → 7.00 mins 95% A; column temperature: 40 °C; flow rate 0.5 ml / min; injection volume: 3 µl; UV-detection range: 210-420 nm.LC-MS, Analytical Method F:

[0306] Column: Phenomenex Kinetix-XB C18, 2.1 × 100 mm, 1.7 µm; Eluent A: Water + 0.1% Formic acid, Eluent B: Acetonitrile + 0.1% Formic acid; Gradient 0.00 mins 95% A → 5.30 mins 100% B → 5.80 mins 100% B → 5.82 mins 95% A → 7.00 mins 95% A; column temperature: 40 °C; flow rate 0.6 ml / min; injection volume: 1 µl; UV-detection range: 200-400 nm.Purification Methods:

[0307] Biotage Isolera ™< chromatography system using pre-packed silica and pre-packed modified silica cartridges.Preparative HPLC, Method A: High pH

[0308] Column : Waters Xbridge C18, 30 × 100 mm, 10 µm; Solvent A: Water + 0.2% Ammonium hydroxide, Solvent B: Acetonitrile + 0.2% Ammonium hydroxide; Gradient 0.00 mins 90% A → 0.55 mins 90% A → 14.44 mins 95% B → 16.55 mins 95% B → 16.75 90% A; column temperature: room temperature; flow rate 40 ml / min; injection volume: 1500 µl; Detection: UV 215 nm.Preparative HPLC, Method B: Low pH

[0309] Column : Waters Sunfire C18, 30 × 100mm, 10 µm; Solvent A: Water + 0.1% Formic acid, Solvent B: Acetonitrile + 0.1% Formic acid; Gradient 0.00 mins 90% A → 0.55 mins 90% A → 14.44 mins 95% B → 16.55 mins 95% B → 16.75 90% A; column temperature: room temperature; flow rate 40 ml / min; injection volume: 1500 µl; Detection: UV 215 nm.Preparative HPLC Methods Preparative HPLC, Method 1:

[0310] System: Waters autopurification system: Pump 2545, Sample Manager 2767, CFO, DAD 2996, ELSD 2424, SQD; Column: XBrigde C18 5µm 100×30 mm; Solvent: A = H2O + 0.1% Vol. formic acid (99%), B = acetonitrile; Gradient: 0-8 min 10-100% B, 8-10 min 100% B; Flow: 50 mL / min; temperature: room temp.; Solution: Max. 250 mg / max. 2.5 mL DMSO o. DMF; Injection: 1 × 2.5 mL; Detection: DAD scan range 210-400 nm; MS ESI+, ESI-, scan range 160-1000 m / z.Preparative HPLC, Method 2:

[0311] System: Waters autopurification system: Pump 2545, Sample Manager 2767, CFO, DAD 2996, ELSD 2424, SQD; Column: XBrigde C18 5µm 100x30 mm; Solvent: A = H2O + 0.1% Vol. ammonia (99%), B = acetonitrile; Gradient: 0-8 min 10-100% B, 8-10 min 100% B; Flow: 50 mL / min; temperature: room temp.; Solution: Max. 250 mg / max. 2.5 mL DMSO o. DMF; Injection: 1 × 2.5 mL; Detection: DAD scan range 210-400 nm; MS ESI+, ESI-, scan range 160-1000 m / z.EXAMPLES

[0312] Chemical naming of the Examples (also referred to as Compound Examples) and Intermediates was performed using ACD software by ACD / LABS or Marvin software by ChemAxon.

[0313] Reaction times are either specified explicitly in the protocols of the experimental section, or reactions were run until completion. Chemical reactions were monitored and their completion was judged using methods well known to the person skilled in the art, such as thin layer chromatography, e.g. on plates coated with silica gel, or by LCMS methods.Intermediate 1A: Methyl 5-amino-2-bromobenzoate

[0314]

[0315] To a 0 °C solution of 5-amino-2-bromobenzoic acid (9.85 g, 45.6 mmol) in methanol (100 mL) was added thionyl chloride (1.1 eq., 3.7 mL, 50 mmol) dropwise at 0°C. The resulting mixture was stirred at 70 °C for 16 h. The mixture was evaporated to dryness. The resulting grey solid was used without further purification.

[0316] 1< H NMR (400 MHz, DMSO-d6) δ [ppm] 3.83 (s, 3H), 6.92 (dd, 1H), 7.22 (d, 1H), 7.49 (d, 1H).

[0317] LCMS (method 3): Rt = 0.87 min, MS (ESIpos) m / z = 230 / 232 (M+H) +< , Br isotope pattern.Intermediate 2A: 1-(5-Bromopyridin-2-yl)propan-1-one

[0318]

[0319] A solution of 5-bromopyridine-2-carbonitrile (5.0 g, 27.3 mmol) was dissolved in dry tetrahydrofuran (100 mL) and cooled to -20 °C. Ethylmagnesium bromide (11.4 mL of a 3M solution in diethyl ether, 34.1 mmol) was added dropwise at this temperature, with the reaction mixture allowed to warm to RT over 2 hours. The reaction mixture was cooled to -20 °C and 1M aqueous HCl solution slowly added and the mixture allowed to re-warm to room temperature. The reaction mixture was diluted with ethyl acetate, the organic layer collected and washed with brine, dried (MgSO 4 ), filtered and concentrated at reduced pressure. The golden coloured oil crystallised to give the title compound (5.25 g, 85% yield).

[0320] 1< H NMR (250 MHz, Chloroform-d) δ [ppm] 8.74 (dd, J = 2.0, 0.9 Hz, 1H), 8.04 - 7.89 (m, 2H), 3.22 (q, J = 7.3 Hz, 2H), 1.23 (t, J = 7.3 Hz, 3H).Intermediate 3A: 5-Bromo-2-(1,1-difluoropropyl)pyridine

[0321]

[0322] To a solution of 1-(5-bromopyridin-2-yl)propan-1-one (Int 2A , 5.25 g, 24.5 mmol) dissolved in 1,2-dichloroethane (61.5 mL) under nitrogen was added diethylaminosulfur trifluoride (12.96 mL, 98.1 mmol) dropwise giving an orange solution. The reaction was warmed to 60 °C and stirred for 16 hours. The cooled reaction mixture was diluted with aqueous NaOH (2M) dropwise (CAUTION: vigorous reaction). The organic layer was removed, washed with brine, dried (MgSO 4 ), filtered and concentrated at reduced pressure and purified by Biotage Isolera ™< chromatography (silica gel, eluting with TBME / Heptane; 0 - 20%) to give the title compound (3.25 g, 50% yield) as a pale yellow oil.

[0323] 1< H NMR (250 MHz, Chloroform-d) δ [ppm] 8.74 (d, J = 2.1 Hz, 1H), 7.95 (dd, J = 8.4, 2.3 Hz, 1H), 7.55 (d, J = 8.4 Hz, 1H), 2.34 (m, 2H), 1.02 (t, J = 7.5 Hz, 3H).Intermediate 4A: 2-(1,1-Difluoropropyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine

[0324]

[0325] A solution of 5-bromo-2-(1,1-difluoropropyl)pyridine (Int 3A , 3.25 g, 12.39 mmol), bis(pinacolato)diboron (3.46 g, 13.63 mmol), potassium acetate (3.65 g, 37.17 mmol) and 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) chloride (453 mg, 0.62 mmol) in 1,4-dioxane (70 mL) was degassed via nitrogen gas balloon for 5 minutes. The reaction mixture was heated at 100 °C for 16 hours, cooled to RT and diluted with EtOAc, filtered through a plug of Celite and concentrated in vacuo. The filtrate was collected and concentrated at reduced pressure and purified by Biotage Isolera ™< chromatography (silica cartridge, eluting with a gradient of eluents; 0 - 30% EtOAc in Heptane) to give the title compound (3.25 g, 83% yield) as a golden oil that crystallised upon standing.

[0326] 1< H NMR (250 MHz, Chloroform-d) δ [ppm] 9.00 (s, 1H), 8.19 (dd, J = 7.8, 1.5 Hz, 1H), 7.62 (dd, J = 7.8, 0.8 Hz, 1H), 2.35 (m, 2H), 1.38 (s, 12H), 1.00 (t, J = 7.5 Hz, 3H).

[0327] LCMS (Analytical Method A): Rt = 0.89 mins; MS (ESIpos) m / z = 201.95 (mass of boronic acid + H) +< .Intermediate 5A: 2-(Difluoromethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine

[0328]

[0329] To a solution of 5-bromo-2-(difluoromethyl)pyridine (1.0 g, 4.8 mmol) and bis(pinacolato)diboron (1.34 g, 5.3 mmol) in dioxane (5 mL) at RT was added potassium acetate (1.4 g, 14.4 mmol). Nitrogen gas was bubbled through the mixture for 5 mins and 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) chloride (264 mg, 0.36 mmol) was added and the mixture heated at 100 °C for 1 hour. The reaction mixture was then diluted with EtOAc (50 mL), filtered over Celite and washed with EtOAc (50 mL). The filtrate was concentrated at reduced pressure and the residue purified by Biotage Isolera ™< chromatography (Biotage SNAP Cartridge KP-Sil 50 g; eluting with 0-100% EtOAc in heptane) to give the title compound (1.15 g, 89% yield) as a pale yellow crystalline solid.

[0330] 1< H NMR (500 MHz, Chloroform-d) δ [ppm] 8.97 (s, 1H), 8.21 (dd, J = 7.7, 1.4 Hz, 1H), 7.62 (d, J = 7.7 Hz, 1H), 6.64 (t, J = 55.4 Hz, 1H), 1.36 (s, 12H).

[0331] LCMS (Analytical Method A): Rt = 0.78 mins, MS (ESIPos) m / z = 173.9 (mass of boronic acid + H) +< .Intermediate 6A: 2-(1,1-Difluoroethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine

[0332]

[0333] To a solution of 5-bromo-2-(1,1-difluoroethyl)pyridine (1.69 g, 6.70 mmol) in dioxane (30 mL) was added bis(pinacolato)diboron (1.87 g, 7.37 mmol), potassium acetate (1.97 g, 20.09 mmol). The resulting mixture was degassed for five minutes with nitrogen prior to the addition of [1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (328 mg, 0.40 mmol). The mixture was heated to 100 °C and was stirred at that temperature for 2.5 hours. After this time no starting material remained according to LCMS analysis. The heat was removed and the reaction allowed to cool to room temperature, at which point it was filtered over a Celite pad, washing with MeOH (3 × 10 mL). The filtrate was concentrated under reduced pressure and purified by Biotage Isolera ™< chromatography (eluting with 0-100% EtOAc in Heptane). The title compound was obtained as an off white powder solid (1.39 g, 66% yield).

