Carboxylic acid aromatic amides as bradykinin B1 receptor antagonists

Abstract

The present invention relates to carboxylic acid aromatic amide compounds of general formula (I) as described and defined herein, pharmaceutical compositions and combinations comprising said compounds, and the use of said compounds as a single agent or in combination with other active ingredients for the preparation of pharmaceutical compositions for the treatment or prevention of diseases.

Description

[0001] This application is a divisional application of the invention patent application No. 201780087290.X entitled "Carboxylic Acid Aromatic Amides as Bradykinin B1 Receptor Antagonists". The original application corresponds to international application PCT / EP2017 / 083290, with a filing date of December 18, 2017 and a priority date of December 23, 2016. Technical Field

[0002] The present invention relates to carboxylic acid aromatic amides of general formula (I) as described and defined herein, pharmacological compositions and combinations comprising said compounds, and the use of said compounds as sole medicament or in combination with other active ingredients for the preparation of pharmaceutical compositions for the treatment or prevention of diseases or disorders and for the treatment of pain associated with these diseases, in particular disorders associated with bradykinin B1 receptors that are associated with inflammation or are at least partially driven by neurogenic events, such as diseases associated with chronic pain or frequent painful conditions (for example, but not limited to osteoarthritis, rheumatoid arthritis, gout, inflammatory bowel disease and endometriosis), and diseases associated with activation and / or upregulation of bradykinin B1 receptors in affected tissues (for example, but not limited to asthma, fibrosis in various tissues or diabetes). Background Art

[0003] The present invention relates to compounds that antagonize the action of human bradykinin B1 receptor (gene name BDKRB1, gene ID 623).

[0004] Bradykinin B1 receptor is a membrane-bound G protein-coupled receptor associated with a second messenger system that triggers an increase in intracellular calcium concentration. The main signal transduction pathway is associated with Gq protein and phospholipase C (Leeb-Lundberg, LM et al., (2005), Pharmacol Rev 57 (1): 27-77). Activation of bradykinin B1 receptor has been shown to be pro-algesic, pro-fibrotic and pro-inflammatory, and bradykinin B1 receptor antagonists have significant anti-inflammatory and analgesic effects in various animal models (Gougat, JB et al., (2004), J Pharmacol Exp Ther 309 (2): 661-669; Dias, JP et al., (2007), Br J Pharmacol 152 (2): 280-287; Schuelert, N. et al., (2015), Eur J Pain 19 (1): 132-142). Since bradykinin B1 receptor activity increases gene expression and protein levels of proinflammatory cytokines such as IL-6 and IL-8 that attract and activate inflammatory leukocytes, increased PGE2 (prostaglandin 2) levels and thus activation of inflammation-related prostaglandin pathways, 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 tissues) are observed (Phagoo, SB et al., (1999). Mol Pharmacol 56(2):325-333; Westermann, D. et al., (2009), Diabetes 58(6):1373-1381; Walsh, DA 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. The system consists of circulating kininogens, the ubiquitously expressed proteolytic enzyme kallikrein activated by tissue damage, and the kinins formed by the kallikrein activated by kininogens (Review Fincham, CI et al., (2009), Expert Opin Ther Pat 19 (7): 919-941). These kinins (e.g. bradykinin, kalidin, des-Arg9-bradykinin, des-Arg10-kallikrein) are proinflammatory peptides that mediate the response of blood vessels and pain to tissue damage, with cardiovascular homeostasis, contraction or relaxation of smooth muscle, inflammation and nociception. They play most of their effects by interacting with two types of G protein-coupled receptors called bradykinin receptors 1 and 2.The classification of kinin receptors was initially achieved through pharmacological studies initially conducted in the late 1970s. In the 1990s, the existence of bradykinin B1 and B2 receptors was further confirmed through cloning and genetic deletion studies (Menke, JG et al. (1994), J Biol Chem 269(34):21583-21586). Research on the kinin system over the past 30 years has shown that both bradykinin B1 and B2 receptors are involved in pain and inflammation (Leeb-Lundberg, LM 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, JJ et al., (2007), Expert Opin Ther Targets 11(1):21-35).

[0005] It has been shown that the B2 receptor is widely expressed in a constitutive manner in most mammalian tissues. In contrast, the bradykinin B1 receptor cannot be constitutively expressed to a large extent under normal conditions, but is upregulated under various inflammatory conditions (such as asthma, arthritis and osteoarthritis, sepsis and type 1 diabetes) and by some neuropathological diseases (such as epilepsy, stroke and multiple sclerosis). The bradykinin B1 receptor upregulation can be induced, for example, by IL-1β (Phagoo, SB et al., (1999), Mol Pharmacol 56 (2): 325-333) and bradykinin B2 receptor activation (NF-kB activation leads to IL1b expression in fibroblasts) (Leeb-Lundberg, LM et al., (2005), Pharmacol Rev 57 (1): 27-77).

[0006] Once upregulated, bradykinin B1 receptors are expressed on neurons, macrophages, neutrophils, fibroblasts, smooth muscle cells, and vascular endothelium (Fincham, CI et al., (2009), Expert Opin Ther Pat 19(7):919-941). Recent findings suggest that bradykinin B1 receptors expressed in the peripheral and central nervous systems are involved in the process of inflammatory pain (Schuelert, N. et al. (2015). Eur J Pain 19(1):132-142).

[0007] In contrast to bradykinin B2 receptors and many other GPCRs (G protein-coupled receptors), bradykinin B1 receptors do not show agonist-induced internalization or associated desensitization (Prado, GN 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 receptors triggers auto-induction of the receptor. This may lead to an enhancement of inflammatory or pain-inducing processes.

[0008] Thus, the bradykinin B1 receptor has been proposed to play a key role, including but not limited to several chronic diseases involved in diabetes, fibrosis, inflammation, neuroinflammation, neurodegeneration, inflammatory pain and neuropathic pain (Campos, MM et al. (2006), Trends Pharmacol Sci 27(12):646-651; Wang, PH et al. (2009), Int Immunopharmacol 9(6):653-657; Passos, GF 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 to inflammatory and pain processes is supported by evidence that bradykinin B1 receptor knockout mice have greatly reduced responses to noxious 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 blockade on inflammation-related diseases is further supported by the pharmacological properties of bradykinin B1 receptor antagonists shown in many inflammatory and neuropathic pain models (Gougat, JB et al. (2004), J Pharmacol Exp Ther 309(2):661-669; Fox, A. et al. (2005), Br J Pharmacol 144(7):889-899).

[0009] The fact that bradykinin B1 receptor expression is induced in disease states clearly raises the possibility that the therapeutic use of bradykinin B1 receptor antagonists should be free of undesirable side effects. This property supports the suitability of bradykinin B1 receptor antagonists for the treatment of benign diseases such as endometriosis because of the expected positive risk-benefit ratio. The patient population for nociceptive and neuropathic pain is large and driven by separate disease trends requiring pain relief. 19% of adult Europeans experience chronic pain of moderate to severe intensity, which significantly affects their quality of social and working life (Breivik et al., 2011). Eur J Pain. 2006May;10(4):287-333). Unfortunately, current treatments for pain are only partially effective, and many result in lifestyle changes, debilitating, and / or dangerous side effects. For example, nonsteroidal anti-inflammatory drugs (NSAIDS) such as aspirin, ibuprofen, and indomethacin have modest effects on inflammatory pain, but they are also nephrotoxic, and high doses tend to cause gastrointestinal irritation, ulcers, bleeding, confusion, and increased cardiovascular risk. Notably, Vioxx was withdrawn from the market in 2004 due to the risk of myocardial infarction and stroke. Patients treated with opioids often experience confusion and constipation, and long-term opioid use is associated with tolerance and addiction. Local anesthetics such as lidocaine and mexiletine simultaneously suppress pain and cause loss of normal sensation. In addition, when used systemically, local anesthetics are associated with adverse cardiovascular effects. Therefore, there is currently an unmet need for the treatment of chronic pain in general.

[0010] Particularly in the area of ​​gynecological care, endometriosis is a disease associated with chronic pelvic pain that significantly affects the patient's quality of life. Globally, approximately 11% of women aged 15-49 are affected by endometriosis, and an additional 6% of women suffer from symptoms suggestive of endometriosis. The main symptoms of endometriosis are chronic or frequent pelvic pain, dyspareunia, difficulty defecating, dysuria, and subfertility or infertility. These symptoms significantly affect the patient's quality of life. The diagnosis of the disease involves a complete medical history, physical examination, and laparoscopy. As the definitive confirmation of endometriosis can only be invasive and the symptoms are often nonspecific, the average time from initial symptoms to the diagnosis of endometriosis is approximately 7-10 years. As a result, endometriosis is underdiagnosed and the number of women affected is likely to be much higher than expected. The recently published EndoCost study showed that the cost of lost productivity of €6,298 per woman was twice the healthcare costs of €3,113 per woman, mainly due to surgery and monitoring visits (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).

[0011] Endometriosis is characterized by the growth of endometrial tissue outside the uterine cavity, forming benign tumors (lesions) in the affected parts of the body. Depending on the location of the lesion, the severity of the innervation of the pain symptoms is observed. The upregulation of various inflammatory markers observed in the affected tissues and peritoneal tissues emphasizes the inflammatory characteristics 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).

[0012] Bradykinin B1 receptors have been identified in endometriotic lesions by immunohistochemical (IHC) staining (Yoshino et al., Journal of Reproductive Immunology 112 (2015) 121–140; www.proteinatlas.org) and analysis of bradykinin B1 receptor mRNA expression in affected tissues showed a positive correlation with pain severity reported by endometriosis patients. Data describing a role for bradykinin B1 receptors in influencing outcomes in a mouse model of endometriosis (Jingwei, C. et al. (2015), J Tradit Chin Med 35(2):184-191) further support the concept of treating endometriosis with bradykinin B1 receptor antagonists.

[0013] Suspected endometriosis is initially treated with nonsteroidal anti-inflammatory drugs (NSAIDs) or combined oral contraceptives (COCs), which are used off-label. This procedure delays the diagnosis of endometriosis. Laparoscopy is the gold standard for the diagnosis of endometriosis and is performed when initial treatment options have failed. During laparoscopy, endometriotic lesions are ablated. However, this procedure is associated with a high recurrence rate. Approximately 70% of treated patients have uncontrolled persistent symptoms. Currently, COC / P (combined oral contraceptive / progestin, C ombined O ral C There are no long-term medications available for patients with endometriosis who are unresponsive to COC / P. Treatment with gonadotropin-releasing hormone (GnRH) agonists is only approved for short-term treatment (6 months), and the agonists are used as second-line treatment (without evidence of superiority over first-line). Following administration of GnRH agonists, systemic estradiol levels are suppressed by up to 90%, resulting in chemical castration, and menopausal side effects such as osteopenia and hot flashes. Therefore, new and long-term treatment options with reduced side effects and high efficacy are urgently needed for patients with endometriosis who are unresponsive to COC / P.

[0014] In this context, bradykinin B1 receptor antagonists are of value for treating conditions associated with inflammation or driven at least in part by neurogenic events, such as diseases associated with chronic pain or frequent painful conditions, such as, but not limited to, osteoarthritis (Kaufman, GN et al., (2011), Arthritis Res Ther 13(3):R76), rheumatoid arthritis (Cassim, B. et al., (2009), Rheumatology 48(5):490-496), gout (Silva, CR et al., (2016), Ann Rheum Dis 75(1):260-268), burns 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), preeclampsia (Moyes, AJ et al., (2014), Hypertens Pregnancy 33(2): 177-190), diabetic neuropathy (Dias, JP et al., (2007), Br J Pharmacol 152(2): 280-287), including neuropathy associated with type 1 and type 2 diabetes, 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 associated with activation and / or upregulation of bradykinin B1 receptors in affected tissues, such as but not limited to asthma and cough (Bertram, CM et al., (2009), J Leukoc Biol 85(3):544-552), atherosclerosis, diabetes (Dias, JP et al., (2012), J Cardiovasc Pharmacol 60(1):61-69), adiposity, including metabolic syndrome (Dias, JP et al., (2012), Diabetes Obes Metab 14(3):244-253), diseases associated with muscle wasting, including cachexia (Parreiras, ESLT 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 itching (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), cardiac fibrosis (Westermann, D. et al., (2009), Diabetes 58(6):1373-1381), renal fibrosis (Huart, A. et al., (2015), Front Pharmacol 6:8) and pulmonary tissue fibrosis, overactive 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 wound healing or pain (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).

[0015] Several new bradykinin B1 receptor antagonists are known in the prior art (Expert Opinion on Therapeutic Patents (2012), 22: 12, 1443-1452). Various methods for discovering new bradykinin B1 receptor antagonists are described, in particular peptide structures and small molecules. In particular, in the past decade, arylsulfonamides and so-called cyclopropyl-carboxamides have been studied as two main types of small molecules.

[0016] WO2003 / 065789 (Merck) discloses bradykinin B1 receptor antagonists or inverse agonists of the following general formula

[0017]

[0018] They can be used to treat or prevent symptoms associated with the bradykinin B1 pathway, such as pain and inflammation.

[0019] Merck is developing MK-0686, a bradykinin B1 receptor antagonist (structure shown below).

[0020]

[0021] For potential treatment of pain and inflammation. Several Phase II trials were initiated in subjects with osteoarthritis and with postherpetic neuralgia. Merck believes that the compound has a suboptimal pharmacokinetic profile due to metabolic instability.

[0022] Jerini AG (now Shire Group) studied active bradykinin B1 receptor antagonists, for example (see WO2009 / 036996)

[0023]

[0024] In addition to its activity and acceptable permeation characteristics, it is reported to have reasonable aqueous solubility and pharmacokinetic characteristics in rats, while its metabolic stability in humans remains poor (Schaudt M, Locardi E, Zischinsky G et al., Bioorg Med Chem Lett 2010; 20: 1225-8). Jerini replaced the cyclopropyl-carboxamide moiety with semicarbazide or a five-membered diamino-heterocycle or even hydroxyurea without any explanation.

[0025] Starting with arylsulfonamides as bradykinin B1 receptor antagonists, Boehringer Ingelheim reported several cyclopropyl-carboxamides from which they further developed compounds such as those having the following structure

[0026]

[0027] Or correlated with those with the highest binding affinity measured on CHO cells expressing human B1R (Expert Opinion on Therapeutic Patents (2012), 22: 12, 1443-1452).

[0028] In WO2012 / 059776, Gedeon Richter reported cyclopropyl-formamide compounds of the formula

[0029]

[0030] Where R 3 Selected from (1) -COOR; (2) -CN; (3) -CONR a R b ;

[0031]

[0032] Most compounds had a K lower than 20 nM for human recombinant bradykinin receptor (expressed in CHO cells). i Several indolyl compounds are disclosed and are represented by the following compounds:

[0033]

[0034] In WO2012 / 112567 (Georgetown University), a small molecule inhibitor of ATP / GTP binding protein-like 2 (AGBL2) of the formula

[0035]

[0036] wherein Ar is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; L is absent or is -(CHR 6 )-, where 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 Each is 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 alkoxy, substituted or unsubstituted aryloxy, substituted or unsubstituted carbonyl, or substituted or unsubstituted carboxyl. Compounds useful in methods of treating or preventing cancer and neurological disorders are described. Aromatic amides having a carboxylic acid group and a cyclopropyl moiety are not specifically disclosed.

[0037] WO2012 / 103583 (Bionomics) discloses a compound of formula (I) 1,2- Cyclopropyl-formamide compounds

[0038]

[0039] Where R 4 is selected from optionally substituted heteroaryl, optionally substituted heterocyclyl or optionally substituted aryl, R 5Selected from hydrogen or optionally substituted alkyl. These compounds can be used for positive regulation of α7 nicotinic acetylcholine receptor (α7nAChR). The disclosure of WO2012103583 also relates to the use of these compounds in the treatment or prevention of a wide range of diseases in which positive regulation of α7nAChR is beneficial, including neurodegenerative and neuropsychiatric diseases and inflammatory diseases. No disclosure 1,1- Cyclopropyl-carboxamide compounds.

[0040] 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"), said compounds having a benzamide core structure (I)

[0041]

[0042] wherein Ring A is an optionally substituted alicyclic group or an optionally substituted heteroalicyclic group, wherein the atom of Ring A adjacent to C* is a carbon atom. 4 is optionally substituted aryl or optionally substituted heteroaryl. 1 is independently optionally substituted C 1 -C 6 aliphatic, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C 3 -C 10 alicyclic or optionally substituted 4- to 10-membered heteroalicyclic, carboxyl, amido, amino, halogen or hydroxyl, provided that at least one R 1 is optionally substituted aryl or optionally substituted heteroaryl, and said R 1 The compound of the present invention is not disclosed.

[0043] Therefore, the above-mentioned prior art does not describe the compounds of the general formula (I) of the present invention as defined herein, or their isomers, enantiomers, diastereomers, racemates, hydrates, solvates or salts, or mixtures thereof, or their pharmacological activity, as described and defined herein and referred to as "compounds of the present invention" hereinafter. Summary of the invention

[0044] The present invention encompasses compounds of the general formula (I):

[0045]

[0046] or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate or salt thereof, or a mixture thereof,

[0047] in

[0048] R 1 represent:

[0049] · Phenyl,

[0050] 5- or 6-membered heteroaryl, wherein the 5-membered heteroaryl contains 1, 2 or 3 heteroatoms or heteroatom-containing groups independently selected from S, N, NH and O, and wherein the 6-membered heteroaryl contains 1 or 2 nitrogen atoms, or

[0051] Contains 1, 2 or 3 independently selected from NH, N, O, S, SO and SO 2 A bicyclic 8- to 10-membered heteroaryl group containing a heteroatom or a heteroatom-containing group,

[0052] Wherein R 1 Optionally, one or more carbon atoms are substituted by 1 to 3 identical or different substituents R 1a Substitution, where 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 lactams, or containing 1 or 2 selected from NH, -NR 4 ,N,O,S,SO and SO 2 a heteroatom or a 4- to 7-membered heterocycloalkyl group containing a heteroatom, and

[0053] Among them, independently, if R 1 represents a 5-membered heteroaryl or a bicyclic 8-10 membered heteroaryl, then the R 1 Each ring nitrogen atom of 1b Substitution, where R 1b Represents C 1 -C 5- Alkyl, -(C1 -C 3 -alkyl)-(C 3 -C 7 -cycloalkyl), C 3 -C 7 -Cycloalkyl, SO 2 R 4 or contains 1 or 2 selected from NH, -NR 4 ,N,O,S,SO and SO 2 a heteroatom or a 4- to 7-membered heterocycloalkyl group containing a heteroatom, and

[0054] 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,

[0055] Then the 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 is optionally substituted with one or more substituents independently selected from methyl, ethyl, OH, OR 4 and F, and

[0056] If R 1a and / or R 1brepresents a 4- to 7-membered heterocycloalkyl group, each carbon atom of the 4- to 7-membered heterocycloalkyl group is optionally substituted by one or more independently selected from OH, OR 4 and F is substituted with a substituent;

[0057] R 2 represent:

[0058] ·-(CH 2 ) p -(C 5 -C 7 -cycloalkyl),

[0059] ·-(CH 2 ) p -phenyl,

[0060] 5- or 6-membered heteroaryl, wherein the 5-membered heteroaryl contains 1, 2 or 3 heteroatoms or heteroatom-containing groups independently selected from S, N, NH and O, and wherein the 6-membered heteroaryl contains 1 or 2 N, or

[0061] Contains 1, 2 or 3 independently selected from NH, N, O, S, SO and SO 2 A bicyclic 8- to 10-membered heteroaryl group containing a heteroatom or a heteroatom-containing group,

[0062] Wherein R 2 Optionally, one or more carbon atoms are substituted by 1 to 3 identical or different substituents R 2a Substitution, where 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

[0063] Among them, independently, if R 2 represents a 5-membered heteroaryl or a bicyclic 8- to 10-membered heteroaryl, then the R 2 Each ring nitrogen atom of is optionally substituted by a substituent R 2b Substitution, where R 2b Represents C 1 -C 5- Alkyl, C 3 -C 7 -cycloalkyl or -(C1 -C 3 -alkyl)-(C 3 -C 7 -cycloalkyl), and

[0064] 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),

[0065] Then the 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 is optionally substituted with one or more substituents independently selected from OH, OR 4 and 1 to 5 fluorine atoms;

[0066] p 0 or 1;

[0067] R 3 Represents H or F;

[0068] R 4 represents C optionally substituted by 1 to 5 fluorine atoms 1 -C 5 -alkyl;

[0069] R 5 Represents H, halogen, CN, C1 -C 5 -alkyl or -OC 1 -C 5 -alkyl, wherein the C 1 -C 5 -alkyl and -OC 1 -C 5 - the alkyl group is optionally substituted by 1 to 5 fluorine atoms; and

[0070] R 6 and R 7 Represents H or C 1 -C 3 -alkyl, wherein the C 1 -C 3 The -alkyl group is optionally substituted by 1 to 5 fluorine atoms.

[0071] The present invention further relates to pharmaceutical compositions and combinations comprising the compounds, to the use of the compounds for the preparation of medicaments for the treatment or prevention of diseases or conditions and for the treatment of pain associated with these diseases and for the treatment of inflammation associated with these diseases. In addition, the present invention relates to pharmaceutical compositions and combinations comprising the compounds, to the use of the compounds for the treatment or prevention of diseases or conditions and for the treatment of pain associated with these diseases and for the treatment of inflammation associated with these diseases.

[0072] It has now been found that the compounds according to the invention have surprising and advantageous properties, which form the basis of the present invention.

[0073] In particular, it has surprisingly been found that the compounds of the invention effectively inhibit bradykinin B1 receptors. Therefore, the present invention particularly relates to the compounds for use in the treatment or prevention of the following diseases or conditions:

[0074] Pain and inflammation, particularly any of the following

[0075] Visceral pain, such as that associated with pancreatitis, interstitial cystitis, painful bladder syndrome, renal colic or prostatitis, chronic pelvic pain or pain associated with infiltrative endometriosis;

[0076] Neuropathic pain, such as postherpetic neuralgia, acute herpes zoster pain, pain associated with nerve damage, including vulvar pain, phantom limb pain, pain associated with root avulsion, pain associated with radiculopathy, painful traumatic mononeuropathy, painful entrapment neuropathy, pain associated with carpal tunnel syndrome, ulnar neuropathy, pain associated with tarsal tunnel syndrome, painful diabetic neuropathy, painful polyneuropathy, trigeminal neuralgia, or pain associated with familial amyloid polyneuropathy;

[0077] Central pain syndromes that may arise from virtually any pathology at any level of the nervous system, including but not limited to pain associated with stroke, multiple sclerosis, and spinal cord injury; and

[0078] Postoperative pain syndrome (including post-mastectomy pain syndrome, post-thoracotomy pain syndrome, stump pain), bone and joint pain (osteoarthritis), spinal pain (including acute and chronic low back pain, neck pain, pain associated with spinal stenosis), shoulder pain, repetitive motion pain, dental pain, pain associated with sore throat, cancer pain, burn pain including sunburn, myofascial pain (pain associated with muscle injury, fibromyalgia), postoperative and perioperative pain (including but not limited to general surgery, orthopedic surgery, and gynecological surgery); and

[0079] Acute and chronic pain, chronic pelvic pain, pain associated with endometriosis, pain associated with dysmenorrhea (primary and secondary), pain associated with uterine fibroids, pain associated with vulvodynia, and pain associated with angina pectoris, or inflammatory pain of various origins (including but not limited to pain associated with osteoarthritis, rheumatoid arthritis, rheumatic diseases, tenosynovitis, gout, ankylosing spondylitis, and bursitis);

[0080] and any of the following or related diseases:

[0081] Gynecological conditions and / or diseases, or effects and / or symptoms that negatively impact women’s health, including endometriosis, uterine fibroids, pre-eclampsia, hormone deficiencies, uterine cramping or heavy menstrual bleeding;

[0082] Respiratory or excretory system, including any inflammatory hyper-responsive airways, inflammatory events associated with airway diseases such as chronic obstructive pulmonary disease, asthma, including allergic asthma (atopic or non-atopic) and exercise-induced bronchoconstriction, occupational asthma, viral or bacterial exacerbations of asthma, other non-allergic asthma and infantile wheezing syndrome, chronic obstructive pulmonary disease, including emphysema, adult respiratory distress syndrome, bronchitis, pneumonia, cough, lung injury, pulmonary fibrosis, allergic rhinitis (seasonal and perennial), vasomotor rhinitis, angioedema (including hereditary angioedema and drug-induced angioedema, including angioedema caused by angiotensin-converting enzyme (ACE) or ACE / neutral endopeptidase inhibitors such as omapatrilat), pneumoconiosis, including aluminum pneumoconiosis, ankylosing pulmonary disease, asbestosis, lithiasis, ostrich pneumoconiosis, siderosis, silicosis, fumigation, and byssinosis, intestinal diseases including Crohn's disease and ulcerative colitis, irritable bowel syndrome, pancreatitis, nephritis, cystitis (interstitial cystitis), painful bladder syndrome, renal fibrosis, renal failure, overactive bladder and overactive bladder syndrome;

[0083] Skin conditions, including pruritic, itchy, inflammatory skin conditions, including psoriasis, eczema, and atopic dermatitis;

[0084] Joint or bone diseases, including rheumatoid arthritis, gout, osteoporosis, osteoarthritis and ankylosing spondylitis;

[0085] Disorders of the central and peripheral nervous systems, including neurodegenerative diseases including Parkinson's and Alzheimer's diseases, amyotrophic lateral sclerosis (ALS), epilepsy, dementia, headache including cluster headache, migraine including both prophylactic and acute use, stroke, closed head trauma and multiple sclerosis;

[0086] Infections, including HIV infection and tuberculosis;

[0087] Trauma associated with: edema including cerebral edema, burns, sunburn and sprains or fractures;

[0088] Poisoning, including aluminum pneumoconiosis, carbon monoxide pneumonia, asbestosis, lithiasis, ostrich pneumoconiosis, siderosis, silicosis, fumigation and byssinusitis;

[0089] Diabetes cluster or metabolism such as type 1 diabetes, type 2 diabetes, diabetic angiopathy, diabetic neuropathy, diabetic retinopathy, post-capillary resistance or diabetic symptoms associated with insulitis (such as hyperglycemia, diuresis, proteinuria and increased urinary excretion of nitrite and kallikrein), diabetic macular edema, metabolic syndrome, insulin resistance, obesity, fat or muscle metabolism;

[0090] Cachexia associated with or caused by any of the following: cancer, AIDS, celiac disease, chronic obstructive pulmonary disease, multiple sclerosis, rheumatoid arthritis, congestive heart failure, tuberculosis, familial amyloid polyneuropathy, mercury poisoning (acral pain), and hormone deficiencies;

[0091] Cardiovascular system including congestive heart failure, atherosclerosis, congestive heart failure, myocardial infarction and cardiac fibrosis; and

[0092] Other conditions, including primary peritonitis, secondary peritonitis, septic shock, sepsis, muscular dystrophy, gastrointestinal spasm, benign prostatic hyperplasia, and liver disease, such as nonalcoholic and alcoholic fatty liver disease, nonalcoholic and alcoholic steatohepatitis, liver fibrosis, or cirrhosis.

[0093] In addition, the compounds of the present invention reduce the release of inflammation-related cytokines such as IL-6 and IL-8. Therefore, the present invention also relates to a method for reducing the production of inflammation-related cytokines, the method comprising the step of administering an effective amount of the compounds of the present invention to a patient in need thereof. The present invention also relates to the compounds of the present invention as defined herein, which are used to treat diseases associated with increased release of inflammation-related cytokines, preferably diseases associated with increased release of IL-6 and / or IL-8. BRIEF DESCRIPTION OF THE DRAWINGS

[0094] Figure 1 Effect of Compound Example 3 on PCNA Expression in Lesions in a 4-Day Rat Endometriosis Model

[0095] Figure 2 : Effect of Compound Example 3 on Tumor Necrosis Factor (TNF) α in Lesions in a 4-Day Rat Endometriosis Model

[0096] Figure 3 : Effect of Compound Example 3 on Interleukin 1 (IL-1) β in Lesions in a 4-Day Rat Endometriosis Model

[0097] Figure 4 : Effect of Compound Example 3 on Interleukin-6 (IL-6) in Lesions in a 4-Day Rat Endometriosis Model

[0098] Figure 5 : Effect of Compound Example 3 on Interleukin 1 (IL-1) α in Lesions in a 15-day Rat Endometriosis Model

[0099] Figure 6 : Effect of Compound Example 3 on Interleukin 1 (IL-1) β in Lesions in a 15-day Rat Endometriosis Model

[0100] Figure 7 : Effect of Compound Example 3 on Peroxidase Signal Reflecting Neutrophil Influx in Mouse Peritonitis Model

[0101] Figure 8 : Effect of Compound Example 3 on thermal stimulation in the STZ model (warm plate)

[0102] Fig. 9 : Efficacy of Compound Example 3 on overactive bladder (measured as number of urinations / hour)

[0103] Fig.10 : AUC during the plateau phase of urination 4 to 10 hours after transfer to the metabolic cage

[0104] Fig.11 : Normalized bladder weight

[0105] Fig.12 : Interval between contractions

[0106] Fig.13 : Maximum pressure of bladder contraction

[0107] Fig.14 : Effect of Compound Example 3 treatment on the severity of arthritis in the rat AIA model. Disease activity scores (A) and joint thickness (B) were assessed on the day of CFA injection (Day 0) and daily thereafter (A) or three times a week (B) after the first symptoms were shown (>Day 8). Treatment with Compound Example 3 (60, 15 or 3 mg / kg QD) was started together with induction of arthritis. The healthy control group (control) and the AIA group (AIA) were treated with vehicle only. Data are shown as mean ± SD of n = 8 rats per group. ANOVA and Dunett test, *p<0.05; **p<0.01; ***p<0.005; ****p<0.001, compared with the AIA group.

[0108] Fig.15 : Effect of treatment with Compound Example 3 on hyperalgesia in the rat AIA model. Grip strength was measured 3 times a week on the day of CFA injection (Day 0) and after the first symptoms appeared (>Day 8). Treatment with Compound Example 3 (60, 15 or 3 mg / kg QD) was started together with the induction of arthritis. The healthy control group (Control) and the AIA group (AIA) were treated with vehicle only. Data are shown as mean ± SD of n = 8 rats per group. ANOVA and Dunett test, *p<0.05; **p<0.01; ***p<0.005; ****p<0.001, compared with the AIA group.

[0109] Fig.16 : Schematic description of the operation and processing of the CCI model. DETAILED DESCRIPTION

[0110] The term "substituted" means that one or more hydrogen atoms on the designated atom or group is replaced with a selection from the indicated group without exceeding the normal valency of the designated atom under the existing circumstances. Combinations of substituents and / or variables are permissible.

[0111] The term "optionally substituted" means that the number of substituents may be equal to or different from zero. Unless otherwise indicated, an optionally substituted group may be substituted with as many optional substituents as can accommodate the replacement of hydrogen atoms with non-hydrogen substituents on any available carbon or nitrogen or sulfur atom. Typically, when present, the number of optional substituents may be 1, 2, 3, 4 or 5, particularly 1, 2 or 3.

[0112] As used herein, the term "one or more", for example in the definition of substituents of the compounds of general formula (I) of the present invention, means "one or more up to the maximum possible amount", for example, if the term refers to "C 7 -cycloalkyl”, it means “1, 2, 3, 4, 5, 6 or 7”. In particular, “one or more” means “1, 2, 3, 4 or 5, in particular 1, 2, 3 or 4, more in particular 1, 2 or 3, even more in particular 1 or 2”.

[0113] When the group in the compound according to the invention is substituted, unless otherwise indicated, the group may be monosubstituted or polysubstituted by one or more substituents. Within the scope of the present invention, the meanings of all groups that are repeated are independent of each other. The group in the compound according to the invention may be substituted by one, two or three identical or different substituents, in particular by one substituent.

[0114] When used in the specification, the term "comprising" includes, but is not limited to, "consisting of.

[0115] The terms mentioned in this text preferably have the following meanings:

[0116] The terms "halogen atom", "halogen", "halo-" or "halo-" are understood to mean a fluorine, chlorine, bromine or iodine atom, preferably a fluorine or chlorine atom.

[0117] The term "C 1 -C 5 "-alkyl" means a straight-chain or branched saturated monovalent hydrocarbon radical having 1, 2, 3, 4 or 5 carbon atoms, for example methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, pentyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl or 1,1-dimethylpropyl or an isomer thereof.

[0118] The term "C 1 -C 3 "-alkyl" refers to a straight or branched chain saturated monovalent hydrocarbon group having 1, 2 or 3 carbon atoms ("C 1 -C 3 -alkyl"), for example methyl, ethyl, n-propyl or isopropyl.

[0119] The term "-OC 1 -C 5 -alkyl" refers to a straight or branched chain saturated monovalent group attached through an oxygen atom, wherein the term "C 1 -C 5-alkyl" is as defined above, for example methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy, tert-butoxy, pentyloxy or isopentyloxy, or isomers thereof. The hyphen at the beginning of the group indicates that the OC 1 -C 5 -The point of attachment of the alkyl group to the rest of the molecule.

[0120] “C 3 -C 7 "-Cycloalkyl" is understood to mean a saturated monovalent monocyclic or bicyclic hydrocarbon ring containing 3, 4, 5, 6 or 7 carbon atoms. 3 -C 7 -Cycloalkyl is, for example, a monocyclic hydrocarbon ring, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, or a bicyclic hydrocarbon ring, such as bicyclo[2.2.1]heptyl or bicyclo[3.2.0]heptyl. In particular, the 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").

[0121] By definition, the term "bicyclic cycloalkyl" includes spirocycloalkyl, bridged and fused bicyclic alkyl groups.

[0122] The term "spirocycloalkyl" refers to a saturated monovalent bicyclic hydrocarbon radical, wherein the two rings share a common ring carbon atom, and wherein the bicyclic hydrocarbon radical contains 5, 6 or 7 carbon atoms, and the spirocycloalkyl radical may be attached to the remainder of the molecule via any one carbon atom other than the spiro carbon atom. The spirocycloalkyl radical is, for example, spiro[2.2]pentyl, spiro[2.3]hexyl or spiro[2.4]heptyl.

[0123] The term "fused bicycloalkyl" refers to a bicyclic saturated hydrocarbon ring having a total of 6 or 7 ring atoms, wherein the two rings share two adjacent ring atoms.

[0124] The fused cycloalkyl group is, for example, bicyclo[3.1.0]hexyl or bicyclo[3.2.0]heptyl.

[0125] The term "bridged bicycloalkyl" refers to a bicyclic saturated hydrocarbon ring having a total of 6 or 7 ring atoms, wherein the two rings share two non-adjacent ring atoms in common.

[0126] The bridged cycloalkyl group is, for example, bicyclo[2.1.1]hexyl or bicyclo[2.2.1]heptyl.

