WO2017153234A1 - Substituted n-cyclo-2-aryl-quinoline-4-carboxamides and use thereof - Google Patents

Abstract

The invention relates to new substituted N-Cyclo-2-aryl-quinoline-4-carboxamide derivatives, to methods for the production thereof, to the use thereof either alone or in combination for treating and/or preventing diseases and to their use for producing drugs for treating and/or preventing diseases, particularly for the treatment and/or prevention of fibrotic and inflammatory diseases.

Description

 SUBSTITUTED N-CYCLO-2-ARYLCHINOLINE-4-CARBOXAMIDES AND THEIR USE

The present application relates to novel substituted N-cyclo-2-arylquinoline-4-carboxamide derivatives, processes for their preparation, their use alone or in combinations for the treatment and / or prevention of diseases and their use for the preparation of medicaments for the treatment and / or disease prevention, in particular for the treatment and / or prevention of fibrotic and inflammatory diseases.

Prostaglandin F2alpha (PGF2a) belongs to the family of bioactive prostaglandins, which are derivatives of arachidonic acid. After release from membrane phospholipids by A2 phospholipases, the arachidonic acid is oxidized by cyclooxygenases to the prostaglandin H2 (PGH2), which is further converted to PGF2a by PGF synthase. To a much lesser extent PGF2a may also be formed enzymatically from other prostaglandins such as PGE2 or PGD2 [Watanabe et al., J. Biol. Chem. 1985, 260, 7035-7041]. PGF2a is not stored, but released immediately after synthesis, causing its effects locally. PGF2a is an unstable molecule (ti / ₂ <1 minute) which rapidly rearranges enzymatically into the lung, liver and kidney to an inactive metabolite, 15-ketodihydro-PGF2a [Basu et al, Acta Chem. Scand. 1992, 46, 108-1 10]. 15- Ketodihydro PGF2a is detectable in large quantities in plasma and later in urine both under physiological and pathophysiological conditions.

The biological effects of PGF2a come about through the binding and activation of a membrane receptor, the PGF2a receptor or the so-called FP receptor. The FP receptor belongs to the G protein-coupled receptors that are characterized by seven transmembrane domains. In addition to the human FP receptor, the mouse and rat FP receptors could also be cloned [Abramovitz et al., J. Biol. Chem. 1994, 269, 2632-2636; Sugimoto et al., J. Biol. Chem. 1994, 269, 1356-1360; Kitanaka et al., Prostaglandins 1994, 48, 31-41]. In humans, there are two isoforms of the FP receptor, FPA and FPB. Of the prostanoid receptors, the FP receptor is the least selective, as PGD2a binds PGD2 and PGE2 with nanomolar affinities [Woodward et al., Pharmacol. Rev. 2011, 63, 471-538]. Stimulation of the FP receptor leads primarily to Gq-dependent activation of phospholipase C, resulting in release of calcium and activation of diacylglycerol-dependent protein kinase C (PKC). The elevated intracellular calcium level leads to calmodulin-mediated stimulation of myosin-linked chain kinase (MLCK). In addition to being coupled to G protein Gq, the FP receptor can also activate the Rho / Rhokinase signaling cascade via G12 / G13 and alternatively stimulate the Raf / MEK / MAP signaling pathway via Gi coupling [Woodward et al., Pharmacol. Rev. 2011, 63, 471-538]. PGF2a is involved in the regulation of numerous physiological functions such as ovarian function, embryonic development, changes in the lining of the uterus, uterine contraction, luteolysis and the induction of labor and delivery. PGF2a is also synthesized in the endometrium in epithelial cells where it stimulates cellular proliferation [Woodward et al., Pharmacol. Rev. 2011, 63, 471-538]. In addition, PGF2a is a potent stimulator of smooth muscle, vascular and bronchoconstriction and is involved in acute and chronic inflammatory processes [Basu, Mol. Cells 2010, 30, 383-391]. It was shown that 15-keto-dihydro-PGF2a, a stable metabolite of PGF2a, could be systemically detected in patients with rheumatoid arthritis, psoriatic arthrosis and osteoarthrosis. In kidney PGF2a is involved in water absorption, natriuresis and diuresis. In the eyes, PGF2a regulates the intraocular pressure. PGF2a also plays an important role in bone metabolism: prostaglandin stimulates the sodium-dependent transport of inorganic phosphate into osteoblasts and increases the release of interleukin-6 and vascular endothelial growth factor (VEGF) into osteoblasts; In addition, PGF2a is a potent mitogen and survival factor for osteoblasts [Agas et al., J. Cell Physiol. 2013, 228, 25-29].

 Increased PGF2a / FP receptor activity also led to up-regulation of tumorigenic and angiogenic genes such as COX-2 (Sales et al., 2007, Endocrinology 148: 3635-44), FGF-2 and VEGF (Sales et al., 2010 Am J Pathol 176: 431) indicating that FP receptor stimulates endometrial tumor growth by regulation of vascular functions. In addition, the FP receptor is involved in the regulation of endometrial epithelial cell proliferation and may affect its adhesion to the extracellular matrix and motility. The findings indicate that PGF2a / FP receptor plays a multifactorial role in endometallic adenocarcinomas (Yang et al., 2013 J Recept Signal Transduct, 33 (1): 14-27 / Increased expression of the FP receptor in progenitor cells of oligodendrocytes (OPCs) may be a marker for damage to oligodendrocyte and active myelin (Soldan et al., Neurology 2015, 84). After autopsy, expression of the FP receptor on tissues of multiple sclerosis (MS) patients was found to be close to that of OPCs No FP receptor expression was found in control samples of white matter, suggesting that the FP receptor plays a role in the development of multiple sclerosis (Carlson et al., 2015, Mult. Sclerosis (1 1) 467-468).