[0334] 1< H NMR (250 MHz, DMSO-d6) δ [ppm] 1.32 (s, 12H), 1.99 (t, J = 19.1 Hz, 3H), 7.71 (dd, J = 7.8, 0.9 Hz, 1H), 8.18 (dd, J = 7.8, 1.7 Hz, 1H), 8.79 - 8.87 (m, 1H).

[0335] LCMS (Analytical Method A): Rt = 0.87 mins; mass ion not observed.Intermediate 7A: 1-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl]ethanone

[0336]

[0337] To a solution of 1-(5-bromopyridin-2-yl)ethanone (2.0 g, 9.98 mmol) in dioxane (50 mL) was added bis(pinacolato)diboron (2.8 g, 11.0 mmol), potassium acetate (2.94 g, 30.0 mmol) and [1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (244 mg, 0.30 mmol) under a nitrogen atmosphere. The mixture was heated at reflux for 4 hours. The mixture was then cooled to room temperature then filtered over Celite (washing with EtOAc) and concentrated at reduced pressure. The residue was purified directly via Biotage Isolera ™< chromatography (eluting with a gradient of eluents; 0 - 50 % EtOAc in heptane) giving the desired product (2.22 g, 90% yield) as a pale yellow solid.

[0338] 1H NMR (500 MHz, DMSO-d6) δ [ppm] 8.89 (s, 1H), 8.20 (dd, J = 7.7, 1.6 Hz, 1H), 7.95 (d, J = 7.7 Hz, 1H), 2.65 (s, 3H), 1.33 (s, 12H).

[0339] LCMS (Analytical Method A): Rt=0.74 mins, mass ion not observed.Intermediate 8A: 5,5,5-Trifluoro-1-(trimethylsilyl)pent-1-yn-3-one

[0340]

[0341] To a stirred solution of ethyne-1,2-diylbis(trimethylsilane) (1.0 g, 5.868 mmol) and 3,3,3-trifluoropropanoyl chloride (0.946 g, 6.455 mmol) in dichloromethane (15 mL) was added aluminium trichloride (0.939 g, 7.042 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 1 hour and then poured into a mixture of 2M HCl (20 mL) and crushed ice (~20 g). Dichloromethane (20 mL) was added and the mixture was left standing for approximately 2 hours. The organic layer was separated and the aqueous layer was extracted with dichloromethane (20 mL). The combined organic layers were washed with brine (20 mL), dried (MgSO 4 ), filtered and concentrated at reduced pressure to give the title compound (1.18 g, 75% yield) as pale yellow oil.

[0342] 1< H NMR (500 MHz, Chloroform-d) δ [ppm] 3.38 (q, J = 10.0 Hz, 2H), 0.26 (s, 9H).Intermediate 9A: 3-(2,2,2-Trifluoroethyl)-1H-pyrazole

[0343]

[0344] To a solution 5,5,5-trifluoro-1-(trimethylsilyl)pent-1-yn-3-one (Int 8A , 1.18 g, 4.82 mmol) in ethanol (10 mL) was added hydrazine hydrate (0.469 mL, 9.63 mmol) at room temperature (an exothermic reaction was observed). The mixture was stirred for 1 hour and then concentrated at reduced pressure (-50 mbar). The residue was dissolved in dichloromethane (50 mL), washed with 2M K 2 CO 3 (20 mL), brine (20 mL), dried (Na 2 SO 4 ), filtered and concentrated at reduced pressure to give the title compound (630 mg, 73% yield) as yellow oil.

[0345] 1< H NMR (500 MHz, Chloroform-d) δ [ppm] 7.57 (d, J = 2.2 Hz, 1H), 6.35 (d, J = 1.8 Hz, 1H), 3.51 (q, J = 10.7 Hz, 2H).

[0346] LCMS (Analytical Method A): Rt = 0.81 mins; MS (ESIPos) m / z = 150.9 (M+H) +< .Intermediate 10A: 1-Cyclobutyl-3-fluoro-1H-pyrazole

[0347]

[0348] 3-Fluoro-1H-pyrazole (150 mg, 2.91 mmol) were dissolved in DMF (10 mL) at RT. Sodium hydride (152 mg, 3.49 mmol, 1.2 eq) was added and the mixture stirred for 10 min. Then cyclobutylbromide (0.82 mL, 8.71 mmol, 3 eq.) was added and the mixture stirred for 2 h at 50°C. After cooling to RT, the mixture was poured into water and extracted 4x with ethyl acetate. The combined organic layers were washed with brine, dried with sodium sulfate and the solvents removed in vacuo. The crude product afforded no further purification: 400 mg (98% of theory) pale yellow oil.

[0349] 1< H NMR (400 MHz, DMSO-d6) δ [ppm] 1.68 - 1.79 (m, 2H), 2.28 - 2.43 (m, 4H), 4.88 (quint, 1H), 5.91 (dd, 1H), 7.71 (t, 1H).

[0350] LCMS (method 1): Rt = 0.84 min; MS (ESIPos) m / z = 141 (M+H) +< .Intermediate 11A: 4-Bromo-1-cyclobutyl-3-fluoro-1H-pyrazole

[0351]

[0352] 1-Cyclobutyl-3-fluoro-1H-pyrazole (Int 10A , 400 mg, 2.85 mmol) were dissolved in 17 mL chloroform and cooled to 0°C for 10 min. Then bromine (480 mg, 3.00 mmol, 1.05 eq), dissolved in 5 mL chloroform, were added drop wise at 0°C. The mixture was stirred for 1 h, then diluted with dichloromethane. The mixture was washed with saturated sodium thiosulfate solution, then with brine, then dried with sodium sulfate and the solvents evaporated. The crude product (400 mg, 63% of theory, colourless oil) was used without further purification.

[0353] 1< H NMR (400 MHz, DMSO-d6) δ [ppm] 1.68 - 1.79 (m, 2H), 2.27 - 2.42 (m, 4H), 4.69 (quint, 1H), 8.07(d, 1H).

[0354] LCMS (method 1): Rt = 1.13 min; MS (ESIPos) m / z = 219 / 212 (M+H) +< , Br isotope pattern.Intermediate 12A: 1-Cyclobutyl-3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

[0355]

[0356] 4-Bromo-1-cyclobutyl-3-fluoro-1H-pyrazole (Int 11A , 400 mg, 1.83 mmol) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi-1,3,2-dioxaborolane (510 mg, 2.01 mmol, 1.1 eq) were dissolved in 1,4-dioxane and degassed in an Argon flow. Then (1,1'-bis(diphenylphosphino)ferrocene)-dichloropalladium(II) (100 mg, 0.14 mmol, 0.075 eq) and potassium acetate (538 mg, 5.48 mmol, 3 eq) were added and the mixture stirred for 1 h at 100 °C and for additional 2 hours at RT. The mixture was diluted with ethyl acetate, filtered through Celite and the filtrate concentrated in vacuo. The residue was filtered through silica gel (hex / EE 0-40%) to yield the title compound (420 mg) as a pale yellow oil, which crystallised on standing.

[0357] LCMS (method 3): Rt = 0.98 min; MS (ESIPos) m / z = 367 (M+H) +< .Intermediate 13A: 1-Tert-butyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

[0358]

[0359] To a solution of 4-bromo-1-tert-butyl-1H-pyrazole (2.40 g, 9.836 mmol) and bis(pinacolato)diboron (1.64 g, 7.995 mmol) in dioxane (30 mL) was added potassium acetate (2.54 g, 29.5 mmol) at room temperature. Nitrogen gas was bubbled through the mixture for 5 mins and 1,1'-bis(diphenylphosphino)-ferrocenepalladium(II) chloride (125 mg, 0.153 mmol) was then added. The mixture was heated at 100 °C for 8 hours. The reaction mixture was diluted with EtOAc (50 mL), filtered over Celite and washed with EtOAc (50 mL). The filtrate was concentrated at reduced pressure and the residue was purified by Biotage Isolera ™< chromatography [SNAP Cartridge KP-Sil 100 g; eluting with a gradient of eluents; 0-100% EtOAc in heptane] giving the title product (0.65 g, 29% yield) as white solid.

[0360] 1< H NMR (500 MHz, Chloroform-d) δ [ppm] 7.78 (d, J = 0.6 Hz, 1H), 7.76 (s, 1H), 1.53 (s, 9H), 1.26 (s, 12H).

[0361] LCMS (Analytical Method A): Rt = 1.18 mins; MS (ESIPos) m / z = 251.05 (M+H) +< .Intermediate 14A: 1-(2,2-Dimethylpropyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

[0362]

[0363] A mixture of 4-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (2.0 g, 10.2 mmol), 1-iodo-2,2-dimethylpropane (3.03 g, 15.3 mmol) and potassium carbonate (4.23 g, 30.6 mmol) in N,N-dimethylformamide (20 mL) was heated at 100 °C for 20 hours. The reaction mixture was then diluted with TBME (100 mL) and water (50 mL). The organic layer was separated, washed with water (2 × 50 mL) and brine (30 mL), dried (Na 2 SO 4 ) and concentrated under reduced pressure. Heptane (50 mL) was added to the residue and the mixture was briefly heated at reflux. After cooling to room temperature, the solid starting material was removed via filtration. The filtrate was concentrated under reduced pressure and purified by Biotage Isolera ™< chromatography [Biotage SNAP Cartridge KP-Sil 25 g; eluting with a gradient of eluents; 0-30% EtOAc in heptane]. The product containing fractions were combined and concentrated in vacuo to afford the title product (0.27 g, 9% yield) as a white solid.

[0364] 1< H NMR (500 MHz, Chloroform-d) δ [ppm] 7.75 (s, 1H), 7.63 (s, 1H), 3.90 (s, 2H), 1.31 (s, 12H), 0.94 (s, 9H).

[0365] LCMS (Analytical Method A): Rt = 1.32 mins; MS (ESIPos) m / z = 264.8 (M+H) +< .Intermediate 15A: 1-(cyclobutylmethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxa-borolan-2-yl)-1H-pyrazole

[0366]

[0367] A mixture of 4-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.58 g, 2.96 mmol), (bromomethyl)cyclobutane (0.50 mL, 4.44 mmol) and potassium carbonate (1.23 g, 8.88 mmol) in N,N-dimethylformamide (6 mL) was heated at 100 °C for 20 hours. The reaction mixture was cooled to RT, diluted with EtOAc (50 mL) and water (50 mL). The organic layer was separated, washed with water (50 mL) and brine (30 mL), dried (MgSO 4 ), concentrated under reduced pressure and purified by Biotage Isolera ™< chromatography (25 g Silica column, using a gradient of eluents; 0-30% EtOAc in heptane) to afford the title compound (330 mg, 41% yield) as a colourless oil.

[0368] 1< H NMR (250 MHz, Chloroform-d) δ [ppm] 7.76 (s, 1H), 7.64 (s, 1H), 4.13 (d, J = 7.3 Hz, 2H), 2.95 - 2.70 (m, 1H), 2.20 - 1.64 (m, 6H), 1.31 (s, 12H).