[0127] The term "-(C 1 -C 3 -alkyl)-(C 3 -C7 -cycloalkyl)" is understood to be C 3 -C 7 -cycloalkyl, which is 3 -C 7 Any carbon atom of the cycloalkyl group is connected to the C 1 -C 3 -Any atom in the alkyl group. The hyphen at the beginning of this group indicates that the (C 1 -C 3 -alkyl)-(C 3 -C 7 -cycloalkyl) group to the rest of the molecule. 1 -C 3 -alkyl)-(C 3 -C 7 A -cycloalkyl) group is, for example, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, 2-cyclopropylethyl, 1-cyclopropylethyl, 2-cyclobutylethyl, 1-cyclobutylethyl, 2-cyclopentylethyl, 1-cyclopentylethyl, 2-cyclobutylpropyl or 1-cyclobutylpropyl.

[0128] The term "-OC 3 -C 7 "-cycloalkyl" refers to a saturated monovalent monocyclic radical containing 3, 4, 5, 6 or 7 carbon atoms, wherein the term "C 3 -C 7 "-Cycloalkyl" is as defined above, for example cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy or cycloheptyloxy.

[0129] The term "heterocycloalkyl" is understood to mean a saturated monovalent monocyclic or bicyclic hydrocarbon ring having the specified number of ring atoms, wherein one or two ring atoms of the hydrocarbon ring are replaced by one or two independently selected from NH, -NR 4 ,N,O,S,SO and SO 2 A heteroatom or a heteroatom-containing group is substituted, where R 4 represents C optionally substituted by 1 to 5 fluorine atoms 1 -C 5 -alkyl.

[0130] In the context of the present invention, 4- to 7-membered heterocycloalkyl refers to a monocyclic or bicyclic saturated heterocycle having a total of 4, 5, 6 or 7 ring atoms, which contains one or two identical or different radicals from the series NH, -NR 4 ,N,O,S,SO and SO 2 A ring heteroatom or a heteroatom-containing group, wherein R 4 represents C optionally substituted by 1 to 5 fluorine atoms 1 -C 5The 4- to 7-membered heterocycloalkyl group may be bonded to the rest of the molecule via a ring carbon or nitrogen atom.

[0131] The heterocycloalkyl group may be attached to the remainder of the molecule through the carbon or nitrogen atom, if present.

[0132] Examples of monocyclic heterocycloalkyl groups are azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrofuranyl, thiolanyl, 1,1-dioxidothiolyl, 1,2-oxazolidinyl, 1,3-oxazolidinyl, 1,3-thiazolidinyl, piperidinyl, piperazinyl, tetrahydropyranyl, tetrahydrothiopyranyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,2-oxazepanyl, morpholinyl, thiomorpholinyl, 1,1-dioxidothiolyl, azepanyl, 1,4-diazepanyl and 1,4-oxazepanyl.

[0133] In particular, without limitation thereto, the heterocycloalkyl group may be a 4-membered ring, such as azetidinyl, oxetanyl or thietanyl, or a 5-membered ring, such as tetrahydrofuranyl, dioxolanyl, thiolanyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, 1,1-dioxythiolanyl, 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-oxazacyclohexanyl, or a 7-membered ring, such as azepanyl, 1,4-diazepanyl or 1,4-oxazepanyl.

[0134] By definition, the term "bicyclic heterocycloalkyl" includes heterospirocycloalkyl, fused and bridged heterobicycloalkyl.

[0135] The term "heterospirocycloalkyl" refers to a bicyclic saturated heterocycle having a total of 6 or 7 ring atoms, wherein the two rings share a common ring carbon atom, wherein the "heterospirocycloalkyl" contains one or two identical or different radicals from the series NH, -NR 4 ,N,O,S,SO and SO 2 A ring heteroatom or a heteroatom-containing group, wherein R 4 represents C optionally substituted by 1 to 5 fluorine atoms 1 -C 5 -alkyl; the heterospirocycloalkyl group may be attached to the rest of the molecule via any one carbon atom other than the spiro carbon atom or, when present, the nitrogen atom.

[0136] The heterospirocycloalkyl group is, for example, azaspiro[2.3]hexyl, azaspiro[2.4]heptyl, azaspiro[3.3]heptyl, oxazaspiro[3.3]heptyl, thiazaspiro[3.3]heptyl, oxazaspiro[3.3]heptyl, diazaspiro[3.3]heptyl or thiazaspiro[3.3]heptyl, or one of other similar skeletons, such as spiro[2.3]-, spiro[2.4]-, spiro[3.3]-.

[0137] The term "fused heterocycloalkyl" refers to a bicyclic saturated heterocycle having a total of 6 or 7 ring atoms, wherein the two rings share two adjacent ring atoms, and the "fused heterocycloalkyl" contains one or two identical or different heterocycles from the series NH, -NR 4 ,N,O,S,SO and SO 2 A ring heteroatom or a heteroatom-containing group, wherein R 4 represents C optionally substituted by 1 to 5 fluorine atoms 1 -C 5 -alkyl; the fused heterocycloalkyl group may be attached to the remainder of the molecule via any one carbon atom or, where present, a nitrogen atom.

[0138] The fused heterocycloalkyl group is, for example, 3-azabicyclo[3.1.0]hexyl or 3-azabicyclo[3.2.0]heptyl.

[0139] The term "bridged heterocycloalkyl" refers to a bicyclic saturated heterocycle having a total of 6 or 7 ring atoms, wherein the two rings share two non-adjacent ring atoms in common, and the "bridged heterocycloalkyl" contains one or two identical or different heterocycles from the series NH, -NR 4 ,N,O,S,SO and SO 2 A ring heteroatom or a heteroatom-containing group, wherein R 4 represents C optionally substituted by 1 to 5 fluorine atoms 1 -C 5 -alkyl; the bridged heterocycloalkyl group may be attached to the remainder of the molecule via any carbon atom other than the bridgehead carbon atom or, when present, the nitrogen atom.

[0140] The 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.

[0141] The term "5- to 7-membered lactam" refers to a cyclic amide of an aminocarboxylic acid having a 1-azacycloalkane-2-one structure with a ring size of 5, 6 or 7 ring system atoms, or an analog with unsaturation or heteroatoms, wherein the heteroatom replaces one or more carbon atoms of the ring. In particular, the "5- to 7-membered lactam" refers to γ-lactam (γ-lactam), δ-lactam (δ-lactam) and ε-lactam (ε-lactam).

[0142] The term "heteroaryl" is understood to mean a monovalent monocyclic or bicyclic hydrocarbon ring system having at least one aromatic ring and wherein at least one ring atom of the monovalent monocyclic or bicyclic hydrocarbon ring system may be substituted by at least one NH, N, O, S, SO and SO 2 The number of ring system atoms is as specified, for example, 5- or 6-membered heteroaryl.

[0143] “5- or 6-membered heteroaryl” is understood to mean a monovalent monocyclic heteroaryl having 5 or 6 ring atoms, and wherein one, two or three ring atoms of the monovalent 5-membered hydrocarbon ring system 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 the monovalent 6-membered hydrocarbon ring system are replaced by one or two nitrogen atoms.

[0144] If the nitrogen atom is present, the 5-membered heteroaryl group may be attached via the carbon or nitrogen atom.

[0145] The 5- or 6-membered heteroaryl group may be a 5-membered heteroaryl group such as thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl or thiadiazolyl; or a 6-membered heteroaryl group such as pyridyl, pyridazinyl, pyrimidinyl or pyrazinyl.

[0146] In general, unless otherwise indicated, the term "heteroaryl" includes all possible isomeric forms thereof, such as tautomers and positional isomers (relating to the point of attachment to the rest of the molecule). Thus, to give some illustrative, non-limiting examples, the term pyridyl 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 thienyl includes 2-thienyl and 3-thienyl; or the term thiazolyl includes 1,3-thiazol-5-yl, 1,3-thiazol-4-yl and 1,3-thiazol-2-yl.

[0147] "Bicyclic 8- to 10-membered heteroaryl" is understood to mean a bicyclic monovalent fused heteroaryl having 8, 9 or 10 ring atoms and having at least one aromatic ring, and wherein one, two or three ring atoms of the monovalent 8- to 10-membered bicyclic hydrocarbon ring system are replaced by one, two or three independently selected from NH, N, O, S, SO and SO 2 The invention may be replaced by a heteroatom or a group containing a heteroatom.

[0148] If the nitrogen atom is present, the bicyclic 8- to 10-membered heteroaryl group may be attached via the carbon or nitrogen atom.

[0149] By definition, the term "bicyclic 8- to 10-membered heteroaryl" includes fused and bridged heterobicycloalkyl groups.

[0150] In particular, the bicyclic heteroaryl is selected from, for example, benzofuranyl, benzothienyl, benzothiazolyl, thienopyridinyl, thienopyrimidinyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzotriazolyl, benzothiadiazolyl, indazolyl, indolyl, isoindolyl, etc., or, for example, quinolyl, quinazolinyl, isoquinolyl, etc.; indolizinyl, or cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, etc.

[0151] The term “C 1 -C 3 " is understood to mean a group having a limited number of carbon atoms from 1 to 3, i.e. 1, 2 or 3 carbon atoms, e.g. in "C 1 -C 3 In the context of the definition of "-alkyl", it should be understood that it refers to an alkyl group having a limited number of carbon atoms from 1 to 3, i.e., 1, 2 or 3 carbon atoms. It should be further understood that the term "C 1 -C 3 " shall be interpreted as any sub-range contained therein, such as C 1 -C 2 or C 2 -C 3 .

[0152] The term “C 1 -C 5 " is understood to mean a group having a limited number of carbon atoms from 1 to 5, i.e. 1, 2, 3, 4 or 5 carbon atoms, for example in "C 1 -C 5 In the context of the definition of "-alkyl", it should be understood that it refers to an alkyl group having a limited number of carbon atoms from 1 to 5, i.e., 1, 2, 3, 4 or 5 carbon atoms. It should be further understood that the term "C 1 -C 5 " shall be interpreted as any sub-range contained therein, such as C 1 -C 5 , C2 -C 5 , C 3 -C 4 , C 2 -C 3 , C 2 -C 4 or C 1 -C 4 .

[0153] In the definition of "-OC 1 -C 3 The term "C-alkyl" is used in the context of 1 -C 3 " is understood to mean an alkyl group having a finite number of carbon atoms of 1 to 3, i.e. 1, 2 or 3 carbon atoms.

[0154] Similarly, the 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".

[0155] In addition, as used herein, the term “C 3 -C 7 " is understood to mean a group having a limited number of carbon atoms of 3 to 7, i.e. 3, 4, 5, 6 or 7 carbon atoms, for example in "C 3 -C 7 -cycloalkyl" in the context of the definition of "cycloalkyl", it is understood to refer to a cycloalkyl group having a limited number of carbon atoms of 3 to 7, i.e. 3, 4, 5, 6 or 7 carbon atoms. It is further understood that the term "C 3 -C 7 " shall be interpreted as including any sub-ranges included therein, such as 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 ; especially C 3 -C 6 .

[0156] In addition, as used herein, the term "C 3 -C 5 ", as used in this text, for example in "C 3 -C 5 In the context of the definition of "-cycloalkyl", it is intended that the cycloalkyl group has a limited number of carbon atoms of 3 to 5, i.e. 3, 4 or 5 carbon atoms.

[0157] When a range of values ​​is given, the range includes every value and sub-range within the range.

[0158] For example:

[0159] “C 1 -C 6 "Including 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 ;

[0160] “C 2 -C 6 "Including C 2 , C 3 , C 4 , C 5 , C 6 , C 2 -C 6 , C 2 -C5 、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 ;

[0161] "C" 3 -C 10 ” including 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 ;

[0162] "C" 3 -C 8 ” including 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 ;

[0163] "C" 3 -C 6 ” including 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 ;

[0164] "C" 4 -C 8 ” including 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 ;

[0165] "C" 4 -C 7 ” including 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 ;

[0166] "C" 4 -C 6 ” including C 4 、C 5 、C 6、C 4 -C 6 、C 4 -C 5 and C 5 -C 6 ;

[0167] "C" 5 -C 10 ” including 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 ;

[0168] "C" 6 -C 10 ” including 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 .

[0169] As used herein, the term "leaving group" refers to an atom or a group of atoms that is replaced with the bonded electrons for a stable species in a chemical reaction. In particular, such leaving groups are selected from the group consisting of halogen, in particular fluorine, chlorine, bromine or iodine, (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-butylphenyl)sulfonyl]oxy and [(4-methoxyphenyl)sulfonyl]oxy.

[0170] The compounds of general formula (I) may exist as isotopic variations. The present invention therefore includes one or more isotopic variations of the compounds of general formula (I), in particular deuterated compounds of general formula (I).

[0171] The term "isotopic variant" of a compound or agent is defined as a compound that exhibits unnatural proportions of one or more isotopes that constitute that compound.

[0172] The term "isotopic variation of a compound of formula (I)" is defined as a compound of formula (I) that exhibits unnatural proportions of one or more of the isotopes that constitute said compound.

[0173] The expression "unnatural ratio" refers to a ratio of such isotopes that is higher than their natural abundance. The natural abundance of isotopes used in this context is described in "Isotopic Compositions of the Elements 1997", Pure Appl. Chem., 70 (1), 217-235, 1998, which is incorporated herein by reference.

[0174] Examples of such isotopes include stable and radioactive isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine and iodine, e.g. 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.

[0175] For the treatment and / or prevention of the conditions specified herein, one or more isotopic variations of the compounds of general formula (I) preferably contain deuterium ("deuterated compounds of general formula (I)"). Incorporation of one or more radioactive isotopes, for example 3 H or 14 Isotopic variations of compounds of formula (I) having a cation or dc are useful, for example, in drug and / or substrate tissue distribution studies. These isotopes are particularly preferred due to their ease of incorporation and detectability. Positron emitting isotopes such as 18 F or 11 C can be incorporated into the compounds of formula (I). These isotopic variants of the compounds of formula (I) can be used for in vivo imaging applications. 13 Compounds of formula (I) of C can be used for mass spectrometry analysis in preclinical or clinical research settings.

[0176] Isotopic variations of compounds of formula (I) can generally be prepared by methods known to those skilled in the art (e.g., those described in the schemes and / or examples herein) by substituting an isotopic variation of a reagent, preferably a deuterated reagent, for the reagent. Depending on the desired deuteration site, in some cases, the isotopic variation from D 2 The deuterium of O can be incorporated directly into the compound or into reagents that can be used to synthesize these compounds. Deuterium gas is also a useful reagent for incorporating deuterium into molecules. Catalytic deuteration of olefinic and acetylenic bonds is a rapid way to incorporate deuterium. Metal catalysts (i.e., Pd, Pt, and Rh) in the presence of deuterium gas can be used to directly exchange hydrogen with deuterium in hydrocarbons containing functional groups. Various deuterated reagents and synthetic building blocks are commercially available from companies such as C / D / N Isotopes, Quebec, Canada; Cambridge Isotope Laboratories Inc., Andover, MA, USA; and CombiPhos Catalysts, Inc., Princeton, NJ, USA.

[0177] The term "deuterated compound of formula (I)" is defined as a compound of formula (I) wherein one or more hydrogen atoms are replaced by one or more deuterium atoms, wherein the deuterium abundance of each deuterated position of the compound of formula (I) is higher than the natural abundance of deuterium, which is about 0.015%. In particular, in the deuterated compound of formula (I), the abundance of deuterium at each deuterated position of the compound of formula (I) at said position (one or more) 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%. It will be understood that the deuterium abundance of each deuterated position is independent of the deuterium abundance of the other deuterated position(s).

[0178] Selective incorporation of one or more deuterium atoms into compounds of general formula (I) may alter the physicochemical properties (e.g. acidity [CL Perrin et al., J. Am. Chem. Soc., 2007, 129, 4490], basicity [CL 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 characteristics of the molecule and may result in an increase in the ratio of the parent compound to the metabolite or in the amount of the metabolite formed. These changes may lead to certain therapeutic advantages and may therefore be preferred in certain circumstances. Reduced metabolic rates and metabolic turnover have been reported with altered metabolite ratios (AEMutlib et al., Toxicol. Appl. Pharmacol., 2000, 169, 102). These changes in parent drug and metabolite exposure may have important effects on the pharmacodynamics, tolerability and efficacy of deuterated compounds of formula (I). In some cases, deuterium substitution reduces or eliminates the formation of undesirable or toxic metabolites and enhances the formation of desired metabolites (e.g. Such as nevirapine: AM Sharma et al., Chem. Res. Toxicol., 2013, 26, 410; efavirenz: AEMutlib et al., Toxicol. Appl. Pharmacol., 2000, 169, 102; both are incorporated herein by reference). In other cases, the main effect of deuteration is to reduce systemic clearance. As a result, the biological half-life of the compound is increased. Potential clinical benefits include the ability to maintain similar systemic exposure, with reduced peaks and increased troughs. This may result in lower side effects and enhanced efficacy, which Depends on the pharmacokinetic / pharmacodynamic relationship of the specific compound. ML-337 (CJ Wenthur et al., J. Med. Chem., 2013, 56, 5208; incorporated herein by reference) and odenkati (K. Kassahun et al., WO2012 / 112363; incorporated herein by reference) are examples of this deuterium effect. Other cases have also been reported where reduced metabolic rates lead to increased drug exposure without changing 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 that show this effect may have reduced dosing requirements (e.g., a lower number of doses or a lower dose to achieve the desired effect) and / or may produce a lower metabolite load.

[0179] Compounds of general formula (I) may have multiple potential sites of metabolic attack. In order to optimize the above-mentioned effects on physicochemical properties and metabolic characteristics, deuterated compounds of general formula (I) with one or more deuterium-hydrogen exchanges may be selected. In particular, one or more deuterium atoms of one or more deuterated compounds of general formula (I) may be attached to carbon atoms and / or located at those of the compounds of general formula (I) that are metabolic enzymes such as cytochrome P 450 The location of the attack site.

[0180] Optical isomers can be obtained by resolving racemic mixtures according to conventional methods, for example, by forming diastereomeric salts using optically active acids or bases, or by forming covalent diastereomers. Examples of suitable acids are tartaric acid, diacetyltartaric acid, ditoluoyltartaric acid and camphorsulfonic acid. A mixture of diastereoisomers can be separated into their single diastereomers by methods known in the art, such as by chromatography or fractional crystallization, based on their physical and / or chemical differences. Then, the optically active base or acid is released from the separated diastereomeric salts. A different method of separating optical isomers involves using chiral chromatography (e.g., chiral HPLC columns) with or without conventional derivatization, which can be optimally selected to maximize the separation of enantiomers. Suitable chiral HPLC columns are produced by Daicel, such as Chiracel OD and Chiracel OJ, etc., all of which can be conventionally selected. Enzymatic separation can also be used with or without derivatization. Similarly, the optically active compounds of the present invention can be obtained by chiral synthesis using optically active raw materials.

[0181] In order to define the different types of isomers from one another, reference is made to the IUPAC Rules Section E (Pure Appl Chem 45, 1130, 1976), which is hereby incorporated herein.

[0182] Additionally, the compounds of the present invention may exist in the form of tautomers.

[0183] The present invention includes all possible tautomers of the compounds of the present invention, either as single tautomers or as any mixture of said tautomers in any ratio.

[0184] 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.

[0185] When the plural form of the words compounds, salts, polymorphs, hydrates, solvates and the like are used herein, it should be understood that it also refers to a single compound, salt, polymorph, isomer, hydrate, solvate and the like.

[0186] 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.

[0187] The compounds of the present invention can exist in the form of hydrates or solvates, wherein the compounds of the present invention contain polar solvents as structural elements of the compound lattice, particularly water, methanol or ethanol. The amount of polar solvents, particularly water, can exist in a stoichiometric ratio or a non-stoichiometric ratio. In the case of stoichiometric solvates (e.g., hydrates), they can be hemi, (half-), mono, sesqui, di, tri, tetra, penta, etc. solvates or hydrates, respectively. The present invention includes all such hydrates or solvates.

[0188] In addition, the compounds of the present invention may exist in free form, for example in the form of a free base or a free acid or a zwitterion, or in the form of a salt. The salt may be any salt, which may be an organic or inorganic addition salt, in particular any pharmaceutically acceptable organic or inorganic addition salt commonly used in pharmacy.

[0189] The term "pharmaceutically acceptable salt" refers to a relatively nontoxic, inorganic or organic acid addition salt of a compound of the invention. For example, see SM Berge et al., "Pharmaceutical Salts", J. Pharm. Sci. 1977, 66, 1-19, which is incorporated herein by reference. Suitable pharmaceutically acceptable salts of the compounds of the invention can be, for example, acid addition salts of the compounds of the invention which are, for example, sufficiently basic, with nitrogen atoms in the chain or ring, for example, with inorganic acids or with organic acids, such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, bisulfuric acid, phosphoric acid or nitric acid, such as formic acid, acetic acid, acetoacetic acid, pyruvic acid, trifluoroacetic acid, propionic acid, butyric acid, hexanoic acid, heptanoic acid, undecanoic acid, lauric acid, benzoic acid, salicylic acid, 2-(4-hydroxybenzoyl)benzoic acid, camphoric acid, cinnamic acid, cyclopentanepropionic acid, digluconic acid (digluconic acid) acid), 3-hydroxy-2-naphthoic acid, nicotinic acid, pamoic acid, pectinic acid, persulfuric acid, 3-phenylpropionic acid, picric acid, pivalic acid, 2-hydroxyethanesulfonic acid, itaconic acid, sulfamic acid, trifluoromethanesulfonic acid, dodecylsulfuric acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, 2-naphthalenesulfonic acid, naphthalenedisulfonic acid, camphorsulfonic acid, citric acid, tartaric acid, stearic acid, lactic acid, oxalic acid, malonic acid, succinic acid, malic acid, adipic acid, alginic acid, maleic acid, fumaric acid, D-gluconic acid, mandelic acid, ascorbic acid, glucoheptonic acid, glycerophosphoric acid, aspartic acid, sulfosalicylic acid, hemisulfuric acid, or thiocyanic acid.

[0190] In addition, another suitable pharmaceutically acceptable salt of the sufficiently acidic compound of the present invention is an alkali metal salt such as a sodium salt or a potassium salt, an alkaline earth metal salt such as a calcium salt or a magnesium salt, an ammonium salt, or a salt with an organic base providing a physiologically acceptable cation, for example, a salt with the following substances: N-methylglucamine, dimethylglucamine, ethylglucamine, lysine, dicyclohexylamine, 1,6-hexanediamine, ethanolamine, glucosamine, sarcosine, serinol, trishydroxymethylaminomethane, aminopropylene glycol, sovak's base, 1-amino-2,3,4-butanetriol. In addition, basic nitrogen-containing groups can be quaternized with the following reagents: lower alkyl halides (e.g., chlorides, bromides, and iodides of methyl, ethyl, propyl, and butyl); dialkyl sulfates (e.g., dimethyl sulfate, diethyl sulfate, dibutyl sulfate, and diamyl sulfate); long chain halides (e.g., chlorides, bromides, and iodides of decyl, lauryl, myristyl, and stearyl), aralkyl halides (e.g., benzyl bromide and phenethyl bromide), and the like.

[0191] Those skilled in the art will also recognize that the acid addition salts of the claimed compounds can be prepared by reacting the compounds with a suitable inorganic or organic acid via any of a variety of known methods. Alternatively, alkali metal and alkaline earth metal salts of acidic compounds of the present invention can be prepared by reacting the compounds of the present invention with a suitable base via various known methods.

[0192] The present invention includes all possible salts of the compounds according to the invention, either as individual salts or as any mixture of said salts in any ratio.

[0193] Unless otherwise indicated, the compounds of the present invention also refer to isomers, enantiomers, diastereomers, racemates, hydrates, solvates, salts or mixtures thereof.

[0194] As used herein, the term "in vivo hydrolyzable ester" is understood to refer to an in vivo hydrolyzable ester of a compound of the invention containing a carboxyl or hydroxyl group, for example, a pharmaceutically acceptable ester that can be hydrolyzed in the human or animal body to produce the parent acid or alcohol. Pharmaceutically acceptable esters suitable for carboxyl groups include, for example, alkyl, cycloalkyl and optionally substituted phenylalkyl, particularly benzyl esters, C 1 -C 6 Alkoxymethyl esters, such as methoxymethyl ester, C 1 -C 6 Alkanoyloxymethyl esters, such as pivaloyloxymethyl ester, phthaloyl ester, C 3 -C 8 Cycloalkoxy-carbonyloxy-C 1 -C 6 Alkyl esters, such as 1-cyclohexylcarbonyloxyethyl ester, 1,3-dioxol-2-one methyl esters, such as 5-methyl-1,3-dioxol-2-one methyl ester, and C1 -C 6 -alkoxycarbonyloxyethyl esters, such as 1-methoxycarbonyloxyethyl ester, and can be formed on any carboxyl group of the compounds of the present invention. Hydrolyzable esters of the compounds of the present invention containing hydroxyl groups include inorganic acid esters (such as phosphates), [α] acyloxyalkyl ethers, and related compounds that break and form the parent hydroxyl group due to the in vivo hydrolysis of the esters. Examples of [α] acyloxyalkyl ethers include acetoxymethyl ether (acetoxymethoxy) and 2,2-dimethylpropionyloxymethyl ether (2,2-dimethylpropionyloxymethoxy). The selection of groups that form hydrolyzable esters in vivo with hydroxyl groups includes alkanoyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl, alkoxycarbonyl (to form alkyl carbonates), dialkylcarbamoyl and N-(dialkylaminoethyl)-N-alkylcarbamoyl (to form carbamates), dialkylaminoacetyl and carboxyacetyl. The present invention includes all such esters.

[0195] Furthermore, the present invention includes all possible crystalline forms or polymorphs of the compounds of the present invention, either as a single polymorph or as a mixture of more than one polymorph in any ratio.

[0196] According to a first aspect, the present invention encompasses compounds of general formula (I)

[0197] in,

[0198] R 1 represent:

[0199] · Phenyl,

[0200] 5- or 6-membered heteroaryl, wherein the 5-membered heteroaryl contains 1, 2 or 3 heteroatoms or heteroatom-containing groups independently selected from S, N, NH and O, and wherein the 6-membered heteroaryl contains 1 or 2 nitrogen atoms, or

[0201] Contains 1, 2 or 3 independently selected from NH, N, O, S, SO and SO 2 A bicyclic 9- to 10-membered heteroaryl group containing a heteroatom or a heteroatom-containing group,

[0202] Where R 1 Optionally substituted as defined in formula (I).

[0203] Also preferred are compounds of general formula (I) wherein

[0204] R 1 represent:

[0205] · Phenyl,

[0206] 5- or 6-membered heteroaryl, wherein the 5-membered heteroaryl contains 1, 2 or 3 heteroatoms or heteroatom-containing groups independently selected from S, N, NH and O, and wherein the 6-membered heteroaryl contains 1 or 2 nitrogen atoms, or

[0207] Contains 1, 2 or 3 independently selected from NH, N, O, S, SO and SO 2 A bicyclic 9- to 10-membered heteroaryl group containing a heteroatom or a heteroatom-containing group,

[0208] Wherein R 1 Optionally, one or more carbon atoms may be substituted by 1 or 2 identical or different substituents R 1a Substitution, where 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

[0209] Among them, independently, if R 1 represents a 5-membered heteroaryl or a bicyclic 9- or 10-membered heteroaryl, then the R 1 Each ring nitrogen atom of 1b Substitution, where 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

[0210] 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 -OC3 -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,

[0211] Then the 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 is optionally substituted by one or more independently selected from methyl, OH, OR 4 and a substituent of F; and

[0212] R 4 have the same meanings as defined in the above general formula (I).

[0213] Also preferred are compounds of general formula (I) wherein

[0214] R 1 represent:

[0215] 6-membered heteroaryl, in particular pyridyl, pyrimidinyl or pyrazinyl,

[0216] Wherein R 1 Optionally, one or more carbon atoms may be substituted by 1 or 2 identical or different substituents R 1a Substitution, where 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

[0217] Wherein 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 is optionally substituted by one or more independently selected from OH, OR 4 and a substituent of F; and wherein

[0218] R 4 have the same meanings as defined in the above general formula (I).

[0219] Also preferred are compounds of general formula (I) wherein

[0220] R 1 represents a pyridyl group, in particular a pyridin-3-yl group, which is optionally substituted at one or more carbon atoms by 1 or 2 identical or different substituents R 1a Substitution, where 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

[0221] wherein a substituent or at least one of the substituents R 1a is preferably located in the para position to the carbon atom which links the pyridyl group, in particular the pyrid-3-yl group, to the rest of the molecule, and

[0222] Wherein C 1 -C 5 -alkyl, C 3 -C 7 -cycloalkyl, -(C 1 -C 3 -alkyl)-(C 3 -C 7 -cycloalkyl), -OC 1 -C5 -alkyl and -OC 3 -C 7 -cycloalkyl is optionally substituted by one or more independently selected from OH, OR 4 and a substituent of F; and wherein

[0223] R 4 have the same meanings as defined in the above general formula (I).

[0224] Also preferred are compounds of general formula (I) wherein

[0225] R 1 represents a pyridyl group, in particular a pyridin-3-yl group, which is substituted at one or more carbon atoms by one or two identical or different substituents R 1a Substitution, where R 1a represents methyl, ethyl, cyclobutyl, methoxy, ethoxy, trifluoromethyl, difluoromethyl, 1,1-difluoroethyl, 1,1-difluoropropyl or 2,2,2-trifluoroethyl, and

[0226] wherein a substituent or at least one of the substituents R 1a It is preferably located in the para position to the carbon atom which links the pyridyl group, in particular the pyrid-3-yl group, to the rest of the molecule.

[0227] Also preferred are compounds of general formula (I) wherein

[0228] R 1 represents a pyridyl group, in particular a pyridin-2-yl group, which is optionally substituted at one or more carbon atoms by 1 or 2 identical or different substituents R 1a Substitution, where 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

[0229] wherein a substituent or at least one of the substituents R 1a is preferably located in the para position to the carbon atom which links the pyridyl group, in particular the pyrid-2-yl group, to the rest of the molecule, and

[0230] Wherein C 1 -C 5 -alkyl, C3 -C 7 -cycloalkyl, -(C 1 -C 3 -alkyl)-(C 3 -C 7 -cycloalkyl), -OC 1 -C 5 -alkyl and -OC 3 -C 7 -cycloalkyl is optionally substituted by one or more independently selected from OH, OR 4 and a substituent of F; and wherein

[0231] R 4 have the same meanings as defined in the above general formula (I).

[0232] Also preferred are compounds of general formula (I) wherein

[0233] R 1 represents a pyridyl group, in particular a pyridin-2-yl group, which is substituted at one or more carbon atoms by one or two identical or different substituents R 1a Substitution, where R 1a represents methyl, ethyl, cyclobutyl, methoxy, ethoxy, trifluoromethyl, difluoromethyl, 1,1-difluoroethyl, 1,1-difluoropropyl or 2,2,2-trifluoroethyl, and

[0234] wherein a substituent or at least one of the substituents R 1a It is preferably located in the para position to the carbon atom which links the pyridyl group, in particular the pyrid-2-yl group, to the rest of the molecule.

[0235] Also preferred are compounds of general formula (I) wherein

[0236] R 1 represent:

[0237] 5-membered heteroaryl, wherein the 5-membered heteroaryl contains 1, 2 or 3 heteroatoms or heteroatom-containing groups independently selected from S, N, NH and O, in particular pyrazolyl, thiazolyl, imidazolyl or thienyl,

[0238] Wherein R 1 Optionally, one or more carbon atoms may be substituted by 1 or 2 identical or different substituents R 1a Substitution, where R 1a Represents C 1 -C 5 -alkyl, C 3 -C 7 -cycloalkyl, -(C 1 -C 3 -alkyl)-(C 3 -C7 -cycloalkyl), -OC 1 -C 5 -alkyl, -OC 3 -C 7 - cycloalkyl, halogen or CN, and

[0239] Wherein R 1 Each ring nitrogen atom of is independently optionally substituted with a substituent R 1b Substitution, where 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

[0240] 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, then the 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 is optionally substituted with one or more independently selected from methyl, ethyl, OH, OR 4and a substituent of F; and wherein

[0241] R 4 have the same meanings as defined in the above general formula (I).

[0242] Also preferred are compounds of general formula (I) wherein

[0243] R 1 represents pyrazolyl, in particular pyrazol-4-yl, which is optionally substituted at one or more carbon atoms by 1 or 2 identical or different substituents R 1a Substitution, where 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

[0244] Wherein R 1 Each ring nitrogen atom of 1b Substitution, where 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

[0245] 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, -(C1 -C 3 -alkyl)-(C 3 -C 7 -cycloalkyl) or C 3 -C 7 -cycloalkyl, then the 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 is optionally substituted with one or more independently selected from methyl, ethyl, OH, OR 4 and a substituent of F; and wherein

[0246] R 4 have the same meanings as defined in the above general formula (I).

[0247] Also preferred are compounds of general formula (I) wherein

[0248] R 1 represents the nitrogen atom at position 1 substituted by a group R 1b Substituted pyrazol-4-yl, 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 the C 1 -C 5 -alkyl, C 3 -C 7 -cycloalkyl and -(C 1 -C 3 -alkyl)-(C 3 -C 7 -cycloalkyl) is optionally substituted by one or more independently selected from methyl, ethyl, OH, OR 4 and a substituent of F; and wherein

[0249] R 4 have the same meanings as defined in the above general formula (I).

[0250] Additionally preferred are compounds of the general formula (I), wherein

[0251] R 1 represents pyrazolyl, in particular pyrazol-4-yl, wherein R 1 Optionally 1 or 2 identical or different R 1b Substitution, where 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

[0252] wherein the substituent R 1b One of the C is connected to the 1-nitrogen atom of the pyrazolyl group, preferably to the 1-nitrogen atom of the pyrazol-4-yl group, and wherein the C 1 -C 5 -alkyl, C 3 -C 7 -cycloalkyl and -(C 1 -C 3 -alkyl)-(C 3 -C 7 -cycloalkyl) are optionally substituted by one or more independently selected from methyl, ethyl, OH, OR 4 and a substituent of F; and wherein

[0253] R 4 have the same meanings as defined in the above general formula (I).

[0254] Additionally preferred are compounds of the general formula (I), wherein

[0255] R 1 represents the nitrogen atom at position 1 is replaced by C 3 -C 7 -cycloalkyl-substituted pyrazol-4-yl, wherein the C 3 -C 7 -cycloalkyl is optionally substituted by one or more independently selected from methyl, ethyl, OH, OR 4 and a substituent of F; and wherein

[0256] R 4 have the same meanings as defined in the above general formula (I).

[0257] Additionally preferred are compounds of the general formula (I), wherein

[0258] R 1 Indicates that the nitrogen atom at position 1 is replaced by C 3 -C7 -cycloalkyl-substituted pyrazol-4-yl, wherein the C 3 -C 7 -cycloalkyl is optionally substituted by one or more independently selected from methyl, OH, OR 4 and a substituent of F; and wherein

[0259] R 4 have the same meanings as defined in the above general formula (I).