Injuries to the brain lead to upregulation of prostaglandins, especially the proinflammatory PGF2a and overactivation of the FP receptor. Thus, FP receptor-deficient mice and treatment with the FP antagonist AI-8810 have been shown to have significant neuroprotective effects after cerebral artery occlusion (Kim et al., 2012, Neurobiol Disease 48, 58-65). In addition, it has been demonstrated that PGF2a FP receptor activation is involved in various cardiovascular dysfunctions such as myocardial fibrosis, myocardial infarction and hypertension [Zhang et al., Frontiers in Pharmacol. 2010, 1, 1-7; Ding et al., Int. J. Biochem. Cell. Biol., 2012, 44, 1031-1039; Ding et al., J. Mol. Med. 2014, 6, 629-640]. Thus, the major metabolite of PGF2a is 15-keto-dihydro-PGF2a in humans with living conditions at increased cardiovascular risk, such as in smokers (Helmersson et al., 2005 Atherosclerosis 181, 201-207), obesity (Sinaiko et al., 2005 Circulation 1 1 1, 1985-91), Type I diabetes (Basu et al., 2005), and Type II diabetes (Helmersson et al., 2004, Circulation 109, 1729-1734). (Zhang et al., Frontiers in Pharmacol 2010, 1: 1-7). It has also been shown that a genetic polymorphism in a Chinese subpopulation leads to increased transcription of the FP gene and increased vasoconstriction (Xiao et al., 2015, Arterioscler Thromb Vase Biol. 35: 1687-1695).

 In addition, the PGF2a receptor (FP) participates in joint inflammation and in the regulation of the signaling cascade of the bone morphogenetic protein (BMP) and promotes the differentiation of chondrocytes [Kim et al., Biochim. Biophys. Acta, 2015, 1853, 500-512]. More stable analogues of PGF2a have been developed for estrus synchronization and for influencing human reproductive functions, as well as for reducing intraocular pressure for the treatment of glaucoma [Basu, Mol. Cells 2010, 30, 383-391]. In the latter application, as a side effect the stimulation of hair growth, eg that of eyelashes, by the chemically more stable PGF2a analogues such as latanoprost was observed. (Johnston et al., Am J Ophthalmol 1997, 124-544-547). Also, the genes of the FP receptor are expressed in human hair follicles of the scalp (Khidhir et al., J Invest Dermatol, 2009, Abstr 607). These findings suggest that the FP receptor is involved in the regulation of hair growth, and also in diseases such as, e.g. Hirsutism may be involved.

In patients with idiopathic pulmonary fibrosis (IPF), it has been shown that the stable PGF2a metabolite 15-ketodihydro-PGF2a is significantly elevated in plasma and that the levels of 15-ketodihydro-PGF2a are correlated with functional parameters, such as forced vital capacity (FVC ), the diffusion distance of carbon monoxide in the lung (DLCO) and the 6-minute walking test correlate. In addition, an association between increased plasma 15-ketodihydro PGF2a and patient mortality was found [Aihara et al, PLoS One 2013, 8, 1-6]. Consistent with this, it has also been shown that stimulation of human lung fibroblasts with naturally occurring silica fumes, which in humans lead to silicosis in chronic inhalation and pulmonary fibrosis, causes strong up-regulation of PGF2a synthesis [O'Reilly et al, Am. J. Physiol. Lung Cell. Mol. Physiol. 2005, 288, L1010-L1016]. In bleomycin-induced lung fibrosis in mice, switching off the FP receptor by knock-down (FP - / -) resulted in markedly reduced pulmonary fibrosis. rose compared to wild-type mice [Oga et al., Nat. Med. 2009, 15, 1426-1430]. In FP - / - mice bleomycin administration showed a significant reduction in hydroxyproline content as well as decreased induction of profibrotic genes in lung tissue. In addition, the function of the lung in FP - / - mice was significantly improved compared to the wild-type mice. In human lung fibroblasts, PGF2a stimulates proliferation and collagen production via the FP receptor. Since this occurs independently of the profibrotic mediator TGFβ, the PGF2a / FP receptor signaling cascade represents an independent pathway in the development of pulmonary fibrosis [Oga et al., Nat. Med. 2009, 15, 1426-1430]. These findings indicate that the FP receptor is a therapeutic target protein for the treatment of IPF [Olman, Nat. Med. 2009, 15, 1360-1361]. The involvement of PGF2a in the induction of fibrotic changes has also been found in mouse cardiac fibroblasts [Ding et al., Int. J. Biochem. & Cell Biol.

2012, 44, 1031-1039], in an animal model of scleroderma [Kanno et al., Arthritis Rheum.

2013, 65, 492-502] as well as synoviocytes from patients with knee arthrosis [Bastiaansen et al. Arthritis Rheum. 2013, 65, 2070-2080].

Therefore, it is believed that the FP receptor plays an important role in many diseases, injuries and pathological changes whose genesis and / or progression is associated with inflammatory events and / or proliferative and fibroproliferative tissue and vascular remodeling. These may be, in particular, diseases and / or damage to the lung, the cardiovascular system or the kidney, or it may be a blood disorder, a cancerous disease or other inflammatory diseases.

 In particular, idiopathic pulmonary fibrosis, pulmonary hypertension, bronchiolitis obliterans syndrome (BOS), chronic obstructive pulmonary disease (COPD), asthma and cystic fibrosis are inflammatory and fibrotic diseases and lung damage to be named in this connection. Diseases and damages of the cardiovascular system in which the FP receptor is involved are, for example, tissue changes after a myocardial infarction and in heart failure. Kidney diseases include kidney failure and kidney failure. A disease of the blood is, for example, sickle cell anemia. Examples of tissue degradation and remodeling in cancer processes are the invasion of cancer cells into the healthy tissue (metastasis) and the reformation of supplying blood vessels (neo-angiogenesis). Other inflammatory diseases in which the FP receptor plays a role are, for example, osteoarthritis and multiple sclerosis.