[0369] LCMS (Analytical Method A): Rt = 1.13 min, MS (ESIpos): m / z = 262.9 (M+H) +< .Intermediate 306A: 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazole

[0370]

[0371] To a solution of methyl 4-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.238 g, 6.316 mmol) in DMF (20 mL) was added potassium carbonate (2.62 g, 18.95 mmol) and [2-(chloromethoxy)ethyl](trimethyl)silane (1.68 mL, 9.48 mmol) at room temperature. The mixture was stirred for 3 hours and then partitioned between TBME (100 mL) and water (50 mL). The organic layer was separated, washed with water (2 × 30 mL) and brine (30 mL), dried (Na 2 SO 4 ) and concentrated at reduced pressure. The residue was purified by Biotage Isolera ™< chromatography [Biotage SNAP Cartridge KP-Sil 50 g; using a gradient of eluents, 0-50% EtOAc in heptane]. The product containing fractions were combined, concentrated in vacuo to give the title compound (1.20 g, 56% yield) as colourless oil.

[0372] 1< H NMR (500 MHz, Chloroform-d) δ [ppm] 7.88 (s, 1H), 7.84 (s, 1H), 5.46 (s, 2H), 3.61 - 3.55 (m, 2H), 1.35 (s, 12H), 0.96 - 0.90 (m, 2H), 0.00 (s, 9H).

[0373] LCMS (Analytical Method A): Rt = 1.34 mins; MS (ESIPos) m / z = 324.95 (M+H) +< .Intermediate 307A: 1-(2-Methoxyethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

[0374]

[0375] To a solution of 4-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.00 g, 5.1 mmol) in DMF (5 mL) was added sodium hydride (245 mg of a 60% dispersion in mineral oil, 6.1 mmol) at room temperature. The mixture was then stirred at room temperature for 60 minutes. The mixture was cooled to 0 °C and 2-bromoethyl methyl ether (0.72 mL, 7.7 mmol) was added drop wise via syringe. After complete addition, the mixture was allowed to warm to room temperature and stirred for an hour prior to addition of ethyl acetate (70 mL) and water (30 mL). The organic layer was separated, washed with water (2 × 30 mL) and brine (30 mL), dried (Na 2 SO 4 ), filtered and concentrated at reduced pressure. The residue was purified by Biotage Isolera ™< chromatography [Biotage SNAP Cartridge KP-Sil 50 g; using a gradient of eluents, 0-50% EtOAc in heptane] to give the title compound (333 mg, 26% yield) as a colourless oil.

[0376] 1< H NMR (250 MHz, DMSO-d6) δ [ppm] 7.88 (s, 1H), 7.57 (s, 1H), 4.32 - 4.20 (m, 2H), 3.73 - 3.60 (m, 2H), 3.21 (s, 3H), 1.25 (s, 12H).

[0377] LCMS (Analytical Method A): Rt = 1.01 mins, MS (ESIPos): m / z = 253 (M+H) +< .Intermediate 308A: 1-(1-cyclopropylethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole as a 1:1 mixture of enantiomers

[0378]

[0379] To an ice-cooled solution of 4-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (600 mg, 3.09 mmol), racemic 1-cyclopropylethanol (346 mg, 4.02 mmol) and triphenylphosphine (1054 mg, 4.02 mmol) in anhydrous THF (40 mL) was dropwise added diisopropyl azodicarboxylate (0.79 mL, 4.02 mmol) and the reaction was allowed to warm up to room temperature and was stirred overnight. The following day further 1-cyclopropylethanol (133 mg, 1.55 mmol), triphenylphosphine (406 mg, 1.55 mmol) and diisopropyl azodicarboxylate (0.30 mL, 1.55 mmol) were added and the reaction was continued to be stirred for further 6 hours. The reaction mixture was then concentrated under reduced pressure and diethyl ether was added. The resulting mixture was cooled 0 °C giving a white precipitate. The precipitate was filtered and removed and the resulting filtrate was concentrated at reduced pressure and then purified by Biotage Isolera ™< chromatography (50 g SiO 2 column; eluting with a gradient of eluents, 0-35% EtOAc in heptane) to afford the title compound (260 mg, 32% yield) as a pale yellow oil.

[0380] 1< H NMR (250 MHz, Chloroform-d) δ [ppm] 7.83 (s, 1H), 7.80 (s, 1H), 3.70 - 3.51 (m, 1H), 1.58 (d, J = 6.1 Hz, 3H), 1.32 (s, 12H), 1.28 - 1.15 (m, 1H), 0.73 - 0.62 (m, 1H), 0.61 - 0.48 (m, 1H), 0.43 - 0.24 (m, 2H).

[0381] LCMS (Analytical Method A): Rt = 1.36 min, MS (ESIpos): m / z = 263.1 (M+H) +< .Intermediate 309A: 2-ethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine

[0382]

[0383] To a solution of 5-bromo-2-ethylpyridine (0.55 g, 2.956 mmol) and bis(pinacolato)diboron (0.826 g, 9.8 mmol) in 1,4-dioxane (8 mL) was added potassium acetate (0.87 g, 8.87 mmol) at room temperature. Nitrogen gas was bubbled through the mixture for 5 mins and 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) chloride (65 mg, 0.089 mmol) was then added. The mixture was heated at 100°C in a sealed tube for 5 hours. The reaction mixture was cooled to room temperature and diluted with EtOAc (20 mL), filtered over Celite and washed with EtOAc (30 mL). The filtrate was concentrated at reduced pressure and the residue was purified by Biotage Isolera ™< chromatography [Biotage SNAP Cartridge KP-Sil 25 g; eluting with a gradient of eluents, 0-100% EtOAc in heptane] to give the title compound (213 mg, 29% yield) as an orange oil.

[0384] 1< H NMR (500 MHz, Chloroform-d) δ [ppm] 8.89 - 8.82 (m, 1H), 7.97 (dd, J = 7.7, 1.8 Hz, 1H), 7.15 (d, J = 7.7 Hz, 1H), 2.83 (q, J = 7.6 Hz, 2H), 1.34 (s, 12H), 1.30 (t, J = 7.6 Hz, 3H).Intermediate 16A: Thieno[2,3-b]pyridin-2-yl boronic acid

[0385]

[0386] Thieno[2,3-b]pyridin (950 mg, 7.09 mmol) was dissolved in THF and the solution cooled to -45 °C. n-Butyl lithium (1.1 eq., 7.73 mmol, 4.83 mL, 1.6 M in hexane) was added dropwise and the mixture stirred for further 1 h at -45 °C. Triisopropyl borate (1.2 eq., 1.59 g, 8.43 mmol, 1.95 mL) was added dropwise and the mixture stirred for further 2 hours at RT. Ortho phosphoric acid (85%, 0.57 mL, 140 mmol) was added dropwise and the mixture stirred for a further 15 min. The resulting yellow suspension was diluted with diethyl ether (40 mL) and water (40 mL). The precipitate collected by filtration, washed with diethyl ether and dried under vacuum to give the title compound (810 mg, 64% yield) as a yellow solid. Upon standing the filtrate at RT, a second precipitate formed which was isolated in the same manner to give an additional title compound (410 mg, 33% yield).

[0387] 1< H NMR (400 MHz, DMSO-d6) δ [ppm] 7.41 (dd, 1H), 7.94 (s, 1H), 8.30 (dd, 1H), 8.58 (dd, 1H), 8.62 (s, br, 2H).

[0388] LCMS (method 2): Rt = 0.50 min; MS (ESIPos) m / z = 180 (M+H) +< .Intermediate 17A: 4-iodo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazole

[0389]

[0390] To a solution of 4-iodo-1H-pyrazole (2.0 g, 10.31 mmol) in tetrahydrofuran (20 mL) was added sodium hydride (619 mg, 15.47 mmol) at 0 °C. The resulting white suspension was stirred at 0 °C for 2 hours. 2-(Chloromethoxyethyl)trimethyl silane (SEM-Cl, 90% purity, 2.101 g, 2.230 mL, 11.34 mmol) was added dropwise at 0 °C. The suspension was then allowed to warm up to room temperature and stirred for 16 hours. The reaction was quenched with water (0.5 mL), and concentrated to ~5 mL at reduced pressure. The mixture was then partitioned between EtOAc (50 mL) and saturated NaHCO 3 solution (30 mL). The organic layer was separated, washed with brine (20 mL), dried (Na 2 SO 4 ) and concentrated at reduced pressure. The residue was purified by Biotage Isolera ™< chromatography [SNAP Cartridge KP-Sil 50 g; eluting with a gradient of eluents; 0-20% EtOAc in heptane] to give the title compound (3.27 g, 91% yield) as a colourless oil.

[0391] 1< H NMR (500 MHz, Chloroform-d) δ [ppm] 7.62 (s, 1H), 7.54 (s, 1H), 5.40 (s, 2H), 3.59 - 3.51 (m, 2H), 0.94 - 0.85 (m, 2H), -0.02 (s, 9H).

[0392] LCMS (Analytical Method A): Rt = 1.36 mins; MS (ESIPos) m / z = 324.9 (M+H) +< .Intermediate 18A: 4-cyclobutyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazole

[0393]

[0394] To a de-gassed mixture of 4-iodo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazole (Int 17A , 1.50 g, 4.626 mmol) in THF (20 mL) was added 1,1'-bis(diphenylphosphino) ferrocenedichloropalladium(II) (50 mg, 0.068 mmol). The mixture was stirred for 5 minutes at room temperature, then a 0.5M solution of bromo(cyclobutyl)zinc in THF (11.5 mL, 5.75 mmol) was added. The mixture was heated at 65 °C for two hours then cooled to room temperature and the reaction was quenched by addition of water (1 mL). The mixture was partitioned between EtOAc (100 mL) and water (30 mL), the organic layer was separated, washed with brine (30 mL), dried (Na 2 SO 4 ) and concentrated under reduced pressure. The residue was purified by Biotage Isolera ™< chromatography [SNAP Cartridge KP-Sil 50 g; eluting with a gradient of eluents; 0-20% EtOAc in heptane], to give the title compound (540 mg, 46% yield) as a colourless oil.

[0395] 1< H NMR (500 MHz, Chloroform-d) δ [ppm] 7.40 (s, 1H), 7.34 (s, 1H), 5.36 (s, 2H), 3.58 - 3.51 (m, 2H), 3.44 - 3.35 (m, 1H), 2.37 - 2.26 (m, 2H), 2.08 - 1.84 (m, 4H), 0.94 - 0.85 (m, 2H), -0.03 (s, 9H).