[0260] Also preferred are compounds of general formula (I) wherein

[0261] R 1 represents a pyrazol-4-yl radical substituted at the nitrogen atom in position 1 by a substituent selected from the group consisting of methyl, ethyl, propyl, prop-2-yl, 2-methylpropyl, tert-butyl, but-2-yl, cyclobutyl, 2,2-dimethylpropyl, 3-methylbut-2-yl, cyclopentyl, cyclohexyl, 1-cyclopropylmethyl, 1-cyclopropylethyl, 1-cyclobutylmethyl, 1-(1-methylcyclopropyl)methyl and 2,2,2-trifluoroethyl, in particular ethyl, prop-2-yl, 2-methylpropyl, but-2-yl, cyclobutyl, cyclopentyl, 2,2-dimethylpropyl, 1-cyclopropylmethyl, 1-cyclopropylethyl, 1-(1-methylcyclopropyl)methyl and 1-cyclobutylmethyl.

[0262] Particularly preferred are compounds of general formula (I) wherein

[0263] R 1 represents a pyrazol-4-yl group substituted at the nitrogen atom in position 1 by a cyclobutyl group.

[0264] Also preferred are compounds of general formula (I) wherein

[0265] R 1 represents a thiazolyl group, in particular a thiazol-5-yl group, which is optionally substituted at one or more carbon atoms by 1 or 2 identical or different substituents R 1a Substitution, where 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,

[0266] Wherein C1 -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 is optionally substituted with one or more independently selected from methyl, ethyl, OH, OR 4 and a substituent of F; and wherein

[0267] R 4 have the same meanings as defined in the above general formula (I).

[0268] Also preferred are compounds of general formula (I) wherein

[0269] R 1 represents a thiazolyl group, in particular a thiazol-5-yl group, which is optionally substituted at one or more carbon atoms by 1 or 2 identical or different substituents R 1a Substitution, where 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,

[0270] wherein the substituent R 1a One of the following is preferably located in the meta position to the carbon atom which links the thiazolyl group, in particular the thiazol-5-yl group, to the rest of the molecule, and

[0271] Wherein 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 is optionally substituted with one or more independently selected from methyl, ethyl, OH, OR 4 and a substituent of F; and wherein

[0272] R 4 have the same meanings as defined in the above general formula (I).

[0273] Also preferred are compounds of general formula (I) wherein

[0274] R 1 represents a thiazol-5-yl group, which is optionally substituted at a carbon atom by a group R 1a Substitution, where R 1a Represents C 1 -C 5 -alkyl, -(C 1 -C 3 -alkyl)-(C 3 -C 7 -cycloalkyl) or C 3 -C 7 - cycloalkyl,

[0275] Wherein C 1 -C 5 -alkyl, C 3 -C 7 -cycloalkyl or -(C 1 -C 3 -alkyl)-(C 3 -C 7 -cycloalkyl) is optionally substituted by one or more independently selected from methyl, ethyl, OH, OR 4 and a substituent of F; and wherein

[0276] R 4 have the same meanings as defined in the above general formula (I).

[0277] Also preferred are compounds of general formula (I) wherein

[0278] R 1 represents a thiazol-5-yl group, which is optionally substituted at a carbon atom by a group R 1a Substitution, where R 1a Represents C 1 -C 5 -alkyl, -(C 1 -C 3 -alkyl)-(C 3 -C 7 -cycloalkyl) or C 3 -C 7 - cycloalkyl,

[0279] wherein the substituent R1a Preferably, it is connected to the carbon atom at position 2 of the thiazol-5-yl group, and

[0280] Wherein C 1 -C 5 -alkyl, C 3 -C 7 -cycloalkyl or -(C 1 -C 3 -alkyl)-(C 3 -C 7 -cycloalkyl) is optionally substituted by one or more independently selected from methyl, ethyl, OH, OR 4 and a substituent of F; and wherein

[0281] R 4 have the same meanings as defined in the above general formula (I).

[0282] Additionally preferred are compounds of the general formula (I), wherein

[0283] R 1 Represents the carbon atom at position 2 is replaced by C 3 -C 7 -cycloalkyl-substituted thiazol-5-yl, wherein the C 3 -C 7 -cycloalkyl is optionally substituted by one or more independently selected from methyl, ethyl, OH, OR 4 and F is substituted with a substituent, and wherein

[0284] R 4 have the same meanings as defined in the above general formula (I).

[0285] Additionally preferred are compounds of the general formula (I), wherein

[0286] R 1 Represents the carbon atom at position 2 is replaced by C 3 -C 7 -cycloalkyl-substituted thiazol-5-yl, wherein the C 3 -C 7 -cycloalkyl is optionally substituted by one or more independently selected from methyl, OH, OR 4 and F is substituted with a substituent, and wherein

[0287] R 4 have the same meanings as defined in the above general formula (I).

[0288] Also preferred are compounds of general formula (I) wherein

[0289] R 1represents a thiazol-5-yl group which is substituted at the carbon atom in position 2 by a substituent selected from the group consisting of methyl, ethyl, propyl, prop-2-yl, 2-methylpropyl, tert-butyl, but-2-yl, cyclopropyl, cyclobutyl, 2,2-dimethylpropyl, 3-methylbut-2-yl, cyclopentyl, cyclohexyl, 1-cyclopropylmethyl, 1-cyclopropylethyl, 1-cyclobutylmethyl, 1-(1-methylcyclopropyl)methyl and 2,2,2-trifluoroethyl, in particular ethyl, prop-2-yl, 2-methylpropyl, but-2-yl, cyclobutyl, cyclopentyl, 2,2-dimethylpropyl, 1-cyclopropylmethyl, 1-cyclopropylethyl, 1-(1-methylcyclopropyl)methyl and 1-cyclobutylmethyl.

[0290] Also preferred are compounds of general formula (I) wherein

[0291] R 1 represents a thiazolyl group, in particular a thiazol-2-yl group, which is optionally substituted at one or more carbon atoms by 1 or 2 identical or different substituents R 1a Substitution, where 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,

[0292] Wherein 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 is optionally substituted with one or more independently selected from methyl, ethyl, OH, OR 4 and a substituent of F; and

[0293] R 4 have the same meanings as defined in the above general formula (I).

[0294] Also preferred are compounds of general formula (I) wherein

[0295] R 1 represents one or more carbon atoms optionally substituted by 1 or 2 identical or different substituents R 1a Substituted thiazol-2-yl, 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,

[0296] wherein the substituent R 1a One of the following is preferably connected to the 5-carbon atom of the thiazol-2-yl group, and

[0297] Wherein 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 is optionally substituted with one or more independently selected from methyl, ethyl, OH, OR 4 and a substituent of F; and wherein

[0298] R 4 have the same meanings as defined in the above general formula (I).

[0299] Also preferred are compounds of general formula (I) wherein

[0300] R 1 represents a thiazol-2-yl group, which is optionally substituted at a carbon atom by a group R 1a Substitution, where R 1a Represents C 1 -C 5 -alkyl, -(C 1 -C 3 -alkyl)-(C 3 -C 7 -cycloalkyl) or C3 -C 7 - cycloalkyl,

[0301] Wherein C 1 -C 5 -alkyl, C 3 -C 7 -cycloalkyl or -(C 1 -C 3 -alkyl)-(C 3 -C 7 -cycloalkyl) is optionally substituted by one or more independently selected from methyl, ethyl, OH, OR 4 and a substituent of F; and wherein

[0302] R 4 have the same meanings as defined in the above general formula (I).

[0303] Also preferred are compounds of general formula (I) wherein

[0304] R 1 represents a thiazol-2-yl group, which is optionally substituted at a carbon atom by a group R 1a Substitution, where R 1a Represents C 1 -C 5 -alkyl, -(C 1 -C 3 -alkyl)-(C 3 -C 7 -cycloalkyl) or C 3 -C 7 - cycloalkyl,

[0305] wherein the substituent R 1a Preferably connected to the 5-carbon atom of the thiazol-2-yl group,

[0306] Wherein C 1 -C 5 -alkyl, C 3 -C 7 -cycloalkyl or -(C 1 -C 3 -alkyl)-(C 3 -C 7 -cycloalkyl) is optionally substituted by one or more independently selected from methyl, ethyl, OH, OR 4 and a substituent of F; and

[0307] R 4 have the same meanings as defined in the above general formula (I).

[0308] Additionally preferred are compounds of the general formula (I), wherein

[0309] R1 represents thiazol-2-yl, which is replaced by C at the 5-carbon atom 3 -C 7 -cycloalkyl substituted, wherein the C 3 -C 7 -cycloalkyl is optionally substituted by one or more independently selected from methyl, ethyl, OH, OR 4 and a substituent of F; and wherein

[0310] R 4 have the same meanings as defined in the above general formula (I).

[0311] Additionally preferred are compounds of the general formula (I), wherein

[0312] R 1 represents thiazol-2-yl, which is replaced by C at the 5-carbon atom 3 -C 7 -cycloalkyl substituted, wherein the C 3 -C 7 -cycloalkyl is optionally substituted by one or more independently selected from methyl, OH, OR 4 and a substituent of F; and wherein

[0313] R 4 have the same meanings as defined in the above general formula (I).

[0314] Also preferred are compounds of general formula (I) wherein

[0315] R 1 represents a thiazol-2-yl group which is substituted at the carbon atom in the 5-position by a substituent selected from the group consisting of methyl, ethyl, propyl, prop-2-yl, 2-methylpropyl, tert-butyl, but-2-yl, cyclopropyl, cyclobutyl, 2,2-dimethylpropyl, 3-methylbut-2-yl, cyclopentyl, cyclohexyl, 1-cyclopropylmethyl, 1-cyclopropylethyl, 1-cyclobutylmethyl, 1-(1-methylcyclopropyl)methyl and 2,2,2-trifluoroethyl, in particular ethyl, prop-2-yl, 2-methylpropyl, but-2-yl, cyclobutyl, cyclopentyl, 2,2-dimethylpropyl, 1-cyclopropylmethyl, 1-cyclopropylethyl, 1-(1-methylcyclopropyl)methyl and 1-cyclobutylmethyl.

[0316] Also preferred are compounds of general formula (I) wherein

[0317] R 1 represent:

[0318] Contains 1, 2 or 3 independently selected from NH, N, O, S, SO and SO 2 A bicyclic 9-membered heteroaryl group containing a heteroatom or a heteroatom-containing group, in particular a benzothienyl group,

[0319] Wherein R 1 Optionally, one or more carbon atoms may be substituted by 1 or 2 identical or different substituents R 1a Substitution, where 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

[0320] Wherein R 1 Each ring nitrogen atom of 1b Substitution, where 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

[0321] 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, then the C 1 -C 5 -alkyl, C3 -C 7 -cycloalkyl, -(C 1 -C 3 -alkyl)-(C 3 -C 7 -cycloalkyl), -OC 1 -C 5 -alkyl and -OC 3 -C 7 -cycloalkyl is optionally substituted with one or more independently selected from methyl, ethyl, OH, OR 4 and a substituent of F; and wherein

[0322] R 4 have the same meanings as defined in the above general formula (I).

[0323] Additionally preferred are compounds of the general formula (I), wherein

[0324] R 1 represents phenyl, pyridyl, pyrazolyl, thiazolyl, imidazolyl, thienyl or benzothienyl, in particular pyridyl, pyrazolyl, thiazolyl or imidazolyl,

[0325] Wherein R 1 Optionally, one or more carbon atoms may be substituted by 1 or 2 identical or different substituents R 1a Substitution, where 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, then the R 1 Each ring nitrogen atom of 1b Substitution, where 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

[0326] 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, then the 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 is optionally substituted with one or more independently selected from methyl, ethyl, OH, OR 4 and a substituent of F; and wherein

[0327] R 4 have the same meanings as defined in the above general formula (I).

[0328] According to another aspect, the present invention encompasses compounds of general formula (I), wherein

[0329] R 4 Represents C 1 -C 5 - alkyl, in particular methyl, ethyl, propyl or butyl, optionally substituted by 1 to 3 fluorine atoms.

[0330] Also preferred are compounds of general formula (I) wherein

[0331] R 4 represents methyl, difluoromethyl or trifluoromethyl.

[0332] According to another aspect, the present invention encompasses compounds of general formula (I), wherein

[0333] R 3 Represents H.

[0334] According to another aspect, the present invention encompasses compounds of general formula (I), wherein

[0335] R 5 represents H, F, Cl or methyl, in particular H or F.

[0336] Particularly preferred are compounds of general formula (I) wherein

[0337] R 5 Represents H.

[0338] Also preferred are compounds of general formula (I) wherein

[0339] R 5 Stands for F.

[0340] Particularly preferred are compounds of general formula (I) wherein

[0341] R 3 represents H; and

[0342] R 5 Represents H.

[0343] Particularly preferred are compounds of general formula (I) wherein

[0344] R 3 represents H; and

[0345] R 5 Stands for F.

[0346] According to another aspect, the present invention encompasses compounds of general formula (I), wherein

[0347] R 2 represent:

[0348] ·-(CH 2 ) p -(C 5 -C 7 -cycloalkyl),

[0349] ·-(CH 2 ) p -phenyl,

[0350] · a 6-membered heteroaryl group containing 1 or 2 N atoms, or

[0351] Contains 1, 2 or 3 independently selected from NH, N, O, S, SO and SO 2 A bicyclic 9- to 10-membered heteroaryl group containing a heteroatom or a heteroatom-containing group,

[0352] Wherein R 2 Optionally, one or more carbon atoms may be substituted by 1 or 2 identical or different substituents R 2a Substitution, where 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

[0353] Wherein R 2 Each nitrogen atom in is optionally substituted with a substituent R 2b Substitution, where 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

[0354] 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, then the C 1 -C5 -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 is optionally substituted by one or more independently selected from OH, OR 4 and a substituent of F; and wherein

[0355] p and R 4 have the same meanings as defined in the general formula (I).

[0356] A preferred embodiment of the present invention encompasses compounds of general formula (I), wherein

[0357] R 2 represent:

[0358] ·-(CH 2 ) p -(C 5 -C 7 -cycloalkyl),

[0359] ·-(CH 2 ) p -phenyl, or

[0360] · a 6-membered heteroaryl group containing 1 or 2 N atoms,

[0361] Wherein R 2 Optionally, one or more carbon atoms may be substituted by 1 or 2 identical or different substituents R 2a Substitution, where R 2a Represents C 1 -C 5 -alkyl, C 3 -C 7 -Cycloalkyl, OC 1 -C 5- Alkyl, halogen or CN,

[0362] Wherein C 1 -C 5 -alkyl, -OC 1 -C 5 -alkyl and C 3 -C 7 -cycloalkyl is independently optionally substituted by OH, OR 4 or 1 to 5 fluorine atoms, and wherein

[0363] p and R 4 have the same meanings as defined in the general formula (I).

[0364] A preferred embodiment of the present invention encompasses compounds of general formula (I), wherein

[0365] R 2 Representative - (CH 2 ) p -(C 5 -C 7 -cycloalkyl), which may be substituted at one or more carbon atoms by 1 or 2 identical or different substituents R 2a Substitution, where R 2a Represents C 1 -C 5 -alkyl, C 3 -C 7 -Cycloalkyl, OC 1 -C 5 - alkyl, halogen or CN,

[0366] Wherein C 1 -C 5 -alkyl, -OC 1 -C 5 -alkyl and C 3 -C 7 -cycloalkyl is independently optionally substituted by OH, OR 4 or 1 to 5 fluorine atoms, and wherein

[0367] p and R 4 have the same meanings as defined in the general formula (I).

[0368] A preferred embodiment of the present invention encompasses compounds of general formula (I), wherein

[0369] R 2 Represents C 5 -C 7 - cycloalkyl, which is optionally substituted at one or more carbon atoms by 1 or 2 identical or different substituents R 2a Substitution, where R 2a Represents C 1 -C 5 -alkyl, C 3 -C 7 -Cycloalkyl, OC 1 -C 5 - alkyl, halogen or CN,

[0370] Wherein C 1 -C 5 -alkyl, -OC 1 -C 5 -alkyl and C3 -C 7 -cycloalkyl is independently optionally substituted by OH, OR 4 or 1 to 5 fluorine atoms, and wherein

[0371] R 4 have the same meanings as defined in the general formula (I).

[0372] A preferred embodiment of the present invention encompasses compounds of general formula (I), wherein

[0373] R 2 Representative - (CH 2 ) p -phenyl, which may be substituted at one or more carbon atoms by 1 or 2 identical or different substituents R 2a Substitution, where R 2a Represents C 1 -C 5 -alkyl, C 3 -C 7 -Cycloalkyl, OC 1 -C 5 - alkyl, halogen or CN,

[0374] Wherein C 1 -C 5 -alkyl, -OC 1 -C 5 -alkyl and C 3 -C 7 -cycloalkyl is independently optionally substituted by OH, OR 4 or 1 to 5 fluorine atoms, and

[0375] p and R 4 have the same meanings as defined in the general formula (I).

[0376] Also preferred are compounds of general formula (I) wherein

[0377] R 2 represents optionally substituted by 1 or 2 identical or different substituents R 2a Substituted phenyl, wherein R 2a Represents C 1 -C 5 -alkyl, C 3 -C 7 -Cycloalkyl, OC 1 -C 5 - alkyl, halogen or CN,

[0378] Wherein C 1 -C 5 -alkyl, -OC 1 -C 5 -alkyl and C3 -C 7 -cycloalkyl is independently optionally substituted by OH, OR 4 or 1 to 5 fluorine atoms, and

[0379] R 4 have the same meanings as defined in the general formula (I).

[0380] Also preferred are compounds of general formula (I) wherein

[0381] R 2 represents optionally substituted by 1 or 2 identical or different substituents R 2a Substituted phenyl, wherein R 2a Represents C 1 -C 5 -Alkyl, OC 1 -C 5 -alkyl, F or Cl,

[0382] Wherein C 1 -C 5 -alkyl and -OC 1 -C 5 -alkyl is optionally substituted independently by OH, OR 4 or 1 to 5 fluorine atoms, and

[0383] R 4 have the same meanings as defined in the general formula (I).

[0384] Also preferred are compounds of general formula (I) wherein

[0385] R 2 represents 1 or 2 identical or different substituents R 2a Substituted phenyl, wherein R 2a Represents C 1 -C 5 -Alkyl, OC 1 -C 5 -alkyl, F or Cl,

[0386] wherein if the or at least one of the substituents is F, it is preferably located in the ortho position to the carbon atom which links the phenyl group to the rest of the molecule, and

[0387] Wherein C 1 -C 5 -alkyl and -OC 1 -C 5 -Alkyl groups are independently optionally substituted with 1 to 5 fluorine atoms.

[0388] Also preferred are compounds of general formula (I) wherein

[0389] R2 represents 1 or 2 identical or different substituents R 2a Substituted phenyl, wherein R 2a Represents C 1 -C 5 -Alkyl, OC 1 -C 5 -alkyl, F or Cl,

[0390] Wherein if the substituent or at least one of the substituents is C 1 -C 5 -alkyl, -OC 1 -C 5 -alkyl or Cl, it is preferably located in the para position to the carbon atom that attaches the phenyl group to the rest of the molecule, and

[0391] Wherein C 1 -C 5 -alkyl and -OC 1 -C 5 -Alkyl groups are independently optionally substituted with 1 to 5 fluorine atoms.

[0392] Also preferred are compounds of general formula (I) wherein

[0393] R 2 represents two identical or different substituents R 2a Substituted phenyl, wherein R 2a Represents C 1 -C 5 -Alkyl, OC 1 -C 5 -alkyl, F or Cl,

[0394] wherein if the or at least one of the substituents is F, it is preferably located in the ortho position to the carbon atom which links the phenyl group to the rest of the molecule, and

[0395] Wherein if the substituent or at least one of the substituents is C 1 -C 5 -alkyl, -OC 1 -C 5 -alkyl or Cl, which is preferably located in the para position to the carbon atom that attaches the phenyl group to the rest of the molecule; and

[0396] Wherein C 1 -C 5 -alkyl and -OC 1 -C 5 -Alkyl groups are independently optionally substituted with 1 to 5 fluorine atoms.

[0397] Also preferred are compounds of general formula (I) wherein

[0398] R 2 represents optionally substituted by 1 or 2 identical or different substituents R 2a Substituted phenyl, wherein R 2a represents methyl, trifluoromethyl, trifluoromethoxy, F or Cl,

[0399] wherein if the or at least one of the substituents is F, it is preferably located in the ortho position to the carbon atom which links the phenyl group to the rest of the molecule, and

[0400] Wherein if the or at least one of the substituents is methyl, trifluoromethyl, trifluoromethoxy or Cl, it is preferably located in the para position to the carbon atom which links the phenyl group to the rest of the molecule.

[0401] Also preferred are compounds of general formula (I) wherein

[0402] R 2 represent:

[0403] · 6-membered heteroaryl containing 1 or 2 N, especially pyridyl,

[0404] Wherein R 2 Optionally, one or more carbon atoms may be substituted by 1 or 2 identical or different substituents R 2a Substitution, where R 2a Represents C 1 -C 5 -Alkyl, OC 1 -C 5 -alkyl, C 3 -C 7- Cycloalkyl, halogen or CN,

[0405] Wherein C 1 -C 5 -alkyl, -OC 1 -C 5 -alkyl and C 3 -C 7 -cycloalkyl is independently optionally substituted by OH, OR 4 or 1 to 5 fluorine atoms, and

[0406] R 4 have the same meanings as defined in the general formula (I).

[0407] Also preferred are compounds of general formula (I) wherein

[0408] R 2 represents a pyridyl group, in particular a pyridin-2-yl group, which is optionally substituted at one or more carbon atoms by 1 or 2 identical or different substituents R 2a Substitution, where R 2a Represents C1 -C 5 -Alkyl, OC 1 -C 5- Alkyl, F or Cl,

[0409] Wherein C 1 -C 5 -alkyl and -OC 1 -C 5 -alkyl is independently optionally substituted with OH, OR 4 or 1 to 5 fluorine atoms, and

[0410] R 4 have the same meanings as defined in the general formula (I).

[0411] According to another aspect, the present invention encompasses compounds of general formula (I), wherein

[0412] p represents 0.

[0413] According to another aspect, the present invention encompasses compounds of general formula (I), wherein

[0414] R 6 and R 7 Represents H.

[0415] According to another aspect, the present invention encompasses compounds of general formula (I), wherein

[0416] R 1 represent:

[0417] · Phenyl,

[0418] 5- or 6-membered heteroaryl, wherein the 5-membered heteroaryl contains 1, 2 or 3 heteroatoms or heteroatom-containing groups independently selected from S, N, NH and O, and wherein the 6-membered heteroaryl contains 1 or 2 nitrogen atoms, or

[0419] Contains 1, 2 or 3 independently selected from NH, N, O, S, SO and SO 2 A bicyclic 9- to 10-membered heteroaryl group containing a heteroatom or a heteroatom-containing group,

[0420] Wherein R 1 Optionally, one or more carbon atoms are substituted by 1 to 3 identical or different substituents R 1a Substitution, where R 1a Represents C 1 -C 5 -alkyl, C 3 -C 7 -cycloalkyl, -(C 1 -C 3- Alkyl)-(C 3 -C7 -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 lactams or containing 1 or 2 selected from NH, -NR 4 ,N,O,S,SO and SO 2 a heteroatom or a 4- to 7-membered heterocycloalkyl group containing a heteroatom, and

[0421] Among them, independently, if R 1 represents a 5-membered heteroaryl or a bicyclic 8-10 membered heteroaryl, then the R 1 Each ring nitrogen atom of 1b Substitution, where 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 contains 1 or 2 selected from NH, -NR 4 ,N,O,S,SO and SO 2 a 4- to 7-membered heterocycloalkyl group containing a heteroatom or a heteroatom-containing group, and

[0422] 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,

[0423] Then the 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 is optionally substituted with one or more independently selected from methyl, ethyl, OH, OR 4 and F is substituted with a substituent, and

[0424] If R 1a and / or R 1b represents a 4- to 7-membered heterocycloalkyl group, each carbon atom of the 4- to 7-membered heterocycloalkyl group is optionally substituted by one or more independently selected from OH, OR 4 and F is substituted with a substituent,

[0425] R 3 Represents H or F, especially H,

[0426] R 5 represents H, F, Cl or methyl, in particular H or F, and

[0427] R 6 and R 7 Represents H.

[0428] According to another aspect, the present invention encompasses compounds of general formula (I), wherein

[0429] R 1 represent:

[0430] · Phenyl,

[0431] · a 6-membered heteroaryl group containing 1 or 2 N atoms,

[0432] Wherein R 1 Optionally, one or more carbon atoms may be substituted by 1 or 2 identical or different substituents R 1a Substitution, where 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,

[0433] Wherein 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 is optionally substituted by one or more independently selected from OH, OR 4 and F is substituted with a substituent,

[0434] R 3 Represents H or F, especially H,

[0435] R 4 represents C optionally substituted by 1 to 5 fluorine atoms 1 -C 5 -alkyl,

[0436] R 5 represents H, F, Cl or methyl, in particular H or F, and

[0437] R 6 and R 7 Represents H.

[0438] According to another aspect, the present invention encompasses compounds of general formula (I), wherein

[0439] R 1 represent:

[0440] 5-membered heteroaryl, wherein the 5-membered heteroaryl contains 1, 2 or 3 heteroatoms or heteroatom-containing groups independently selected from S, N, NH and O, in particular pyrazolyl, thiazolyl, imidazolyl or thienyl,

[0441] Wherein R 1 Optionally, one or more carbon atoms may be substituted by 1 or 2 identical or different substituents R1a Substitution, where 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

[0442] Wherein R 1 Each ring nitrogen atom of 1b Substitution, where R 1b Represents C 1 -C 5 -alkyl, -(C 1 -C 3 -alkyl)-(C 3 -C 7 -cycloalkyl) and C 3 -C 7 - cycloalkyl,

[0443] 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, then the C 1 -C 5 -alkyl, C 3 -C 7 -cycloalkyl, -(C 1 -C3 -alkyl)-(C 3 -C 7 -cycloalkyl), -OC 1 -C 5 -alkyl and -OC 3 -C 7 -cycloalkyl is optionally substituted with one or more independently selected from methyl, ethyl, OH, OR 4 and F is substituted with a substituent,

[0444] R 3 Represents H or F, especially H,

[0445] R 4 represents C optionally substituted by 1 to 5 fluorine atoms 1 -C 5 -alkyl,

[0446] R 5 represents H, F, Cl or methyl, in particular H or F, and

[0447] R 6 and R 7 Represents H.

[0448] According to another aspect, the present invention encompasses compounds of general formula (I), wherein

[0449] R 1 represents a pyridyl group, in particular a pyridin-3-yl group, which is optionally substituted at one or more carbon atoms by 1 or 2 identical or different substituents R 1a Substitution, where 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

[0450] wherein one of the substituents is preferably located in the 1a one of which is preferably located in the para position to the carbon atom which links the pyridyl group, in particular the pyridin-3-yl group, to the rest of the molecule, and

[0451] Wherein C 1 -C 5 -alkyl, C 3 -C7 -cycloalkyl, -(C 1 -C 3 -alkyl)-(C 3 -C 7 -cycloalkyl), -OC 1 -C 5 -alkyl and -OC 3 -C 7 -cycloalkyl is optionally substituted with one or more independently selected from methyl, ethyl, OH, OR 4 and F is substituted with a substituent,

[0452] R 3 Represents H or F, especially H,

[0453] R 4 represents C optionally substituted by 1 to 5 fluorine atoms 1 -C 5 -alkyl,

[0454] R 5 represents H, F, Cl or methyl, in particular H or F, and

[0455] R 6 and R 7 Represents H.

[0456] According to another aspect, the present invention encompasses compounds of general formula (I), wherein

[0457] R 1 represents a pyridyl group, in particular a pyridin-3-yl group, which is substituted at one or more carbon atoms by one or two identical or different substituents R 1a Substitution, where R 1a represents methyl, ethyl, methoxy, ethoxy, cyclobutyl, trifluoromethyl, difluoromethyl, 1,1-difluoroethyl, 1,1-difluoropropyl or 2,2,2-trifluoroethyl, and

[0458] wherein the substituent or at least one of the substituents is preferably located in the para position to the carbon atom which links the pyridyl group, in particular the pyridin-3-yl group, to the rest of the molecule, and

[0459] R 3 Represents H or F, especially H,

[0460] R 5 represents H, F, Cl or methyl, in particular H or F, and

[0461] R 6 and R 7 Represents H.

[0462] According to another aspect, the present invention encompasses compounds of general formula (I), wherein

[0463] R 1 represents a pyridyl group, in particular a pyridin-2-yl group, which is optionally substituted at one or more carbon atoms by 1 or 2 identical or different substituents R 1a Substitution, where 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

[0464] wherein the substituent R 1a one of which is preferably located in the para position to the carbon atom which links the pyridyl group, in particular the pyridin-2-yl group, to the rest of the molecule, and

[0465] Wherein 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 is optionally substituted with one or more independently selected from methyl, ethyl, OH, OR 4 and F is substituted with a substituent,

[0466] R 3 Represents H or F, especially H,

[0467] R 4 represents C optionally substituted by 1 to 5 fluorine atoms 1 -C 5 -alkyl,

[0468] R 5 represents H, F, Cl or methyl, in particular H or F, and

[0469] R 6 and R 7 Represents H.

[0470] According to another aspect, the present invention encompasses compounds of general formula (I), wherein

[0471] R 1 represents a pyridyl group, in particular a pyridin-2-yl group, which is substituted at one or more carbon atoms by one or two identical or different substituents R 1a Substitution, where R 1a represents methyl, ethyl, methoxy, ethoxy, cyclobutyl, trifluoromethyl, difluoromethyl, 1,1-difluoroethyl, 1,1-difluoropropyl or 2,2,2-trifluoroethyl, and

[0472] wherein the substituent or at least one of the substituents is preferably located in the para position to the carbon atom which links the pyridyl group, in particular the pyridin-2-yl group, to the rest of the molecule, and

[0473] R 3 Represents H or F, especially H,

[0474] R 5 represents H, F, Cl or methyl, in particular H or F, and

[0475] R 6 and R 7 Represents H.

[0476] According to another aspect, the present invention encompasses compounds of general formula (I), wherein

[0477] R 1 represents pyrazolyl, in particular pyrazol-4-yl, which is optionally substituted at one or more carbon atoms by 1 or 2 identical or different substituents R 1a Substitution, where 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

[0478] Wherein R 1 Each nitrogen atom of 1b Substitution, where R 1b Represents C 1 -C 5 -alkyl, -(C 1 -C 3 -alkyl)-(C3 -C 7 -cycloalkyl) and C 3 -C 7 -cycloalkyl, and

[0479] 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, then the 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 is optionally substituted by one or more independently selected from methyl, OH, OR 4 and F is substituted with a substituent,

[0480] R 3 Represents H or F, especially H,

[0481] R 4 represents C optionally substituted by 1 to 5 fluorine atoms 1 -C 5 -alkyl,

[0482] R 5 represents H, F, Cl or methyl, in particular H or F, and

[0483] R 6 and R 7 Represents H.

[0484] A preferred embodiment of the present invention encompasses compounds of general formula (I), wherein

[0485] R 1 represents pyrazolyl, in particular pyrazol-4-yl, which is optionally substituted at one or more carbon atoms by 1 or 2 identical or different substituents R 1a Substitution, where 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

[0486] Wherein R 1 Each nitrogen atom is independently optionally substituted by the same or different substituents R 1b Substitution, where 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

[0487] 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, then the 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 is optionally substituted by one or more independently selected from methyl, OH, OR 4 and F is substituted with a substituent,

[0488] R 3 Represents H or F, especially H,

[0489] R 4 represents C optionally substituted by 1 to 5 fluorine atoms 1 -C 5 -alkyl,

[0490] R 5 represents H, F, Cl or methyl, in particular H or F, and

[0491] R 6 and R 7 Represents H.

[0492] A preferred embodiment of the present invention encompasses compounds of general formula (I), wherein

[0493] R 1 represents a pyrazol-4-yl group, which is optionally substituted at the nitrogen atom by one substituent R 1b Substitute, the R 1b Selected from C 1 -C 5 -alkyl, -(C 1 -C 3 -alkyl)-(C 3 -C 7 -cycloalkyl) and C 3 -C 7 -cycloalkyl, wherein the C 1 -C 5 -alkyl, C 3 -C 7 -cycloalkyl and -(C 1 -C 3 -alkyl)-(C 3 -C 7-cycloalkyl) are optionally substituted by one or more independently selected from methyl, OH, OR 4 and F is substituted with a substituent,

[0494] R 3 Represents H or F, especially H,

[0495] R 4 represents C optionally substituted by 1 to 5 fluorine atoms 1 -C 5 -alkyl,

[0496] R 5 represents H, F, Cl or methyl, in particular H or F, and

[0497] R 6 and R 7 Represents H.

[0498] A preferred embodiment of the present invention encompasses compounds of general formula (I), wherein

[0499] R 1 Represents the substituted group R at the nitrogen atom 1b Substituted pyrazol-4-yl, wherein R 1b is selected from the group consisting of methyl, ethyl, propyl, prop-2-yl, 2-methylpropyl, cyclopropyl, tert-butyl, but-2-yl, cyclobutyl, 2,2-dimethylpropyl, 3-methylbut-2-yl, cyclopentyl, cyclohexyl, 1-cyclopropylmethyl, 1-cyclopropylethyl, 1-cyclobutylmethyl, 1-(1-methylcyclopropyl)methyl and 2,2,2-trifluoroethyl, in particular ethyl, prop-2-yl, 2-methylpropyl, but-2-yl, cyclobutyl, cyclopentyl, 2,2-dimethylpropyl, 1-cyclopropylmethyl, 1-cyclopropylethyl, 1-(1-methylcyclopropyl)methyl and 1-cyclobutylmethyl,

[0500] R 3 Represents H or F, especially H,

[0501] R 5 represents H, F, Cl or methyl, in particular H or F, and

[0502] R 6 and R 7 Represents H.

[0503] According to another aspect, the present invention encompasses compounds of general formula (I), wherein

[0504] R 1 represents a thiazolyl group, in particular a thiazol-5-yl group, which is substituted at one or more carbon atoms by one or two identical or different substituents R 1a Substitution, where 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,

[0505] Wherein 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 is optionally substituted by one or more independently selected from methyl, OH, OR 4 and F is substituted with a substituent,

[0506] R 3 Represents H or F, especially H,

[0507] R 4 represents C optionally substituted by 1 to 5 fluorine atoms 1 -C 5 -alkyl,

[0508] R 5 represents H, F, Cl or methyl, in particular H or F, and

[0509] R 6 and R 7 Represents H.