Idiopathic pulmonary fibrosis or idiopathic pulmonary fibrosis (IPF) is a progressive lung disease that, if left untreated, leads to an average death within 2.5 to 3.5 years after diagnosis. Patients are usually older than 60 years of age at the time of diagnosis, and men are more likely to be affected than women. Of the Onset of IPF is insidious and characterized by an increased shortness of breath and dry irritated cough. IPF belongs to the group of idiopathic interstitial pneumonias (IIP), a heterogeneous group of lung diseases characterized by varying degrees of fibrosis and inflammation, which are distinguished by clinical, imaging and histologic criteria. Within this group, idiopathic pulmonary fibrosis is of particular importance due to its frequency and its aggressive nature [Ley et al, Am. J. Respir. Cht. Care Med. 2011, 183, 431-440]. IPF can be either sporadic or familial. The causes are currently not clear. In recent years, however, numerous indications have been found that chronic damage to the alveolar epithelium results in the release of profibrotic cytokines / mediators, followed by increased fibroblast proliferation and increased collagen fiber formation, resulting in patchy fibrosis and the typical honeycomb structure of the Lung comes [Strieter et al., Chest 2009, 136, 1364-1370]. The clinical consequences of fibrosis are a decrease in the elasticity of the lung tissue, a reduction in the diffusion capacity and the development of severe hypoxia. In terms of lung function, a worsening of forced vital capacity (FVC) and diffusion capacity (DLCO) can be detected. Significant and prognostically significant comorbidities of IPF are acute exacerbations and pulmonary hypertension [Beck et al., The Pneumologist 2013, 10 (2), 105-1 1 1]. The prevalence of pulmonary hypertension in interstitial lung disease is 10-40% [Lettieri et al, Chest 2006, 129, 746-752; Behr et ai, Eur. Respir. J. 2008, 31, 1357-1367]. There is currently no curative treatment for IPF, except for lung transplantation.

Pulmonary hypertension (PH) is a progressive lung disease that, if left untreated, leads to death on average within 2.8 years of diagnosis. By definition, chronic pulmonary hypertension has a pulmonary arterial mean pressure (mPAP) of> 25 mmHg at rest or> 30 mmHg under exercise (normal value <20 mmHg). The pathophysiology of pulmonary hypertension is characterized by vasoconstriction and remodeling of the pulmonary vessels. Chronic PH neo- muscularizes primarily non-muscularized pulmonary vessels, and the vascular musculature of already muscularized vessels increases in size. As a result of this increasing obstruction of the pulmonary circulation, there is a progressive load on the right heart, which leads to a reduced output of the right heart and ultimately ends in right heart failure [M. Humbert et al., J. Am. Coli Carulol. 2004, 43, 13S-24S]. Although idiopathic (or primary) pulmonary arterial hypertension (IPAH) is a very rare disease, secondary pulmonary hypertension (non-PAH PH, NPAHPH) is widespread and it is currently believed that PH is the third most common cardiovascular disease Disease group after coronary heart disease and systemic hypertension is [Naeije, in: AJ Peacock et al. (Eds.), Pulmonary Circulation. Diseases and their treatment, 3 ^rd edition, Hodder Arnold Publ., 2011, 3]. The classification of pulmonary hypertension into different groups according to the respective etiology has been carried out since 2008 according to the Dana Point classification [D. Montana and G. Simonneau, in: AJ Peacock et al. (Eds.), Pulmonary Circulation. Disease and their treatment, 3 ^rd edition, Hodder Arnold Publ., 2011, 197-206].

 Despite advances in PH treatment, there is no prospect of healing for this serious condition. Marketed therapies (e.g., prostacyclin analogs, endothelin receptor antagonists, phosphodiesterase inhibitors) are able to improve the quality of life, exercise tolerance, and prognosis of patients. These are systemically applied, primarily hemodynamically acting therapeutic principles that influence vascular tone. The applicability of these drugs is confirmed by the z.T. restricted serious side effects and / or complex application forms. The period over which the clinical situation of patients can be stabilized or improved under specific monotherapy is limited (for example due to tolerance development). Finally, there is a therapy escalation and thus a combination therapy in which several drugs have to be given at the same time. At present, these standard therapies are only approved for the treatment of pulmonary arterial hypertension (PAH). For secondary forms of PH, such as e.g. PH-COPD failed these therapeutic principles (e.g., sildenafil, bosentan) in clinical trials as they resulted in a decrease (desaturation) of arterial oxygen content in patients due to nonselective vasodilation. The reason for this is probably an unfavorable influence on the ventilation-perfusion adaptation within the lungs in heterogeneous lung diseases due to the systemic administration of unselective vasodilators [I. Blanco et al., Am. J. Respir. Crit. Care Med. 2010, 181, 270-278; D. Stolz et al., Eur. Respir. J. 2008, 32, 619-628]. New combination therapies are one of the most promising future treatment options for the treatment of pulmonary hypertension. In this context, the exploration of new pharmacological mechanisms for the treatment of PH is of particular interest [Ghofrani et al., Herz 2005, 30, 296-302; E. B. Rosenzweig, Expert Opinion. Emerging Drugs 2006, 11, 609-619; T. Ito et al., Curr. Med. Chem. 2007, 14, 719-733]. Above all, such new therapeutic approaches, which can be combined with the therapy concepts already on the market, could form the basis of a more efficient treatment and thus bring a great advantage for the patients.