[0396] LCMS (Analytical Method A): Rt = 1.52 mins; MS (ESI) m / z = 253.05 (M+H) +< .Intermediate 19A: (3S)-Tetrahydrofuran-3-yl methanesulfonate

[0397]

[0398] To a solution of (3S)-tetrahydrofuran-3-ol (1.00 g, 11.4 mmol) and N,N-diisopropylethylamine (2.4 mL, 13.6 mmol) at 0 °C in dichloromethane (20 mL) was added dropwise methanesulfonyl chloride (1.05 mL, 13.6 mmol) and the reaction mixture was allowed to warm up to room temperature and was stirred for 2 h. The reaction mixture was diluted with dichloromethane (20 mL) and washed with saturated sodium bicarbonate (30 mL), the organic layer dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the title compound (1.58 g) as an orange oil. This was used in the next step without purification.

[0399] 1< H NMR (250 MHz, Chloroform-d) δ [ppm] 5.40 - 5.24 (m, 1H), 4.09 - 3.82 (m, 4H), 3.04 (s, 3H), 2.30 - 2.17 (m, 2H).

[0400] In analogy to the procedure described for Intermediate 19A , the following intermediate was prepared using methanesulfonyl chloride and the appropriate alcohol. Int. Structure Name Analytical Data 20A (3R)-tetrahydrofuran -3-yl methanesulfona te 1< H NMR (250 MHz, Chloroform-d) δ 5.37 - 5.25 (m, 1H), 4.10 - 3.79 (m, 4H), 3.04 (s, 3H), 2.34 - 2.16 (m, 2H). Intermediate 21A: (2R)-butan-2-yl methanesulfonate

[0401]

[0402] To a solution of (2R)-butan-2-ol (0.90 g, 12.2 mmol) and N,N-diisopropylethylamine (1.88 mL, 15.6 mmol) at 0 °C in dichloromethane (21 mL) was added dropwise methanesulfonyl chloride (1.67 mL, 14.6 mmol). The reaction mixture was allowed to warm to RT and stirred for 16 hours. The reaction mixture was washed with saturated aqueous sodium chloride solution, dried (MgSO 4 ), filtered and concentrated at reduced pressure to give the title compound (1.60 g) as a pale yellow oil. This was used in the next step without further purification.

[0403] 1< H NMR (250 MHz, Chloroform-d) δ [ppm] 4.77 (m, 1H), 3.02 (s, 3H), 1.79 - 1.66 (m, 2H), 1.44 (d, J = 6.3 Hz, 3H), 1.01 (t, J = 7.4 Hz, 3H).

[0404] In analogy to the procedure described for Intermediate 21A , the following intermediate was prepared using methanesulfonyl chloride and the appropriate alcohol. Int. Structure Name Analytical Data 22A (2S)-butan-2-yl methanesulfona te 1< H NMR (250 MHz, Chloroform-d) δ [ppm] 4.81 - 4.72 (m, 1H), 3.02 (s, 3H), 1.79 - 1.66 (m, 2H), 1.44 (d, J = 6.3 Hz, 3H), 1.01 (t, J = 7.4 Hz, 3H). Intermediate 23A: 1-[(3R)-Tetrahydrofuran-3-yl]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

[0405]

[0406] To a solution of 4-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (674 mg, 3.47 mmol) in anhydrous DMF (14 mL) was added NaH (60% dispersion in mineral oil, 180 mg, 4.51 mmol) and the reaction mixture was stirred at 0 °C for 15 mins. (3S)-Tetrahydrofuran-3-yl methanesulfonate (750 mg, 4.51 mmol) was then added and the reaction was heated to 100 °C for 2 hours. The reaction was cooled to room temperature, concentrated under reduced pressure and partitioned between EtOAc and water. The aqueous layer was extracted once with EtOAc and the combined organic extracts were dried over MgSO 4 , filtered, concentrated under reduced pressure and purified by Biotage Isolera ™< chromatography (50 g silica cartridge, eluting with a gradient of eluents; 0-60% EtOAc in heptane) to afford the title compound (380 mg, 40% yield) as a colourless oil that solidified on standing.

[0407] 1< H NMR (250 MHz, Chloroform-d) δ [ppm] 7.78 (s, 2H), 5.05 - 4.91 (m, 1H), 4.19 - 4.02 (m, 3H), 4.00 - 3.86 (m, 1H), 2.55 - 2.21 (m, 2H), 1.31 (s, 12H).

[0408] LCMS (Analytical Method A): Rt = 1.10 min, MS (ESIpos): m / z = 264.8 (M+H) +< .

[0409] In analogy to the procedure described for Intermediate 23A , the following intermediates were prepared using 4-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole and the appropriate mesylate. Int. Structure Name Analytical Data 24A 1-[(3S)-tetrahydrofuran -3-yl]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole 1< H NMR (250 MHz, Chloroform-d) δ [ppm] 7.78 (s, 2H), 5.07 - 4.85 (m, 1H), 4.19 - 4.02 (m, 3H), 3.99 - 3.88 (m, 1H), 2.55 - 2.16 (m, 2H), 1.31 (s, 12H). LCMS (Analytical Method A): Rt = 1.12 min, MS (ESIpos): m / z = 264.9 (M+H) +< .25A 1-[(2S)-butan-2-yl]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole 1< H NMR (250 MHz, Chloroform-d) δ [ppm] 7.82 (s, 1H), 7.73 (s, 1H), 4.35 - 4.19 (m, 1H), 2.03 - 1.72 (m, 2H), 1.51 (d, J = 6.8 Hz, 3H), 1.35 (s, 12H), 0.83 (t, J = 7.4 Hz, 3H). LCMS (Analytical Method A): Rt = 1.20 min, MS (ESIPos): m / z = 250.85 (M+H) +< .26A 1-[(2R)-butan-2-yl]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole 1< H NMR (250 MHz, Chloroform-d) δ [ppm] 7.82 (s, 1H), 7.73 (s, 1H), 4.35 - 4.17 (m, 1H), 2.02 - 1.72 (m, 2H), 1.61 (s, 3H), 1.51 (d, J = 6.8 Hz, 3H), 0.82 (t, J = 7.4 Hz, 3H). LCMS (Analytical Method A): Rt = 1.34 min, MS (ESIPos): m / z = 251 (M+H) +< .27A 1-cyclopentyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole 1< H NMR (250 MHz, Chloroform-d) δ [ppm] 7.78 (s, 1H), 7.73 (s, 1H), 4.66 (m, 1H), 2.28 - 1.50 (m, 8H), 1.32 (s, 12H). LCMS (Analytical Method A): Rt = 1.34 min, MS (ESIpos): m / z = 262.9 (M+H) +< . Intermediate 297A: 5-bromo-2-cyclobutyl-1,3-thiazole

[0410]

[0411] Bromo(cyclobutyl)zinc (9.1 mL of a 0.5 M solution in THF, 4.5 mmol) was added to 2,5-dibromo-1,3-thiazole (1.0 g, 4.1 mmol) and dry THF (10 mL) under a nitrogen atmosphere. To this was added 1,1'-Bis(diphenylphosphino)ferrocenedichloro-palladium(II) (60 mg, 82 □mol) and the resulting mixture was heated at 70 °C for 2 hours in a sealed tube. The mixture was then cooled to room temperature. The reaction was quenched by addition of water (20 mL) and the mixture was then extracted with ethyl acetate (50 mL). The organics were then washed with brine (20 mL), dried (Na 2 SO 4 ), filtered and concentrated at reduced pressure. The residue was purified by Biotage Isolera ™< chromatography (eluting with a gradient of eluents; 0-40% ethyl acetate in heptane) giving the title compound (800 mg, 89% yield) as a pale yellow oil.

[0412] 1< H NMR (500 MHz, Chloroform-d) δ [ppm] 7.54 (s, 1H), 3.85 - 3.74 (m, 1H), 2.49 - 2.40 (m, 2H), 2.38 - 2.28 (m, 2H), 2.13 - 2.00 (m, 1H), 2.00 - 1.91 (m, 1H).

[0413] LCMS (Analytical Method A): Rt = 1.24 mins, MS (ESIPos): m / z = 218 & 220 (M+H) +< .Intermediate 310A: 5-bromo-2-cyclopentyl-1,3-thiazole

[0414]

[0415] Cyclopentylzinc bromide (9.1 mL of a 0.5 M solution in THF, 4.5 mmol) was added to 2,5-dibromo-1,3-thiazole (1.0 g, 4.1 mmol) and dry THF (10 mL) under a nitrogen atmosphere. To this was added 1,1'-Bis(diphenylphosphino)ferrocenedichloro-palladium(II) (60 mg, 82 □mol) and the resulting mixture was heated at 70 °C for 2 hours in a sealed tube. The mixture was then cooled to room temperature. The reaction was quenched by addition of water (20 mL) and the mixture was then extracted with ethyl acetate (50 mL). The organics were then washed with brine (20 mL), dried (Na 2 SO 4 ), filtered and concentrated at reduced pressure. The residue was purified by Biotage Isolera ™< chromatography (eluting with a gradient of eluents, 0-40% ethyl acetate in heptane) giving the title compound (780 mg, 78% yield) as a pale yellow oil.

[0416] 1< H NMR (500 MHz, Chloroform-d) δ [ppm] 7.52 (s, 1H), 3.43 - 3.32 (m, 1H), 2.23 - 2.09 (m, 2H), 1.87 - 1.63 (m, 6H).

[0417] LCMS (Analytical Method A): Rt = 1.30 mins, MS (ESIPos): m / z = 233 (M+H) +< .Intermediate 311A: 1-cyclobutyl-4-iodo-1H-imidazole

[0418]

[0419] To a solution of 4-iodo-1H-imidazole (4.0 g, 20.62 mmol) in N,N-dimethylformamide (30 mL) was added sodium hydride (60% in mineral oil, 907 mg, 22.68 mmol) at room temperature. The mixture was stirred for 15 minutes until the production of gas ceased. Bromocyclobutane (3.88 mL, 41.24 mmol) was added and the mixture was stirred at 80°C for 16 hours. After cooling to room temperature, the reaction mixture was diluted with TBME (50 mL) and the solids were removed by filtration. The filtrate was concentrated at reduced pressure and the residue obtained was purified by Biotage Isolera ™< chromatography [Biotage SNAP Cartridge KP-Sil 50 g; using a gradient of eluents, 0-100% EtOAc in heptane] and the residue obtained was recrystallized from TBME / heptane to afford the title compound (2.06 g, 40% yield) as colourless crystalline solid.

[0420] 1< H NMR (500 MHz, Chloroform-d) δ [ppm] 7.40 (s, 1H), 7.07 (d, J = 1.4 Hz, 1H), 4.66 - 4.49 (m, 1H), 2.54 - 2.44 (m, 2H), 2.38 - 2.26 (m, 2H), 1.96 - 1.80 (m, 2H).