[0510] A preferred embodiment of the present invention encompasses compounds of general formula (I), wherein

[0511] R 1 represents a thiazolyl group, in particular a thiazol-5-yl group, which is substituted at one or more carbon atoms by one or two identical or different substituents R 1a Substitution, where R 1a Represents C 1 -C 5 -alkyl, C 3 -C 7 -cycloalkyl, -(C 1 -C3 -alkyl)-(C 3 -C 7 -cycloalkyl), -OC 1 -C 5 -alkyl, -OC 3 -C 7 - cycloalkyl, halogen or CN,

[0512] wherein the substituent R 1a One of the following is preferably located in the meta position to the carbon atom which links the thiazolyl group, in particular the thiazol-5-yl group, to the rest of the molecule, and

[0513] Wherein 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 is optionally substituted by one or more independently selected from methyl, OH, OR 4 and F is substituted with a substituent,

[0514] R 3 Represents H or F, especially H,

[0515] R 4 represents C optionally substituted by 1 to 5 fluorine atoms 1 -C 5 -alkyl,

[0516] R 5 represents H, F, Cl or methyl, in particular H or F, and

[0517] R 6 and R 7 Represents H.

[0518] A preferred embodiment of the present invention encompasses compounds of general formula (I), wherein

[0519] R 1 represents a thiazol-5-yl group, which is optionally substituted at a carbon atom by a group R 1a Substitution, where R 1a Represents C 1 -C 5 -alkyl, -(C 1 -C 3 -alkyl)-(C 3 -C7 -cycloalkyl) or C 3 -C 7 - cycloalkyl,

[0520] wherein the substituent R 1a Preferably, it is connected to the 2-carbon atom of the thiazol-5-yl group,

[0521] Wherein C 1 -C 5 -alkyl, C 3 -C 7 -cycloalkyl and -(C 1 -C 3 -alkyl)-(C 3 -C 7 -cycloalkyl) are optionally substituted by one or more independently selected from methyl, OH, OR 4 and F is substituted with a substituent,

[0522] R 3 Represents H or F, especially H,

[0523] R 4 represents C optionally substituted by 1 to 5 fluorine atoms 1 -C 5 -alkyl,

[0524] R 5 represents H, F, Cl or methyl, in particular H or F, and

[0525] R 6 and R 7 Represents H.

[0526] A preferred embodiment of the present invention encompasses compounds of general formula (I), wherein

[0527] R 1 Represents the carbon atom at position 2 is replaced by C 3 -C 7 - cycloalkyl-substituted thiazol-5-yl,

[0528] Wherein C 3 -C 7 -cycloalkyl is optionally substituted by one or more independently selected from methyl, OH, OR 4 and F is substituted with a substituent,

[0529] R 3 Represents H or F, especially H,

[0530] R 4 represents C optionally substituted by 1 to 5 fluorine atoms 1 -C 5 -alkyl,

[0531] R 5 represents H, F, Cl or methyl, in particular H or F, and

[0532] R 6 and R 7 Represents H.

[0533] A preferred embodiment of the present invention encompasses compounds of general formula (I), wherein

[0534] R 1 represents a thiazol-5-yl group which is substituted at the carbon atom in position 2 by a substituent selected from the group consisting of methyl, ethyl, propyl, prop-2-yl, 2-methylpropyl, cyclopropyl, tert-butyl, but-2-yl, cyclobutyl, 2,2-dimethylpropyl, 3-methylbut-2-yl, cyclopentyl, cyclohexyl, 1-cyclopropylmethyl, 1-cyclopropylethyl, 1-cyclobutylmethyl, 1-(1-methylcyclopropyl)methyl and 2,2,2-trifluoroethyl, in particular ethyl, prop-2-yl, cyclopropyl, 2-methylpropyl, but-2-yl, cyclobutyl, cyclopentyl, 2,2-dimethylpropyl, 1-cyclopropylmethyl, 1-cyclopropylethyl, 1-(1-methylcyclopropyl)methyl and 1-cyclobutylmethyl,

[0535] R 3 Represents H or F, especially H,

[0536] R 5 represents H, F, Cl or methyl, in particular H or F, and

[0537] R 6 and R 7 Represents H.

[0538] According to another aspect, the present invention encompasses compounds of general formula (I), wherein

[0539] R 1 represents a thiazol-2-yl group, which is optionally substituted at a carbon atom by a group R 1a Substitution, where R 1a Represents C 1 -C 5 -alkyl, -(C 1 -C 3 -alkyl)-(C 3 -C 7 -cycloalkyl) or C 3 -C 7 - cycloalkyl,

[0540] wherein the substituent R 1a Preferably, it is connected to the carbon atom at position 5 of the thiazol-2-yl group, and

[0541] Wherein C 1 -C5 -alkyl, C 3 -C 7 -cycloalkyl and -(C 1 -C 3 -alkyl)-(C 3 -C 7 -cycloalkyl) are optionally substituted by one or more independently selected from methyl, OH, OR 4 and F is substituted with a substituent,

[0542] R 3 Represents H or F, especially H,

[0543] R 4 represents C optionally substituted by 1 to 5 fluorine atoms 1 -C 5 -alkyl,

[0544] R 5 represents H, F, Cl or methyl, in particular H or F, and

[0545] R 6 and R 7 Represents H.

[0546] A preferred embodiment of the present invention encompasses compounds of general formula (I), wherein

[0547] R 1 Represents the carbon atom at position 5 is replaced by C 3 -C 7 -cycloalkyl-substituted thiazol-2-yl, and

[0548] Wherein C 3 -C 7 -cycloalkyl is optionally substituted by one or more independently selected from methyl, OH, OR 4 and F is substituted with a substituent,

[0549] R 3 Represents H or F, especially H,

[0550] R 4 represents C optionally substituted by 1 to 5 fluorine atoms 1 -C 5 -alkyl,

[0551] R 5 represents H, F, Cl or methyl, in particular H or F, and

[0552] R 6 and R 7 Represents H.

[0553] A preferred embodiment of the present invention encompasses compounds of general formula (I), wherein

[0554] R 1 represents a thiazol-2-yl radical substituted at the carbon atom in position 5 by a substituent selected from the group consisting of methyl, ethyl, propyl, prop-2-yl, cyclopropyl, 2-methylpropyl, tert-butyl, but-2-yl, cyclobutyl, 2,2-dimethylpropyl, 3-methylbut-2-yl, cyclopentyl, cyclohexyl, 1-cyclopropylmethyl, 1-cyclopropylethyl, 1-cyclobutylmethyl, 1-(1-methylcyclopropyl)methyl and 2,2,2-trifluoroethyl, in particular ethyl, prop-2-yl, cyclopropyl, 2-methylpropyl, but-2-yl, cyclobutyl, cyclopentyl, 2,2-dimethylpropyl, 1-cyclopropylmethyl, 1-cyclopropylethyl, 1-(1-methylcyclopropyl)methyl and 1-cyclobutylmethyl,

[0555] R 3 Represents H or F, especially H,

[0556] R 5 represents H, F, Cl or methyl, in particular H or F, and

[0557] R 6 and R 7 Represents H.

[0558] According to another aspect, the present invention encompasses compounds of general formula (I), wherein

[0559] R 2 represent:

[0560] ·C 5 -C 7 - cycloalkyl,

[0561] · Phenyl, or

[0562] · 6-membered heteroaryl containing 1 or 2 N, especially pyridin-2-yl,

[0563] Wherein R 2 Optionally, one or more carbon atoms may be substituted by 1 or 2 identical or different substituents R 2a Substitution, where R 2a Represents C 1 -C 5 -alkyl, C 3 -C 7 -Cycloalkyl, OC 1 -C 5- Alkyl, halogen or CN,

[0564] Wherein C 1 -C 5 -alkyl, -OC 1 -C 5 -alkyl and C 3 -C 7-cycloalkyl is independently optionally substituted by OH, OR 4 or 1 to 5 fluorine atoms,

[0565] R 3 Represents H or F, especially H,

[0566] R 4 represents C optionally substituted by 1 to 5 fluorine atoms 1 -C 5 -alkyl,

[0567] R 5 represents H, F, Cl or methyl, in particular H or F, and

[0568] R 6 and R 7 Represents H.

[0569] A preferred embodiment of the present invention relates to compounds of general formula (I), wherein

[0570] R 2 represents one or more carbon atoms optionally substituted by 1 or 2 identical or different substituents R 2a Substituted phenyl, wherein R 2a Represents C 1 -C 5 -alkyl, C 3 -C 7 -Cycloalkyl, OC 1 -C 5 -alkyl, F and Cl, wherein the C 1 -C 5 -alkyl, -OC 1 -C 5 -alkyl or C 3 -C 7 - cycloalkyl is optionally substituted by 1 to 5 fluorine atoms,

[0571] R 3 Represents H or F, especially H,

[0572] R 5 represents H, F, Cl or methyl, in particular H or F, and

[0573] R 6 and R 7 Represents H.

[0574] A preferred embodiment of the present invention relates to compounds of general formula (I), wherein

[0575] R 2 represents 1 or 2 identical or different substituents R 2a Substituted phenyl, wherein R 2a Represents C1 -C 5 -Alkyl, OC 1 -C 5 -alkyl, F or Cl, and

[0576] wherein if the or at least one of the substituents is F, it is preferably located in the ortho position to the carbon atom which links the phenyl group to the rest of the molecule, and

[0577] Wherein C 1 -C 5 -alkyl and -OC 1 -C 5 -alkyl is independently optionally substituted by 1 to 5 fluorine atoms,

[0578] R 3 Represents H or F, especially H,

[0579] R 5 represents H, F, Cl or methyl, in particular H or F, and

[0580] R 6 and R 7 Represents H.

[0581] A preferred embodiment of the present invention relates to compounds of general formula (I), wherein

[0582] R 2 represents 1 or 2 identical or different substituents R 2a Substituted phenyl, wherein R 2a Represents C 1 -C 5 -Alkyl, OC 1 -C 5 -alkyl, F or Cl, and

[0583] Wherein if the substituent or at least one of the substituents is C 1 -C 5 -alkyl, -OC 1 -C 5 -alkyl or Cl, it is preferably located in the para position to the carbon atom that attaches the phenyl group to the rest of the molecule, and

[0584] Wherein C 1 -C 5 -alkyl and -OC 1 -C 5 -alkyl is independently optionally substituted by 1 to 5 fluorine atoms,

[0585] R 3 Represents H or F, especially H,

[0586] R 5represents H, F, Cl or methyl, in particular H or F, and

[0587] R 6 and R 7 Represents H.

[0588] A preferred embodiment of the present invention relates to compounds of general formula (I), wherein

[0589] R 2 represents 1 or 2 identical or different substituents R 2a Substituted phenyl, wherein R 2a Represents C 1 -C 5 -Alkyl, OC 1 -C 5 -alkyl, F or Cl, and

[0590] wherein if the or at least one of the substituents is F, it is preferably located in the ortho position to the carbon atom which links the phenyl group to the rest of the molecule, and

[0591] Wherein if the substituent or at least one of the substituents is C 1 -C 5 -alkyl, -OC 1 -C 5 -alkyl or Cl, it is preferably located in the para position to the carbon atom that attaches the phenyl group to the rest of the molecule, and

[0592] Wherein C 1 -C 5 -alkyl and -OC 1 -C 5 -alkyl is independently optionally substituted by 1 to 5 fluorine atoms,

[0593] R 3 Represents H or F, especially H,

[0594] R 5 represents H, F, Cl or methyl, in particular H or F, and

[0595] R 6 and R 7 Represents H.

[0596] A preferred embodiment of the present invention relates to compounds of general formula (I), wherein

[0597] R 2 represents 1 or 2 identical or different substituents R 2a Substituted phenyl, wherein R 2a represents methyl, trifluoromethyl, trifluoromethoxy, F or Cl, and

[0598] wherein if the or at least one of the substituents is F, it is preferably located in the ortho position to the carbon atom which links the phenyl group to the rest of the molecule, and

[0599] wherein if the or at least one of the substituents is methyl, trifluoromethyl, trifluoromethoxy or Cl, it is preferably located in the para position to the carbon atom that attaches the phenyl group to the rest of the molecule, and

[0600] R 3 Represents H or F, especially H,

[0601] R 5 represents H, F, Cl or methyl, in particular H or F, and

[0602] R 6 and R 7 Represents H.

[0603] According to another aspect, the present invention encompasses compounds of general formula (I), wherein

[0604] R 1 represents pyridinyl, in particular pyridin-3-yl, which is optionally substituted as defined in the general formula (I), and

[0605] R 2 represents phenyl or pyridin-2-yl, in particular phenyl,

[0606] Where R 2 as defined in general formula (I) are optionally substituted,

[0607] R 3 Represents H or F, especially H,

[0608] R 5 represents H, F, Cl or methyl, in particular H or F, and

[0609] R 6 and R 7 Represents H.

[0610] A preferred embodiment of the present invention encompasses compounds of general formula (I), wherein

[0611] R 1 represents a pyridyl group, in particular a pyridin-3-yl group, which is optionally substituted at one or more carbon atoms by 1 or 2 identical or different substituents R 1a Substitution, where R 1a Represents C 1 -C 5 -alkyl, C 3 -C 7 -cycloalkyl, -(C 1 -C 3 -alkyl)-(C3 -C 7 -cycloalkyl), -OC 1 -C 5 -alkyl, -OC 3 -C 7 - cycloalkyl, halogen or CN,

[0612] wherein the substituent or at least one of the substituents is preferably located in the para position to the carbon atom which links the pyridyl group, in particular the pyridin-3-yl group, to the rest of the molecule, and

[0613] Wherein 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 is optionally substituted by one or more independently selected from OH, OR 4 and F is substituted with a substituent,

[0614] R 2 represents optionally substituted by 1 or 2 identical or different substituents R 2a Substituted phenyl, wherein R 2a Represents C 1 -C 5 -Alkyl, OC 1 -C 5 -alkyl, F or Cl, and

[0615] Wherein C 1 -C 5 -alkyl and -OC 1 -C 5 -alkyl is independently optionally substituted by 1 to 5 fluorine atoms,

[0616] R 3 Represents H or F, especially H,

[0617] R 4 represents C optionally substituted by 1 to 5 fluorine atoms 1 -C 5 -alkyl,

[0618] R 5 represents H, F, Cl or methyl, in particular H or F, and

[0619] R 6 and R7 Represents H.

[0620] A preferred embodiment of the present invention encompasses compounds of general formula (I), wherein

[0621] R 1 represents a pyridyl group, in particular a pyridin-3-yl group, which is optionally substituted at one or more carbon atoms by 1 or 2 identical or different substituents R 1a Substitution, where 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,

[0622] wherein the substituent or at least one of the substituents is preferably located in the para position to the carbon atom which links the pyridyl group, in particular the pyridin-3-yl group, to the rest of the molecule, and

[0623] Wherein 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 is optionally substituted by one or more independently selected from OH, OR 4 and F is substituted with a substituent,

[0624] R 2 represents 1 or 2 identical or different substituents R 2a Substituted phenyl, wherein R 2a Represents C 1 -C 5 -Alkyl, OC 1 -C 5 -alkyl, F or Cl, and

[0625] wherein if the or at least one of the substituents is F, it is preferably located in the ortho position to the carbon atom which links the phenyl group to the rest of the molecule, and

[0626] Wherein C 1 -C 5 -alkyl and -OC 1 -C 5 -alkyl is independently optionally substituted by 1 to 5 fluorine atoms,

[0627] R 3 Represents H or F, especially H,

[0628] R 4 represents C optionally substituted by 1 to 5 fluorine atoms 1 -C 5 -alkyl,

[0629] R 5 represents H, F, Cl or methyl, in particular H or F, and

[0630] R 6 and R 7 Represents H.

[0631] A preferred embodiment of the present invention encompasses compounds of general formula (I), wherein

[0632] R 1 represents a pyridyl group, in particular a pyridin-3-yl group, which is optionally substituted at one or more carbon atoms by 1 or 2 identical or different substituents R 1a Substitution, where 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,

[0633] wherein the substituent or at least one of said substituents is preferably located in the para position to the carbon atom which links the pyridyl group, in particular the pyridin-3-yl group, to the rest of the molecule; and

[0634] Wherein C 1 -C 5 -alkyl, C 3 -C 7 -cycloalkyl, -(C 1 -C3 -alkyl)-(C 3 -C 7 -cycloalkyl), -OC 1 -C 5 -alkyl and -OC 3- C 7 -cycloalkyl is optionally substituted by one or more independently selected from OH, OR 4 and F is substituted with a substituent,

[0635] R 2 represents 1 or 2 identical or different substituents R 2a Substituted phenyl, wherein R 2a Represents C 1 -C 5 -Alkyl, OC 1 -C 5 -alkyl, F or Cl,

[0636] Wherein if the substituent or at least one of the substituents is C 1 -C 5 -alkyl, -OC 1 -C 5 -alkyl or Cl, it is preferably located in the para position to the carbon atom that attaches the phenyl group to the rest of the molecule, and

[0637] Wherein C 1 -C 5 -alkyl and -OC 1 -C 5 -alkyl is independently optionally substituted by 1 to 5 fluorine atoms,

[0638] R 3 Represents H or F, especially H,

[0639] R 4 represents C optionally substituted by 1 to 5 fluorine atoms 1 -C 5 -alkyl,

[0640] R 5 represents H, F, Cl or methyl, in particular H or F, and

[0641] R 6 and R 7 Represents H.

[0642] A preferred embodiment of the present invention encompasses compounds of general formula (I), wherein

[0643] R 1 represents a pyridyl group, in particular a pyridin-3-yl group, which is optionally substituted at one or more carbon atoms by 1 or 2 identical or different substituents R 1a Substitution, where R1a 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,

[0644] wherein one of the substituents is preferably located in the para position to the carbon atom which links the pyridyl group, in particular the pyridin-3-yl group, to the rest of the molecule, and

[0645] Wherein 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 is optionally substituted by one or more independently selected from OH, OR 4 and F is substituted with a substituent,

[0646] R 2 represents two identical or different substituents R 2a Substituted phenyl, wherein R 2a Represents C 1 -C 5 -Alkyl, OC 1 -C 5 -alkyl, F and Cl, and

[0647] wherein if the or at least one of the substituents is F, it is preferably located in the ortho position to the carbon atom which links the phenyl group to the rest of the molecule, and

[0648] Wherein if the substituent or at least one of the substituents is C 1 -C 5 -alkyl, -OC 1 -C 5 -alkyl or Cl, it is preferably located in the para position to the carbon atom that attaches the phenyl group to the rest of the molecule, and

[0649] Wherein C 1 -C 5 -alkyl and -OC 1 -C 5 -alkyl is independently optionally substituted by 1 to 5 fluorine atoms,

[0650] R 3 Represents H or F, especially H,

[0651] R 4 represents C optionally substituted by 1 to 5 fluorine atoms 1 -C 5 -alkyl,

[0652] R 5 represents H, F, Cl or methyl, in particular H or F, and

[0653] R 6 and R 7 Represents H.

[0654] A preferred embodiment of the present invention encompasses compounds of general formula (I), wherein

[0655] R 1 represents a pyridyl group, in particular a pyridin-3-yl group, which is substituted at one or more carbon atoms by one or two identical or different substituents R 1a Substitution, where R 1a represents methyl, ethyl, methoxy, ethoxy, cyclobutyl, trifluoromethyl, difluoromethyl, 1,1-difluoroethyl, 1,1-difluoropropyl or 2,2,2-trifluoroethyl, and

[0656] wherein the substituent or at least one of the substituents is preferably located in the para position to the carbon atom which links the pyridyl group, in particular the pyridin-3-yl group, to the rest of the molecule, and

[0657] R 2 represents 1 or 2 identical or different substituents R 1a Substituted phenyl, wherein R 1a represents methyl, trifluoromethyl, trifluoromethoxy, F or Cl, and

[0658] wherein if the or at least one of the substituents is F, it is preferably located in the ortho position to the carbon atom which links the phenyl group to the rest of the molecule, and

[0659] wherein if the or at least one of the substituents is methyl, trifluoromethyl, trifluoromethoxy or Cl, it is preferably located in the para position to the carbon atom that attaches the phenyl group to the rest of the molecule, and

[0660] R 3 Represents H or F, especially H,

[0661] R 5 represents H, F, Cl or methyl, in particular H or F, and

[0662] R 6 and R 7 Represents H.

[0663] According to another aspect, the present invention encompasses compounds of general formula (I), wherein

[0664] R 1 represents pyridinyl, in particular pyridin-2-yl, which is optionally substituted as defined in the general formula (I),

[0665] R 2 represents phenyl or pyridin-2-yl, in particular phenyl, which is optionally substituted as defined in the general formula (I),

[0666] R 3 Represents H or F, especially H,

[0667] R 5 represents H, F, Cl or methyl, in particular H or F, and

[0668] R 6 and R 7 Represents H.

[0669] A preferred embodiment of the present invention encompasses compounds of general formula (I), wherein

[0670] R 1 represents a pyridyl group, in particular a pyridin-2-yl group, which is optionally substituted at one or more carbon atoms by 1 or 2 identical or different substituents R 1a Substitution, where 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,

[0671] wherein the substituent or at least one of the substituents is preferably located in the para position to the carbon atom which links the pyridyl group, in particular the pyridin-2-yl group, to the rest of the molecule, and

[0672] Wherein 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 is optionally substituted by one or more independently selected from OH, OR 4 and F is substituted with a substituent,

[0673] R 2 represents 1 or 2 identical or different substituents R 2a Substituted phenyl, wherein R 2a Represents C 1 -C 5 -Alkyl, OC 1 -C 5 -alkyl, F or Cl,

[0674] Wherein if the substituent or at least one of the substituents is C 1 -C 5 -alkyl, -OC 1 -C 5 -alkyl or Cl, it is preferably located in the para position to the carbon atom that attaches the phenyl group to the rest of the molecule, and

[0675] Wherein C 1 -C 5 -alkyl and -OC 1 -C 5 -alkyl is independently optionally substituted by 1 to 5 fluorine atoms,

[0676] R 3 Represents H or F, especially H,

[0677] R 4 represents C optionally substituted by 1 to 5 fluorine atoms 1 -C 5 -alkyl,

[0678] R 5 represents H, F, Cl or methyl, in particular H or F, and

[0679] R 6 and R 7 Represents H.

[0680] A preferred embodiment of the present invention encompasses compounds of general formula (I), wherein

[0681] R 1represents a pyridyl group, in particular a pyridin-2-yl group, which is optionally substituted at one or more carbon atoms by 1 or 2 identical or different substituents R 1a Substitution, where 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,

[0682] wherein one of the substituents is preferably located in the para position to the carbon atom which links the pyridyl group, in particular the pyridin-2-yl group, to the rest of the molecule, and

[0683] Wherein 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 is optionally substituted by one or more independently selected from OH, OR 4 and F is substituted with a substituent,

[0684] R 2 represents two identical or different substituents R 2a Substituted phenyl, wherein R 2a Represents C 1 -C 5 -Alkyl, OC 1 -C 5 -alkyl, F and Cl, and

[0685] wherein if the or at least one of the substituents is F, it is preferably located in the ortho position to the carbon atom which links the phenyl group to the rest of the molecule, and

[0686] Wherein if the substituent or at least one of the substituents is C 1 -C 5 -alkyl, -OC 1 -C 5-alkyl or Cl, it is preferably located in the para position to the carbon atom that attaches the phenyl group to the rest of the molecule, and

[0687] Wherein C 1 -C 5 -alkyl and -OC 1 -C 5 -alkyl is independently optionally substituted by 1 to 5 fluorine atoms,

[0688] R 3 Represents H or F, especially H,

[0689] R 4 represents C optionally substituted by 1 to 5 fluorine atoms 1 -C 5 -alkyl,

[0690] R 5 represents H, F, Cl or methyl, in particular H or F, and

[0691] R 6 and R 7 Represents H.

[0692] A preferred embodiment of the present invention encompasses compounds of general formula (I), wherein

[0693] R 1 represents a pyridyl group, in particular a pyridin-2-yl group, which is substituted at one or more carbon atoms by one or two identical or different substituents R 1a Substitution, where R 1a represents methyl, ethyl, methoxy, ethoxy, cyclobutyl, trifluoromethyl, difluoromethyl, 1,1-difluoroethyl, 1,1-difluoropropyl or 2,2,2-trifluoroethyl, and

[0694] wherein the substituent or at least one of the substituents is preferably located in the para position to the carbon atom which links the pyridyl group, in particular the pyridin-2-yl group, to the rest of the molecule, and

[0695] R 2 represents 1 or 2 identical or different substituents R 1a Substituted phenyl, wherein R 1a represents methyl, trifluoromethyl, trifluoromethoxy, F or Cl, and

[0696] wherein if the or at least one of the substituents is F, it is preferably located in the ortho position to the carbon atom which links the phenyl group to the rest of the molecule, and

[0697] wherein if the or at least one of the substituents is methyl, trifluoromethyl, trifluoromethoxy or Cl, it is preferably located in the para position to the carbon atom that attaches the phenyl group to the rest of the molecule, and

[0698] R 3 Represents H or F, especially H,

[0699] R 5 represents H, F, Cl or methyl, in particular H or F, and

[0700] R 6 and R 7 Represents H.

[0701] A preferred embodiment of the present invention encompasses compounds of general formula (I), wherein

[0702] R 1 represents a 5-membered heteroaryl group containing 1, 2 or 3 heteroatoms or heteroatom-containing groups independently selected from S, N, NH and O, in particular pyrazolyl, thiazolyl, imidazolyl or thienyl,

[0703] Where R 1 is optionally substituted as defined in formula (I), and

[0704] R 2 represents optionally substituted by 1 or 2 identical or different substituents R 2a Substituted phenyl, wherein R 2a Represents C 1 -C 5 -Alkyl, OC 1 -C 5 -alkyl, F or Cl, and

[0705] Wherein C 1 -C 5 -alkyl and -OC 1 -C 5 - alkyl is optionally substituted by 1 to 5 fluorine atoms,

[0706] R 3 Represents H or F, especially H,

[0707] R 5 represents H, F, Cl or methyl, in particular H or F, and

[0708] R 6 and R 7 Represents H.

[0709] A preferred embodiment of the present invention encompasses compounds of general formula (I), wherein

[0710] R 1 represents a 5-membered heteroaryl group containing 1, 2 or 3 heteroatoms or heteroatom-containing groups independently selected from S, N, NH and O, in particular pyrazolyl, thiazolyl, imidazolyl or thienyl,

[0711] Where R 1 is optionally substituted as defined in formula (I), and

[0712] R 2 represents 1 or 2 identical or different substituents R 2a Substituted phenyl, wherein R 2a Represents C 1 -C 5 -Alkyl, OC 1 -C 5 -alkyl, F or Cl, and

[0713] wherein if the or at least one of the substituents is F, it is preferably located in the ortho position to the carbon atom which links the phenyl group to the rest of the molecule, and

[0714] Wherein C 1 -C 5 -alkyl and -OC 1 -C 5 -alkyl is independently optionally substituted by 1 to 5 fluorine atoms,

[0715] R 3 Represents H or F, especially H,

[0716] R 5 represents H, F, Cl or methyl, in particular H or F, and

[0717] R 6 and R 7 Represents H.

[0718] A preferred embodiment of the present invention encompasses compounds of general formula (I), wherein

[0719] R 1 represents a 5-membered heteroaryl group containing 1, 2 or 3 heteroatoms or heteroatom-containing groups independently selected from S, N, NH and O, in particular pyrazolyl, thiazolyl, imidazolyl or thienyl,

[0720] Where R 1 is optionally substituted as defined in formula (I), and

[0721] R 2 represents 1 or 2 identical or different substituents R 2a Substituted phenyl, wherein R 2a Represents C 1 -C 5 -Alkyl, OC 1 -C 5 -alkyl, F or Cl,

[0722] Wherein if the substituent or at least one of the substituents is C1 -C 5 -alkyl, -OC 1 -C 5 -alkyl or Cl, it is preferably located in the para position to the carbon atom that attaches the phenyl group to the rest of the molecule, and

[0723] Wherein C 1 -C 5 -alkyl and -OC 1 -C 5 -alkyl is independently optionally substituted by 1 to 5 fluorine atoms,

[0724] R 3 Represents H or F, especially H,

[0725] R 5 represents H, F, Cl or methyl, in particular H or F, and

[0726] R 6 and R 7 Represents H.

[0727] A preferred embodiment of the present invention encompasses compounds of general formula (I), wherein

[0728] R 1 represents a 5-membered heteroaryl group containing 1, 2 or 3 heteroatoms or heteroatom-containing groups independently selected from S, N, NH and O, in particular pyrazolyl, thiazolyl, imidazolyl or thienyl,

[0729] Where R 1 is optionally substituted as defined in formula (I), and

[0730] R 2 represents two identical or different substituents R 2a Substituted phenyl, wherein R 2a Represents C 1 -C 5 -Alkyl, OC 1 -C 5 -alkyl, F or Cl, and

[0731] wherein if the or at least one of the substituents is F, it is preferably located in the ortho position to the carbon atom which links the phenyl group to the rest of the molecule, and

[0732] Wherein if the substituent or at least one of the substituents is C 1 -C 5 -alkyl, -OC 1 -C 5 -alkyl or Cl, it is preferably located in the para position to the carbon atom that attaches the phenyl group to the rest of the molecule, and

[0733] Wherein C 1 -C 5 -alkyl and -OC 1 -C 5 -alkyl is independently optionally substituted by 1 to 5 fluorine atoms,

[0734] R 3 Represents H or F, especially H,

[0735] R 5 represents H, F, Cl or methyl, in particular H or F, and

[0736] R 6 and R 7 Represents H.

[0737] A preferred embodiment of the present invention encompasses compounds of general formula (I), wherein

[0738] R 1 represents a 5-membered heteroaryl group containing 1, 2 or 3 heteroatoms or heteroatom-containing groups independently selected from S, N, NH and O, in particular pyrazolyl, thiazolyl, imidazolyl or thienyl,

[0739] Where R 1 is optionally substituted as defined in formula (I), and

[0740] R 2 represents 1 or 2 identical or different substituents R 2a Substituted phenyl, wherein R 2a represents methyl, trifluoromethyl, trifluoromethoxy, F or Cl, and

[0741] wherein if the or at least one of the substituents is F, it is preferably located in the ortho position to the carbon atom which links the phenyl group to the rest of the molecule, and

[0742] wherein if the or at least one of the substituents is methyl, trifluoromethyl, trifluoromethoxy or Cl, it is preferably located in the para position to the carbon atom that attaches the phenyl group to the rest of the molecule, and

[0743] R 3 Represents H or F, especially H,

[0744] R 5 represents H, F, Cl or methyl, in particular H or F, and

[0745] R 6 and R 7 Represents H.

[0746] A preferred embodiment of the present invention encompasses compounds of general formula (I), wherein

[0747] R 1 represents pyrazolyl, in particular pyrazol-4-yl, which is substituted at one or more carbon atoms by 1 or 2 identical or different substituents R 1a Substitution, where 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

[0748] Wherein R 1 Each nitrogen atom is independently optionally substituted by the same or different substituents R 1b Substitution, where 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

[0749] 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, then the 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 is optionally substituted by one or more independently selected from methyl, OH, OR 4 and F is substituted with a substituent, and

[0750] R 2 represents optionally substituted by 1 or 2 identical or different substituents R 2a Substituted phenyl, wherein R 2a Represents C 1 -C 5 -Alkyl, OC 1 -C 5 -alkyl, F or Cl, and

[0751] Wherein C 1 -C 5 -alkyl and -OC 1 -C 5 -alkyl is independently optionally substituted by 1 to 5 fluorine atoms,

[0752] R 3 Represents H or F, especially H,

[0753] R 4 represents C optionally substituted by 1 to 5 fluorine atoms 1 -C 5 -alkyl,

[0754] R 5 represents H, F, Cl or methyl, in particular H or F, and

[0755] R 6 and R 7 Represents H.

[0756] A preferred embodiment of the present invention encompasses compounds of general formula (I), wherein

[0757] R 1 represents pyrazolyl, in particular pyrazol-4-yl, which is optionally substituted at one or more carbon atoms by 1 or 2 identical or different substituents R 1a Substitution, where 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

[0758] Wherein R 1 Each nitrogen atom is independently optionally substituted by the same or different substituents R 1b Substitution, where 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

[0759] 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, then the 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 is optionally substituted by one or more independently selected from methyl, OH, OR 4 and F is substituted with a substituent, and

[0760] R 2 represents 1 or 2 identical or different substituents R 2a Substituted phenyl, wherein R 2a Represents C 1 -C 5 -Alkyl, OC 1 -C 5 -alkyl, F or Cl, and

[0761] wherein if the or at least one of the substituents is F, it is preferably located in the ortho position to the carbon atom which links the phenyl group to the rest of the molecule, and

[0762] Wherein C 1 -C 5 -alkyl and -OC 1 -C 5 -alkyl is independently optionally substituted by 1 to 5 fluorine atoms,

[0763] R 3 Represents H or F, especially H,

[0764] R 4 represents C optionally substituted by 1 to 5 fluorine atoms 1 -C 5 -alkyl,

[0765] R 5 represents H, F, Cl or methyl, in particular H or F, and

[0766] R 6 and R 7 Represents H.

[0767] A preferred embodiment of the present invention encompasses compounds of general formula (I), wherein

[0768] R 1 represents pyrazolyl, in particular pyrazol-4-yl, which is optionally substituted at one or more carbon atoms by 1 or 2 identical or different substituents R 1a Substitution, where R 1a Represents C 1 -C 5 -alkyl, C 3 -C 7 -cycloalkyl, -(C 1 -C 3 -alkyl)-(C 3 -C 7 -cycloalkyl), -OC1 -C 5 -alkyl, -OC 3 -C 7 - cycloalkyl, halogen or CN, and

[0769] Wherein R 1 Each nitrogen atom is independently optionally substituted by the same or different substituents R 1b Substitution, where R 1b Represents C 1 -C 5 -alkyl, -(C 1 -C 3 -alkyl)-(C 3 -C 7 -cycloalkyl) or C 3 -C 7 - cycloalkyl,

[0770] 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, then the 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 is optionally substituted by one or more independently selected from methyl, OH, OR 4 and F is substituted with a substituent, and

[0771] R 2 represents 1 or 2 identical or different substituents R 2a Substituted phenyl, wherein R 2a Represents C 1 -C 5 -Alkyl, OC 1 -C 5 -alkyl, F or Cl,

[0772] Wherein if the substituent or at least one of the substituents is C 1 -C 5 -alkyl, -OC 1 -C 5 -alkyl or Cl, it is preferably located in the para position to the carbon atom that attaches the phenyl group to the rest of the molecule, and

[0773] Wherein C 1 -C 5 -alkyl and -OC 1 -C 5 -alkyl is independently optionally substituted by 1 to 5 fluorine atoms,

[0774] R 3 Represents H or F, especially H,

[0775] R 4 represents C optionally substituted by 1 to 5 fluorine atoms 1 -C 5 -alkyl,

[0776] R 5 represents H, F, Cl or methyl, in particular H or F, and

[0777] R 6 and R 7 Represents H.