For the purposes of the present invention, the term pulmonary hypertension includes both primary and secondary subforms (NPAHPH), as defined by the Dana Point classification according to their respective etiology [D. Montana and G. Simonneau, in: AJ Peacock et al. (Eds.), Pulmonary Circulation. Diseases and Their treatment, 3 ^rd edition, Hodder Arnold Publ, 201 1, 197-206. Hoeper et al., J. Am. Coli. Cardio!., 2009, 54 (1), Suppl. S, S85- S96]. In particular, group 1 includes pulmonary arterial hypertension (PAH), which includes idiopathic and familial forms (IPAH and FPAH, respectively). In addition, PAH also includes persistent pulmonary hypertension in newborns and associated pulmonary arterial hypertension (APAH), which is associated with collagenosis, congenital systemic pulmonary shunt veins, portal hypertension, HIV infection, use of certain drugs and medications (eg Appetite suppressants), with diseases with significant venous / capillary involvement such as pulmonary veno-occlusive disease and pulmonary capillary hemangiomatosis, or with other diseases such as thyroid disorders, glycogen storage disorders, Gaucher disease, hereditary telangiectasia, hemoglobinopathies, myeloproliferative disorders, and splenectomy. Group 2 of the Dana Point classification summarizes PH patients with causative left ventricular disease, such as ventricular, atrial or valvular disease. Group 3 includes forms of pulmonary hypertension associated with a lung disease, such as chronic obstructive pulmonary disease (COPD), interstitial lung disease (ILD), pulmonary fibrosis (IPF), and / or hypoxemia (eg sleep apnea syndrome, alveolar hypoventilation, chronic altitude sickness, plant-related Malformations) are associated. Group 4 includes PH patients with chronic thrombotic and / or embolic diseases, eg in thromboembolic obstruction of proximal and distal pulmonary arteries (CTEPH) or in non-thrombotic embolization (eg as a result of tumor diseases, parasites, foreign bodies). Rarer forms of pulmonary hypertension, such as in patients with sarcoidosis, histiocytosis X or lymphangiomatosis, are summarized in Group 5.

Bronchiolitis obliterans syndrome (BOS) is a chronic rejection reaction after lung transplantation. Within the first five years after lung transplantation, approximately 50-60% of all patients are affected and over 90% of patients within the first nine years [Estenne et al., Am. J. Respir. Crit. Care Med. 2003, 166, 440-444]. The cause of the disease is not clear. Despite many advances in the treatment of transplant patients, BOS case numbers have barely changed in recent years. BOS is the most important long-term complication of lung transplants and is considered the main reason that survival rates are still significantly lower than those of other organ transplants. BOS is an inflammatory event associated with changes in the lung tissue, especially those affecting the small airways. The damage and inflammatory changes in the epithelial cells and the subepithelial structures of the smaller airways lead to excessive fibroproliferation due to ineffective regeneration of the epithelium and aberrant tissue repair. There is scarring and eventually destruction of the bronchioles as well as grafting of granulation tissue in the small airways and alveoli, sometimes with vascular involvement. Diagnosis is based on lung function. provides. BOS worsens FEV1 compared to the average of the two best measured postoperatively. At present, there is no curative treatment for BOS. Part of the patients improves under intensified immunosuppression, non-responsive patients experience a persistent deterioration, so that a new transplantation (retransplantation) is indicated.

 Chronic obstructive pulmonary disease (COPD) is a slowly progressive lung disease characterized by obstruction of respiratory flow, which is caused by pulmonary emphysema and / or chronic bronchitis. The first symptoms of the disease usually appear from the fourth to fifth decade of life. In the following years, the shortness of breath is often aggravated and it manifests cough, associated with an extensive and sometimes purulent sputum and a stenosis breathing to a dyspnea. COPD is primarily a disease of smokers: smoking is responsible for 90% of all COPD cases and 80-90% of all COPD deaths. COPD is a major medical problem and is the sixth most common cause of death worldwide. About 4-6% of over-45s are affected. Although the obstruction of the respiratory flow can be only partially and temporally limited, COPD is not curable. The aim of the treatment is thus to improve the quality of life, alleviate the symptoms, prevent acute worsening and slow down the progressive impairment of lung function. Existing pharmaceutical therapies, which have barely changed over the past two to three decades, include the use of bronchodilators to open blocked airways and, in certain situations, corticosteroids to control the inflammation of the lungs [P. J. Barnes, N. Engl. J. Med. 2000, 343, 269-280]. The chronic inflammation of the lungs, caused by cigarette smoke or other irritants, is the driving force behind the development of the disease. The underlying mechanism involves immune cells that release proteases and various cytokines as a result of the lung's inflammatory response, leading to pulmonary emphysema and bronchial remodeling.

 The object of the present invention is to identify and provide novel substances which are potent, chemically and metabolically stable, non-prostanoid antagonists of the FP receptor and are suitable as such for the treatment and / or prevention, in particular of fibrotic and inflammatory diseases.

WO 95/32948-A1, WO 96/02509-A1, WO 97/19926-A1 and WO 2000/031038-A1, inter alia, disclose 2-arylquinoline-4-carboxamides as NK ₃ - or dual NK ₂ / NK ₃ - Antagonists are known which are suitable for the treatment of diseases of the lung and the central nervous system. WO 2016/004035 discloses 2-arylquinoline-4-carboxamides as TSH receptor agonists which can be used to treat dysfunctions and malignant thyroid changes. WO 2000/064877 discloses quinoline-4-carboxamide derivatives. which can be used as NK ₃ antagonists for the treatment of various diseases, including the lungs and the central nervous system. In WO 2006/094237-A2 quinoline derivatives are disclosed as sirtuin modulators, which can be used for the treatment of various diseases. WO 2011/153553-A2 various bicyclic heteroaryl compounds are claimed as kinase inhibitors for the treatment of particular cancers. WO 2013/074059 A2 lists various quinoline-4-carboxamide derivatives which can serve as inhibitors of cytosine deaminases for enhancing a DNA transfection of cells. WO 2013/164326-A1 discloses Λ / 3-diphenylnaphthalene-1-carboxamides as agonists of the EP2 prostaglandin receptor for the treatment of respiratory diseases. In WO 2014/117090-A1 various 2-aryl quinoline derivatives are described as inhibitors of metalloenzymes. WO 2012/122370-A2 discloses quinoline-4-carboxamide derivatives which can be used for the treatment of autoimmune and cancer diseases.