[0421] LCMS (Analytical Method A): Rt = 0.67 mins; MS (ESIPos) m / z = 248.85 (M+H) +< .Intermediate 312A: 2-Cyclobutyl-5-(tributylstannyl)-1,3-thiazole

[0422]

[0423] 5-bromo-2-cyclobutyl-1,3-thiazole (410 mg, 1.88 mmol) was dissolved in THF (5 mL) and cooled to -78 °C. n-Butyllithium (1.41 mL of a 1.6M solution in hexane, 2.26 mmol) was added dropwise over 5 minutes giving a brown solution. After 15 minutes at -78 °C, tri-n-butyltin chloride (0.61 mL, 2.26 mmol) was added dropwise over 5 minutes and the mixture was then allowed to warm to room temperature. The reaction was diluted with water (20 mL) and then extracted with ethyl acetate (50 mL). The organics were then washed with brine (20 mL), dried (Na 2 SO 4 ), filtered and concentrated at reduced pressure. The residue was purified by Biotage Isolera ™< chromatography (Biotage SNAP Cartridge KP-Sil 50 g; eluting with a gradient of eluents, 0-30% EtOAc in heptane) giving the title compound (540 mg, 54% yield) as a colourless oil.

[0424] 1< H NMR (500 MHz, Chloroform-d) δ [ppm] 7.59 (s, 1H), 4.00 - 3.85 (m, 1H), 2.54 - 2.31 (m, 4H), 2.15 - 2.00 (m, 1H), 2.00 - 1.91 (m, 1H), 1.58 - 1.50 (m, 6H), 1.37 - 1.26 (m, 6H), 1.15 - 1.04 (m, 6H), 0.89 (t, J = 7.3 Hz, 9H).

[0425] LCMS (Analytical Method A): Rt = 1.22 mins, the product did not ionise.Intermediate 28A: Methyl 5-amino-2-(6-ethoxypyridin-3-yl)benzoate

[0426]

[0427] Under an atmosphere of nitrogen, methyl 5-amino-2-bromobenzoate (Int 1A , 1.0 g, 4.35 mmol), (6-ethoxypyridin-3-yl)boronic acid (1.09 mg, 6.52 mmol) and potassium carbonate (1.98 g, 14.3 mmol) were dissolved in 1,2-dimethoxyethane (15.8 mL) and water (7.8 mL). Pd(PPh 3 ) 2 Cl 2 (36.7 mg, 0.052 mmol) was added and the reaction mixture heated at 90 °C until completion. The reaction mixture was cooled to RT, diluted with water (30 mL) and extracted with ethyl acetate (20 mL). The organic layer was washed with water (15 mL), brine (15 mL), dried (Na 2 SO 4 ), filtered and concentrated at reduced pressure to give the title compound (1.37 g, 115% yield, approximately 87% purity) as a yellow solid. The material was used in the next step without further purification.

[0428] LCMS (method 4): Rt = 1.03 min, MS (ESIpos) m / z = 273 (M+H) +< .Intermediate 29A: Methyl 5-amino-2-(1-cyclobutyl-1H-pyrazol-4-yl)benzoate

[0429]

[0430] Methyl 5-amino-2-bromobenzoate (Int 1A , 4.21 g, 18.3 mmol), 1-cyclobutyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (5.00 g, 20.2 mmol) and potassium carbonate (8.36 g, 60.5 mmol) were dissolved in 1,2-dimethoxyethane (67 mL) and water (33 mL) under an atmosphere of nitrogen. Pd(PPh 3 ) 2 Cl 2 (155 mg, 0.22 mmol) w...

Claims

1. A compound of general formula (I): R1 represents • phenyl, • 5- or 6-membered heteroaryl, wherein said 5-membered heteroaryl contains 1, 2 or 3 heteroatoms or heteroatom-containing groups independently selected from the group consisting of S, N, NH, and O, and wherein said 6-membered heteroaryl contains 1 or 2 nitrogen atoms, or • bicyclic 8- to 10-membered heteroaryl containing 1, 2 or 3 heteroatoms or heteroatom-containing groups independently selected from NH, N, O, S, SO and SO2, wherein said R1 is optionally substituted at one or more carbon atoms with 1 to 3 substituents R1a which are the same or different, wherein R1a represents C1-C5-alkyl, C3-C7-cycloalkyl, -(C1-C3-alkyl)-(C3-C7-cycloalkyl), -OC1-C5-alkyl, -OC3-C7-cycloalkyl, NHR4, N(R4)2, NH(C3-C7-cycloalkyl), halogen, CN, NHSO2R4, SO2R4, 5- to 7-membered lactam, or 4- to 7-membered heterocycloalkyl containing 1 or 2 heteroatoms or heteroatom-containing groups selected from NH, -NR4, N, O, S, SO and SO2,and wherein independently, if R1 represents 5- membered heteroaryl or bicyclic 8- to 10-membered heteroaryl, each ring nitrogen atom, if present, of said R1 is optionally substituted with a substituent R1b, wherein R1b represents C1-C5-alkyl,-(C1-C3-alkyl)-(C3-C7-cycloalkyl), C3-C7-cycloalkyl, SO2R4, or 4- to 7-membered heterocycloalkyl containing 1 or 2 heteroatoms or heteroatom-containing groups selected from NH, -NR4, N, O, S, SO and SO2,and if R1a represents C1-C5-alkyl, C3-C7-cycloalkyl, -(C1-C3-alkyl)-(C3-C7-cycloalkyl), -OC1-C5-alkyl or -OC3-C7-cycloalkyl and / or if R1b represents C1-C5-alkyl, -(C1-C3-alkyl)-(C3-C7-cycloalkyl), or C3-C7-cycloalkyl, said C1-C5-alkyl, C3-C7-cycloalkyl, -(C1-C3-alkyl)-(C3-C7-cycloalkyl), -OC1-C5-alkyl and -OC3-C7-cycloalkyl independently are optionally substituted with one or more substituents independently selected from the group consisting of methyl, ethyl, OH, OR4 and F, and if R1a and / or R1b represent 4- to 7-membered heterocycloalkyl, each carbon atom of said 4- to 7-membered heterocycloalkyl is optionally substituted with one or more substituents independently selected from the group consisting of OH, OR4 and F; R2 represents • -(CH2)p-(C5-C7-cycloalkyl), • -(CH2)p-phenyl, • 5- or 6-membered heteroaryl wherein said 5-membered heteroaryl contains 1, 2 or 3 heteroatoms or heteroatom-containing groups independently selected from the group consisting of S, N, NH, and O, and wherein said 6-membered heteroaryl contains 1 or 2 nitrogen atoms, or • bicyclic 8- to 10-membered heteroaryl containing 1, 2 or 3 heteroatoms or heteroatom-containing groups independently selected from NH, N, O, S, SO and SO2, wherein said R2 is optionally substituted at one or more carbon atoms with 1 to 3 substituents R2a which are the same or different, wherein R2a represents C1-C5-alkyl, C3-C7-cycloalkyl, -(C1-C3-alkyl)-(C3-C7-cycloalkyl), -OC1-C5-alkyl, -OC3-C7-cycloalkyl, halogen, OH or CN, and wherein independently, if R2 represents 5-membered heteroaryl or bicyclic 8- to 10-membered heteroaryl, each ring nitrogen atom, if present, of said R2 is optionally substituted with a substituent R2b, wherein R2b represents C1-C5-alkyl, C3-C7-cycloalkyl or -(C1-C3-alkyl)-(C3-C7-cycloalkyl), and if R2a represents C1-C5-alkyl, C3-C7-cycloalkyl, -(C1-C3-alkyl)-(C3-C7-cycloalkyl), -OC1-C5-alkyl or -OC3-C7-cycloalkyl and / or if R2b represents C1-C5-alkyl, C3-C7-cycloalkyl or -(C1-C3-alkyl)-(C3-C7-cycloalkyl), said C1-C5-alkyl, C3-C7-cycloalkyl, -(C1-C3-alkyl)-(C3-C7-cycloalkyl), -OC1-C5-alkyl and -OC3-C7-cycloalkyl independently are optionally substituted with one or more substituents independently selected from the group consisting of OH, OR4, and F; p represents 0 or 1; R3 represents H or F; R4 represents C1-C5-alkyl, optionally substituted with 1 to 5 fluorine atoms; R5 represents H, halogen, CN, C1-C5-alkyl, or -OC1-C5-alkyl, wherein said C1-C5-alkyl and -OC1-C5-alkyl are optionally substituted with 1 to 5 fluorine atoms; and R6 and R7 independently represent H or C1-C3-alkyl, wherein said C1-C3-alkyl is optionally substituted with 1 to 5 fluorine atoms; or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate, or a salt thereof, particularly a pharmaceutically acceptable salt thereof, or a mixture of the same.

2. The compound according to claim 1, wherein R1 represents 5-membered heteroaryl containing 1, 2 or 3 heteroatoms or heteroatom-containing groups independently selected from the group consisting of S, N, NH, and O, in particular pyrazolyl, thiazolyl, imidazolyl or thiophenyl, wherein said R1 is optionally substituted at one or more carbon atoms with 1 or 2 substituents R1a which are the same or different, wherein R1a represents C1-C5-alkyl, C3-C7-cycloalkyl, -(C1-C3-alkyl)-(C3-C7-cycloalkyl), -OC1-C5-alkyl,-OC3-C7-cycloalkyl, halogen or CN, and wherein independently each ring nitrogen atom, if present, of said R1 is optionally substituted with a substituent R1b, wherein R1b represents C1-C5-alkyl, -(C1-C3-alkyl)-(C3-C7-cycloalkyl) or C3-C7-cycloalkyl, and if R1a represents C1-C5-alkyl, C3-C7-cycloalkyl, -(C1-C3-alkyl)-(C3-C7-cycloalkyl), -OC1-C5-alkyl or -OC3-C7-cycloalkyl and / or if R1b represents C1-C5-alkyl, -(C1-C3-alkyl)-(C3-C7-cycloalkyl) or C3-C7-cycloalkyl, said C1-C5-alkyl, C3-C7-cycloalkyl, -(C1-C3-alkyl)-(C3-C7-cycloalkyl), -OC1-C5-alkyl and -OC3-C7-cycloalkyl independently are optionally substituted with one or more substituents independently selected from the group consisting of methyl, ethyl, OH, OR4 and F.

3. The compound according to any one of claims 1 or 2, wherein R1 represents pyrazol-4-yl, unsubstituted or substituted at the nitrogen atom at position 1 with a substituent R1b, wherein R1b represents C1-C5-alkyl, -(C1-C3-alkyl)-(C3-C7-cycloalkyl) or C3-C7-cycloalkyl, wherein said R1b is optionally substituted with one or more substituents independently selected from the group consisting of methyl, ethyl, OH, OR4 and F.