[0778] A preferred embodiment of the present invention encompasses compounds of general formula (I), wherein

[0779] R 1 represents pyrazolyl, in particular pyrazol-4-yl, which is optionally substituted at one or more carbon atoms by 1 or 2 identical or different substituents R 1a Substitution, where 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 -C5 -alkyl, -OC 3 -C 7 - cycloalkyl, halogen or CN, and

[0780] Wherein R 1 Each nitrogen atom is independently optionally substituted by the same or different substituents R 1b Substitution, where R 1b Represents C 1 -C 5 -alkyl, -(C 1 -C 3 -alkyl)-(C 3 -C 7 -cycloalkyl) or C 3 -C 7 - cycloalkyl,

[0781] 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, then the 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 is optionally substituted by one or more independently selected from methyl, OH, OR 4 and F is substituted with a substituent, and

[0782] R2 represents two identical or different substituents R 2a Substituted phenyl, wherein R 2a Represents C 1 -C 5 -Alkyl, OC 1 -C 5 -alkyl, F or Cl, and

[0783] wherein if the or at least one of the substituents is F, it is preferably located in the ortho position to the carbon atom which links the phenyl group to the rest of the molecule, and

[0784] Wherein if the substituent or at least one of the substituents is C 1 -C 5 -alkyl, -OC 1 -C 5 -alkyl or Cl, it is preferably located in the para position to the carbon atom that attaches the phenyl group to the rest of the molecule, and

[0785] Wherein C 1 -C 5 -alkyl and -OC 1 -C 5 -alkyl is independently optionally substituted by 1 to 5 fluorine atoms,

[0786] R 3 Represents H or F, especially H,

[0787] R 4 represents C optionally substituted by 1 to 5 fluorine atoms 1 -C 5 -alkyl,

[0788] R 5 represents H, F, Cl or methyl, in particular H or F, and

[0789] R 6 and R 7 Represents H.

[0790] A preferred embodiment of the present invention encompasses compounds of general formula (I), wherein

[0791] R 1 represents pyrazolyl, in particular pyrazol-4-yl, which is optionally substituted at one or more carbon atoms by 1 or 2 identical or different substituents R 1a Substitution, where 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

[0792] Wherein R 1 Each nitrogen atom is independently optionally substituted by the same or different substituents R 1b Substitution, where R 1b Represents C 1 -C 5 -alkyl, -(C 1 -C 3 -alkyl)-(C 3 -C 7 -cycloalkyl) or C 3 -C 7 - cycloalkyl,

[0793] 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, then the 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 is optionally substituted by one or more independently selected from methyl, OH, OR 4 and F is substituted with a substituent, and

[0794] R 2 represents 1 or 2 identical or different substituents R 2a Substituted phenyl, wherein R 2a represents methyl, trifluoromethyl, trifluoromethoxy, F or Cl, and

[0795] wherein if the or at least one of the substituents is F, it is preferably located in the ortho position to the carbon atom which links the phenyl group to the rest of the molecule, and

[0796] wherein if the substituent or at least one of the substituents is methyl, trifluoromethyl, trifluoromethoxy or Cl, it is preferably located in the para position to the carbon atom that attaches the phenyl group to the rest of the molecule,

[0797] R 3 Represents H or F, especially H,

[0798] R 4 represents C optionally substituted by 1 to 5 fluorine atoms 1 -C 5 -alkyl,

[0799] R 5 represents H, F, Cl or methyl, in particular H or F, and

[0800] R 6 and R 7 Represents H.

[0801] A preferred embodiment of the present invention encompasses compounds of general formula (I), wherein

[0802] R 1 represents an optionally substituted group R at the nitrogen atom 1b Substituted pyrazol-4-yl, R 1b Selected from C 1 -C 5 -alkyl, -(C 1 -C 3 -alkyl)-(C 3 -C 7 -cycloalkyl) and C 3 -C 7 - cycloalkyl,

[0803] Wherein C 1 -C 5 -alkyl, C 3 -C 7 -cycloalkyl and -(C 1 -C 3-alkyl)-(C 3 -C 7 -cycloalkyl) are optionally substituted by one or more independently selected from methyl, OH, OR 4 and F is substituted with a substituent,

[0804] R 2 represents 1 or 2 identical or different substituents R 2a Substituted phenyl, wherein R 2a represents methyl, trifluoromethyl, trifluoromethoxy, F or Cl, and

[0805] wherein if the or at least one of the substituents is F, it is preferably located in the ortho position to the carbon atom which links the phenyl group to the rest of the molecule, and

[0806] wherein if the or at least one of the substituents is methyl, trifluoromethyl, trifluoromethoxy or Cl, it is preferably located in the para position to the carbon atom that attaches the phenyl group to the rest of the molecule, and

[0807] R 3 Represents H or F, especially H,

[0808] R 4 represents C optionally substituted by 1 to 5 fluorine atoms 1 -C 5 -alkyl,

[0809] R 5 represents H, F, Cl or methyl, in particular H or F, and

[0810] R 6 and R 7 Represents H.

[0811] A preferred embodiment of the present invention encompasses compounds of general formula (I), wherein

[0812] R 1 Represents the substituted group R at the nitrogen atom 1b Substituted pyrazol-4-yl, R 1b is selected from the group consisting of methyl, ethyl, propyl, prop-2-yl, cyclopropyl, 2-methylpropyl, tert-butyl, but-2-yl, cyclobutyl, 2,2-dimethylpropyl, 3-methylbut-2-yl, cyclopentyl, cyclohexyl, 1-cyclopropylmethyl, 1-cyclopropylethyl, 1-cyclobutylmethyl, 1-(1-methylcyclopropyl)methyl and 2,2,2-trifluoroethyl, in particular ethyl, prop-2-yl, 2-methylpropyl, but-2-yl, cyclobutyl, cyclopentyl, 2,2-dimethylpropyl, 1-cyclopropylmethyl, 1-cyclopropylethyl, 1-(1-methylcyclopropyl)methyl or 1-cyclobutylmethyl,

[0813] R2 represents 1 or 2 identical or different substituents R 2a Substituted phenyl, wherein R 2a represents methyl, trifluoromethyl, trifluoromethoxy, F or Cl, and

[0814] wherein if the or at least one of the substituents is F, it is preferably located in the ortho position to the carbon atom which links the phenyl group to the rest of the molecule, and

[0815] wherein if the or at least one of the substituents is methyl, trifluoromethyl, trifluoromethoxy or Cl, it is preferably located in the para position to the carbon atom that attaches the phenyl group to the rest of the molecule, and

[0816] R 3 Represents H or F, especially H,

[0817] R 5 represents H, F, Cl or methyl, in particular H or F, and

[0818] R 6 and R 7 Represents H.

[0819] A preferred embodiment of the present invention encompasses compounds of general formula (I), wherein

[0820] R 1 represents the nitrogen atom at position 1 substituted by a group R 1b Substituted pyrazol-4-yl, R 1b is selected from the group consisting of methyl, ethyl, propyl, propan-2-yl, cyclopropyl, 2-methylpropyl, tert-butyl, but-2-yl, cyclobutyl, 2,2-dimethylpropyl, 3-methylbut-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, but-2-yl, cyclobutyl, cyclopentyl, 2,2-dimethylpropyl, 1-cyclopropylmethyl, 1-cyclopropylethyl, 1-(1-methylcyclopropyl)methyl or 1-cyclobutylmethyl.

[0821] R 2 represents 1 or 2 identical or different substituents R 2a Substituted phenyl, wherein R 2a represents methyl, trifluoromethyl, trifluoromethoxy, F or Cl, and

[0822] wherein if the or at least one of the substituents is F, it is preferably located in the ortho position to the carbon atom which links the phenyl group to the rest of the molecule, and

[0823] wherein if the or at least one of the substituents is methyl, trifluoromethyl, trifluoromethoxy or Cl, it is preferably located in the para position to the carbon atom that attaches the phenyl group to the rest of the molecule, and

[0824] R 3 Represents H,

[0825] R 5 represents H, and

[0826] R 6 and R 7 Represents H.

[0827] A preferred embodiment of the present invention encompasses compounds of general formula (I), wherein

[0828] R 1 represents the nitrogen atom at position 1 substituted by a group R 1b Substituted pyrazol-4-yl, R 1b is selected from the group consisting of methyl, ethyl, propyl, prop-2-yl, cyclopropyl, 2-methylpropyl, tert-butyl, but-2-yl, cyclobutyl, 2,2-dimethylpropyl, 3-methylbut-2-yl, cyclopentyl, cyclohexyl, 1-cyclopropylmethyl, 1-cyclopropylethyl, 1-cyclobutylmethyl, 1-(1-methylcyclopropyl)methyl and 2,2,2-trifluoroethyl, in particular ethyl, prop-2-yl, 2-methylpropyl, but-2-yl, cyclobutyl, cyclopentyl, 2,2-dimethylpropyl, 1-cyclopropylmethyl, 1-cyclopropylethyl, 1-(1-methylcyclopropyl)methyl or 1-cyclobutylmethyl,

[0829] R 2 represents 1 or 2 identical or different substituents R 2a Substituted phenyl, wherein R 2a represents methyl, trifluoromethyl, trifluoromethoxy, F or Cl, and

[0830] wherein if the or at least one of the substituents is F, it is preferably located in the ortho position to the carbon atom which links the phenyl group to the rest of the molecule, and

[0831] wherein if the or at least one of the substituents is methyl, trifluoromethyl, trifluoromethoxy or Cl, it is preferably located in the para position to the carbon atom that attaches the phenyl group to the rest of the molecule, and

[0832] R 3 Represents H,

[0833] R 5 represents F, and

[0834] R 6 and R 7 Represents H.

[0835] A preferred embodiment of the present invention encompasses compounds of general formula (I), wherein

[0836] R 1 Represents the substituted group R at the nitrogen atom 1b Substituted pyrazol-4-yl, R 1b Selected from C 1 -C 5 -alkyl, -(C 1 -C 3 -alkyl)-(C 3 -C 7 -cycloalkyl) and C 3 -C 7 - cycloalkyl,

[0837] Wherein C 1 -C 5 -alkyl, C 3 -C 7 -cycloalkyl and -(C 1 -C 3 -alkyl)-(C 3 -C 7 -cycloalkyl) are optionally substituted by one or more independently selected from OH, OR 4 and F is substituted with a substituent,

[0838] R 2 represents optionally substituted by 1 or 2 identical or different substituents R 2a Substituted C 5 -C 7 -cycloalkyl, where R 2a Represents C 1 -C 5 -Alkyl, OC 1 -C 5 -alkyl, F or Cl, and

[0839] Wherein C 1 -C 5 -alkyl and -OC 1 -C 5 -alkyl is independently optionally substituted by 1 to 5 fluorine atoms,

[0840] R 3 Represents H or F, especially H,

[0841] R 4 represents C optionally substituted by 1 to 5 fluorine atoms 1 -C 5 -alkyl,

[0842] R 5 represents H, F, Cl or methyl, in particular H or F, and

[0843] R 6 and R 7 Represents H.

[0844] According to another aspect, the present invention encompasses compounds of general formula (I), wherein

[0845] R 1 represents a thiazolyl group, in particular a thiazol-5-yl group, which is optionally substituted at one or more carbon atoms by 1 or 2 identical or different substituents R 1a Substitution, where 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,

[0846] Wherein 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 is optionally substituted by one or more independently selected from methyl, OH, OR 4 and F is substituted with a substituent,

[0847] R 2 represents optionally substituted by 1 or 2 identical or different substituents R 2a Substituted phenyl, wherein R 2a Represents C 1 -C 5 -Alkyl, OC 1 -C 5 -alkyl, F or Cl, and

[0848] Wherein C 1 -C 5 -alkyl and -OC 1 -C 5 -alkyl is independently optionally substituted by 1 to 5 fluorine atoms,

[0849] R 3 Represents H or F, especially H,

[0850] R 4 represents C optionally substituted by 1 to 5 fluorine atoms 1 -C 5 -alkyl,

[0851] R 5 represents H, F, Cl or methyl, in particular H or F, and

[0852] R 6 and R 7 Represents H.

[0853] A preferred embodiment of the present invention encompasses compounds of general formula (I), wherein

[0854] R 1 represents a thiazolyl group, in particular a thiazol-5-yl group, which is substituted at one or more carbon atoms by one or two identical or different substituents R 1a Substitution, where 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,

[0855] wherein the substituent or at least one of said substituents is preferably located in the meta position to the carbon atom which links the thiazolyl group, in particular the thiazol-5-yl group, to the rest of the molecule; and

[0856] Wherein 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 is optionally substituted by one or more independently selected from methyl, OH, OR 4and F is substituted with a substituent, and

[0857] R 2 represents 1 or 2 identical or different substituents R 2a Substituted phenyl, wherein R 2a Represents C 1 -C 5 -Alkyl, OC 1 -C 5 -alkyl, F or Cl, and

[0858] wherein if the or at least one of the substituents is F, it is preferably located in the ortho position to the carbon atom which links the phenyl group to the rest of the molecule, and

[0859] Wherein C 1 -C 5 -alkyl and -OC 1 -C 5 -alkyl is independently optionally substituted by 1 to 5 fluorine atoms,

[0860] R 3 Represents H or F, especially H,

[0861] R 4 represents C optionally substituted by 1 to 5 fluorine atoms 1 -C 5 -alkyl,

[0862] R 5 represents H, F, Cl or methyl, in particular H or F, and

[0863] R 6 and R 7 Represents H.

[0864] A preferred embodiment of the present invention encompasses compounds of general formula (I), wherein

[0865] R 1 represents a thiazol-5-yl group, wherein R 1 The carbon atom is substituted by a group R 1a Replacement, R 1a Selected from C 1 -C 5 -alkyl, -(C 1 -C 3 -alkyl)-(C 3 -C 7 -cycloalkyl) and C 3 -C 7 - cycloalkyl,

[0866] wherein the substituent R 1a Preferably, it is attached to the carbon atom at position 2 of the thiazol-5-yl group; and

[0867] Wherein C 1 -C 5 -alkyl, C 3 -C 7 -cycloalkyl and -(C 1 -C 3 -alkyl)-(C 3 -C 7 -cycloalkyl) are optionally substituted by one or more independently selected from methyl, OH, OR 4 and F is substituted with a substituent,

[0868] R 2 represents 1 or 2 identical or different substituents R 2a Substituted phenyl, wherein R 2a Represents C 1 -C 5 -Alkyl, OC 1 -C 5 -alkyl, F or Cl,

[0869] Wherein if the substituent or at least one of the substituents is C 1 -C 5 -alkyl, -OC 1 -C 5 -alkyl or Cl, it is preferably located in the para position to the carbon atom that attaches the phenyl group to the rest of the molecule, and

[0870] Wherein C 1 -C 5 -alkyl and -OC 1 -C 5 -alkyl is independently optionally substituted by 1 to 5 fluorine atoms,

[0871] R 3 Represents H or F, especially H,

[0872] R 4 represents C optionally substituted by 1 to 5 fluorine atoms 1 -C 5 -alkyl,

[0873] R 5 represents H, F, Cl or methyl, in particular H or F, and

[0874] R 6 and R 7 Represents H.

[0875] A preferred embodiment of the present invention encompasses compounds of general formula (I), wherein

[0876] R 1 Represents the carbon atom at position 2 is replaced by C 3-C 7 -cycloalkyl-substituted thiazol-5-yl, wherein the C 3 -C 7 -cycloalkyl is optionally substituted by one or more independently selected from methyl, OH, OR 4 and F is substituted with a substituent,

[0877] R 2 represents 1 or 2 identical or different substituents R 2a Substituted phenyl, wherein R 2a represents methyl, trifluoromethyl, trifluoromethoxy, F or Cl, and

[0878] wherein if the or at least one of the substituents is F, it is preferably located in the ortho position to the carbon atom which links the phenyl group to the rest of the molecule, and

[0879] wherein if the or at least one of the substituents is methyl, trifluoromethyl, trifluoromethoxy or Cl, it is preferably located in the para position to the carbon atom that attaches the phenyl group to the rest of the molecule, and

[0880] R 3 Represents H or F, especially H,

[0881] R 4 represents C optionally substituted by 1 to 5 fluorine atoms 1 -C 5 -alkyl,

[0882] R 5 represents H, F, Cl or methyl, in particular H or F, and

[0883] R 6 and R 7 Represents H.

[0884] A preferred embodiment of the present invention encompasses compounds of general formula (I), wherein

[0885] R 1 represents a thiazol-5-yl group, which is optionally substituted at the carbon atom in the 2-position by a group R 1a Substitute, the R 1ais selected from the group consisting of methyl, ethyl, propyl, prop-2-yl, cyclopropyl, 2-methylpropyl, tert-butyl, but-2-yl, cyclobutyl, 2,2-dimethylpropyl, 3-methylbut-2-yl, cyclopentyl, cyclohexyl, 1-cyclopropylmethyl, 1-cyclopropylethyl, 1-cyclobutylmethyl, 1-(1-methylcyclopropyl)methyl and 2,2,2-trifluoroethyl, in particular ethyl, prop-2-yl, cyclopropyl, 2-methylpropyl, but-2-yl, cyclobutyl, 2,2-dimethylpropyl, cyclopentyl, 1-cyclopropylmethyl, 1-cyclopropylethyl, 1-(1-methylcyclopropyl)methyl and 1-cyclobutylmethyl,

[0886] R 2 represents 1 or 2 identical or different substituents R 2a Substituted phenyl, wherein R 2a represents methyl, trifluoromethyl, trifluoromethoxy, F or Cl, and

[0887] wherein if the or at least one of the substituents is F, it is preferably located in the ortho position to the carbon atom which links the phenyl group to the rest of the molecule, and

[0888] wherein if the substituent or at least one of the substituents is methyl, trifluoromethyl, trifluoromethoxy or Cl, it is preferably located in the para position to the carbon atom that attaches the phenyl group to the rest of the molecule,

[0889] R 3 Represents H or F, especially H,

[0890] R 5 represents H, F, Cl or methyl, in particular H or F, and

[0891] R 6 and R 7 Represents H.

[0892] A preferred embodiment of the present invention encompasses compounds of general formula (I), wherein

[0893] R 1 represents a thiazol-5-yl group, which is optionally substituted at the carbon atom in the 2-position by a group R 1a Substitute, the R 1ais selected from the group consisting of methyl, ethyl, propyl, prop-2-yl, cyclopropyl, 2-methylpropyl, tert-butyl, but-2-yl, cyclobutyl, 2,2-dimethylpropyl, 3-methylbut-2-yl, cyclopentyl, cyclohexyl, 1-cyclopropylmethyl, 1-cyclopropylethyl, 1-cyclobutylmethyl, 1-(1-methylcyclopropyl)methyl and 2,2,2-trifluoroethyl, in particular ethyl, prop-2-yl, cyclopropyl, 2-methylpropyl, but-2-yl, cyclobutyl, 2,2-dimethylpropyl, cyclopentyl, 1-cyclopropylmethyl, 1-cyclopropylethyl, 1-(1-methylcyclopropyl)methyl and 1-cyclobutylmethyl,

[0894] R 2 represents 1 or 2 identical or different substituents R 2a Substituted phenyl, wherein R 2a represents methyl, trifluoromethyl, trifluoromethoxy, F or Cl, and

[0895] wherein if the or at least one of the substituents is F, it is preferably located in the ortho position to the carbon atom which links the phenyl group to the rest of the molecule, and

[0896] wherein if the substituent or at least one of the substituents is methyl, trifluoromethyl, trifluoromethoxy or Cl, it is preferably located in the para position to the carbon atom that attaches the phenyl group to the rest of the molecule,

[0897] R 3 Represents H,

[0898] R 5 represents H, and

[0899] R 6 and R 7 Represents H.

[0900] A preferred embodiment of the present invention encompasses compounds of general formula (I), wherein

[0901] R 1 represents a thiazol-5-yl group, which is optionally substituted at the carbon atom in the 2-position by a group R 1a Substitution, the R 1a is selected from the group consisting of methyl, ethyl, propyl, prop-2-yl, cyclopropyl, 2-methylpropyl, tert-butyl, but-2-yl, cyclobutyl, 2,2-dimethylpropyl, 3-methylbut-2-yl, cyclopentyl, cyclohexyl, 1-cyclopropylmethyl, 1-cyclopropylethyl, 1-cyclobutylmethyl, 1-(1-methylcyclopropyl)methyl and 2,2,2-trifluoroethyl, in particular ethyl, prop-2-yl, cyclopropyl, 2-methylpropyl, but-2-yl, cyclobutyl, 2,2-dimethylpropyl, cyclopentyl, 1-cyclopropylmethyl, 1-cyclopropylethyl, 1-(1-methylcyclopropyl)methyl and 1-cyclobutylmethyl,

[0902] R 2 represents 1 or 2 identical or different substituents R 2a Substituted phenyl, wherein R 2a represents methyl, trifluoromethyl, trifluoromethoxy, F or Cl, and

[0903] wherein if the or at least one of the substituents is F, it is preferably located in the ortho position to the carbon atom which links the phenyl group to the rest of the molecule, and

[0904] wherein if the substituent or at least one of the substituents is methyl, trifluoromethyl, trifluoromethoxy or Cl, it is preferably located in the para position to the carbon atom that attaches the phenyl group to the rest of the molecule,

[0905] R 3 Represents H,

[0906] R 5 represents F, and

[0907] R 6 and R 7 Represents H.

[0908] According to another aspect, the present invention encompasses compounds of general formula (I), wherein

[0909] R 1 represents a thiazolyl group, in particular a thiazol-2-yl group, which is optionally substituted at one or more carbon atoms by 1 or 2 identical or different substituents R 1a Substitution, where 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,

[0910] Wherein 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 is optionally substituted by one or more independently selected from methyl, OH, OR 4 and F is substituted with a substituent,

[0911] R 2 represents optionally substituted by 1 or 2 identical or different substituents R 2a Substituted phenyl, wherein R 2a Represents C 1 -C 5 -Alkyl, OC 1 -C 5 -alkyl, F or Cl, and

[0912] Wherein C 1 -C 5 -alkyl and -OC 1 -C 5 -alkyl is independently optionally substituted by 1 to 5 fluorine atoms,

[0913] R 3 Represents H or F, especially H,

[0914] R 4 represents C optionally substituted by 1 to 5 fluorine atoms 1 -C 5 -alkyl,

[0915] R 5 represents H, F, Cl or methyl, in particular H or F, and

[0916] R 6 and R 7 Represents H.

[0917] A preferred embodiment of the present invention encompasses compounds of general formula (I), wherein

[0918] R 1 Represents the substituted group R at the carbon atom 1a Substituted thiazol-2-yl, wherein R 1a Selected from C 1 -C 5 -alkyl, -(C 1 -C 3 -alkyl)-(C 3 -C 7 -) cycloalkyl and C 3 -C 7 - cycloalkyl,

[0919] wherein the substituent R 1a Preferably attached to the 5-carbon atom of the thiazol-2-yl group; and

[0920] Wherein C 1 -C 5 -alkyl, C 3 -C 7 -cycloalkyl and -(C 1 -C 3 -alkyl)-(C 3 -C 7 -cycloalkyl) are optionally substituted by one or more independently selected from methyl, OH, OR 4 and F is substituted with a substituent,

[0921] R 2 represents 1 or 2 identical or different substituents R 2a Substituted phenyl, wherein R 2a Represents C 1 -C 5 -Alkyl, OC 1 -C 5 -alkyl, F or Cl,

[0922] Wherein if the substituent or at least one of the substituents is C 1 -C 5 -alkyl, -OC 1 -C 5 -alkyl or Cl, it is preferably located in the para position to the carbon atom that attaches the phenyl group to the rest of the molecule, and

[0923] Wherein C 1 -C 5 -alkyl and -OC 1 -C 5 -alkyl is independently optionally substituted by 1 to 5 fluorine atoms,

[0924] R 3 Represents H or F, especially H,

[0925] R 4 represents C optionally substituted by 1 to 5 fluorine atoms 1 -C 5 -alkyl,

[0926] R 5 represents H, F, Cl or methyl, in particular H or F, and

[0927] R 6 and R 7 Represents H.

[0928] A preferred embodiment of the present invention encompasses compounds of general formula (I), wherein

[0929] R 1 Represents the carbon atom at position 5 is replaced by C 3 -C 7-cycloalkyl-substituted thiazol-2-yl, wherein the C 3 -C 7 -cycloalkyl is optionally substituted by one or more independently selected from methyl, OH, OR 4 and F is substituted with a substituent,

[0930] R 2 represents 1 or 2 identical or different substituents R 2a Substituted phenyl, wherein R 2a represents methyl, trifluoromethyl, trifluoromethoxy, F or Cl, and

[0931] wherein if the or at least one of the substituents is F, it is preferably located in the ortho position to the carbon atom which links the phenyl group to the rest of the molecule, and

[0932] wherein if the or at least one of the substituents is methyl, trifluoromethyl, trifluoromethoxy or Cl, it is preferably located in the para position to the carbon atom that attaches the phenyl group to the rest of the molecule, and

[0933] R 3 Represents H or F, especially H,

[0934] R 4 represents C optionally substituted by 1 to 5 fluorine atoms 1 -C 5 -alkyl,

[0935] R 5 represents H, F, Cl or methyl, in particular H or F, and

[0936] R 6 and R 7 Represents H.

[0937] A preferred embodiment of the present invention encompasses compounds of general formula (I), wherein

[0938] R 1 represents a thiazol-2-yl group, which is optionally substituted at the carbon atom in the 5-position by a group R 1a Substituted, the substituent R 1a is selected from the group consisting of methyl, ethyl, propyl, prop-2-yl, cyclopropyl, 2-methylpropyl, tert-butyl, but-2-yl, cyclobutyl, 2,2-dimethylpropyl, 3-methylbut-2-yl, cyclopentyl, cyclohexyl, 1-cyclopropylmethyl, 1-cyclopropylethyl, 1-cyclobutylmethyl, 1-(1-methylcyclopropyl)methyl and 2,2,2-trifluoroethyl, in particular ethyl, prop-2-yl, cyclopropyl, 2-methylpropyl, but-2-yl, cyclobutyl, 2,2-dimethylpropyl, cyclopentyl, 1-cyclopropylmethyl, 1-cyclopropylethyl, 1-(1-methylcyclopropyl)methyl and 1-cyclobutylmethyl,

[0939] R 2 represents 1 or 2 identical or different substituents R 2a Substituted phenyl, wherein R 2a represents methyl, trifluoromethyl, trifluoromethoxy, F or Cl, and

[0940] wherein if the or at least one of the substituents is F, it is preferably located in the ortho position to the carbon atom which links the phenyl group to the rest of the molecule, and

[0941] wherein if the substituent or at least one of the substituents is methyl, trifluoromethyl, trifluoromethoxy or Cl, it is preferably located in the para position to the carbon atom that attaches the phenyl group to the rest of the molecule,

[0942] R 3 Represents H or F, especially H,

[0943] R 5 represents H, F, Cl or methyl, in particular H or F, and

[0944] R 6 and R 7 Represents H.

[0945] A preferred embodiment of the present invention encompasses compounds of general formula (I), wherein

[0946] R 1 represents a thiazol-2-yl group, which is optionally substituted at the carbon atom in the 5-position by a group R 1a Substitution, the R 1a is selected from the group consisting of methyl, ethyl, propyl, prop-2-yl, cyclopropyl, 2-methylpropyl, tert-butyl, but-2-yl, cyclobutyl, 2,2-dimethylpropyl, 3-methylbut-2-yl, cyclopentyl, cyclohexyl, 1-cyclopropylmethyl, 1-cyclopropylethyl, 1-cyclobutylmethyl, 1-(1-methylcyclopropyl)methyl and 2,2,2-trifluoroethyl, in particular ethyl, prop-2-yl, cyclopropyl, 2-methylpropyl, but-2-yl, cyclobutyl, 2,2-dimethylpropyl, cyclopentyl, 1-cyclopropylmethyl, 1-cyclopropylethyl, 1-(1-methylcyclopropyl)methyl and 1-cyclobutylmethyl,

[0947] R 2 represents 1 or 2 identical or different substituents R 2a Substituted phenyl, wherein R 2a represents methyl, trifluoromethyl, trifluoromethoxy, F or Cl, and

[0948] wherein if the or at least one of the substituents is F, it is preferably located in the ortho position to the carbon atom which links the phenyl group to the rest of the molecule, and

[0949] wherein if the substituent or at least one of the substituents is methyl, trifluoromethyl, trifluoromethoxy or Cl, it is preferably located in the para position to the carbon atom that attaches the phenyl group to the rest of the molecule,

[0950] R 3 Represents H,

[0951] R 5 represents H, and

[0952] R 6 and R 7 Represents H.

[0953] A preferred embodiment of the present invention encompasses compounds of general formula (I), wherein

[0954] R 1 represents a thiazol-2-yl group, which is optionally substituted at the carbon atom in the 5-position by a group R 1a Substitution, the R 1a is selected from the group consisting of methyl, ethyl, propyl, prop-2-yl, cyclopropyl, 2-methylpropyl, tert-butyl, but-2-yl, cyclobutyl, 2,2-dimethylpropyl, 3-methylbut-2-yl, cyclopentyl, cyclohexyl, 1-cyclopropylmethyl, 1-cyclopropylethyl, 1-cyclobutylmethyl, 1-(1-methylcyclopropyl)methyl and 2,2,2-trifluoroethyl, in particular ethyl, prop-2-yl, cyclopropyl, 2-methylpropyl, but-2-yl, cyclobutyl, 2,2-dimethylpropyl, cyclopentyl, 1-cyclopropylmethyl, 1-cyclopropylethyl, 1-(1-methylcyclopropyl)methyl and 1-cyclobutylmethyl,

[0955] R 2 represents 1 or 2 identical or different substituents R 2a Substituted phenyl, wherein R 2a represents methyl, trifluoromethyl, trifluoromethoxy, F or Cl, and

[0956] wherein if the or at least one of the substituents is F, it is preferably located in the ortho position to the carbon atom which links the phenyl group to the rest of the molecule, and

[0957] wherein if the substituent or at least one of the substituents is methyl, trifluoromethyl, trifluoromethoxy or Cl, it is preferably located in the para position to the carbon atom that attaches the phenyl group to the rest of the molecule,

[0958] R 3 Represents H,

[0959] R 5 represents F, and

[0960] R 6 and R7 Represents H.

[0961] The preferred compounds are

[0962] 2-(1-Benzothiophen-2-yl)-5-[({1-[2-fluoro-4-(trifluoromethyl)phenyl]cyclopropyl}carbonyl)amino]benzoic acid

[0963] 2-[6-(1,1-difluoropropyl)pyridin-3-yl]-5-[({1-[2-fluoro-4-(trifluoromethyl)phenyl]cyclopropyl}carbonyl)amino]benzoic acid

[0964] 2-(1-Cyclobutyl-1H-pyrazol-4-yl)-5-[({1-[2-fluoro-4-(trifluoromethyl)phenyl]cyclopropyl}carbonyl)amino]benzoic acid

[0965] 2-(6-Ethoxypyridin-3-yl)-5-[({1-[2-fluoro-4-(trifluoromethyl)phenyl]cyclopropyl}carbonyl)amino]benzoic acid

[0966] 2-(6-ethoxypyridin-3-yl)-5-[({1-[2-fluoro-4-(trifluoromethoxy)phenyl]cyclopropyl}carbonyl)amino]benzoic acid

[0967] 2-(1-Cyclobutyl-1H-pyrazol-4-yl)-3-fluoro-5-({[1-(2-fluoro-4-methylphenyl)cyclopropyl]carbonyl}amino)benzoic acid

[0968] 2-[6-(1,1-difluoropropyl)pyridin-3-yl]-5-[({1-[2-fluoro-4-(trifluoromethoxy)phenyl]cyclopropyl}carbonyl)amino]benzoic acid

[0969] 3-Fluoro-5-[({1-[2-fluoro-4-(trifluoromethyl)phenyl]cyclopropyl}carbonyl)amino]-2-[6-(trifluoromethyl)pyridin-3-yl]benzoic acid

[0970] 5-[({1-[2-Fluoro-4-(trifluoromethyl)phenyl]cyclopropyl}carbonyl)amino]-2-[1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl]benzoic acid

[0971] 5-({[1-(4-chlorophenyl)cyclopropyl]carbonyl}amino)-2-(1-cyclobutyl-1H-pyrazol-4-yl)-3-fluorobenzoic acid

[0972] 2-(1-Cyclobutyl-1H-pyrazol-4-yl)-3-fluoro-5-[({1-[4-(trifluoromethyl)phenyl]cyclopropyl}carbonyl)amino]benzoic acid

[0973] 2-(1-Cyclobutyl-1H-pyrazol-4-yl)-3-fluoro-5-[({1-[4-(trifluoromethoxy)phenyl]cyclopropyl}carbonyl)amino]benzoic acid

[0974] 2-(1-cyclobutyl-1H-pyrazol-4-yl)-5-({[1-(3,4-difluorophenyl)cyclopropyl]carbonyl}amino)-3-fluorobenzoic acid

[0975] 2-(1-Cyclobutyl-1H-pyrazol-4-yl)-3-fluoro-5-[({1-[3-fluoro-4-(trifluoromethyl)phenyl]cyclopropyl}carbonyl)amino]benzoic acid

[0976] 2-(1-cyclobutyl-1H-pyrazol-4-yl)-5-({[1-(2,4-difluorophenyl)cyclopropyl]carbonyl}amino)-3-fluorobenzoic acid

[0977] 5-({[1-(4-chloro-2-fluorophenyl)cyclopropyl]carbonyl}amino)-2-(1-cyclobutyl-1H-pyrazol-4-yl)-3-fluorobenzoic acid

[0978] 2-(1-Cyclobutyl-1H-pyrazol-4-yl)-3-fluoro-5-[({1-[2-fluoro-4-(trifluoromethyl)phenyl]cyclopropyl}carbonyl)amino]benzoic acid

[0979] 2-(1-Cyclobutyl-1H-pyrazol-4-yl)-3-fluoro-5-[({1-[2-fluoro-4-(trifluoromethoxy)phenyl]cyclopropyl}carbonyl)amino]benzoic acid

[0980] 2-(1-cyclobutyl-1H-pyrazol-4-yl)-3-fluoro-5-({[1-(5-fluoropyridin-2-yl)cyclopropyl]carbonyl}amino)benzoic acid

[0981] 2-(1-Cyclobutyl-3-fluoro-1H-pyrazol-4-yl)-5-[({1-[2-fluoro-4-(trifluoromethyl)phenyl]cyclopropyl}carbonyl)amino]benzoic acid

[0982] 5-({[1-(4-chloro-3-fluorophenyl)cyclopropyl]carbonyl}amino)-2-(1-cyclobutyl-1H-pyrazol-4-yl)benzoic acid

[0983] 2-(1-Cyclobutyl-1H-pyrazol-4-yl)-5-[({1-[2-fluoro-4-(trifluoromethoxy)phenyl]cyclopropyl}carbonyl)amino]benzoic acid

[0984] 5-({[1-(4-chloro-2-fluorophenyl)cyclopropyl]carbonyl}amino)-2-(1-cyclobutyl-1H-pyrazol-4-yl)benzoic acid

[0985] 5-({[1-(5-chloro-2-fluorophenyl)cyclopropyl]carbonyl}amino)-2-(1-cyclobutyl-1H-pyrazol-4-yl)benzoic acid

[0986] 2-(1-ethyl-1H-pyrazol-4-yl)-5-[({1-[2-fluoro-4-(trifluoromethyl)phenyl]cyclopropyl}carbonyl)amino]benzoic acid