 The present invention relates to compounds of the general formula (I)

in which

the ring Q for a group of the formula

stands, where

# ^{1 represents} the point of attachment to R ⁶ ,

# ^{2 represents} the point of attachment to the nitrogen atom,

Y represents a group of the formula -O-, -CF ₂ -, -C (H) (OH) -, -CHF- or -C (= O) - stands

R ^{A is} hydrogen, halogen, pentafluorosulfanyl, cyano, nitro, (C 1 -C ₄ ) -alkyl, hydroxy, (C 1 -C ₄ ) -alkoxy, amino or a group of the formula -NH-C (= O) -R ⁷ , -NH-C (= O) -NH-R ⁷ or -S (= O) _n -R ⁸ ,

where (C 1 -C ₄ ) -alkyl and (C 1 -C ₄ ) -alkoxy can be substituted up to three times by fluorine,

 and in which

R ^{7 is} hydrogen or (C 1 -C ₄ ) -alkyl which may be substituted up to three times by fluorine,

R ^{8 is} (C 1 -C ₄ ) -alkyl which may be substituted by hydroxy, methoxy or ethoxy or up to three times by fluorine

 and

 n is the number 0, 1 or 2,

D is CR ^D or N,

E is CR ^E or N,

G is CR ^G or N,

 wherein a maximum of two of the ring members D, E and G are also N, and wherein

R ^D and R ^E independently of one another are hydrogen, fluorine, chlorine, methyl, trifluoromethyl, methoxy or trifluoromethoxy

 and

R ^{G is} hydrogen, fluorine, chlorine, bromine, methyl or trifluoromethyl,

R ^{1 is} halogen, up to five times fluorine-substituted (C 1 -C ₄ ) -alkyl, up to three times fluorine-substituted methoxy, (trifluoromethyl) sulfanyl, pentafluorosulfanyl, trimethylsilyl, ethynyl, cyclopropyl, or cyclobutyl,

 where cyclopropyl and cyclobutyl can be substituted up to fourfold by fluorine,

R ² , R ³ and R ⁴ independently of one another represent hydrogen, halogen or up to three times fluorine-substituted methyl, R ^{5 is} halogen, up to five times fluorine-substituted (C 1 -C ₄ ) -alkyl, up to three times fluorine-substituted methoxy, hydroxyl, methylsulfanyl, cyano, ethenyl, cyclopropyl or cyclobutyl,

where cyclopropyl and cyclobutyl may be substituted up to four times by fluorine, R ^{6 is} a group of the formula

stands, where

^{* stands} for the point of attachment to the ring Q,

and

Ar is phenyl which may be substituted up to three times, identically or differently, by fluorine, chlorine, methyl substituted up to three times by fluorine and methoxy substituted up to three times by fluorine, or by thienyl which is mono- or di-methyl or monosubstituted may be substituted by chlorine or bromine, or represents thiazolyl or pyridyl,

and their N-oxides, salts, solvates, salts of N-oxides and solvates of N-oxides and salts. Compounds according to the invention are the compounds of the formula (I) and their salts, solvates and solvates of the salts comprising the compounds of the formulas below and their salts, solvates and solvates of the salts and of the formula (I) encompassed by formula (I), hereinafter referred to as exemplary compounds and their salts, solvates and solvates of the salts, as far as the compounds of formula (I), the compounds mentioned below are not already salts, solvates and solvates of the salts.

 Compounds of the invention are also N-oxides of the compounds of formula (I) and their salts, solvates and solvates of the salts.

Salts used in the context of the present invention are physiologically acceptable salts of the compounds according to the invention. Also included are salts which are not suitable for pharmaceutical applications themselves, but can be used, for example, for the isolation, purification or storage of the compounds according to the invention. Physiologically acceptable salts of the compounds according to the invention include, in particular, the salts derived from customary bases, such as, by way of example and by way of preference, alkali metal salts (eg sodium and potassium salts), alkaline earth salts (eg calcium and magnesium salts), zinc salts and ammonium salts derived from ammonia or organic amines having 1 to 16 C atoms, such as, by way of example and by way of preference, ethylamine, diethylamine, triethylamine, DIPEA, monoethanolamine, diethanolamine, triethanolamine, dimethylaminoethanol, diethylaminoethanol, tris (hydroxymethyl) aminomethane, choline (2-hydroxy-N, N, N-trimethylethanediamine) , Procaine, dicyclohexylamine, dibenzylamine, N-methylmorpholine, N-methylpiperidine, arginine, lysine and 1,2-ethylenediamine.

In addition, physiologically acceptable salts of the compounds of the invention also include acid addition salts of mineral acids, carboxylic acids and sulfonic acids, e.g. Salts of hydrochloric, hydrobromic, sulfuric, phosphoric, methanesulfonic, ethanesulfonic, benzenesulfonic, toluenesulfonic, naphthalenedisulfonic, formic, acetic, trifluoroacetic, propionic, succinic, fumaric, maleic, lactic, tartaric, malic, citric, gluconic, Benzoic acid and embonic acid.

 Solvates in the context of the invention are those forms of the compounds according to the invention which form a complex in the solid or liquid state by coordination with solvent molecules. Hydrates are a special form of solvates that coordinate with water. As solvates, hydrates are preferred in the context of the present invention.