4. The compound according to any one of claims 1 to 3, wherein R2 represents phenyl substituted with 1 or 2 substituents R2a which are the same or different, wherein R2a represents C1-C5-alkyl, OC1-C5-alkyl, F or Cl, wherein if the substituent or at least one of said substituents is C1-C5-alkyl,-OC1-C5-alkyl or Cl, it is preferably positioned para to the carbon atom which links the phenyl to the rest of the molecule, and wherein said C1-C5-alkyl and -OC1-C5-alkyl independently are optionally substituted with 1 to 5 fluorine atoms.

5. The compound according to any one of claims 1 to 4, wherein R6 and R7 represent H.

6. The compound according to any one of claims 1, 2, 4 and 5, wherein R1 represents pyrazolyl, in particular pyrazol-4-yl, optionally substituted at one or more carbon atoms with 1 or 2 substituents R1a which are the same or different, wherein R1a represents C1-C5-alkyl, C3-C7-cycloalkyl, -(C1-C3-alkyl)-(C3-C7-cycloalkyl), -OC1-C5-alkyl, -OC3-C7-cycloalkyl, halogen or CN, and wherein independently each nitrogen atom of said R1 is optionally substituted with a substituent R1b, wherein R1b represents C1-C5-alkyl, -(C1-C3-alkyl)-(C3-C7-cycloalkyl) or C3-C7-cycloalkyl, and if R1a represents C1-C5-alkyl, C3-C7-cycloalkyl, -(C1-C3-alkyl)-(C3-C7-cycloalkyl), - OC1-C5-alkyl or -OC3-C7-cycloalkyl and / or if R1b represents C1-C5-alkyl, -(C1-C3-alkyl)-(C3-C7-cycloalkyl) or C3-C7-cycloalkyl, said C1-C5-alkyl, C3-C7-cycloalkyl, - (C1-C3-alkyl)-(C3-C7cycloalkyl), -OC1-C5-alkyl and -OC3-C7-cycloalkyl independently are optionally substituted with one or more substituents independently selected from the group consisting of methyl, OH, OR4 and F; R5 represents H, F, Cl or methyl, in particular H or F; and R6 and R7 represent H.

7. The compound according to any one of claims 1 to 6, wherein R2 represents phenyl substituted with 1 or 2 substituents R2a which are the same or different, wherein R2a represents C1-C5-alkyl, -OC1-C5-alkyl, F or Cl, and wherein if the substituent or at least one of said substituents is C1-C5-alkyl,-OC1-C5-alkyl or Cl, it is preferably positioned para to the carbon atom which links the phenyl to the rest of the molecule, and wherein said C1-C5-alkyl and -OC1-C5-alkyl independently are optionally substituted with 1 to 5 fluorine atoms; R5 represents H, F, Cl or methyl, in particular H or F; and R6 and R7 represent H.

8. The compound according to any one of claims 1 to 7, wherein R1 represents pyrazolyl, in particular pyrazol-4-yl, optionally substituted at one or more carbon atoms with 1 or 2 substituents R1a which are the same or different, wherein R1a represents C1-C5-alkyl, C3-C7-cycloalkyl, -(C1-C3-alkyl)-(-C3-C7-cycloalkyl), -OC1-C5-alkyl, -OC3-C7-cycloalkyl, halogen or CN, wherein independently each nitrogen atom of said R1 is optionally substituted with a substituent R1b, wherein R1b represents C1-C5-alkyl, -(C1-C3-alkyl)-(C3-C7-cycloalkyl) or C3-C7-cycloalkyl, and if R1a represents C1-C5-alkyl, C3-C7-cycloalkyl, -(C1-C3-alkyl)-(C3-C7-cycloalkyl), - OC1-C5-alkyl or -OC3-C7-cycloalkyl and / or if R1b represents C1-C5-alkyl, -(C1-C3-alkyl)-(C3-C7-cycloalkyl) or C3-C7-cycloalkyl, said C1-C5-alkyl, C3-C7-cycloalkyl, - (C1-C3-alkyl)-(C3-C7-cycloalkyl), -OC1-C5-alkyl and -OC3-C7-cycloalkyl independently are optionally substituted with one or more substituents independently selected from the group consisting of methyl, OH, OR4 and F; R2 represents phenyl substituted with 1 or 2 substituents R2a which are the same or different, wherein R2a represents C1-C5-alkyl, -OC1-C5-alkyl, F or Cl, wherein if the substituent or at least one of said substituents is C1-C5-alkyl,-OC1-C5-alkyl or Cl, it is preferably positioned para to the carbon atom which links the phenyl to the rest of the molecule, and wherein said C1-C5-alkyl and -OC1-C5-alkyl independently are optionally substituted with 1 to 5 fluorine atoms; R5 represents H, F, Cl or methyl, in particular H or F; and R6 and R7 represent H.

9. The compound according to any one of claims 1 to 8, wherein R1 represents pyrazol-4-yl, substituted at the nitrogen atom at position 1 with a substituent R1b, wherein R1b represents C1-C5-alkyl, -(C1-C3-alkyl)-(C3-C7-cycloalkyl) or C3-C7-cycloalkyl, wherein said R1b is optionally substituted with one or more substituents independently selected from the group consisting of methyl, OH, OR4 and F; R2 represents phenyl substituted with 1 or 2 substituents R2a which are the same or different, wherein R2a represents methyl, trifluoromethyl, trifluoromethoxy, F or Cl, and wherein if the substituent or at least one of said substituents is F, it is preferably positioned ortho to the carbon atom which links the phenyl to the rest of the molecule, and wherein if the substituent or at least one of said substituents is methyl, trifluoromethyl, trifluoromethoxy or Cl, it is preferably positioned para to the carbon atom which links the phenyl to the rest of the molecule; R5 represents H, F, Cl or methyl, in particular H or F; and R6 and R7 represent H.

10. The compound according to any one of claims 1 to 9, wherein R3 represents H; and R5 represents H.

11. The compound according to any one of claim 1 to 9, wherein R3 represents H; and R5 represents F.

12. The compound according to any one of claim 1 to 10, wherein R1 represents pyrazol-4-yl substituted at the nitrogen atom at position 1 with a substituent selected from the group consisting of methyl, ethyl, propyl, propan-2-yl, 2-methylpropyl, tertbutyl, butan-2-yl, cyclobutyl, 2,2-dimethylpropyl, 3-methylbutan-2-yl, cyclopentyl, cyclohexyl, 1-cyclopropylmethyl, 1-cyclopropylethyl, 1-cyclobutylmethyl, 1-(1-methylcyclopropyl)methyl and 2,2,2-trifluoroethyl, in particular ethyl, propan-2-yl, 2-methylpropyl, butan-2-yl, cyclobutyl, 2,2-dimethylpropyl, 1-cyclopropylmethyl, 1-cyclopropylethyl, 1-(1-methylcyclopropyl)methyl, and 1-cyclobutylmethyl; R2 represents phenyl substituted with 1 or 2 substituents R2a which are the same or different, wherein R2a represents methyl, trifluoromethyl, trifluoromethoxy, F or Cl, wherein if the substituent or at least one of said substituents is F , it is preferably positioned ortho to the carbon atom which links the phenyl to the rest of the molecule, and wherein if the substituent or at least one of said substituents is methyl, trifluoromethyl, trifluoromethoxy or Cl, it is preferably positioned para to the carbon atom which links the phenyl to the rest of the molecule; R3 represents H; R5 represents H or F, preferably H; and R6 and R7 represent H.

13. The compound according to any one of claims 1 or 2, wherein R1 represents thiazol-5-yl, optionally substituted at the carbon atom at position 2 with a substituent R1a selected from the group consisting of methyl, ethyl, propyl, propan-2-yl, cyclopropyl, 2-methylpropyl, tertbutyl, butan-2-yl, cyclobutyl, 2,2-dimethylpropyl, 3-methylbutan-2-yl, cyclopentyl, cyclohexyl, 1-cyclopropylmethyl, 1-cyclopropylethyl, 1-cyclobutylmethyl, 1-(1-methylcyclopropyl)methyl and 2,2,2-trifluoroethyl, in particular ethyl, propan-2-yl, 2-methylpropyl, butan-2-yl, cyclobutyl, 2,2-dimethylpropyl, cyclopentyl, 1-cyclopropylmethyl, 1-cyclopropylethyl, 1-(1-methylcyclopropyl)methyl and 1-cyclobutylmethyl; R2 represents phenyl substituted with 1 or 2 substituents R2a which are the same or different, wherein R2a represents methyl, trifluoromethyl, trifluoromethoxy, F or Cl, and wherein if the substituent or at least one of said substituents is F, it is preferably positioned ortho to the carbon atom which links the phenyl to the rest of the molecule, and wherein if the substituent or at least one of said substituents is methyl, trifluoromethyl, trifluoromethoxy or Cl, it is preferably positioned para to the carbon atom which links the phenyl to the rest of the molecule; R5 represents H, F, Cl or methyl, in particular H or F; and R6 and R7 represent H.