[0987] 2-(1-ethyl-1H-pyrazol-4-yl)-5-[({1-[2-fluoro-4-(trifluoromethoxy)phenyl]cyclopropyl}carbonyl)amino]benzoic acid

[0988] 5-[({1-[2-Fluoro-4-(trifluoromethyl)phenyl]cyclopropyl}carbonyl)amino]-2-[1-(propan-2-yl)-1H-pyrazol-4-yl]benzoic acid

[0989] 5-[({1-[2-Fluoro-4-(trifluoromethoxy)phenyl]cyclopropyl}carbonyl)amino]-2-[1-(propan-2-yl)-1H-pyrazol-4-yl]benzoic acid

[0990] 2-(1-tert-Butyl-1H-pyrazol-4-yl)-5-[({1-[2-fluoro-4-(trifluoromethyl)phenyl]cyclopropyl}carbonyl)amino]benzoic acid

[0991] 2-(1-tert-Butyl-1H-pyrazol-4-yl)-5-[({1-[2-fluoro-4-(trifluoromethoxy)phenyl]cyclopropyl}carbonyl)amino]benzoic acid

[0992] 5-[({1-[2-Fluoro-4-(trifluoromethyl)phenyl]cyclopropyl}carbonyl)amino]-2-[1-(2-methylpropyl)-1H-pyrazol-4-yl]benzoic acid

[0993] 5-[({1-[2-fluoro-4-(trifluoromethoxy)phenyl]cyclopropyl}carbonyl)amino]-2-[1-(2-methylpropyl)-1H-pyrazol-4-yl]benzoic acid

[0994] 2-[1-(2,2-dimethylpropyl)-1H-pyrazol-4-yl]-5-[({1-[2-fluoro-4-(trifluoromethyl)phenyl]cyclopropyl}carbonyl)amino]benzoic acid

[0995] 2-[1-(2,2-dimethylpropyl)-1H-pyrazol-4-yl]-5-[({1-[2-fluoro-4-(trifluoromethoxy)phenyl]cyclopropyl}carbonyl)amino]benzoic acid

[0996] 3-Fluoro-5-({[1-(2-fluoro-4-methylphenyl)cyclopropyl]carbonyl}amino)-2-[1-(propan-2-yl)-1H-pyrazol-4-yl]benzoic acid

[0997] 3-Fluoro-5-[({1-[2-fluoro-4-(trifluoromethyl)phenyl]cyclopropyl}carbonyl)amino]-2-[1-(propan-2-yl)-1H-pyrazol-4-yl]benzoic acid

[0998] 3-Fluoro-5-[({1-[2-fluoro-4-(trifluoromethoxy)phenyl]cyclopropyl}carbonyl)amino]-2-[1-(propan-2-yl)-1H-pyrazol-4-yl]benzoic acid

[0999] 2-(4-tert-Butyl-1H-imidazol-1-yl)-3-fluoro-5-[({1-[2-fluoro-4-(trifluoromethyl)phenyl]cyclopropyl}carbonyl)amino]benzoic acid

[1000] 2-(4-tert-Butyl-1H-imidazol-1-yl)-3-fluoro-5-[({1-[2-fluoro-4-(trifluoromethoxy)phenyl]cyclopropyl}carbonyl)amino]benzoic acid

[1001] 3-Fluoro-5-[({1-[2-fluoro-4-(trifluoromethyl)phenyl]cyclopropyl}carbonyl)amino]-2-[1-(2-methylpropyl)-1H-pyrazol-4-yl]benzoic acid

[1002] 2-[6-(Difluoromethyl)pyridin-3-yl]-3-fluoro-5-[({1-[2-fluoro-4-(trifluoromethyl)phenyl]cyclopropyl}carbonyl)amino]benzoic acid

[1003] 2-[6-(Difluoromethyl)pyridin-3-yl]-3-fluoro-5-[({1-[2-fluoro-4-(trifluoromethoxy)phenyl]cyclopropyl}carbonyl)amino]benzoic acid

[1004] 2-[6-(1,1-difluoropropyl)pyridin-3-yl]-3-fluoro-5-[({1-[2-fluoro-4-(trifluoromethyl)phenyl]cyclopropyl}carbonyl)amino]benzoic acid

[1005] 2-[6-(1,1-difluoropropyl)pyridin-3-yl]-3-fluoro-5-[({1-[2-fluoro-4-(trifluoromethoxy)phenyl]cyclopropyl}carbonyl)amino]benzoic acid

[1006] 3-Chloro-2-(1-cyclobutyl-1H-pyrazol-4-yl)-5-[({1-[2-fluoro-4-(trifluoromethyl)phenyl]cyclopropyl}carbonyl)amino]benzoic acid

[1007] 3-Chloro-2-(1-cyclobutyl-1H-pyrazol-4-yl)-5-[({1-[2-fluoro-4-(trifluoromethoxy)phenyl]cyclopropyl}carbonyl)amino]benzoic acid

[1008] 3-Chloro-2-[6-(1,1-difluoropropyl)pyridin-3-yl]-5-[({1-[2-fluoro-4-(trifluoromethyl)phenyl]cyclopropyl}carbonyl)amino]benzoic acid

[1009] 3-Chloro-2-[6-(1,1-difluoropropyl)pyridin-3-yl]-5-[({1-[2-fluoro-4-(trifluoromethoxy)phenyl]cyclopropyl}carbonyl)amino]benzoic acid

[1010] 2-(1-Cyclobutyl-1H-pyrazol-4-yl)-5-[({1-[2-fluoro-4-(trifluoromethyl)phenyl]cyclopropyl}carbonyl)amino]-3-methylbenzoic acid

[1011] 2-(1-Cyclobutyl-1H-pyrazol-4-yl)-5-[({1-[2-fluoro-4-(trifluoromethoxy)phenyl]cyclopropyl}carbonyl)amino]-3-methylbenzoic acid

[1012] 2-[1-(Cyclobutylmethyl)-1H-pyrazol-4-yl]-5-[({1-[2-fluoro-4-(trifluoromethyl)phenyl]cyclopropyl}carbonyl)amino]benzoic acid

[1013] 2-[1-(Cyclobutylmethyl)-1H-pyrazol-4-yl]-5-[({1-[2-fluoro-4-(trifluoromethoxy)phenyl]cyclopropyl}carbonyl)amino]benzoic acid

[1014] 2-(1-Cyclopentyl-1H-pyrazol-4-yl)-5-[({1-[2-fluoro-4-(trifluoromethyl)phenyl]cyclopropyl}carbonyl)amino]benzoic acid

[1015] 2-(1-cyclohexyl-1H-pyrazol-4-yl)-5-[({1-[2-fluoro-4-(trifluoromethyl)phenyl]cyclopropyl}carbonyl)amino]benzoic acid

[1016] 2-(1-cyclohexyl-1H-pyrazol-4-yl)-5-[({1-[2-fluoro-4-(trifluoromethoxy)phenyl]cyclopropyl}carbonyl)amino]benzoic acid

[1017] 2-[1-(Cyclopropylmethyl)-1H-pyrazol-4-yl]-3-fluoro-5-[({1-[2-fluoro-4-(trifluoromethyl)phenyl]cyclopropyl}carbonyl)amino]benzoic acid

[1018] 2-[1-(Cyclopropylmethyl)-1H-pyrazol-4-yl]-3-fluoro-5-[({1-[2-fluoro-4-(trifluoromethoxy)phenyl]cyclopropyl}carbonyl)amino]benzoic acid

[1019] 3-Fluoro-5-[({1-[2-fluoro-4-(trifluoromethyl)phenyl]cyclopropyl}carbonyl)amino]-2-(6-methylpyridin-3-yl)benzoic acid

[1020] 2-{1-[(2S)-But-2-yl]-1H-pyrazol-4-yl}-5-[({1-[2-fluoro-4-(trifluoromethyl)phenyl]cyclopropyl}carbonyl)amino]benzoic acid

[1021] 2-{1-[(2R)-But-2-yl]-1H-pyrazol-4-yl}-5-[({1-[2-fluoro-4-(trifluoromethoxy)phenyl]cyclopropyl}carbonyl)amino]benzoic acid

[1022] 2-{1-[(2S)-But-2-yl]-1H-pyrazol-4-yl}-3-fluoro-5-[({1-[2-fluoro-4-(trifluoromethyl)phenyl]cyclopropyl}carbonyl)amino]benzoic acid

[1023] 2-{1-[(2R)-But-2-yl]-1H-pyrazol-4-yl}-3-fluoro-5-[({1-[2-fluoro-4-(trifluoromethyl)phenyl]cyclopropyl}carbonyl)amino]benzoic acid

[1024] 2-(1-ethyl-1H-pyrazol-4-yl)-3-fluoro-5-[({1-[2-fluoro-4-(trifluoromethyl)phenyl]cyclopropyl}carbonyl)amino]benzoic acid

[1025] 2-(1-ethyl-1H-pyrazol-4-yl)-3-fluoro-5-[({1-[2-fluoro-4-(trifluoromethoxy)phenyl]cyclopropyl}carbonyl)amino]benzoic acid

[1026] 5-({[1-(4-chloro-2-fluorophenyl)cyclopropyl]carbonyl}amino)-3-fluoro-2-[1-(propan-2-yl)-1H-pyrazol-4-yl]benzoic acid

[1027] 5-({[1-(4-chloro-2-fluorophenyl)cyclopropyl]carbonyl}amino)-2-(2-cyclobutyl-1,3-thiazol-5-yl)benzoic acid

[1028] 2-(2-Cyclobutyl-1,3-thiazol-5-yl)-5-({[1-(2-fluoro-4-methylphenyl)cyclopropyl]carbonyl}amino)benzoic acid

[1029] 2-(2-Cyclobutyl-1,3-thiazol-5-yl)-5-[({1-[2-fluoro-4-(trifluoromethyl)phenyl]cyclopropyl}carbonyl)amino]benzoic acid

[1030] 2-(2-Cyclobutyl-1,3-thiazol-5-yl)-5-[({1-[2-fluoro-4-(trifluoromethoxy)phenyl]cyclopropyl}carbonyl)amino]benzoic acid

[1031] 5-[({1-[2-Fluoro-4-(trifluoromethyl)phenyl]cyclopropyl}carbonyl)amino]-2-{1-[(1-methylcyclopropyl)methyl]-1H-pyrazol-4-yl}benzoic acid

[1032] 5-[({1-[2-Fluoro-4-(trifluoromethoxy)phenyl]cyclopropyl}carbonyl)amino]-2-{1-[(1-methylcyclopropyl)methyl]-1H-pyrazol-4-yl}benzoic acid

[1033] 2-{1-[(1S)-1-cyclopropylethyl]-1H-pyrazol-4-yl}-5-[({1-[2-fluoro-4-(trifluoromethyl)phenyl]cyclopropyl}carbonyl)amino]benzoic acid

[1034] 2-(6-ethylpyridin-3-yl)-5-[({1-[2-fluoro-4-(trifluoromethyl)phenyl]cyclopropyl}carbonyl)amino]benzoic acid

[1035] 2-(6-ethylpyridin-3-yl)-5-[({1-[2-fluoro-4-(trifluoromethoxy)phenyl]cyclopropyl}carbonyl)amino]benzoic acid

[1036] 2-(6-ethylpyridin-3-yl)-3-fluoro-5-[({1-[2-fluoro-4-(trifluoromethyl)phenyl]cyclopropyl}carbonyl)amino]benzoic acid

[1037] 3-Fluoro-5-[({1-[2-fluoro-4-(trifluoromethoxy)phenyl]cyclopropyl}carbonyl)amino]-2-(1-methyl-1H-indazol-6-yl)benzoic acid

[1038] 2-(2-Cyclopentyl-1,3-thiazol-5-yl)-5-[({1-[2-fluoro-4-(trifluoromethyl)phenyl]cyclopropyl}carbonyl)amino]benzoic acid

[1039] 2-(2-Cyclobutyl-1,3-thiazol-5-yl)-3-fluoro-5-[({1-[2-fluoro-4-(trifluoromethyl)phenyl]cyclopropyl}carbonyl)amino]benzoic acid

[1040] 3-Fluoro-5-[({1-[2-fluoro-4-(trifluoromethyl)phenyl]cyclopropyl}carbonyl)amino]-2-[1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl]benzoic acid

[1041] or an isomer, enantiomer, diastereomer, tautomer, racemate, hydrate, solvate or salt thereof, or a mixture thereof.

[1042] It will be understood that the present invention also relates to any combination of the preferred embodiments described above.

[1043] As described above, the compounds of the present invention effectively inhibit bradykinin B1 receptors and are therefore useful in treating or preventing diseases associated with pain and inflammation.

[1044] Additionally, the compounds of the present invention reduce the release of inflammation-related cytokines such as IL-6 and IL-8.

[1045] Pharmaceutical compositions of the compounds of the present invention

[1046] The compounds according to the invention may have systemic and / or local activity. For this purpose, they can be used in a suitable manner, for example, by oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, vaginal, dermal, transdermal, conjunctival, ear canal route or as an implant or stent.

[1047] For these administration routes, the compounds according to the invention can be administered in suitable administration forms.

[1048] For oral administration, the compounds according to the present invention can be formulated into dosage forms known in the art for fast and / or improved delivery of the compounds of the present invention, such as tablets (uncoated or coated tablets, for example, with delayed dissolution or insoluble enteric or controlled release coatings), orally disintegrating tablets, films / thin sheets, films / lyophylisates, capsules (e.g., hard or soft gelatin capsules), sugar-coated tablets, granules, pellets, powders, emulsions, suspensions, aerosols or solutions. The compounds according to the present invention can be incorporated into the dosage forms in crystalline and / or amorphous and / or dissolved forms.

[1049] Parenteral administration can be effective by bypassing an absorption step (e.g., intravenously, intraarterially, intracardially, intraspinally or intralumbarly) or by including absorption (e.g., intramuscularly, subcutaneously, intradermally, percutaneously or intraperitoneally). Suitable administration forms for parenteral administration are, in particular, preparations for injection or infusion in the form of solutions, suspensions, emulsions, lyophilizates or sterile powders.

[1050] Examples of suitable pharmaceutical forms for other administration routes are pharmaceutical forms for inhalation [especially 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, eye inserts, ear drops, ear sprays, ear powders, ear washes, ear plugs; vaginal capsules, aqueous suspensions (emulsions, mixturae agitandae), lipophilic suspensions, emulsions, ointments, creams, transdermal therapeutic systems (e.g. patches), milks, pastes, foams, powders, implants or stents.

[1051] The compounds according to the invention can be incorporated into the administration forms described. This can be achieved in a manner known per se by mixing with pharmaceutically suitable excipients. Pharmaceutically suitable excipients include in particular

[1052] Fillers and carriers (e.g., cellulose, microcrystalline cellulose (e.g., ), lactose, mannitol, starch, calcium phosphate (such as, for example, Di- )),

[1053] ointment bases (e.g. petrolatum, paraffin, triglycerides, waxes, wool wax, wool alcohol, lanolin, hydrophilic ointments, polyethylene glycols),

[1054] Suppository base (e.g. polyethylene glycol, cocoa butter, hard fat),

[1055] Solvents (e.g. water, ethanol, isopropanol, glycerol, propylene glycol, medium-chain triglyceride fatty oils, liquid polyethylene glycol, paraffin),

[1056] Surfactants, emulsifiers, dispersants or wetting agents (e.g. sodium lauryl sulfate), lecithin, phospholipids, fatty alcohols (e.g. ), sorbitan fatty acid esters (such as, for example, ), polyoxyethylene sorbitan fatty acid esters (such as, for example, ), polyoxyethylene fatty acid glycerides (such as, for example, ), polyoxyethylene fatty acid esters, polyoxyethylene fatty alcohol ethers, glycerol fatty acid esters, poloxamers (such as, for example, ),

[1057] Buffers, acids and bases (e.g. phosphates, carbonates, citric acid, acetic acid, hydrochloric acid, sodium hydroxide solution, ammonium carbonate, tromethamine, triethanolamine),

[1058] Isotonic agents (e.g. glucose, sodium chloride),

[1059] Adsorbents (e.g. highly dispersed silica),

[1060] viscosity-increasing agents, gel-forming agents, thickeners and / or binders (e.g. polyvinylpyrrolidone, methylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, sodium carboxymethylcellulose, starch, carbomer, polyacrylic acid (e.g. ); alginate, gelatin),

[1061] Disintegrants (e.g. modified starch, sodium carboxymethylcellulose, sodium starch glycolate (e.g. ), cross-linked polyvinyl pyrrolidone, cross-linked sodium carboxymethyl cellulose (such as, for example, )),

[1062] Flow regulators, lubricants, glidants and mold release agents (e.g. magnesium stearate, stearic acid, talc, highly dispersed silicon dioxide (e.g. )),

[1063] Coating materials (e.g. sugar, shellac) and film formers for films that dissolve quickly or in an improved manner or for diffusion films (e.g. polyvinylpyrrolidone (e.g. ), polyvinyl alcohol, hydroxypropyl methylcellulose, hydroxypropyl cellulose, ethyl cellulose, hydroxypropyl methylcellulose phthalate, cellulose acetate, cellulose acetate phthalate, polyacrylates, polymethacrylates such as, for example, )),

[1064] Capsule materials (e.g. gelatin, hydroxypropyl methylcellulose),

[1065] Synthetic polymers (e.g., polylactide, polyglycolide, polyacrylate, polymethacrylate (e.g., ), polyvinylpyrrolidone (such as, for example, ), polyvinyl alcohol, polyvinyl acetate, polyethylene oxide, polyethylene glycol and copolymers and block copolymers thereof,

[1066] Plasticizers (e.g. polyethylene glycol, propylene glycol, glycerol, triacetin, triacetyl citrate, dibutyl phthalate),

[1067] Penetration enhancers,

[1068] Stabilizers (e.g. antioxidants such as ascorbic acid, ascorbyl palmitate, sodium ascorbate, butylated hydroxyanisole, butylated hydroxytoluene, propyl gallate),

[1069] Preservatives (e.g. parabens, sorbic acid, thimerosal, benzalkonium chloride, chlorhexidine acetate, sodium benzoate),

[1070] Colorants (e.g. inorganic pigments, such as iron oxide, titanium dioxide),

[1071] Flavorings, sweeteners, flavor- and / or odor-masking agents.

[1072] The invention furthermore relates to pharmaceutical compositions comprising at least one compound according to the invention, usually together with one or more pharmaceutically suitable excipients, and their use according to the invention.

[1073] Combination therapy

[1074] The term "combination" in the present invention is used in a manner known to those skilled in the art, and may exist as a fixed combination, a non-fixed combination or a kit-of-parts.

[1075] A "fixed combination" in the present invention is used in a manner known to those skilled in the art, and is defined as a combination in which the first active ingredient and the second active ingredient are present together in one unit dose or in a single entity. An example of a "fixed combination" is a pharmaceutical composition in which the first active ingredient and the second active ingredient are present in a mixture for simultaneous administration, such as in a formulation. Another example of a "fixed combination" is a pharmaceutical combination in which the first active ingredient and the second active ingredient are present in one unit, but not in the form of a mixture.

[1076] The non-fixed combination or "kit of parts" in the present invention is used in a manner known to those skilled in the art and is defined as a combination in which the first active ingredient and the second active ingredient are present in more than one unit. An example of a non-fixed combination or kit of parts is a combination in which the first active ingredient and the second active ingredient are present separately. The components of a non-fixed combination or kit of parts may be administered separately, sequentially, simultaneously, concurrently or chronologically staggered.

[1077] The compounds of the invention can be administered as a single agent or in combination with one or more other agents where the combination does not cause unacceptable adverse effects. The invention also relates to such combinations.

[1078] For example, the compounds of the invention may be combined with known hormonal therapeutic agents.

[1079] In particular, the compounds of the invention can be administered in combination with or as a co-administration with hormonal contraceptives. Hormonal contraceptives are, for example, combined oral contraceptives (COC) or progestogen-only pills (POP) or hormone-containing devices.

[1080] COCs include, but are not limited to, contraceptive pills or methods that include a combination of an estrogen (estradiol) and a progestin (progesterone). The estrogen portion is ethinyl estradiol in most COCs. Some COCs contain estradiol or estradiol valerate.

[1081] The COC contains the progestins norethindrone, norethindrone, norethindrone acetate, norethindrone acetate, norgestrel, levonorgestrel, norgestimate, desogestrel, gestodene, drospirenone, dienogest or nomegestrol acetate.

[1082] Contraceptive pills include, for example, but are not limited to, Yasmin and Yaz, both of which contain ethinyl estradiol and drospirenone; Microgynon or Miranova, which contain levonorgestrel and ethinyl estradiol; Marvelon, which contains ethinyl estradiol and desogestrel; Valette, which contains ethinyl estradiol and dienogest; Belara and Enriqa, which contain ethinyl estradiol and chlormadinol acetate; Qlaira, which contains estradiol valerate and dienogest as active ingredients; and Zoely, which contains estradiol and nomegestrol.

[1083] POPs are birth control pills that contain only synthetic progestogen (progesterone) and no estrogen. They are colloquially called mini-pills.

[1084] POPs include, but are not limited to, Cerazette, which contains desogestrel; and Micronor, which contains norethindrone.

[1085] Other progestin-only forms are intrauterine devices (IUDs) such as Mirena, which contains levonorgestrel, or injections such as Depo-Provera, which contains medroxyprogesterone acetate, or implants such as Implanon, which contains etonogestrel.

[1086] Other hormone-containing devices with contraceptive effects suitable for combination with the compounds of the present invention are vaginal rings such as Nuvaring, which contains ethinyl estradiol and etonogestrel, or transdermal systems such as contraceptive patches, for example Ortho-Evra, which contains ethinyl estradiol and methylprogesterone, or Apleek (Lisvy), which contains ethinyl estradiol and gestodene.

[1087] A preferred embodiment of the invention is the administration of a compound of general formula (I) in combination with a COC or POP or other pure progestin forms, as well as in combination with a vaginal ring or a contraceptive patch as described above.

[1088] Furthermore, the compounds of the present invention may be combined with therapeutic agents or active ingredients that are already approved or are still under development for the treatment and / or prevention of diseases associated with or mediated by the bradykinin B1 receptor.

[1089] For the treatment and / or prevention of urinary tract diseases, the compounds of the present invention may be administered in combination or as a combined drug with any substance which can be used as a therapeutic agent for the following indications:

[1090] Urinary tract disease states associated with bladder outlet obstruction; urinary incontinence conditions, such as reduced bladder capacity, increased urination frequency, urge incontinence, stress incontinence or overreactive bladder; benign prostatic hypertrophy; prostatic hyperplasia; prostatitis; detrusor hyperreflexia; overactive bladder and symptoms associated with overactive bladder, wherein the symptoms are particularly increased urinary frequency, nocturia, urgency or urge incontinence; pelvic hypersensitivity; urethritis; prostatitis; prostatodynia; cystitis, especially interstitial cystitis; painful bladder syndrome; idiopathic hypersensitive bladder.

[1091] For the treatment and / or prevention of overactive bladder and symptoms associated with overactive bladder, in addition to behavioral therapy such as diet, lifestyle or bladder training, the compounds of the present invention can be combined or administered as a co-medication with anticholinergics such as oxybutynin, tolterodine, propiverine, solifenacin, darifenacin, trospium, fesoterodine; beta-3 agonists such as mirabegron; neurotoxins such as onabutolinumtoxin A; or antidepressants such as imipramine, duloxetine.

[1092] For the treatment and / or prevention of interstitial cystitis and / or painful bladder syndrome, the compounds of the present invention may be administered in combination or as a co-medication with pentosans such as elmiron; antidepressants such as amitriptyline, imipramine; or antihistamines such as loratadine, in addition to behavioral therapy such as diet, lifestyle or bladder training.

[1093] For the treatment and / or prevention of gynecological diseases, the compounds of the present invention can be administered in combination or as a combined drug with any substance that can be used as a therapeutic agent for the following indications:

[1094] Dysmenorrhea, both primary and secondary; dyspareunia; endometriosis; endometriosis-related pain; endometriosis-related symptoms, such as, in particular, dysmenorrhea, dysuria or dysuria.

[1095] For the treatment and / or prevention of dysmenorrhea, including primary and secondary; dyspareunia; endometriosis and endometriosis-related pain, the compounds of the invention may be administered in combination with ovulation inhibition therapy, particularly a COC as described above or a contraceptive patch such as Ortho-Evra or Apleek (Lisvy); or with a progestin such as dienogest (Visanne); or with a GnRH analog, particularly a GnRH agonist and antagonist, for example leuprolide, nafarelin, goserelin, cetrorelix, abarelix, ganirelix, degarelix; or with the androgen: danazol.

[1096] For the treatment and / or prevention of diseases associated with pain or pain syndromes, the compounds of the present invention may be administered in combination or as a combined drug with any substance that can be used as a therapeutic agent for the following indications:

[1097] Pain-related diseases or conditions such as 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 headaches, nerve injury, traumatic nerve injury, post-traumatic injury (including fractures and sports injuries), neuritis, neuralgia, poisoning, ischemic injury, interstitial cystitis, painful bladder syndrome, viral, trigeminal neuralgia, small fiber neuropathy, diabetic neuropathy, chronic arthritis and related neuralgia, HIV and HIV treatment-induced neuropathy.

[1098] The compounds of the invention may be combined with other pharmacological agents and compounds intended for the treatment of inflammatory diseases, inflammatory pain, or general pain conditions.

[1099] In addition to known drugs that have been approved and marketed, the compound of the present invention can be administered in combination with an inhibitor of the P2X purine receptor family (P2X3, P2X4), an IRAK4 inhibitor, and a prostanoid EP4 receptor antagonist.

[1100] In particular, the compounds of the invention can be administered in combination with pharmacological endometriosis drugs aimed at treating inflammatory diseases, inflammatory pain or general pain conditions and / or interfering with endometriotic hyperplasia and endometriosis-related symptoms, i.e. with inhibitors of aldo-keto-reductase 1C3 (AKR1C3) and with functional blocking antibodies of the prolactin receptor.

[1101] The compounds of the present invention may be combined with other pharmacological agents and compounds intended to treat, prevent or control cancer.

[1102] In particular, the compounds of the present invention can be combined with the following substances: 131I-chTNT, abarelix, abiraterone, aclarubicin, ado-trastuzumab emtansine), afatinib, aflibercept, aldesleukin, alemtuzumab, alendronic acid, alitretinoin, hexamethylenetetramine, amifostine, aminoglutethimide, aminolevulinate hexyl, amrubicin, amsacrine, anastrozole, ancilastin, anethiol, angiotensin II, antithrombin III, aprepitant, acitumomab, arglabin, arsenic trioxide, asparaginase, axitinib, azacitidine, basiliximab, belotecan, bendamustine, belinostat, bevacizumab, bexarotene, bicalutamide, bisantrene, bleomycin, bortezomib, buserelin, bosutinib, brentuximab vedotin, busulfan, cabazitaxel, cabozantinib, leucovorin, leucovorin, capecitabine, capromab, carboplatin, carfilzomib, carmofur, carmustine, catumaxomab, celecoxib, cimoleukin, ceritinib, cetuximab, chlorambucil, chlormadinone, nitrogen mustard, cidofovir, cinacalcet, cisplatin, cladribine, clodronic acid, clofarabine, copanlisib, crisantaspase, cyclophosphamide, cyproterone acetate, cytarabine, dacarbazine, actinomycin D, darbepoetin alfa, dabrafenib, dasatinib, daunorubicin, decitabine, degarelix, denileukin diftitox), denosumab, depo-opeptide, deslorelin, dexrazoxane, dibromospironium chloride, didehydrodulcitol, diclofenac, docetaxel, dolasetron, doxifluridine, doxorubicin, doxorubicin + estrone, dronabinol, eculizumab, edrecolomab, eltrimonium acetate, eltrombopag, endostatin, enocitabine, enzalutamide, epirubicin, cyclosulfide androstol, epoetin alpha, epoetin beta, epoetin zeta, epoetin platinum, eribulin, erlotinib, esomeprazole, estradiol, estramustine, etoposide, everolimus, exemestane, fadrozole, fentanyl, filgrastim, fluoxymesterone, floxuridine, fludarabine, fluorouracil, flutamide, folinic acid, formestane, fosaprepitant, fomastine, fulvestrant, gadobutrol, gadoteridol, gadoteric acid meglumine, gadoversetamide, gadoxetic acid, gallium nitrate, ganirelix,Gefitinib, gemcitabine, gemtuzumab, carboxypeptidase, oxidized glutathione (glutoxim), GM-CSF, goserelin, granisetron, granulocyte colony-stimulating factor, histamine dihydrochloride, histrelin, hydroxyurea, I-125 particles, lansoprazole, ibandronate, ibritumomab tiuxetan tiuxetan), ibrutinib, idarubicin, ifosfamide, imatinib, imiquimod, improsulfan, indesitron, incadronic acid, ingenol methylbutyrate, interferon α, interferon β, interferon γ, iobitrol, iodobenzylguanidine (123I), iomeprol, ipilimumab, irinotecan, itraconazole, ixabepilone, lanreotide, lapatinib, lasocholine, lenalidomide, levofloxacin, mushrooms polysaccharide, letrozole, leuprorelin, levamisole, levonorgestrel, levothyroxine sodium, lisuride, loplatin, cyclohexyl lomustine, lonidamine, masoprofen, medroxyprogesterone, megestrol, melarsoprol, melphalan, melastrane, mercaptopurine, mesna, methadone, methotrexate, methoxsalen, methylaminolevulinate, methylprednisolone, methyltestosterone, methyltyrosine, mifamurtide, miltefosine, miriplatin, dibromomannitol, propionamide, dibromodulanol, mitomycin, mitotane, mitoxantrone, mogamulizumab, morasporastin , mopiridol, morphine hydrochloride, morphine sulfate, nabilone, nabiximols, nafarelin, naloxone + pentozosin, naltrexone, narostim, nedaplatin, nelarabine, neridronic acid, nivolumabpentetreotide, nilotinib, nilutamide, nimozole, nimotuzumab, pyrimidine nitrosourea, diamine nitrazolium, nitraerine, nivolumab, obinutuzumab, octreotide, ofatumumab b), homoharringtonine, omeprazole, ondansetron, oprelvekin, oguptin, orilotimod, oxaliplatin, oxycodone, oxymetholone, ozogamicine, p53 gene therapy, paclitaxel, palifermin, palladium-103 particles, palonosetron, pamidronate, panitumumab, pantoprazole, pazopanib, pegaspase, PEG-beta-epoetin (methoxy PEG-beta-epoetin), pembrolizumab, pegfilgrastim,Peginterferon alpha-2b, pemetrezole, analgesic, pentostatin, pelocybin, perfluorobutane, perfosfamide, pertuzumab, picibanil, pilocarpine, pirarubicin, pixanol, plerixafor, plicamycin, poliglusam, polyestradiol phosphate, polyvinylpyrrolidone + sodium hyaluronate, polysaccharide-K, pomalidomide, ponatinib, porfimer sodium, pralatrexate, phenylephrine, prednisone, procarbazine, procodazole, propranolol, quinagolide, rabeprazole, racotumomab, radium 22 chloride 3. Radotinib, raltitrexed, ramucitron, ramucirumab, ranimustine, rasburicase, aprotinib, refametinib, regorafenib, risedronic acid, rhenium-186 etidronate, rituximab, romidepsin, romiplostim, romotide, roniciclib, samarium 153Sm, samotron, satumomab, secretin, sipuleucel-T, sizoran, sobuzosane, sodium glycidazole glycididazole), sorafenib, stanozolol, streptozotocin, sunitinib, talaporfin, tamibarotene, tamoxifen, tapentadol, tasonermin, teceleukin, technetium [99mTc] thionomolgus, 99mTc-HYNIC-[Tyr3]-octreotide, tegafur, tegafur + gimeracil + oteracil, temoporphine, temozolomide, temsirolimus, teniposide, testosterone, tetrofosmi n), thalidomide, thiotepa, thymalfasin, thyrotropin alfa, tioguanine, tocilizumab, topotecan, toremifene, tositumomab, trabectedin, tramadol, trastuzumab, trastuzumab-emtansine conjugate, treosulfan, retinoic acid, trifluridine + tipiracil, trilostane, triptorelin, trametinib, trofosfamide, thrombopoietin, tryptophan, ubenimex, vatalanib, valrubicin, vandetanib, vapreotide,Vemurafenib, vinblastine, vincristine, vindesine, vinflunine, vinorelbine, vismodegib, vorinostat, vorozole, yttrium-90 glass microspheres, neocarcinomatidylserine, statins, zoledronic acid, or daunorubicin.

[1103] Furthermore, the compounds of the present invention may be combined with active ingredients that are well known for the treatment of cancer-related pain and chronic pain. These combinations include, but are not limited to, Step II opioids such as codeine phosphate, dextropropoxyphene, dihydrocodeine, tramadol; Step III opioids such as morphine, fentanyl, buprenorphine, oxymorphone, oxycodone, and hydromorphone; and other drugs used to treat cancer pain, such as steroids such as dexamethasone and methylprednisolone; bisphosphonates such as etidronate, clodronate, alendronate, risedronate, and zoledronate; tricyclic antidepressants such as amitriptyline, clomipramine, desipramine, imipramine, and doxepin; Class I antiarrhythmics such as mexiletine and lidocaine; and anticonvulsants such as carbamazepine, gabapentin, oxcarbazepine, phenytoin, pregabalin, topiramate, alprazolam, diazepam, flurazepam, pentobarbital, and phenobarbital.