 The compounds of the invention may exist in different stereoisomeric forms depending on their structure, i. in the form of configurational isomers or optionally also as conformational isomers (enantiomers and / or diastereomers, including those in atropisomers). The present invention therefore includes the enantiomers and diastereomers as well as their respective mixtures. From such mixtures of enantiomers and / or diastereomers, the stereoisomerically uniform components can be isolated in a known manner. Preferably, for this purpose, chromatographic methods are used, in particular HPLC chromatography on achiral or chiral separation phases. Alternatively, in the case of carboxylic acids as intermediates or end products, separation may also be via diastereomeric salts using chiral amine bases.

 If the compounds according to the invention can occur in tautomeric forms, the present invention encompasses all tautomeric forms.

The present invention also encompasses all suitable isotopic variants of the compounds according to the invention. An isotopic variant of a compound according to the invention is understood to mean a compound in which at least one atom is present half of the compound of the invention against another atom of the same atomic number, but with a different atomic mass than the usual or predominantly occurring in nature atomic mass is exchanged. Examples of isotopes which can be incorporated into a compound of the invention are those of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine and iodine, such as ² H (deuterium), ³ H (tritium), ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁷ 0, ¹⁸ 0, ³² P, ³³ P, ³³ S, ³⁴ S, ³⁵ S, ³⁶ S, ¹⁸ F, ³⁶ CI, ⁸² Br, ¹²³ l, ¹²⁴ l, ¹²⁹ l and ¹³¹ 1. Certain isotopic variants of a compound of the invention, such as, in particular, those in which one or more radioactive isotopes are incorporated, may be useful, for example, for the study of the mechanism of action or drug distribution in the body; due to the comparatively easy production and detectability, compounds labeled with ³ H or ¹⁴ C isotopes in particular are suitable for this purpose. In addition, the incorporation of isotopes such as deuterium may result in certain therapeutic benefits as a result of greater metabolic stability of the compound, such as prolonging the body's half-life or reducing the required effective dose; Such modifications of the compounds of the invention may therefore optionally also constitute a preferred embodiment of the present invention. Isotopic variants of the compounds according to the invention can be prepared by generally customary processes known to the person skilled in the art, for example by the methods described below and the rules reproduced in the exemplary embodiments, by using appropriate isotopic modifications of the respective reagents and / or starting compounds become.

 In addition, the present invention also includes prodrugs of the compounds of the invention. The term "prodrugs" here denotes compounds which may themselves be biologically active or inactive, but are converted during their residence time in the body by, for example, metabolic or hydrolytic routes to compounds of the invention.

In particular, the present invention comprises, as prodrugs, hydrolyzable ester derivatives of the carboxylic acids of the formula (I) according to the invention [where Z = OH]. These are understood to mean esters which can be hydrolyzed in physiological media under the conditions of the biological tests described below and in particular enzymatically or chemically in vivo to the free carboxylic acids, as the biologically mainly active compounds. As such esters, (C 1 -C ₄ ) -alkyl esters in which the alkyl group may be straight-chain or branched are preferred. Particularly preferred are methyl, ethyl or tert-butyl esters.

Unless otherwise specified, in the context of the present invention, the substituents have the following meaning: (C 1 -C ₄ ) -alkyl in the context of the invention is a straight-chain or branched alkyl radical having 1 to 4 carbon atoms. Examples which may be mentioned are: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl.

In the context of the invention, (C 1 -C ₄ ) -alkoxy represents a straight-chain or branched alkoxy radical having 1 to 4 carbon atoms. For example and preferably, the following may be mentioned: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy and tert-butoxy.

 Halogen in the context of the invention includes fluorine, chlorine, bromine and iodine.

 In the context of the present invention, the meaning is independent of each other for all radicals which occur repeatedly. If radicals are substituted in the compounds according to the invention, the radicals can, unless otherwise specified, be monosubstituted or polysubstituted. Substitution with one or two identical or different substituents is preferred. Particularly preferred is the substitution with a substituent.

Preferred in the context of the present invention are compounds of the formula (I) in which the ring Q is a group of the formula

is the point of attachment to R ⁶ ,

 represents the point of attachment to the nitrogen atom,

 represents a group of the formula -C (H) (OH) - or -CHF-,

is hydrogen, fluorine, chlorine, bromine, cyano, methyl, trifluoromethyl, methoxy, trifluoromethoxy or a group of the formula -S (= O) _n -R ⁸ , in which

R ^{8 is} methyl or trifluoromethyl

 and

 n is the number 0 or 2,

is CR ^D or N, in which

R ^{D is} hydrogen or fluorine,

stands for CH, G is CR ^G or N, in which

R ^{G is} hydrogen, fluorine or chlorine,

 is chlorine, bromine, iodine, methyl, isopropyl, tert-butyl, difluoromethyl, trifluoromethyl, trifluoromethoxy, (trifluoromethyl) sulfanyl, trimethylsilyl, ethynyl, cyclopropyl or cyclobutyl,

 stands for hydrogen,

and R ⁴ independently of one another represent hydrogen, chlorine or methyl,

 is fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, monofluoromethyl, difluoromethyl, trifluoromethyl, methoxy, trifluoromethoxy, hydroxy, methylsulfanyl or cyclopropyl, is a group of the formula

stands, where

 * stands for the point of attachment to the ring Q,

and

Ar is phenyl which may be mono- or di-substituted by fluorine, thienyl which may be mono- or di-substituted by methyl or simply by chlorine or bromine, or by a group of the formula

 stands, where

# ^{3 represents} the point of attachment to the quinoline ring,

R ^{9 is} chlorine or methyl, and R ^{10 is} chlorine or methoxy,

and their salts, solvates and solvates of the salts.