14. The compound according to any one of claims 1 to 13 selected from the group consisting of 2-(1-benzothiophen-2-yl)-5-[({1-[2-fluoro-4-(trifluoromethyl)phenyl]cyclopropyl}carbonyl)amino]benzoic acid; 2-[6-(1,1-difluoropropyl)pyridin-3-yl]-5-[({1-[2-fluoro-4-(trifluoromethyl)phenyl]cyclopropyl}carbonyl)amino]benzoic acid; 2-(1-cyclobutyl-1H-pyrazol-4-yl)-5-[({1-[2-fluoro-4-(trifluoromethyl)phenyl]cyclopropyl}carbonyl)amino]benzoic acid; 2-(6-ethoxypyridin-3-yl)-5-[({1-[2-fluoro-4-(trifluoromethyl)phenyl]cyclopropyl}carbonyl)amino]benzoic acid; 2-(6-ethoxypyridin-3-yl)-5-[({1-[2-fluoro-4-(trifluoromethoxy)phenyl]cyclopropyl}carbonyl)amino]benzoic acid; 2-(1-cyclobutyl-1H-pyrazol-4-yl)-3-fluoro-5-({[1-(2-fluoro-4-methylphenyl)cyclopropyl]carbonyl}amino)benzoic acid; 2-[6-(1,1-difluoropropyl)pyridin-3-yl]-5-[({1-[2-fluoro-4-(trifluoromethoxy)phenyl]cyclopropyl}carbonyl)amino]benzoic acid; 3-fluoro-5-[({1-[2-fluoro-4-(trifluoromethyl)phenyl]cyclopropyl}carbonyl)amino]-2-[6-(trifluoromethyl)pyridin-3-yl]benzoic acid; 5-[({1-[2-fluoro-4-(trifluoromethyl)phenyl]cyclopropyl}carbonyl)amino]-2-[1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl]benzoic acid; 5-({[1-(4-chlorophenyt)cyclopropyt]carbonyl}amino)-2-(l-cyclobutyt-lH-pyrazol-4-yt)-3-fluorobenzoic acid; 2-(1-cyclobutyl-1H-pyrazol-4-yl)-3-fluoro-5-[({1-[4-(trifluoromethyl)phenyl]cyclopropyl}carbonyl)amino]benzoic acid; 2-(1-cyclobutyt-1H-pyrazol-4-yt)-3-fluoro-5-[([1-[4-(trifluoromethoxy)phenyl]cyclopropyl}carbonyl)amino]benzoic acid; 2-(1-cyclobutyl-1H-pyrazol-4-yl)-5-({[1-(3,4-difluorophenyl)cyclopropyl]carbonyl}amino)-3-fluorobenzoic acid; 2-(1-cyclobutyt-1H-pyrazol-4-yl)-3-fluoro-5-[({1-[3-fluoro-4-(trifluoromethyl)phenyl]cyclopropyl}carbonyl)amino]benzoic acid; 2-(1-cyclobutyl-1H-pyrazol-4-yl)-5-({[1-(2,4-difluorophenyl)cyclopropyl]carbonyl}amino)-3-fluorobenzoic acid; 5-({[1-(4-chloro-2-fluorophenyl)cyclopropyl]carbonyl}amino)-2-(1-cyclobutyl-1H-pyrazol-4-yl)-3-fluorobenzoic acid; 2-(1-cyclobutyl-1H-pyrazol-4-yl)-3-fluoro-5-[({1-[2-fluoro-4-(trifluoromethyl)phenyl]cyclopropyl}cabonyl)amino]benzoic acid; 2-(1-cyclobutyl-1H-pyrazol-4-yl)-3-fluoro-5-[({1-[2-fluoro-4-(trifluoromethoxy)phenyl]cyclopropyl}carbonyl)amino]benzoic acid; 2-(1-cyclobutyt-1H-pyrazol-4-yt)-3-fluoro-5-([{1-(5-fluoropyridin-2-yl)cyclopropyl]carbonyl}amino)benzoic acid; 2-(1-cyclobutyl-3-fluoro-1H-pyrazol-4-yl)-5-[({1-[2-fluoro-4-(trifluoromethyl)phenyl]cyclopropyl}carbonyl)amino]benzoic acid; 5-([{1-(4-chloro-3-fluorophenyl)cyclopropyl]carbonyl}amino)-2-(1-cyclobutyt-1H-pyrazol-4-yl)benzoic acid; 2-(1-cyclobutyl-1H-pyrazol-4-yl)-5-[({1-[2-fluoro-4-(trifluoromethoxy)phenyl]cyclopropyl}carbonyl)amino]benzoic acid; 5-({[1-(4-chloro-2-fluorophenyl)cyclopropyt]carbonyl}amino)-2-(1-cyclobutyl-1H-pyrazol-4-yl)benzoic acid; 5-({[1-(5-chloro-2-fluorophenyl)cyclopropyl]carbonyl}amino)-2-(1-cyclobutyl-1H-pyrazol-4-yl)benzoic acid; 2-(1-ethyl-1H-pyrazol-4-yl)-5-[({1-[2-fluoro-4-(trifluoromethyl)phenyl]cyclopropyl}carbonyl)amino]benzoic acid; 2-(1-ethyl-1H-pyrazol-4-yl)-5-[({1-[2-fluoro-4-(trifluoromethoxy)phenyl]cyclopropyl}carbonyl)amino]benzoic acid; 5-[({1-[2-fluoro-4-(trifluoromethyl)phenyl]cyclopropyl}carbonyl)amino]-2-[1-(propan-2-yl)-1H-pyrazol-4-yl]benzoic acid; 5-[([1-[2-fluoro-4-(trifluoromethoxy)phenyt]cyclopropyl}carbonyl)amino]-2-[1-(propan-2-yl)-1H-pyrazol-4-yl]benzoic acid; 2-(1-tert-butyl-1H-pyrazol-4-yl)-5-[({1-[2-fluoro-4-(trifluoromethyl)phenyl]cyclopropyl}carbonyl)amino]benzoic acid; 2-(1-tert-butyl-1H-pyrazol-4-yl)-5-[({1-[2-fluoro-4-(trifluoromethoxy)phenyl]cyclopropyl}carbonyl)amino]benzoic acid; 5-[({1-[2-fluoro-4-(trifluoromethyl)phenyl]cyclopropyl}carbonyl)amino]-2-[1-(2-methylpropyl)-1H-pyrazol-4-yl]benzoic acid; 5-[({1-[2-fluoro-4-(trifluoromethoxy)phenyl]cyclopropyl}carbonyl)amino]-2-[1-(2-methylpropyl)-1H-pyrazol-4-yl]benzoic acid; 2-[1-(2,2-dimethylpropyl)-1H-pyrazol-4-yl]-5-[({1-[2-fluoro-4-(trifluoromethyl)phenyl]cyclopropyl}carbonyl)amino]benzoic acid; 2-[1-(2,2-dimethylpropyl)-1H-pyrazol-4-yl]-5-[({1-[2-fluoro-4-(trifluoromethoxy)phenyl]cyclopropyl}carbonyl)amino]benzoic acid; 3-fluoro-5-({[1-(2-fluoro-4-methylphenyl)cyclopropyl]carbonyl}amino)-2-[1-(propan-2-yl)-1H-pyrazol-4-yl]benzoic acid; 3-fluoro-5-[({1-[2-fluoro-4-(trifluoromethyl)phenyl]cyclopropyl}carbonyl)amino]-2-[1-(propan-2-yl)-1H-pyrazol-4-yl]benzoic acid; 3-fluoro-5-[({1-[2-fluoro-4-(trifluoromethoxy)phenyl]cyclopropyl}carbonyl)amino]-2-[1-(propan-2-yl)-1H-pyrazol-4-yl]benzoic acid; 2-(4-tert-butyl-1H-imidazol-1-yl)-3-fluoro-5-[({1-[2-fluoro-4-(trifluoromethyl)phenyl]cyclopropyl}carbonyl)amino]benzoic acid; 2-(4-tert-butyl-1H-imidazol-1-yl)-3-fluoro-5-[({1-[2-fluoro-4-(trifluoromethoxy)phenyl]cyclopropyl}carbonyl)amino]benzoic acid; 3-fluoro-5-[({1-[2-fluoro-4-(trifluoromethyl)phenyl]cyclopropyl}carbonyl)amino]-2-[1-(2-methylpropyl)-1H-pyrazol-4-yl]benzoic acid; 2-[6-(difluoromethyl)pyridin-3-yl]-3-fluoro-5-[({1-[2-fluoro-4-(trifluoromethyl)phenyl]cyclopropyl}carbonyl)amino]benzoic acid; 2-[6-(difluoromethyl)pyridin-3-yl]-3-fluoro-5-[({1-[2-fluoro-4-(trifluoromethoxy)phenyl]cyclopropyl}carbonyl)amino]benzoic acid; 2-[6-(1,1-difluoropropyl)pyridin-3-yl]-3-fluoro-5-[({1-[2-fluoro-4-(trifluoromethyl)phenyl]cyclopropyl}carbonyl)amino]benzoic acid; 2-[6-(1,1-difluoropropyl)pyridin-3-yl]-3-fluoro-5-[({1-[2-fluoro-4-(trifluoromethoxy)phenyl]cyclopropyl}carbonyl)amino]benzoic acid; 3-chloro-2-(1-cyclobutyl-1H-pyrazol-4-yl)-5-[({1-[2-fluoro-4-(trifluoromethyl)phenyl]cyclopropyl}carbonyl)amino]benzoic acid; 3-chloro-2-(1-cyclobutyl-1H-pyrazol-4-yl)-5-[({1-[2-fluoro-4-(trifluoromethoxy)phenyl]cyclopropyl}carbonyl)amino]benzoic acid; 3-chloro-2-[6-(1,1-difluoropropyl)pyridin-3-yl]-5-[({1-[2-fluoro-4-(trifluoromethyl)phenyl]cyclopropyl}carbonyl)amino]benzoic acid; 3-chloro-2-[6-(1,1-difluoropropyl)pyridin-3-yl]-5-[({1-[2-fluoro-4-(trifluoromethoxy)phenyl]cyclopropyl}carbonyl)amino]benzoic acid; 2-(1-cyclobutyl-1H-pyrazol-4-yl)-5-[({1-[2-fluoro-4-(trifluoromethyl)phenyl]cyclopropyl}carbonyl)amino]-3-methylbenzoic acid; 2-(1-cyclobutyl-1H-pyrazol-4-yl)-5-[({1-[2-fluoro-4-(trifluoromethoxy)phenyl]cyclopropyl}carbonyl)amino]-3-methylbenzoic acid; 2-[1-(cyclobutylmethyl)-1H-pyrazol-4-yl]-5-[({1-[2-fluoro-4-(trifluoromethyl)phenyl]cyclopropyl}carbonyl)amino]benzoic acid; 2-[1-(cyclobutylmethyl)-1H-pyrazol-4-yl]-5-[({1-[2-fluoro-4-(trifluoromethoxy)phenyl]cyclopropyl}carbonyl)amino]benzoic acid; 2-(1-cyclopentyl-1H-pyrazol-4-yl)-5-[({1-[2-fluoro-4-(trifluoromethyl)phenyl]cyclopropyl}carbonyl)amino]benzoic acid; 2-(1-cyclohexyl-1H-pyrazol-4-yl)-5-[({1-[2-fluoro-4-(trifluoromethyl)phenyl]cyclopropyl}carbonyl)amino]benzoic acid; 2-(1-cyclohexyl-1H-pyrazol-4-yl)-5-[({1-[2-fluoro-4-(trifluoromethoxy)phenyl]cyclopropyl}carbonyl)amino]benzoic acid; 2-[1-(cyclopropylmethyl)-1H-pyrazol-4-yl]-3-fluoro-5-[({1-[2-fluoro-4-(trifluoromethyl)phenyl]cyclopropyl}carbonyl)amino]benzoic acid; 2-[1-(cyclopropylmethyl)-1H-pyrazol-4-yl]-3-fluoro-5-[({1-[2-fluoro-4-(trifluoromethoxy)phenyl]cyclopropyl}carbonyl)amino]benzoic acid; 3-fluoro-5-[({1-[2-fluoro-4-(trifluoromethyl)phenyl]cyclopropyl}carbonyl)amino]-2-(6-methylpyridin-3-yl)benzoic acid; 2-{1-[(2S)-butan-2-yl]-1H-pyrazol-4-yl}-5-[({1-[2-fluoro-4-(trifluoromethyl)phenyl]cyclopropyl}carbonyl)amino]benzoic acid; 2-{1-[(2R)-butan-2-yl]-1H-pyrazol-4-yl}-5-[({1-[2-fluoro-4-(trifluoromethoxy)phenyl]cyclopropyl}carbonyl)amino]benzoic acid; 2-{1-[(2S)-butan-2-yl]-1H-pyrazol-4-yl}-3-fluoro-5-[({1-[2-fluoro-4-(trifluoromethyl)phenyl]cyclopropyl}carbonyl)amino]benzoic acid; 2-{1-[(2R)-butan-2-yl]-1H-pyrazol-4-yl}-3-fluoro-5-[({1-[2-fluoro-4-(trifluoromethyl)phenyl]cyclopropyl}carbonyl)amino]benzoic acid; 2-(1-ethyl-1H-pyrazol-4-yl)-3-fluoro-5-[({1-[2-fluoro-4-(trifluoromethyl)phenyl]cyclopropyl}carbonyl)amino]benzoic acid; 2-(1-ethyl-1H-pyrazol-4-yl)-3-fluoro-5-[({1-[2-fluoro-4-(trifluoromethoxy)phenyl]cyclopropyl}carbonyl)amino]benzoic acid; 5-({[1-(4-chloro-2-fluorophenyl)cyclopropyl]carbonyl}amino)-3-fluoro-2-[1-(propan-2-yl)-1H-pyrazol-4-yl]benzoic acid; 5-({[1-(4-chloro-2-fluorophenyl)cyclopropyl]carbonyl}amino)-2-(2-cyclobutyl-1,3-thiazol-5-yl)benzoic acid; 2-(2-cyclobutyl-1,3-thiazol-5-yl)-5-({[1-(2-fluoro-4-methylphenyl)cyclopropyl]carbonyl}amino)benzoic acid; 2-(2-cyclobutyl-1,3-thiazol-5-yl)-5-[({1-[2-fluoro-4-(trifluoromethyl)phenyl]cyclopropyl}carbonyl)amino]benzoic acid; 2-(2-cyclobutyl-1,3-thiazol-5-yl)-5-[({1-[2-fluoro-4-(trifluoromethoxy)phenyl]cyclopropyl}carbonyl)amino]benzoic acid; 5-[({1-[2-fluoro-4-(trifluoromethyl)phenyl]cyclopropyl}carbonyl)amino]-2-{1-[(1-methylcyclopropyl)methyl]-1H-pyrazol-4-yl}benzoic acid; 5-[({1-[2-fluoro-4-(trifluoromethoxy)phenyl]cyclopropyl}carbonyl)amino]-2-{1-[(1-methylcyclopropyl)methyl]-1H-pyrazol-4-yl}benzoic acid; 2-{1-[(1S)-1-cyclopropylethyl]-1H-pyrazol-4-yl}-5-[({1-[2-fluoro-4-(trifluoromethyl)phenyl]cyclopropyl}carbonyl)amino]benzoic acid; 2-(6-ethylpyridin-3-yl)-5-[({1-[2-fluoro-4-(trifluoromethyl)phenyl]cyclopropyl}carbonyl)amino]benzoic acid; 2-(6-ethylpyridin-3-yl)-5-[({1-[2-fluoro-4-(trifluoromethoxy)phenyl]cyclopropyl}carbonyl)amino]benzoic acid; 2-(6-ethylpyridin-3-yl)-3-fluoro-5-[({1-[2-fluoro-4-(trifluoromethyl)phenyl]cyclopropyl}carbonyl)amino]benzoic acid; 3-fluoro-5-[({1-[2-fluoro-4-(trifluoromethoxy)phenyl]cyclopropyl}carbonyl)amino]-2-(1-methyl-1H-indazol-6-yl)benzoic acid; 2-(2-cyclopentyl-1,3-thiazol-5-yt)-5-[(fl-[2-fluoro-4-(trifluoromethyl)phenyl]cyclopropyl}carbonyl)amino]benzoic acid; 2-(2-cyclobutyl-1,3-thiazol-5-yl)-3-fluoro-5-[({1-[2-fluoro-4-(trifluoromethyl)phenyl]cyclopropyl}carbonyl)amino]benzoic acid; and 3-fluoro-5-[({1-[2-fluoro-4-(trifluoromethyl)phenyl]cyclopropyl}carbonyl)amino]-2-[1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl]benzoic acid; or a pharmaceutically acceptable salt thereof.