[1104] In addition to those described above, the bradykinin B1 inhibitor of the present invention may also be combined with any of the following active ingredients:

[1105] Active ingredients for the treatment of Alzheimer's disease, such as 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) for the treatment of Parkinson's disease, COMT (catechol-O-methyltransferase) inhibitors (e.g. entacapone), dopamine agonists (e.g. ropivacaine, pramipexole, bromocriptine), MAO-B (monoamino oxidase-B) inhibitors (e.g. selegiline), anticholinergics (e.g. trihexyphenidyl), and NMDA antagonists (e.g. amantadine); beta-interferons (IFN-β) for the treatment of multiple sclerosis (e.g. IFNβ-1b, IFNβ-1a and ), glatiramer acetate, immunoglobulins, natalizumab, fingolimod and immunosuppressants such as mitoxantrone, azathioprine and cyclophosphamide; substances for the treatment of pulmonary disorders, such as beta-2-sympathomimetics (such as salbutamol), anticholinergics (such as glycopyrronium), methylxanthines (such as theophylline), leukotriene receptor antagonists (such as montelukast), PDE-4 (phosphodiesterase type 4) inhibitors (such as roflumilast), methotrexate, IgE antibodies, azathioprine and cyclophosphamide, preparations containing cortisol; substances for the treatment of osteoarthritis, such as nonsteroidal anti-inflammatory substances (NSAIDs). In addition to the two therapies mentioned, methotrexate and biologics for B-cell and T-cell therapy (such as rituximab, abatacept) should be mentioned for rheumatoid disorders, such as rheumatoid arthritis and juvenile idiopathic arthritis. Neurotrophic substances, such as acetylcholinesterase inhibitors (such as donepezil), MAO (monoamino oxidase) inhibitors (such as selegiline), interferons and anticonvulsants (such as gabapentin); Active ingredients for the treatment of cardiovascular disorders, such as beta-blockers (such as metoprolol), ACE inhibitors (such as benazepril), diuretics (such as hydrochlorothiazide), calcium channel blockers (such as nifedipine), statins (such as simvastatin); Antidiabetic drugs such as metformin and glibenclamide, sulfonylureas (such as tolbutamide) and insulin therapy for the treatment of diabetes and metabolic syndrome. Active ingredients for the treatment of chronic inflammatory bowel disease such as mesalamine, sulfasalazine, azathioprine, 6-mercaptopurine or methotrexate, probiotics (Mutaflor, VSL# , Lactobacillus GG, Lactobacillus plantarum, Lactobacillus acidophilus, Lactobacillus casei, Bifidobacterium infantis 35624, Enterococcus SF68, Bifidobacterium longum, Escherichia coli Nissle 1917), antibiotics such as ciprofloxacin and metronidazole, antidiarrheal drugs such as loperamide, or laxatives (bisacodyl). Immunosuppressants such as glucocorticoids and nonsteroidal anti-inflammatory substances (NSAIDs) used to treat lupus erythematosus, cortisone, chloroquine, cyclosporine, azathioprine, belimumab, rituximab, cyclophosphamide. For example, but not exclusively, calcineurin inhibitors for organ transplantation (such as tacrolimus and cyclosporine), cell division inhibitors (such as azathioprine, mycophenolate mofetil, mycophenolic acid, everolimus or sirolimus), rapamycin, basiliximab, daclizumab, anti-CD3 antibodies, anti-T-lymphocyte globulin / antilymphocyte globulin, vitamin D3 analogs for skin diseases, such as calcipotriol, tacalcitol or calcitriol, salicylic acid, urea, cyclosporine, methotrexate or efalizumab.

[1106] Treatment

[1107] The present invention relates to methods of inhibiting bradykinin B1 receptors using the compounds of the present invention and compositions thereof.

[1108] The present invention relates to methods of using the compounds of the present invention and compositions thereof to treat mammalian conditions and diseases, including but not limited to:

[1109] Diseases associated with pain and inflammation, particularly those selected from the following

[1110] Visceral pain, such as that associated with pancreatitis, interstitial cystitis, painful bladder syndrome, renal colic or prostatitis, chronic pelvic pain or pain associated with infiltrative endometriosis;

[1111] Neuropathic pain, such as postherpetic neuralgia, acute herpes zoster pain, pain associated with nerve damage, including vulvar pain, phantom limb pain, pain associated with root avulsion, pain associated with radiculopathy, painful traumatic mononeuropathy, painful entrapment neuropathy, pain associated with carpal tunnel syndrome, ulnar neuropathy, pain associated with tarsal tunnel syndrome, painful diabetic neuropathy, painful polyneuropathy, trigeminal neuralgia, or pain associated with familial amyloid polyneuropathy;

[1112] Central pain syndromes that may arise from virtually any pathology at any level of the nervous system, including but not limited to pain associated with stroke, multiple sclerosis, and spinal cord injury; and

[1113] Postoperative pain syndrome (including post-mastectomy pain syndrome, post-thoracotomy pain syndrome, stump pain), bone and joint pain (osteoarthritis), spinal pain (including acute and chronic low back pain, neck pain, pain associated with spinal stenosis), shoulder pain, repetitive motion pain, dental pain, pain associated with sore throat, cancer pain, burn pain including sunburn, myofascial pain (pain associated with muscle injury, fibromyalgia), postoperative and perioperative pain (including but not limited to general surgery, orthopedic surgery, and gynecological surgery); and

[1114] Acute and chronic pain, chronic pelvic pain, pain associated with endometriosis, pain associated with dysmenorrhea (primary and secondary), pain associated with uterine fibroids, pain associated with vulvodynia, and pain associated with angina pectoris, or inflammatory pain of various origins (including but not limited to pain associated with osteoarthritis, rheumatoid arthritis, rheumatic diseases, tenosynovitis, gout, ankylosing spondylitis, and bursitis);

[1115] and a disease, such as or associated with a disease selected from:

[1116] Gynecological conditions and / or diseases, or effects and / or symptoms that negatively impact women’s health, including endometriosis, uterine fibroids, pre-eclampsia, hormone deficiencies, uterine cramping or heavy menstrual bleeding;

[1117] Respiratory or excretory system, including any inflammatory hyper-responsive airways, inflammatory events associated with airway diseases such as chronic obstructive pulmonary disease, asthma, including allergic asthma (atopic or non-atopic) and exercise-induced bronchoconstriction, occupational asthma, viral or bacterial exacerbations of asthma, other non-allergic asthma and infantile wheezing syndrome, chronic obstructive pulmonary disease, including emphysema, adult respiratory distress syndrome, bronchitis, pneumonia, cough, lung injury, pulmonary fibrosis, allergic rhinitis (seasonal and perennial), vasomotor rhinitis, angioedema (including hereditary angioedema and drug-induced angioedema, including angioedema caused by angiotensin-converting enzyme (ACE) or ACE / neutral endopeptidase inhibitors such as omapatrilat), pneumoconiosis, including aluminum pneumoconiosis, ankylosing pulmonary disease, asbestosis, lithiasis, ostrich pneumoconiosis, siderosis, silicosis, fumigation, and byssinosis, intestinal diseases including Crohn's disease and ulcerative colitis, irritable bowel syndrome, pancreatitis, nephritis, cystitis (interstitial cystitis), painful bladder syndrome, renal fibrosis, renal failure, overactive bladder and overactive bladder syndrome;

[1118] Skin conditions, including pruritic, itchy, inflammatory skin conditions, including psoriasis, eczema, and atopic dermatitis;

[1119] Joint or bone diseases, including rheumatoid arthritis, gout, osteoporosis, osteoarthritis and ankylosing spondylitis;

[1120] Disorders of the central and peripheral nervous systems, including neurodegenerative diseases including Parkinson's and Alzheimer's diseases, amyotrophic lateral sclerosis (ALS), epilepsy, dementia, headache including cluster headache, migraine including both prophylactic and acute use, stroke, closed head trauma and multiple sclerosis;

[1121] Infections, including HIV infection and tuberculosis;

[1122] Trauma associated with: edema including cerebral edema, burns, sunburn and sprains or fractures;

[1123] Poisoning, including aluminum pneumoconiosis, carbon monoxide pneumonia, asbestosis, lithiasis, ostrich pneumoconiosis, siderosis, silicosis, fumigation and byssinusitis;

[1124] Diabetes cluster or metabolism such as type 1 diabetes, type 2 diabetes, diabetic angiopathy, diabetic neuropathy, diabetic retinopathy, post-capillary resistance or diabetic symptoms associated with insulitis (such as hyperglycemia, diuresis, proteinuria and increased urinary excretion of nitrite and kallikrein), diabetic macular edema, metabolic syndrome, insulin resistance, obesity, fat or muscle metabolism;

[1125] Cachexia associated with or caused by any of the following: cancer, AIDS, celiac disease, chronic obstructive pulmonary disease, multiple sclerosis, rheumatoid arthritis, congestive heart failure, tuberculosis, familial amyloid polyneuropathy, mercury poisoning (acral pain), and hormone deficiencies;

[1126] Cardiovascular system including congestive heart failure, atherosclerosis, congestive heart failure, myocardial infarction and cardiac fibrosis; and

[1127] Other conditions, including primary peritonitis, secondary peritonitis, septic shock, sepsis, muscular dystrophy, gastrointestinal spasm, benign prostatic hyperplasia, and liver disease, such as nonalcoholic and alcoholic fatty liver disease, nonalcoholic and alcoholic steatohepatitis, liver fibrosis, or cirrhosis.

[1128] A preferred embodiment of the present invention relates to a method for treating gynecological diseases, preferably dysmenorrhea, dyspareunia or endometriosis, endometriosis-related pain or other endometriosis-related symptoms using the compounds of the present invention and their compositions, wherein the symptoms include dysmenorrhea, dyspareunia, dysuria or dysdefecation. In addition, the present invention relates to a method for treating osteoarthritis, rheumatoid arthritis, gout, neuropathic pain, asthma, cough, lung injury, pulmonary fibrosis, pneumonia, renal fibrosis, renal failure, pruritus, irritable bowel disease, overactive bladder, type 1 diabetes, type 2 diabetes, diabetic neuropathy, diabetic retinopathy, diabetic macular edema, metabolic syndrome, obesity, cardiac fibrosis, cachexia, muscular atrophy, Alzheimer's disease, bladder pain syndrome and interstitial cystitis using the compounds of the present invention and their compositions.

[1129] These disorders have been well characterized in humans, but also exist in other mammals with similar etiology, and can be treated by administering the pharmaceutical compositions of the present invention.

[1130] The terms "treating" or "treatment" described throughout this document are used in a conventional manner, such as to manage or care for a subject with the purpose of resisting, alleviating, reducing, relieving, improving the condition of a disease or disorder, such as a gynecological disease, etc.

[1131] Dosage and Administration

[1132] Based on standard laboratory techniques known to evaluate compounds useful for treating disorders and / or diseases mediated by bradykinin B1 receptors, by standard toxicity tests and by standard pharmacological assays (for determining treatment of the conditions in mammals indicated above), and by comparing these results with those of known drugs for treating these conditions, effective doses of the compounds of the invention can be readily determined for the treatment of each desired indication. The amount of active ingredient to be administered in the treatment of one of these conditions can vary widely depending on considerations such as the specific compound and dosage unit used, the mode of administration, the course of treatment, the age and sex of the patient being treated, and the nature and extent of the condition being treated.

[1133] The total amount of active ingredient to be administered is generally about 0.001 mg / kg to about 200 mg / kg body weight / day, preferably about 0.01 mg / kg to about 20 mg / kg body weight / day. The administration of the preferred compounds of the present invention includes but is not limited to 0.1 mg / kg to about 10 mg / kg body weight / day. A clinically useful dosing regimen is administration once to three times a day to once every four weeks. In addition, a "drug-free period" in which the patient's drug is not given for a period of time may be advantageous for the overall balance between pharmacological effects and tolerance. The unit dose may contain about 0.5 mg to about 1500 mg of active ingredient and may be administered once or more daily, or less than once a day. The preferred oral unit dose for administering 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. For administration by injection (including intravenous, intramuscular, subcutaneous and parenteral injections) and using infusion techniques, the average daily dose is preferably 0.01 to 200 mg / kg total body weight. The average daily rectal dosage regimen is preferably 0.01 to 200 mg / kg total body weight. The average daily vaginal dosage regimen is preferably 0.01 to 200 mg / kg total body weight. The average daily topical dosage regimen is preferably 0.1 to 200 mg applied once to four times daily. The transdermal concentration is preferably the concentration required to maintain a daily dose of 0.01 to 200 mg / kg total body weight. The average daily inhalation dosage regimen is preferably 0.01 to 100 mg / kg total body weight.

[1134] Of course, for each patient, the specific initial and continued dosing regimen will vary depending on the nature and severity of the condition as determined by the attending diagnostician, the activity of the specific compound used, the age and general condition of the patient, the time of administration, the route of administration, the rate of excretion of the drug, drug combination, etc. The desired treatment mode and dosage of the compound of the present invention or its pharmaceutically acceptable salt or ester or composition can be determined by those skilled in the art using routine therapeutic tests.

[1135] Preferably, the disease treated by the method is a gynecological disorder, more preferably dysmenorrhea, dyspareunia or endometriosis, endometriosis-related pain or other endometriosis-related symptoms, wherein the symptoms include dysmenorrhea, dyspareunia, dysuria or dysfecation. Other diseases that can be treated by the method are osteoarthritis, rheumatoid arthritis, gout, neuropathic pain, asthma, cough, lung injury, pulmonary fibrosis, pneumonia, renal fibrosis, renal failure, pruritus, irritable bowel disease, overactive bladder, type 1 diabetes, type 2 diabetes, diabetic neuropathy, diabetic retinopathy, diabetic macular edema, metabolic syndrome, obesity, cardiac fibrosis, cachexia, muscular atrophy, Alzheimer's disease, bladder pain syndrome and interstitial cystitis.

[1136] Preferably, the method for treating the above-mentioned diseases is not limited to treating the diseases, but also includes treating pain associated with or related to the diseases.

[1137] The compounds of the invention are particularly useful for the treatment and prophylaxis, ie prevention, of genitourinary, gastrointestinal, respiratory or pain-related diseases, conditions or disorders.

[1138] Testing methods for specific pharmacological or pharmaceutical properties are well known to those skilled in the art.

[1139] The example test experiments described herein are intended to illustrate the invention, and the invention is not limited to the examples given.

[1140] Synthesis of the compound of general formula (I) of the present invention

[1141] Having R as defined in the general formula (I) 1 , R 2 , R 3 , R 5 , R 6 and R 7 Compounds of general formula (I) having the meaning of can be synthesized according to various general procedures.

[1142] Scheme 1 describes the synthesis starting from a synthon of formula (II), wherein Hal represents Cl, Br or I, preferably Br; and wherein ALK represents C 1 -C 5-alkyl, preferably methyl, ethyl and propyl. Aryl halides of general formula (II) can be cross-coupled with boronic acids of general formula (III), or with their respective pinacol esters, to obtain compounds of general formula (IV) by Pd-mediated reactions (Suzuki coupling) known to those skilled in the art. A suitable solvent (e.g., N,N-dimethylformamide, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane and optionally water) is used, and a base (e.g., triethylamine, potassium carbonate, cesium carbonate) and a catalyst ligand mixture (e.g., palladium acetate (II) / triphenylphosphine, tetrakis (triphenylphosphine) palladium (0), bis (triphenylphosphine) dichloropalladium (II), bis (diphenylphosphino) ferrocene dichloropalladium (II)) is used at a temperature of 20°C-120°C, preferably at 100°C.

[1143] Aromatic amines of general formula (IV) can be reacted with carboxylic acids of general formula (V) by methods known to those skilled in the art to give amide compounds of general formula (VI). The reaction is mediated by activating the carboxylic acid of general formula (V) with a reagent 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)methylene]-N-methylmethanaminium hexafluorophosphate (HATU) or propylphosphonic anhydride (T3P). For example, the reaction with HATU is carried out in an inert solvent such as N,N-dimethylformamide, dichloromethane or dimethyl sulfoxide in the presence of an appropriate aniline of general formula (IV) and a tertiary amine (e.g. triethylamine or diisopropylethylamine) at a temperature of -30°C to +60°C.

[1144] The carboxylic acid of general formula (V) can also be converted into the corresponding carboxylic acid chloride using an inorganic acid chloride (e.g., phosphorus pentachloride, phosphorus trichloride or thionyl chloride), and then converted into the amide compound of general formula (VI) in pyridine or a solvent (e.g., dichloromethane or N,N-dimethylformamide) in the presence of an appropriate amine of formula (IV) and a tertiary amine (e.g., triethylamine) at a temperature of -30°C to +60°C. The ester portion of the compound of general formula (VI) is then converted into the final target compound of general formula (I) by ester saponification using an appropriate base (e.g., aqueous lithium hydroxide or aqueous sodium hydroxide) in a solvent (e.g., tetrahydrofuran, methanol or N,N-dimethylformamide) at a temperature of 0°C to +80°C. Alternatively, the ester compound of general formula (VI) can be converted into the final target compound of general formula (I) by ester saponification using an appropriate inorganic acid (e.g., hydrochloric acid or sulfuric acid) at 0°C to 80°C (usually at about +60°C).

[1145] Aryl halides of general formula (II) are commercially available or can be synthesized by those skilled in the art from the corresponding carboxylic acid compounds, for example, by reacting the corresponding carboxylic acid with an alcohol (e.g., methanol, ethanol or propanol) in a mineral acid (e.g., hydrochloric acid or sulfuric acid) at a temperature of 0°C to 100°C.

[1146] The raw materials of general formula (II) can be commercially available, or can be synthesized from suitable precursors by methods known to those skilled in the art. For example, the amino group can be obtained by reducing the corresponding nitro group with hydrogen in a solvent such as ethanol, ethyl acetate or a mixture thereof in the presence of a palladium catalyst. Alternatively, the nitro group can be reduced using iron powder in a solvent such as methanol or ethanol in the presence of an acid (e.g., hydrochloric acid or acetic acid). The nitro group can be introduced by classical methods, for example, treated with nitric acid / sulfuric acid or potassium nitrate / sulfuric acid (with appropriate concentration and volume ratio) at a temperature of 0°C to 25°C. The order of the reaction steps (nitro reduction, Suzuki reaction, amide formation, nitrile hydrolysis) can be appropriately changed.

[1147] Carboxylic acids of general formula (V) are commercially available or can be synthesized from appropriate precursors by methods known to those skilled in the art. For example, arylcyclopropanecarboxylic acids can be prepared from the corresponding arylacetonitrile by cyclopropanation with 1-bromo-2-chloroethane (1.5 equivalents) in aqueous base (e.g. sodium hydroxide solution) in the presence of benzyltriethylammonium chloride (0.02 equivalents) and subsequent acidic or basic hydrolysis of the nitrile with, e.g., lithium hydroxide in water or concentrated hydrochloric acid at a temperature of 20° C. to 100° C.

[1148] Solution 1

[1149]

[1150] Scheme 2 describes the synthesis starting from synthons of formula (VII), wherein Hal represents Cl, Br or I, preferably Br. Aryl halides of general formula (VII) can be cross-coupled with boronic acids of general formula (III) or with their respective pinacol esters to give compounds of general formula (VIII) by Pd-mediated reactions (Suzuki coupling) known to those skilled in the art. A suitable solvent (e.g. N,N-dimethylformamide, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane and optionally water) is used and a base (e.g. potassium carbonate or cesium carbonate) and a catalyst-ligand mixture (e.g. palladium(II) acetate / triphenylphosphine, tetrakis(triphenylphosphine)palladium(0), bis(triphenylphosphine)-dichloropalladium(II), bis(diphenylphosphino)ferrocenedichloropalladium(II)) is used at a temperature of 20°C to 120°C, preferably at 100°C. The nitro group of the compound of general formula (VIII) is then reduced to the corresponding aniline of general formula (IX) by reaction in a suitable solvent (e.g. ethanol or ethyl acetate) at a temperature of 0°C to 100°C under a hydrogen atmosphere in the presence of a palladium catalyst (e.g. 5-10% palladium / carbon). Amide coupling gives compounds of general formula (X) in analogy to the procedure described for Scheme 1. The nitrile moiety of formula (X) is hydrolyzed to the carboxylic acid of general formula (I) by reaction with an inorganic base (e.g. aqueous lithium hydroxide or aqueous sodium hydroxide) or an inorganic acid (e.g. hydrochloric acid or sulfuric acid), optionally in an inert solvent (e.g. tetrahydrofuran, 1,4-dioxane or N,N-dimethylformamide) at a temperature of 10°C to 100°C.

[1151] Solution 2

[1152]

[1153] Scheme 3 shows an alternative process in which the order of the reaction steps is changed and the nitrile part of general formula (IX) is converted in two steps to an ester group (wherein ALK represents methyl, ethyl or propyl) and subsequently displayed as a carboxylic acid group. Starting from the synthon of general formula (IX), the nitrile is first converted to a carboxylic acid of general formula (XI) and then reacted with a suitable alcohol (e.g. methanol, ethanol or propanol) in a mineral acid (e.g. hydrochloric acid or sulfuric acid) at a temperature of 0°C to 100°C to form an ester compound of general formula (IV). Similar to the procedure described for Scheme 1, amide coupling gives compounds of general formula (VI) and then ester saponification gives the target compound of general formula (I).

[1154] Solution 3

[1155]

[1156] Scheme 4 shows an alternative method for synthesizing compounds of general formula (I) wherein R 1is an N-linked optionally substituted 5-membered heteroaryl, such as pyrazolyl or imidazolyl, or R 1 is an N-linked optionally substituted bicyclic 8 to 10 membered heteroaryl, such as indole. Starting from synthons of general formula (VII) (wherein Hal represents F, Cl or Br), the aryl halide can first be substituted by a nucleophile of general formula (XIV) to give compounds of general formula (VIII). The substitution is carried out in a dipolar aprotic solvent such as acetonitrile, dimethyl sulfoxide or N,N-dimethylformamide in the presence of a suitable base (such as potassium carbonate or sodium hydride) at a temperature of 20°C to 100°C, preferably at 60°C. Similar to the procedure described for Scheme 2, reduction of the nitro group followed by amide formation gives compounds of general formula (X), which are subsequently converted to the final target of general formula (I) by hydrolysis of the nitrile group.

[1157] Solution 4

[1158]

[1159] In Scheme 4, the general formula (XIV) represents R 1 -H, where R 1 is an optionally substituted 5-membered heteroaryl group attached to a hydrogen atom via a ring nitrogen atom, or R 1 is an optionally substituted bicyclic 8- to 10-membered heteroaryl group linked to a hydrogen atom via a ring nitrogen atom.

[1160] Scheme 5 shows an alternative method for synthesizing compounds of general formula (I) wherein R 1 is an N-linked optionally substituted 5-membered heteroaryl, such as pyrazolyl or imidazolyl, or R 1 is an N-linked optionally substituted bicyclic 8 to 10 membered heteroaryl, such as indole. Starting from a synthon of general formula (XII) (wherein Hal represents F, Cl or Br; and wherein ALK represents methyl, ethyl or propyl), the aryl halide can first be substituted by a nucleophile of general formula (XIV) to give a compound of general formula (XIII). The substitution is carried out in a dipolar aprotic solvent such as acetonitrile, dimethyl sulfoxide or N,N-dimethylformamide in the presence of a suitable base (such as potassium carbonate or sodium hydride) at a temperature of 20°C to 100°C, preferably at 60°C. Similar to the procedure described for Scheme 2, nitro reduction gives a compound of general formula (IV), followed by amide coupling to give a compound of general formula (VI), followed by ester saponification to give the target compound of general formula (I).

[1161] Solution 5

[1162]

[1163] In Scheme 5, the general formula (XIV) represents R 1 -H, where R 1is an optionally substituted 5-membered heteroaryl group attached to a hydrogen atom via a ring nitrogen atom, or R 1 is an optionally substituted bicyclic 8- to 10-membered heteroaryl group linked to a hydrogen atom via a ring nitrogen atom.

[1164] Scheme 6 describes the synthesis starting from synthons of formula (XV), wherein Hal represents Br or I, preferably Br. Aryl halides of general formula (XV) can be cross-coupled with boronic acids of general formula (III), or with their respective pinacol esters, to give compounds of general formula (XVI) by Pd-mediated reactions (Suzuki coupling) known to those skilled in the art. A suitable solvent (e.g. N,N-dimethylformamide, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane and optionally water) is used, and a base (e.g. triethylamine, potassium carbonate, cesium carbonate) and a catalyst-ligand mixture (e.g. palladium(II) acetate / triphenylphosphine, tetrakis(triphenylphosphine)palladium(0), bis(triphenylphosphine)-dichloropalladium(II), bis(diphenylphosphino)ferrocenedichloropalladium(II)) is used at a temperature of 20°C to 120°C, preferably at 100°C. The chloro group of the compound of general formula (XVI) is converted to the nitrile group by a Pd-mediated cyanation reaction with potassium ferrocyanide known to those skilled in the art to give the compound of general formula (IX). Using a suitable solvent mixture (e.g. 1,4-dioxane or tetrahydrofuran and optionally water), and using a base (e.g. potassium acetate) and a catalyst-ligand mixture (e.g. tris[dibenzylideneacetone]dipalladium / dicyclohexyl[2',4',6'-tri(propan-2-yl)biphenyl-2-yl]phosphine) at a temperature of 20°C to 120°C, typically 100°C. Analogously to the procedure described for Scheme 3, the nitrile part of general formula (IX) is converted to a carboxylic acid of general formula (XI) and then reacted with a suitable alcohol (e.g. methanol, ethanol or propanol; wherein ALK represents methyl, ethyl or propyl) at a temperature of 0°C to 100°C in an inorganic acid (e.g. hydrochloric acid or sulfuric acid) to form an ester compound of general formula (IV). Similar to the procedure described for Scheme 1, amide coupling gives compounds of formula (VI), which are then subjected to ester saponification to give the target compounds of formula (I). The order of the reaction steps (nitrile hydrolysis, amide formation) can be varied appropriately. Similar to Scheme 2, the final compounds of formula (I) can be obtained directly by hydrolysis of the nitrile group as the final transformation.

[1165] Solution 6

[1166]

[1167] Scheme 7 shows an alternative method for synthesizing compounds of general formula (I) wherein R 1 , R 2 , X and R 3The meaning is as defined in the general formula (I). The aryl group of the general formula (XVII) can be nitrated by reaction with a mixture of nitric acid and sulfuric acid at a temperature of -20°C to +20°C (preferably below +10°C). The carboxylic acid group of the compound of the general formula (XVIII) is reacted with a suitable alcohol (e.g. methanol, ethanol or propanol; wherein ALK represents methyl, ethyl or propyl) in an inorganic acid (e.g. hydrochloric acid or sulfuric acid) at a temperature of 0°C to 100°C to form an ester compound of the general formula (XIX). The hydroxyl group of the compound of the general formula (XIX) is converted into a triflate group by reaction with trifluoromethanesulfonic anhydride in a base (e.g. triethylamine) and an inert solvent (e.g. dichloromethane) at a temperature of -20°C to +40°C (usually at 0°C) to obtain a compound of the general formula (XX). Aryl trifluoromethanesulfonates of general formula (XX) can be cross-coupled with boronic acids of general formula (III) or with their respective pinacol esters to give compounds of general formula (XIII) by Pd-mediated reactions known to those skilled in the art (Suzuki coupling). A suitable solvent (e.g. N,N-dimethylformamide, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane and optionally water) is used, and a base (e.g. triethylamine, potassium carbonate, cesium carbonate) and a catalyst-ligand mixture (e.g. palladium(II) acetate / triphenylphosphine, tetrakis(triphenylphosphine)palladium(0), bis(triphenylphosphine)-dichloropalladium(II), bis(diphenylphosphino)ferrocenedichloropalladium(II)) is used at a temperature of 20°C to 120°C, preferably at 100°C. Analogously to the procedure described for Scheme 2, nitro reduction followed by amide formation affords compounds of general formula (VI), which are subsequently converted to the final targets of general formula (I) by hydrolysis of the ester group as detailed in Scheme 1.

[1168] Solution 7

[1169]

[1170] Scheme 8 shows an alternative method for synthesizing compounds of general formula (I). Starting from the synthon of general formula (XXI), the aniline can first be protected using a combination of two equivalents of a strong base (e.g., nBuLi) and 1,2-bis(chlorodimethylsilyl)ethane. The intermediate obtained can then be lithiated in situ using nBuLi and then quenched with an alkyl chloroformate (e.g., ethyl chloroformate). Subsequent treatment with an inorganic aqueous acid (e.g., hydrochloric acid) affords compounds of general formula (XXII), wherein ALK represents methyl, ethyl, or propyl. Similar to the procedure described for Scheme 1, Suzuki coupling followed by amide coupling affords compounds of general formula (VI). Subsequent saponification of the ester group produces the target compound of general formula (I).

[1171] Solution 8

[1172]

[1173] Scheme 9 shows an alternative method for the synthesis of compounds of general formula (I) in which the order of the reaction steps is changed compared to Scheme 1, wherein Hal represents Cl, Br or I, preferably Br; and wherein ALK represents methyl, ethyl or propyl. Starting from synthons of general formula (II), aromatic amines can be reacted with carboxylic acids of general formula (V) by methods known to those skilled in the art to give amide compounds of general formula (XXIII). The reaction is mediated by activating the 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)methylene]-N-methylmethylammonium hexafluorophosphate (HATU) or propylphosphonic anhydride (T3P). For example, the reaction with T3P is carried out in an inert solvent such as N,N-dimethylformamide or dichloromethane in the presence of a suitable aniline of formula (II) and a tertiary amine such as triethylamine or diisopropylethylamine at a temperature of -30°C to +60°C.

[1174] Aryl halides of general formula (XXIII) can be cross-coupled with boronic acids of general formula (III) or with their respective pinacol esters to give compounds of general formula (VI) by Pd-mediated reactions (Suzuki coupling) known to those skilled in the art. Using a suitable solvent (e.g. N,N-dimethylformamide, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane and optionally water), and at a temperature of 20°C to 120°C, preferably at 100°C, using a base (e.g. potassium carbonate or cesium carbonate) and a catalyst-ligand mixture (e.g. palladium(II) acetate / triphenylphosphine, tetrakis(triphenylphosphine)palladium(0), bis(triphenylphosphine)-dichloropalladium(II), bis(diphenylphosphino)ferrocenedichloropalladium(II)). Similar to the procedure described for Scheme 1, ester saponification of the intermediate compound of general formula (VI) yields the target compound of general formula (I).

[1175] Solution 9

[1176]

[1177] Scheme 10 shows an alternative method for the synthesis of compounds of general formula (I). Alkylation of 2-acetylbutyrolactone of general formula (XXIV) can be achieved with an alkylating agent of general formula (XXV) (wherein X represents Cl, Br or I, preferably Br) in the presence of a base (e.g. potassium carbonate or sodium carbonate) in a non-polar solvent (e.g. acetonitrile or tetrahydrofuran) at a temperature of 20°C to 60°C. Subsequent rearrangement of the compound of general formula (XXVI) to give the cyclopropane of general formula (XXVII) can be achieved by reaction with lithium iodide in a polar solvent (e.g. dimethylformamide or 1-methyl-2-pyrrolidone) at a temperature of 100°C to 200°C. The carboxylic acid of general formula (V) is then formed by reaction of the compound of general formula (XXVII) with bromine or iodine in the presence of sodium hydroxide in a solvent (e.g. tetrahydrofuran or 1,4-dioxane) at a temperature of 0°C to 20°C. Amide coupling gives the compound of general formula (VI) in analogy to the procedure described for Scheme 1. Subsequent saponification of the ester group yields the target compound of general formula (I).

[1178] Solution 10

[1179]

[1180] Scheme 11 shows an alternative method for the synthesis of compounds of general formula (I). Starting from synthons of general formula (XII) (wherein Hal represents Cl, Br or I; and where ALK represents methyl, ethyl or propyl), aryl halides can first be converted to stannanes of general formula (XXVIII) by reaction with hexabutyldistanane in the presence of a palladium catalyst (e.g. tetrakis(triphenylphosphine)palladium(0), bis(triphenylphosphine)-palladium(II) dichloride) in a suitable solvent (e.g. N,N-dimethylformamide, tetrahydrofuran, 1,4-dioxane or 1,2-dimethoxyethane) at a temperature of 20°C to 120°C, preferably at 100°C. The arylstannanes of general formula (XXVIII) can then be reacted with aryl halides (R) of general formula (XXIX) by Pd-mediated reactions known to those skilled in the art (Stille coupling). 1 The meaning is as defined in the general formula (I)). Use a suitable solvent (such as N,N-dimethylformamide, tetrahydrofuran, 1,4-dioxane or 1,2-dimethoxyethane) and a catalyst-ligand mixture such as palladium (II) acetate / triphenylphosphine, tetrakis (triphenylphosphine) palladium (0), bis (triphenylphosphine)-dichloropalladium (II), bis (diphenylphosphino) ferrocene dichloropalladium (II) at a temperature of 20°C to 120°C, preferably at 100°C. Similar to the procedure described for Scheme 1, nitro reduction gives the compound of the general formula (IV), followed by amide coupling to give the compound of the general formula (VI), followed by ester saponification to give the target compound of the general formula (I).

[1181] Solution 11

[1182]

[1183] Experimental Section

[1184] The example test experiments described herein are intended to illustrate the invention, and the invention is not limited to the examples given.

[1185] The following table lists the abbreviations used in this paragraph and in the Examples section.

[1186]

[1187]

[1188]

[1189] Analytical methods

[1190] Analytical LCMS method

[1191] Method 1 :Instrument: Waters Acquity Platform ZQ4000; Column: Waters BEHC18, 50mm x2.1mm, 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 rate: 1.3 ml / min; Column temperature: 60°C; UV detection: 200-400 nm.

[1192] Method 2 :Instrument: Waters Acquity LCT; Column: Phenomenex Kinetex C18, 50mm x 2.1mm, 2.6μ; Eluent A: water / 0.05% formic acid, Eluent B: acetonitrile / 0.05% formic acid; Gradient: 0.0min 98% A→0.2min: 98% A→1.7min: 10% A→1.9min: 10% A→2min: 98% A→2.5min: 98% A; Flow rate: 1.3ml / min; Column temperature: 60℃; UV detection: 200-400nm.

[1193] Method 3: Instrument: Waters Acquity UPLCMS SingleQuad; Column: Acquity UPLC BEH C18 1.7 μm, 50x2.1 mm; 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 rate 0.8 ml / min; Temperature: 60°C; DAD scan: 210-400 nm.

[1194] Method 4 : Instrument: Waters Acquity UPLCMS SingleQuad; Column: Acquity UPLC BEH C18 1.7 μm, 50x2.1 mm; Eluent A: water + 0.2 vol% ammonia (32%), eluent B: acetonitrile; Gradient: 0-1.6 min 1-99% B, 1.6-2.0 min 99% B; Flow rate 0.8 ml / min; Temperature: 60°C; DAD scan: 210-400 nm.

[1195] LC-MS, analytical method A: conventional high-throughput analysis

[1196] Column: Kinetex Core-Shell C18, 2.1x 50mm, 5μm; eluent A: water + 0.1% formic acid, eluent B: acetonitrile + 0.1% formic acid; gradient 0.00min 95% A→1.20min 100% B→1.30min 100% B→1.31min 95% A; column temperature: 40℃; flow rate 1.2ml / min; injection volume: 3μl; UV detection range: 210-420nm.

[1197] LC-MS, analytical method B: conventional high-throughput analysis

[1198] Column: Waters Atlantis dC18, 2.1x 50mm, 3μm; eluent A: water + 0.1% formic acid, eluent B: acetonitrile + 0.1% formic acid; gradient 0.00min 95% A→2.5min 100% B→2.7min 100% B→2.71min 5% A→3.5min 5% A; column temperature: 40℃; flow rate 1.0ml / min; injection volume: 3μl; UV detection range: 210-420nm.

[1199] LC-MS, Analytical Method C: Routine High-Throughput Analysis at High pH

[1200] Column: Phenomenex Gemini-NX C18, 2.0×50mm, 3μm; eluent A: 2mM ammonium bicarbonate, buffered to pH10, eluent B: acetonitrile; gradient 0.00min 99% A→1.80min 100% B→2.10min 100% B→2.30min99% A→3.50min99% A; column temperature: 40℃; flow rate 1.0ml / min; injection volume: 3μl; UV detection range: 210-420nm.

[1201] LC-MS, Analytical Method D:

[1202] Column: Waters Atlantis dC18, 2.1x 100mm, 3μm; eluent A: water + 0.1% formic acid, eluent B: acetonitrile + 0.1% formic acid; gradient 0.00min 95% A→5.00min 100% B→5.40min 100% B→5.42min 95% A→7.00min 95% A; column temperature: 40℃; flow rate 0.6ml / min; injection volume: 3μl; UV detection range: 210-420nm.