 Preferred in the context of the present invention are compounds of the formula (I) in which the ring Q is a group of the formula

 stands, where

# ^{1 represents} the point of attachment to R ⁶ ,

# ^{2 represents} the point of attachment to the nitrogen atom,

R ^{A is} fluorine, chlorine, cyano, methyl, trifluoromethyl, methoxy, trifluoromethoxy or a group of the formula -S (= O) _n -R ⁸ , in which

R ^{8 is} methyl or trifluoromethyl

 and

 n is the number 0 or 2,

 D stands for C-H,

 E stands for C-H,

G is CR ^G or N, in which

R ^{G is} hydrogen, fluorine or chlorine,

 is chlorine, bromine, iodine, methyl, tert-butyl, difluoromethyl, trifluoromethyl, trimethylsilyl, ethynyl or cyclopropyl,

 stands for hydrogen,

and R ⁴ independently of one another represent hydrogen, chlorine or methyl,

wherein at least one of R ³ and R ^{4 is in} each case hydrogen,

 is fluorine, chlorine, methyl, ethyl, methoxy, hydroxy, methylsulfanyl or cyclopropyl,

for a group of the formula

stands, where

 * stands for the point of attachment to the ring Q,

and

 Ar represents phenyl, which may simply be substituted by fluorine,

and their salts, solvates and solvates of the salts.

 Particularly preferred in the context of the present invention are compounds of the formula (I) in which the ring Q is a group of the formula

 stands, where

# ^{1 represents} the point of attachment to R ⁶ ,

# ^{2 represents} the point of attachment to the nitrogen atom,

R ^{A is} hydrogen, fluorine or a group of the formula -S (= ^O ) ₂ CH ₃ ,

 D stands for C-H,

 E stands for C-H,

 G stands for C-H,

R ^{1 is} bromine,

R ² , R ³ and R ^{4 are} hydrogen,

R ^{5 is} methyl, cyclopropyl or chlorine, for a group of the formula

l, l or l, where

 * stands for the point of attachment to the ring Q,

and

 Ar is phenyl,

and their salts, solvates and solvates of the salts.

 Very particularly preferred in the context of the present invention are compounds of the formula (I) in which the ring Q is a group of the formula

 stands, where

# ^{1 represents} the point of attachment to R ⁶ ,

# ^{2 represents} the point of attachment to the nitrogen atom,

R ^{A is} hydrogen, fluorine or a group of the formula -S (= ^O ) ₂ CH ₃ ,

 D stands for C-H,

 E stands for C-H,

 G stands for C-H,

 stands for bromine,

R ³ and R ^{4 are} hydrogen, R ^{5 is} methyl, cyclopropyl or chlorine,

R ^{6 is} a group of the formula

stands, where

 * stands for the point of attachment to the ring Q,

and

 Ar is phenyl,

and their salts, solvates and solvates of the salts.

 A particular embodiment of the present invention comprises compounds of the formula (I) in which the ring Q is a group of the formula

 stands, where

# ^{1 represents} the point of attachment to R ⁶ , and

# ^{2 represents} the point of attachment to the nitrogen atom,

and their N-oxides, salts, solvates, salts of N-oxides and solvates of N-oxides and salts.

Another particular embodiment of the present invention comprises compounds of the formula (I) in which the ring Q is a group of the formula

 stands, where

# ^{1 represents} the point of attachment to R ⁶ ,

# ^{2 represents} the point of attachment to the nitrogen atom, and R ^{A is} hydrogen, fluorine or a group of the formula -S (= ^O ) ₂ CH ₃ , and their N-oxides, salts, solvates, salts of N-oxides and solvates of N-oxides and salts.

Another particular embodiment of the present invention comprises compounds of formula (I) in which R ^{6 is} a group of formula

stands, where

^{* stands} for the point of attachment to the ring Q,

and their N-oxides, salts, solvates, salts of N-oxides and solvates of N-oxides and salts.

Another particular embodiment of the present invention comprises compounds of formula (I) in which R ^{6 is} a group of formula

stands, where

^{* stands} for the point of attachment to the ring Q,

and their N-oxides, salts, solvates, salts of N-oxides and solvates of N-oxides and salts. Another particular embodiment of the present invention comprises compounds of formula (I) in which R ^{6 is} a group of formula

stands, where

^{* stands} for the point of attachment to the ring Q,

and their N-oxides, salts, solvates, salts of N-oxides and solvates of N-oxides and salts. Another particular embodiment of the present invention comprises compounds of formula (I) in which R ^{6 is} a group of formula

stands, where

^{* stands} for the point of attachment to the ring Q,

and their N-oxides, salts, solvates, salts of N-oxides and solvates of N-oxides and salts.

Another particular embodiment of the present invention comprises compounds of formula (I) in which R ^{6 is} a group of formula

stands, where

^{* stands} for the point of attachment to the ring Q,

and their N-oxides, salts, solvates, salts of N-oxides and solvates of N-oxides and salts.

Another particular embodiment of the present invention comprises compounds of formula (I) in which R ^{6 is} a group of formula

stands, where

^{* stands} for the point of attachment to the ring Q,

and their N-oxides, salts, solvates, salts of N-oxides and solvates of N-oxides and salts.

Another particular embodiment of the present invention comprises compounds of formula (I) in which R ^{6 is} a group of formula

stands, where

^{* stands} for the point of attachment to the ring Q,

and their N-oxides, salts, solvates, salts of N-oxides and solvates of N-oxides and salts. Another particular embodiment of the present invention comprises compounds of formula (I) in which R ^{6 is} a group of formula

stands, where

 * stands for the point of attachment to the ring Q,

and their N-oxides, salts, solvates, salts of N-oxides and solvates of N-oxides and salts.