15. The compound according to any one of claims 1 to 14, wherein the compound is 2-(1-cyclobutyl-1H-pyrazol-4-yl)-5-[({1-[2-fluoro-4-(trifluoromethyl)phenyl]cyclopropyl}carbonyl)amino]benzoic acid; or a pharmaceutically acceptable salt thereof.

16. A pharmaceutical composition comprising a compound according to any one of claims 1 to 15, and a pharmaceutically acceptable diluent or carrier.

17. A compound according to any one of claims 1 to 15, or a pharmaceutical composition of claim 16 for use in the treatment or prophylaxis of a disease or disease syndromes, conditions, or symptoms.

18. The compound for use according to claim 17, wherein said disease or disease syndromes, conditions, or symptoms that are associated with pain and / or inflammation.

19. The compound for use according to any one of claims 17 or 18, wherein said disease or disease syndromes, conditions, or symptoms are associated with pain selected from the group consisting of • visceral pain e.g. related to pancreatitis, interstitial cystitis, renal colic, or prostatitis, chronic pelvic pain, or pain related to infiltrating endometriosis; • neuropathic pain such as post herpetic neuralgia, acute zoster pain, pain related to nerve injury, the dynias, including vulvodynia, phantom limb pain, pain related to root avulsions, pain related to radiculopathy, painful traumatic mononeuropathy, painful entrapment neuropathy, pain related to carpal tunnel syndrome, ulnar neuropathy, pain related to tarsal tunnel syndrome, painful diabetic neuropathy, painful polyneuropathy, trigeminal neuralgia, or pain related to familial amyloid polyneuropathy; • central pain syndromes potentially caused by virtually any lesion at any level of the nervous system including but not limited to pain related to stroke, multiple sclerosis, and spinal cord injury; • postsurgical pain syndromes (including postmastectomy pain syndrome, postthoracotomy pain syndrome, stump pain), bone and joint pain (osteoarthritis), spine pain (including acute and chronic low back pain, neck pain, pain related to spinal stenosis), shoulder pain, repetitive motion pain, dental pain, pain related to sore throat, cancer pain, burn pain including sun-burn pain, myofascial pain (pain related to muscular injury, fibromyalgia), postoperative and perioperative pain (including but not limited to general surgery, orthopaedic, and gynaecological surgery); and • acute and chronic pain, chronic pelvic pain, endometriosis associated pain, dysmenorrhea associated pain (primary and secondary), pain associated with uterine fibroids, vulvodynia associated pain, as well as pain associated with angina, or inflammatory pain of varied origins (including but not limited to pain associated with osteoarthritis, rheumatoid arthritis, rheumatic disease, tenosynovitis, gout, ankylosing spondylitis, and bursitis).

20. The compound for use according to any one of claims 17 to 19, wherein said disease or disease syndromes, conditions, or symptoms are selected from or related to any one of the group consisting of • gynaecological disorders and / or diseases, or effects and / or symptoms which negatively influence women health including endometriosis, uterine fibroids, pre-eclampsia, hormonal deficiency, spasms of the uterus, or heavy menstrual bleeding; • the respiratory or excretion system including any of inflammatory hyperreactive airways, inflammatory events associated with airways disease like chronic obstructive pulmonary disease, asthma including allergic asthma (atopic or non-atopic) as well as exercise-induced bronchoconstriction, occupational asthma, viral or bacterial exacerbation of asthma, other non-allergic asthmas and wheezy-infant syndrome, chronic obstructive pulmonary disease including emphysema, adult respiratory distress syndrome, bronchitis, pneumonia, cough, lung injury, lung fibrosis, allergic rhinitis (seasonal and perennial), vasomotor rhinitis, angioedema (including hereditary angioedema and drug-induced angioedema including that caused by angiotensin converting enzyme (ACE) or ACE / neutral endopeptidase inhibitors like omepatrilat), pneumoconiosis, including aluminosis, anthracosis, asbestosis, chalicosis, ptilosis, siderosis, silicosis, tabacosis and byssinosis, bowel disease including Crohn's disease and ulcerative colitis, irritable bowel syndrome, pancreatitis, nephritis, cystitis (interstitial cystitis), kidney fibrosis, kidney failure, hyperactive bladder, and overactive bladder; • dermatology including pruritus, itch, inflammatory skin disorders including psoriasis, eczema, and atopic dermatitis; • affection of the joints or bones including rheumatoid arthritis, gout, osteoporosis, osteoarthritis, and ankylosing spondylitis; • affection of the central and peripheral nervous system including neurodegenerative diseases including Parkinson's and Alzheimer's disease, amyotrophic lateral sclerosis (ALS), epilepsy, dementia, headache including cluster headache, migraine including prophylactic and acute use, stroke, closed head trauma, and multiple sclerosis; • infection including HIV infection, and tuberculosis; • trauma associated with oedema including cerebral oedema, burns, sunburns, and sprains or fracture; • poisoning including aluminosis, anthracosis, asbestosis, chalicosis, ptilosis, siderosis, silicosis, tabacosis, and byssinosis uveitis; • diabetes cluster or metabolism like diabetes type 1, diabetes type 2, diabetic vasculopathy, diabetic neuropathy, diabetic retinopathy, post capillary resistance or diabetic symptoms associated with insulitis (e.g. hyperglycaemia, diuresis, proteinuria and increased nitrite and kallikrein urinary excretion), diabetic macular oedema, metabolic syndrome, insulin resistance, obesity, or fat or muscle metabolism; • cachexia associated with or induced by any of cancer, AIDS, coeliac disease, chronic obstructive pulmonary disease, multiple sclerosis, rheumatoid arthritis, congestive heart failure, tuberculosis, familial amyloid polyneuropathy, mercury poisoning (acrodynia), and hormonal deficiency; • cardio-vascular system including congestive heart failure, atherosclerosis, congestive heart failure, myocardial infarct, and heart fibrosis; and • other conditions including septic shock, sepsis, muscle atrophy, spasms of the gastrointestinal tract, benign prostatic hyperplasia, and liver diseases such as non-alcoholic and alcoholic fatty liver disease, non-alcoholic and alcoholic steatohepatitis, liver fibrosis, or liver cirrhosis.

21. The compound for use according to claim 20 wherein said disease or disease syndromes, conditions, or symptoms is related to endometriosis or endometriosis-associated pain, in particular to dysmenorrhea, dyspareunia, dysuria, or dyschezia.

22. The compound for use according to claim 20 wherein said disease or disease syndromes, conditions, or symptoms are selected from or related to overactive bladder, fibrosis of lung, kidney, heart and / or liver, diabetes type 1 and / or type 2, metabolic syndrome, gout, rheumatoid arthritis, and osteoarthritis including the related symptoms.