[1203] LC-MS, Analytical Method E: High pH

[1204] Column: Phenomenex Gemini-NX C18, 2.0x100 mm, 3μm; eluent A: 2mM ammonium bicarbonate, buffered to pH10, eluent B: acetonitrile; gradient 0.00min 95% A→5.50min 100% B→5.90min 100% B→5.92min95% A→7.00min95% A; column temperature: 40℃; flow rate 0.5ml / min; injection volume: 3μl; UV detection range: 210-420nm.

[1205] LC-MS, analytical method F:

[1206] Column: Phenomenex Kinetix-XB C18, 2.1×100mm, 1.7μm; eluent A: water + 0.1% formic acid, eluent B: acetonitrile + 0.1% formic acid; gradient 0.00min 95% A→5.30min 100% B→5.80min 100% B→5.82min 95% A→7.00min 95% A; column temperature: 40℃; flow rate 0.6ml / min; injection volume: 1μl; UV detection range: 200-400nm.

[1207] Purification method:

[1208] Biotage IsoleraTM Chromatography systems using pre-packed silica and pre-packed modified silica cartridges.

[1209] Preparative HPLC, Method A: High pH

[1210] Column: Waters Xbridge C18, 30x 100mm, 10μm; solvent A: water + 0.2% ammonium hydroxide, solvent B: acetonitrile + 0.2% ammonium hydroxide; gradient 0.00min 90% A→0.55min90% A→14.44min 95% B→16.55min95% B→16.75 90% A; column temperature: room temperature; flow rate 40ml / min; injection volume: 1500μl; detection: UV 215nm.

[1211] Preparative HPLC, Method B: Low pH

[1212] Column: Waters Sunfire C18, 30x 100mm, 10μm; solvent A: water + 0.1% formic acid, solvent B: acetonitrile + 0.1% formic acid; gradient 0.00min 90% A→0.55min 90% A→14.44min 95% B→16.55min 95% B→16.75 90% A; column temperature: room temperature; flow rate 40ml / min; injection volume: 1500μl; detection: UV 215nm.

[1213] Preparative HPLC method

[1214] Preparative HPLC, Method 1:

[1215] System: Waters automated purification system: pump 2545, sample manager 2767, CFO, DAD 2996, ELSD 2424, SQD; column: XBrigde C18 5μm 100x30 mm; solvent: A=H2O+0.1% Vol. formic acid (99%), B=acetonitrile; gradient: 0-8min10-100% B, 8-10min100% B; flow rate: 50mL / min; temperature: room temperature; solution: max. 250mg / max. 2.5mL DMSO o.DMF; injection: 1x 2.5mL; detection: DAD scan range 210-400nm; MS ESI+, ESI-, scan range 160-1000m / z.

[1216] Preparative HPLC, Method 2:

[1217] System: Waters automated purification 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: 0-8min 10-100% B, 8-10min 100% B; flow rate: 50mL / min; temperature: room temperature; solution: max. 250mg / max. 2.5mL DMSO o.DMF; injection: 1x 2.5mL; detection: DAD scan range 210-400nm; MS ESI+, ESI-, scan range 160-1000m / z.

[1218] Example

[1219] Chemical nomenclature of the Examples (also referred to as Compound Examples) and intermediates was performed using ACD software from ACD / LABS or Marvin software from ChemAxon.

[1220] Reaction times are either specified in the protocols in the experimental section or the reactions are run until completion. Chemical reactions are monitored and their completion is judged using methods well known to those skilled in the art, such as thin layer chromatography on plates coated with silica gel, or by LCMS methods.

[1221] Intermediate 1A: 5-amino-2-bromobenzoic acid methyl ester

[1222]

[1223] 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 hours. The mixture was evaporated to dryness. The resulting grey solid was used without further purification.

[1224] 1 H NMR (400MHz, DMSO-d6) δ [ppm] 3.83 (s, 3H), 6.92 (dd, 1H), 7.22 (d, 1H), 7.49 (d, 1H).

[1225] LCMS (method 3): Rt = 0.87 min, MS (ESIpos) m / z = 230 / 232 (M+H) + ,Br

[1226] Isotope pattern.

[1227] Intermediate 2A: 1-(5-bromopyridin-2-yl)propan-1-one

[1228]

[1229] 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. Ethyl magnesium bromide (11.4 mL of 3 M ether solution, 34.1 mmol) was added dropwise at this temperature and the reaction mixture was allowed to warm to room temperature over 2 hours. The reaction mixture was cooled to -20 °C and 1 M HCl aqueous solution was slowly added and the mixture was allowed to warm to room temperature again. The reaction mixture was diluted with ethyl acetate, the organic layer was collected, washed with brine, dried (MgSO 4 ), filtered and concentrated under reduced pressure. The golden oil crystallized to give the title compound (5.25 g, 85% yield).

[1230] 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).

[1231] Intermediate 3A: 5-bromo-2-(1,1-difluoropropyl)pyridine

[1232]

[1233] To a solution of 1-(5-bromopyridin-2-yl)propan-1-one (Int2A, 5.25 g, 24.5 mmol) dissolved in 1,2-dichloroethane (61.5 mL) was added diethylaminosulfur trifluoride (12.96 mL, 98.1 mmol) dropwise under nitrogen to give an orange solution. The reaction was warmed to 60 °C and stirred for 16 hours. The cooled reaction mixture was diluted dropwise with aqueous NaOH (2 M) (Caution: Violent reaction). The organic layer was removed, washed with brine, and dried (MgSO 4 ), filtered and concentrated under reduced pressure, and purified by BiotageIsolera TM Chromatography (silica gel, elution with TBME / heptane; 0-20%) afforded the title compound (3.25 g, 50% yield) as a light yellow oil.

[1234] 1H 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).

[1235] Intermediate 4A: 2-(1,1-difluoropropyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine

[1236]

[1237] A solution of 5-bromo-2-(1,1-difluoropropyl)pyridine (Int 3A, 3.25 g, 12.39 mmol), bis(pinacol)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 with a nitrogen balloon for 5 minutes. The reaction mixture was heated at 100 °C for 16 hours, cooled to room temperature and diluted with EtOAc, filtered through a celite plug and concentrated in vacuo. The filtrate was collected and concentrated under reduced pressure and purified by Biotage Isolera TM Purification by chromatography (silica cartridge, eluting with a gradient of eluent; 0-30% EtOAc / heptane) afforded the title compound (3.25 g, 83% yield) as a golden oil which crystallized on standing.

[1238] 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).

[1239] LCMS (analysis method A): Rt = 0.89 min; MS (ESIpos) m / z = 201.95 (boric acid mass + H) + .

[1240] Intermediate 5A: 2-(Difluoromethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine

[1241]

[1242] Potassium acetate (1.4 g, 14.4 mmol) was added 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 room temperature. Nitrogen was bubbled through the mixture for 5 minutes, 1,1'-bis(diphenylphosphino)ferrocenepalladium dichloride (II) (264 mg, 0.36 mmol) was added, and the mixture was heated at 100 ° C for 1 hour. The reaction mixture was then diluted with EtOAc (50 mL), filtered through celite and washed with EtOAc (50 mL). The filtrate was concentrated under reduced pressure, and the residue was purified by Biotage Isolera TM Chromatography (BiotageSNAP Cartridge KP-Sil 50 g; eluting with 0-100% EtOAc / heptane) afforded the title compound (1.15 g, 89% yield) as a light yellow crystalline solid.

[1243] 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).

[1244] LCMS (analysis method A): Rt = 0.78 min, MS (ESIPos) m / z = 173.9 (mass of boronic acid + H) + .

[1245] Intermediate 6A: 2-(1,1-difluoroethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine

[1246]

[1247] 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 with nitrogen for 5 minutes, and then [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (328 mg, 0.40 mmol) was added. The mixture was heated to 100 °C and stirred at this temperature for 2.5 hours. After this time, no starting material remained according to LCMS analysis. The heat was removed and the reaction was cooled to room temperature, at which time it was filtered on a pad of celite and washed with MeOH (3×10 mL). The filtrate was concentrated under reduced pressure and purified by Biotage Isolera TM Chromatography (eluting with 0-100% EtOAc / heptane) afforded the title compound as an off-white powdery solid (1.39 g, 66% yield).

[1248] 1 H NMR (250MHz, DMSO-d6) δ [ppm] 1.32 (s, 12H), 1.99 (t, J = 19.1Hz, 3H), 7.71 (dd, J = 7.8, 0.9Hz, 1H), 8.18 (dd, J = 7.8, 1.7Hz, 1H), 8.79–8.87 (m, 1H).

[1249] LCMS (Analytical Method A): Rt = 0.87 min; no mass ion observed.

[1250] Intermediate 7A: 1-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl]ethanone

[1251]

[1252] Under nitrogen atmosphere, 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) were added to a solution of 1-(5-bromopyridin-2-yl)ethanone (2.0 g, 9.98 mmol) in dioxane (50 mL). The mixture was heated at reflux for 4 hours. The mixture was then cooled to room temperature, filtered through diatomaceous earth (washed with EtOAc) and concentrated under reduced pressure. The residue was purified by Biotage Isolera TMDirect purification by chromatography (eluting with a gradient of eluent; 0-50% EtOAc / heptane) afforded the desired product (2.22 g, 90% yield) as a light yellow solid.

[1253] 1H NMR (500MHz, DMSO-d6) δ [ppm] 8.89 (s, 1H), 8.20 (dd, J = 7.7, 1.6Hz, 1H), 7.95 (d, J = 7.7Hz, 1H), 2.65 (s, 3H), 1.33 (s, 12H).

[1254] LCMS (Analytical Method A): Rt = 0.74 min, no mass ion observed.

[1255] Intermediate 8A: 5,5,5-trifluoro-1-(trimethylsilyl)pent-1-yn-3-one

[1256]

[1257] To a stirred solution of acetylene-1,2-diylbis(trimethylsilane) (1.0 g, 5.868 mmol) and 3,3,3-trifluoropropionyl chloride (0.946 g, 6.455 mmol) in dichloromethane (15 mL) at 0°C was added aluminum chloride (0.939 g, 7.042 mmol). 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 allowed to stand for about 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) and dried (MgSO 4 ), filtered and concentrated under reduced pressure to give the title compound (1.18 g, 75% yield) as a light yellow oil.

[1258] 1 H NMR (500 MHz, CHLOROFORM-d) δ [ppm] 3.38 (q, J = 10.0 Hz, 2H), 0.26 (s, 9H).

[1259] Intermediate 9A: 3-(2,2,2-trifluoroethyl)-1H-pyrazole

[1260]

[1261] To a solution of 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 (exothermic reaction observed). The mixture was stirred for 1 hour and then concentrated under reduced pressure (~50 mbar). The residue was dissolved in dichloromethane (50 mL) and washed with 2M K 2 CO 3 (20 mL), washed with brine (20 mL), dried (Na 2 SO 4 ), filtered and concentrated under reduced pressure to give the title compound (630 mg, 73% yield) as a yellow oil.

[1262] 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).

[1263] LCMS (analytical method A): Rt = 0.81 min; MS (ESIPos) m / z = 150.9 (M+H) + .

[1264] Intermediate 10A: 1-cyclobutyl-3-fluoro-1H-pyrazole

[1265]

[1266] 3-Fluoro-1H-pyrazole (150 mg, 2.91 mmol) was dissolved in DMF (10 mL) at room temperature. Sodium hydride (152 mg, 3.49 mmol, 1.2 eq.) was added and the mixture was stirred for 10 minutes. Cyclobutyl bromide (0.82 mL, 8.71 mmol, 3 eq.) was then added and the mixture was stirred at 50 ° C for 2 hours. After cooling to room temperature, the mixture was poured into water and extracted 4 times with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and the solvent was removed in vacuo. The crude product was obtained without further purification: 400 mg (98% of theoretical value) of light yellow oil.

[1267] 1 H NMR(400MHz, 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).

[1268] LCMS (method 1): Rt = 0.84 min; MS (ESIPos) m / z = 141 (M+H) + .

[1269] Intermediate 11A: 4-Bromo-1-cyclobutyl-3-fluoro-1H-pyrazole

[1270]

[1271] 1-Cyclobutyl-3-fluoro-1H-pyrazole (Int 10A, 400 mg, 2.85 mmol) was dissolved in 17 mL of chloroform and cooled to 0 ° C for 10 minutes. Bromine (480 mg, 3.00 mmol, 1.05 equiv.) dissolved in 5 mL of chloroform was then added dropwise at 0 ° C. The mixture was stirred for 1 hour and then diluted with dichloromethane. The mixture was washed with saturated sodium thiosulfate solution, then with brine, then dried over sodium sulfate and the solvent was evaporated. The crude product (400 mg, 63% of theoretical value, colorless oil) was used without further purification.

[1272] 1 H NMR(400MHz, DMSO-d6)δ[ppm]1.68–1.79(m,2H),2.27–2.42(m,4H),4.69(quint,1H),8.07(d,1H).

[1273] LCMS (method 1): Rt = 1.13 min; MS (ESIPos) m / z = 219 / 212 (M+H) + , Br isotope pattern.

[1274] Intermediate 12A: 1-cyclobutyl-3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

[1275]

[1276] 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 a stream of argon. (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 then added and the mixture was stirred at 100°C for 1 hour and at room temperature for another 2 hours. The mixture was diluted with ethyl acetate, filtered through celite, and the filtrate was concentrated in vacuo. The residue was filtered through silica gel (hexane / EE 0-40%) to give the title compound (420 mg) as a pale yellow oil which crystallized on standing.

[1277] LCMS (method 3): Rt = 0.98 min; MS (ESIPos) m / z = 367 (M+H) + .

[1278] Intermediate 13A: 1-tert-butyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

[1279]

[1280] Potassium acetate (2.54 g, 29.5 mmol) was added to a solution of 4-bromo-1-tert-butyl-1H-pyrazole (2.40 g, 9.836 mmol) and bis(pinacol)diboron (1.64 g, 7.995 mmol) in dioxane (30 mL) at room temperature. Nitrogen was bubbled through the mixture for 5 minutes, followed by the addition of 1,1'-bis(diphenylphosphino)ferrocenepalladium dichloride (II) (125 mg, 0.153 mmol). The mixture was heated at 100 ° C for 8 hours. The reaction mixture was diluted with EtOAc (50 mL), filtered through diatomaceous earth and washed with EtOAc (50 mL). The filtrate was concentrated under reduced pressure and the residue was purified by Biotage Isolera TM Chromatography [SNAP Cartridge KP-Sil 100 g; eluting with a gradient of eluent; 0-100% EtOAc / heptane] afforded the title product (0.65 g, 29% yield) as a white solid.

[1281] 1H 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).

[1282] LCMS (analytical method A): Rt = 1.18 min; MS (ESIPos) m / z = 251.05 (M+H) + .

[1283] Intermediate 14A: 1-(2,2-dimethylpropyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

[1284]

[1285] 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), and dried (Na 2 O). 2 SO 4 ) and concentrated under reduced pressure. Heptane (50 mL) was added to the residue and the mixture was briefly heated under reflux. After cooling to room temperature, the solid starting material was removed by filtration. The filtrate was concentrated under reduced pressure and purified by Biotage Isolera TM Purify by chromatography [Biotage SNAP Cartridge KP-Sil 25 g; eluting with a gradient of eluent; 0-30% EtOAc / heptane]. Fractions containing product were combined and concentrated in vacuo to give the title product (0.27 g, 9% yield) as a white solid.

[1286] 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).

[1287] LCMS (analytical method A): Rt = 1.32 min; MS (ESIPos) m / z = 264.8 (M+H) + .

[1288] Intermediate 15A: 1-(Cyclobutylmethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

[1289]

[1290] 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 room temperature and diluted with EtOAc (50 mL) and water (50 mL). The organic layer was separated, washed with water (50 mL) and brine (30 mL), and dried (MgSO 4 ), concentrated under reduced pressure and purified by BiotageIsolera TM Chromatography (25 g silica column using a gradient of eluent; 0-30% EtOAc / heptane) afforded the title compound (330 mg, 41% yield) as a colorless oil.

[1291] 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).

[1292] LCMS (analysis method A): Rt = 1.13 min, MS (ESIpos): m / z = 262.9 (M+H) + .

[1293] Intermediate 306A: 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazole

[1294]

[1295] To a solution of 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), and dried (Na 2 O). 2 SO 4 ) and concentrated under reduced pressure. The residue was purified by Biotage Isolera TM Purification by chromatography [Biotage SNAP Cartridge KP-Sil 50 g; using a gradient of eluent, 0-50% EtOAc / heptane]. Fractions containing product were combined and concentrated in vacuo to give the title compound (1.20 g, 56% yield) as a colorless oil.

[1296] 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).

[1297] LCMS (analytical method A): Rt = 1.34 min; MS (ESIPos) m / z = 324.95 (M+H) + .

[1298] Intermediate 307A: 1-(2-methoxyethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

[1299]

[1300] 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, 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 dropwise via syringe. After the addition was complete, the mixture was allowed to warm to room temperature and stirred for 1 hour, then ethyl acetate (70 mL) and water (30 mL) were added. The organic layer was separated, washed with water (2×30 mL) and brine (30 mL), dried (Na 2 O 4 3 O 4 5 N 2 O 4 6 N 2 O 4 7 ...2 SO 4 ), filtered and concentrated under reduced pressure. The residue was purified by Biotage Isolera TM Chromatography [Biotage SNAP Cartridge KP-Sil 50 g; using a gradient of eluent, 0-50% EtOAc / heptane] afforded the title compound (333 mg, 26% yield) as a colorless oil.

[1301] 1 H NMR (250MHz, 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).

[1302] LCMS (Analytical Method A): Rt = 1.01 min, MS (ESIPos): m / z = 253 (M+H) + .

[1303] 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

[1304]

[1305] 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 added diisopropyl azodicarboxylate (0.79 mL, 4.02 mmol), the reaction was allowed to warm to room temperature and stirred overnight. The next day, additional 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 stirring reaction was continued for another 6 hours. The reaction mixture was then concentrated under reduced pressure and ether was added. The resulting mixture was cooled to 0 ° C to give a white precipitate. The precipitate was removed by filtration, and the obtained filtrate was concentrated under reduced pressure and then purified by Biotage Isolera TM Chromatographic purification (50 g SiO 2 column; eluting with a gradient of eluent, 0-35% EtOAc / heptane) to afford the title compound (260 mg, 32% yield) as a light yellow oil.

[1306] 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).

[1307] LCMS (analysis method A): Rt = 1.36 min, MS (ESIpos): m / z = 263.1 (M+H) + .

[1308] Intermediate 309A: 2-Ethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine

[1309]

[1310] Potassium acetate (0.87 g, 8.87 mmol) was added 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) at room temperature. Nitrogen was bubbled through the mixture for 5 minutes, followed by the addition of 1,1'-bis(diphenylphosphino)ferrocenepalladium dichloride (II) (65 mg, 0.089 mmol). 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 through diatomaceous earth and washed with EtOAc (30 mL). The filtrate was concentrated under reduced pressure and the residue was purified by Biotage Isolera TM Chromatography [Biotage SNAP Cartridge KP-Sil 25 g; eluting with a gradient of 0-100% EtOAc / heptane] gave the title compound (213 mg, 29% yield) as an orange oil.

[1311] 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).

[1312] Intermediate 16A: Thieno[2,3-b]pyridin-2-ylboronic acid

[1313]

[1314] Thieno[2,3-b]pyridine (950 mg, 7.09 mmol) was dissolved in THF and the solution was 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 was stirred at -45 °C for another hour. Triisopropyl borate (1.2 eq, 1.59 g, 8.43 mmol, 1.95 mL) was added dropwise and the mixture was stirred at room temperature for another 2 hours. Orthophosphoric acid (85%, 0.57 mL, 140 mmol) was added dropwise and the mixture was stirred for another 15 minutes. The resulting yellow suspension was diluted with ether (40 mL) and water (40 mL). The precipitate was collected by filtration, washed with ether and dried in vacuo to give the title compound (810 mg, 64% yield) as a yellow solid. After standing the filtrate at room temperature, a second precipitate formed and was isolated in the same manner to give additional title compound (410 mg, 33% yield).

[1315] 1 H NMR (400MHz, 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).

[1316] LCMS (method 2): Rt = 0.50 min; MS (ESIPos) m / z = 180 (M+H) + .

[1317] Intermediate 17A: 4-iodo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazole

[1318]

[1319] At 0°C, sodium hydride (619 mg, 15.47 mmol) was added to a solution of 4-iodo-1H-pyrazole (2.0 g, 10.31 mmol) in tetrahydrofuran (20 mL). The resulting white suspension was stirred at 0°C for 2 hours. 2-(Chloromethoxyethyl)trimethylsilane (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 to room temperature and stirred for 16 hours. The reaction was quenched with water (0.5 mL) and concentrated to ~5 mL under reduced pressure. The mixture was then stirred in EtOAc (50 mL) and saturated NaHCO 3 The organic layer was separated, washed with brine (20 mL), and dried (Na2 SO 4 ) and concentrated under reduced pressure. The residue was purified by Biotage Isolera TM Chromatography [SNAP Cartridge KP-Sil 50g; eluting with a gradient of eluent; 0-20% EtOAc / heptane] afforded the title compound (3.27 g, 91% yield) as a colorless oil.

[1320] 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).

[1321] LCMS (analytical method A): Rt = 1.36 min; MS (ESIPos) m / z = 324.9 (M+H) + .

[1322] Intermediate 18A: 4-cyclobutyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazole

[1323]

[1324] To a degassed mixture of 4-iodo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazole (Int17A, 1.50 g, 4.626 mmol) in THF (20 mL) was added 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) chloride (50 mg, 0.068 mmol). The mixture was stirred at room temperature for 5 minutes, then a 0.5 M solution of bromo(cyclobutyl)zinc in THF (11.5 mL, 5.75 mmol) was added. The mixture was heated at 65 °C for 2 hours, then cooled to room temperature and water (1 mL) was added to quench the reaction. The mixture was partitioned between EtOAc (100 mL) and water (30 mL), the organic layer was separated, washed with brine (30 mL), and dried (Na2O3). 2 SO 4 ) and concentrated under reduced pressure. The residue was purified by Biotage Isolera TM Chromatography [SNAP Cartridge KP-Sil 50g; eluting with a gradient of eluent; 0-20% EtOAc / heptane] afforded the title compound (540 mg, 46% yield) as a colorless oil.

[1325] 1H NMR(500MHz, 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).

[1326] LCMS (analytical method A): Rt = 1.52 min; MS (ESI) m / z = 253.05 (M+H) + .

[1327] Intermediate 19A: (3S)-tetrahydrofuran-3-yl methanesulfonate

[1328]

[1329] To a solution of (3S)-tetrahydrofuran-3-ol (1.00 g, 11.4 mmol) and N,N-diisopropylethylamine (2.4 mL, 13.6 mmol) in dichloromethane (20 mL) was added methanesulfonyl chloride (1.05 mL, 13.6 mmol) dropwise at 0°C, and the reaction mixture was allowed to warm to room temperature and stirred for 2 hours. The reaction mixture was diluted with dichloromethane (20 mL), washed with saturated sodium bicarbonate (30 mL), and the organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the title compound (1.58 g) as an orange oil. It was used in the next step without purification.

[1330] 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).

[1331] The following intermediates were prepared analogously to the procedure described for intermediate 19A using methanesulfonyl chloride and the appropriate alcohol.

[1332]

[1333]

[1334] Intermediate 21A: (2R)-Butyl-2-methanesulfonate

[1335]

[1336] To a solution of (2R)-butan-2-ol (0.90 g, 12.2 mmol) and N,N-diisopropylethylamine (1.88 mL, 15.6 mmol) in dichloromethane (21 mL) was added methanesulfonyl chloride (1.67 mL, 14.6 mmol) dropwise at 0°C. The reaction mixture was allowed to warm to room temperature and stirred for 16 hours. The reaction mixture was washed with saturated aqueous sodium chloride solution and dried (MgSO 4 ), filtered and concentrated under reduced pressure to give the title compound (1.60 g) as a pale yellow oil, which was used in the next step without further purification.

[1337] 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).

[1338] The following intermediates were prepared analogously to the procedure described for intermediate 21A using methanesulfonyl chloride and the appropriate alcohol.

[1339]

[1340] Intermediate 23A: 1-[(3R)-tetrahydrofuran-3-yl]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

[1341]

[1342] 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 minutes. Then (3S)-tetrahydrofuran-3-yl methanesulfonate (750 mg, 4.51 mmol) was 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 purified by chromatography over MgSO 4 Dry, filter, concentrate under reduced pressure and obtain the product by BiotageIsolera TM Purification by chromatography (50 g silica cartridge, eluting with a gradient of eluent; 0-60% EtOAc / heptane) afforded the title compound (380 mg, 40% yield) as a colorless oil which solidified upon standing.

[1343] 1H 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).

[1344] LCMS (analysis method A): Rt = 1.10 min, MS (ESIpos): m / z = 264.8 (M+H) + .

[1345] The following intermediates were prepared analogously to the procedure described for Intermediate 23A using 4-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole and the appropriate mesylate.

[1346]

[1347]

[1348]

[1349] Intermediate 297A: 5-Bromo-2-cyclobutyl-1,3-thiazole

[1350]

[1351] Under a nitrogen atmosphere, bromo(cyclobutyl)zinc (9.1 mL of a 0.5 M THF solution, 4.5 mmol) was added to 2,5-dibromo-1,3-thiazole (1.0 g, 4.1 mmol) and dry THF (10 mL). 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) chloride (60 mg, 82 μmol) was added thereto, 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 adding 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 O) and purified by HPLC. 2 SO 4 ), filtered and concentrated under reduced pressure. The residue was purified by Biotage Isolera TM Chromatography (eluting with a gradient of eluent; 0-40% ethyl acetate / heptane) afforded the title compound (800 mg, 89% yield) as a light yellow oil.

[1352] 1H 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).

[1353] LCMS (Analytical Method A): Rt = 1.24 min, MS (ESIPos): m / z = 218 and 220 (M+H) + .

[1354] Intermediate 310A: 5-bromo-2-cyclopentyl-1,3-thiazole

[1355]

[1356] Under a nitrogen atmosphere, cyclopentylzinc bromide (9.1 mL of a 0.5 M THF solution, 4.5 mmol) was added to 2,5-dibromo-1,3-thiazole (1.0 g, 4.1 mmol) and dry THF (10 mL). 1,1'-bis(diphenylphosphino)ferrocenepalladium dichloride (II) (60 mg, 82 μmol) was added thereto, 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 adding 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 O) and purified by HPLC. 2 SO 4 ), filtered and concentrated under reduced pressure. The...

Claims

1. Compounds of general formula (I): or its enantiomers, diastereomers, racemates, hydrates or pharmaceutically acceptable salts, or mixtures thereof for use in the preparation of a medicament for treating or preventing a disease or disease syndrome or symptom, wherein the disease or disease syndrome or symptom is associated with pain and / or inflammation and is selected from endometriosis or endometriosis-associated pain or endometriosis-associated symptoms, diabetic neuropathy or diabetic neuropathy pain or symptoms of neuropathic pain, and diabetic retinopathy, wherein the endometriosis-associated symptoms are dysmenorrhea, dyspareunia, dysuria or dyspnea; the symptoms of neuropathic pain are pain that occurs spontaneously or in response to touch, R 1 represent: · Phenyl, 5- or 6-membered heteroaryl, wherein the 5-membered heteroaryl contains 1, 2 or 3 heteroatoms or heteroatom-containing groups independently selected from S, N, NH and O, and wherein the 6-membered heteroaryl contains 1 or 2 nitrogen atoms, or a bicyclic 8- to 10-membered heteroaryl group containing 1, 2 or 3 heteroatoms or heteroatom-containing groups independently selected from NH, N, O, S, SO and SO2, Wherein R 1 Optionally, one or more carbon atoms are substituted by 1 to 3 identical or different substituents R 1a Substitution, where R 1a represents C1-C5-alkyl, C3-C7-cycloalkyl, -(C1-C3-alkyl)-(C3-C7-cycloalkyl), -OC1-C5-alkyl, -OC3-C7-cycloalkyl, NHR 4 、N(R 4 )2, NH(C3-C7-cycloalkyl), halogen, CN, NHSO2R 4 、SO2R 4 , 5 to 7 membered lactams, or containing 1 or 2 selected from NH, -NR 4 , N, O, S, SO and SO2 heteroatoms or heteroatom-containing groups, and in, Independently, if R 1 represents a 5-membered heteroaryl or a bicyclic 8 to 10-membered heteroaryl, then the R 1 Each ring nitrogen atom of 1b Substitution, where R 1b represents C1-C5-alkyl, -(C1-C3-alkyl)-(C3-C7-cycloalkyl), C3-C7-cycloalkyl, SO2R 4 or contains 1 or 2 selected from NH, -NR 4 , N, O, S, SO and SO2 heteroatoms or heteroatom-containing groups, and If R 1a represents C1-C5-alkyl, C3-C7-cycloalkyl, -(C1-C3-alkyl)-(C3-C7-cycloalkyl), -OC1-C5-alkyl or -OC3-C7-cycloalkyl and / or if R 1b represents C1-C5-alkyl, -(C1-C3-alkyl)-(C3-C7-cycloalkyl) or C3-C7-cycloalkyl, The C1-C5-alkyl, C3-C7-cycloalkyl, -(C1-C3-alkyl)-(C3-C7-cycloalkyl), -OC1-C5-alkyl and -OC3-C7-cycloalkyl are independently optionally substituted by one or more substituents independently selected from methyl, ethyl, OH, OR 4 and F, and If R 1a and / or R 1b represents a 4- to 7-membered heterocycloalkyl group, each carbon atom of the 4- to 7-membered heterocycloalkyl group is optionally substituted by one or more independently selected from OH, OR 4 and F is substituted with a substituent; R 2 represent: -(CH2) p -(C5-C7-cycloalkyl), -(CH2) p -phenyl, · a 6-membered heteroaryl group, wherein the 6-membered heteroaryl group contains 1 or 2 nitrogen atoms, Wherein R 2 Optionally, one or more carbon atoms are substituted by 1 to 3 identical or different substituents R 2a Substitution, where R 2a represents C1-C5-alkyl, C3-C7-cycloalkyl, -(C1-C3-alkyl)-(C3-C7-cycloalkyl), -OC1-C5-alkyl, -OC3-C7-cycloalkyl, halogen, OH or CN, and If R 2a represents C1-C5-alkyl, C3-C7-cycloalkyl, -(C1-C3-alkyl)-(C3-C7-cycloalkyl), -OC1-C5-alkyl or -OC3-C7-cycloalkyl, The C1-C5-alkyl, C3-C7-cycloalkyl, -(C1-C3-alkyl)-(C3-C7-cycloalkyl), -OC1-C5-alkyl and -OC3-C7-cycloalkyl are independently optionally substituted by one or more substituents independently selected from OH, OR 4 and F; p represents 0; R 3 Represents H or F; R 4 represents a C1-C5-alkyl group which is optionally substituted by 1 to 5 fluorine atoms; R 5 represents H, halogen, CN, C1-C5-alkyl or -OC1-C5-alkyl, wherein said C1-C5-alkyl and -OC1-C5-alkyl are optionally substituted by 1 to 5 fluorine atoms; and R 6 and R 7 independently represents H or C1-C3-alkyl, wherein the C1-C3-alkyl is optionally substituted by 1 to 5 fluorine atoms.

2. The use according to claim 1, wherein R 1 represents a 5-membered heteroaryl group containing 1, 2 or 3 heteroatoms or heteroatom-containing groups independently selected from S, N, NH and O, Wherein R 1 Optionally, one or more carbon atoms may be substituted by 1 or 2 identical or different substituents R 1a Substitution, where R 1a represents C1-C5-alkyl, C3-C7-cycloalkyl, -(C1-C3-alkyl)-(C3-C7-cycloalkyl), -OC1-C5-alkyl, -OC3-C7-cycloalkyl, halogen or CN, and Wherein R 1 Each ring nitrogen atom of is independently optionally substituted with a substituent R 1b Substitution, where R 1b represents C1-C5-alkyl, -(C1-C3-alkyl)-(C3-C7-cycloalkyl) or C3-C7-cycloalkyl, and If R 1a represents C1-C5-alkyl, C3-C7-cycloalkyl, -(C1-C3-alkyl)-(C3-C7-cycloalkyl), -OC1-C5-alkyl or -OC3-C7-cycloalkyl and / or if R 1b represents C1-C5-alkyl, -(C1-C3-alkyl)-(C3-C7-cycloalkyl) or C3-C7-cycloalkyl, then the C1-C5-alkyl, C3-C7-cycloalkyl, -(C1-C3-alkyl)-(C3-C7-cycloalkyl), -OC1-C5-alkyl and -OC3-C7-cycloalkyl are independently optionally substituted by one or more substituents independently selected from methyl, ethyl, OH, OR 4 and F.

3. The use according to claim 1, wherein R 1 represents an unsubstituted or substituted group R at the nitrogen atom in position 1 1b Substituted pyrazol-4-yl, wherein R 1b represents C1-C5-alkyl, -(C1-C3-alkyl)-(C 3- C7-cycloalkyl) or C3-C7-cycloalkyl, wherein R 1b Optionally substituted with one or more substituents independently selected from methyl, ethyl, OH, OR 4 and F.

4. The use according to claim 1, wherein R 6 and R 7 Represents H.

5. The use according to claim 1, wherein R 1 represents a pyrazolyl group, which is optionally substituted at one or more carbon atoms by 1 or 2 identical or different substituents R 1a Substitution, where R 1a represents C1-C5-alkyl, C3-C7-cycloalkyl, -(C1-C3-alkyl)-(C3-C7-cycloalkyl), -OC1-C5-alkyl, -OC3-C7-cycloalkyl, halogen or CN, and Wherein R 1 Each nitrogen atom of 1b Substitution, where R 1b represents C1-C5-alkyl, -(C1-C3-alkyl)-(C3-C7-cycloalkyl) or C3-C7-cycloalkyl, and If R 1a represents C1-C5-alkyl, C3-C7-cycloalkyl, -(C1-C3-alkyl)-(C3-C7-cycloalkyl), -OC1-C5-alkyl or -OC3-C7-cycloalkyl and / or if R 1b represents C1-C5-alkyl, -(C1-C3-alkyl)-(C3-C7-cycloalkyl) or C3-C7-cycloalkyl, then the C1-C5-alkyl, C3-C7-cycloalkyl, -(C1-C3-alkyl)-(C3-C7-cycloalkyl), -OC1-C5-alkyl and -OC3-C7-cycloalkyl are independently optionally substituted by one or more independently selected from methyl, OH, OR 4 and F is substituted with a substituent; R 5 represents H, F, Cl or methyl; and R 6 and R 7 Represents H.

6. The use according to claim 1, wherein R 3 represents H; and R 5 Represents H.

7. The use according to claim 1, wherein R 3 represents H; and R 5 Stands for F.

Images