Another particular embodiment of the present invention comprises compounds of the formula (I) in which

R ^{1 is} bromine, and

R ² , R ³ and R ^{4 are} each hydrogen,

and their N-oxides, salts, solvates, salts of N-oxides and solvates of N-oxides and salts.

Another particular embodiment of the present invention comprises compounds of the formula (I) in which

R ^{1 is} iodine, and

R ² , R ³ and R ^{4 are} each hydrogen,

and their N-oxides, salts, solvates, salts of N-oxides and solvates of N-oxides and salts.

Another particular embodiment of the present invention comprises compounds of the formula (I) in which

R ^{5 is} methyl, cyclopropyl or chlorine,

and their N-oxides, salts, solvates, salts of N-oxides and solvates of N-oxides and salts. Another particular embodiment of the present invention comprises compounds of the formula (I) in which

R ^{5 is} methyl,

and their N-oxides, salts, solvates, salts of N-oxides and solvates of N-oxides and salts. Another particular embodiment of the present invention comprises compounds of the formula (I) in which

 Ar is phenyl,

and their N-oxides, salts, solvates, salts of N-oxides and solvates of N-oxides and salts.

The residue definitions given in detail in the respective combinations or preferred combinations of residues are also replaced by residue definitions of other combinations, regardless of the particular combinations of the residues indicated.

Very particular preference is given to combinations of two or more of the abovementioned preferred ranges.

 The radical definitions mentioned as being preferred, particularly preferred and very particularly preferred apply both to the compounds of the formula (I) and, correspondingly, to all intermediates.

 Another object of the invention is a process for the preparation of the compounds of formula (I) according to the invention, characterized in that either

 [A] a compound of the formula (II)

in which R ¹ , R ² , R ³ , R ⁴ , R ⁵ , Q and Ar have the abovementioned meanings, with a suitable azide compound to give a compound of the formula (IA)

in which R ¹ , R ² , R ³ , R ⁴ , R ⁵ , Q and Ar have the meanings given above,

or

 a compound of the formula

in which R ¹ , R ³ , R ⁴ , R ⁵ , Q and Ar have the meanings given above, either

[B-1] with thionyl chloride to give a compound of the formula (1B)

in which R ¹ , R ³ , R ⁴ , R ⁵ , Q and Ar have the meanings given above,

or

 [B-2] with Λ /, Λ / '- thiocarbonyldiimidazole and a suitable additive in each case to give a compound of the formula (I-C) or (I-D)

in which R ¹ , R ² , R ³ , R ⁴ , R ⁵ , Q and Ar have the meanings given above,

or

[B-3] with Λ /, Λ / '- carbonyldiimidazole, phosgene or a suitable phosgene analogue to give a compound of the formula (I)

in which R ¹ , R ² , R ³ , R ⁴ , R ⁵ , Q and Ar have the meanings given above,

or

[C] a compound of the formula (IV)

in which R ¹ , R ³ , R ⁴ , R ⁵ , Q and Ar have the abovementioned meanings, with Λ /, Λ / '- carbonyldiimidazole, phosgene or a suitable P osgenanalogon to a compound of formula (lF)

in which R ¹ , R ² , R ³ , R ⁴ , R ⁵ , Q and Ar have the meanings given above,

or

[D] a compound of formula (V)

in which R ¹ , R ³ , R ⁴ , R ⁵ , Q and Ar have the abovementioned meanings, with (phenylsulfonyl) acetonitrile and sodium azide to give a compound of the formula (I)

in which R ¹ , R ³ , R ⁴ , R ⁵ , Q and Ar have the meanings given above,

or

 [E] a compound of the formula (VI)

in which R ¹ , R ² , R ³ , R ⁴ , R ⁵ , Q and Ar have the abovementioned meanings, with semicarbazide hydrochloride to give a compound of the formula (1H)

in which R ¹ , R ² , R ³ , R ⁴ , R ⁵ , Q and Ar have the meanings given above, is reacted

and the compounds according to the invention thus obtained are optionally converted with the corresponding (i) solvents and / or (ii) acids or bases into their solvates, salts and / or solvates of the salts.

 The compounds of formulas (I-A), (I-B), (I-C), (I-D), (I-E), (I-F), (I-G) and (I-H) together form the amount of the compounds of formula (I) according to the invention.

Inert solvents for process steps (II) (IA), (III) (IB), (III) (IC), (III) (ID), (III) -> (IE), (IV) -> (IF) , (V) -> (lG) and (VI) -> (lH) are - depending on the method used - For example, ethers such as diethyl ether, methyl-Fe / t-butyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, hydrocarbons such as benzene, toluene, xylene, hexane, cyclohexane or petroleum fractions, halogenated hydrocarbons such as dichloromethane, trichloromethane, carbon tetrachloride, 1, 2nd Dichloroethane, trichloroethane, tetrachloroethane, trichlorethylene, chlorobenzene or chlorotoluene, or other solvents such as dimethylsulfoxide (DMSO), dimethylformamide (DMF), Λ /, Λ / '- dimethylpropyleneurea (DMPU), N-methylpyrrolidone (NMP) or acetonitrile. It is likewise possible to use mixtures of the solvents mentioned. Preference is given to dichloromethane for process step (VI) -> (1H), tetrahydrofuran for process steps (III) -> (IB), (III) -> (IC), (III) -> (ID), (III) > (IE) and (IV) → (IF) and dimethylformamide or toluene, depending on the azide compound, for process steps (II) -> (IA) and (V) -> (LG) or mixtures of these solvents.

Suitable bases for process steps (III) -> (IB), (III) -> (IC) and (III) -> (IE) are - depending on the process used - conventional inorganic or organic bases. These include preferably alkali metal hydroxides such as lithium, sodium or potassium hydroxide, alkali metal or alkaline earth metal carbonates such as lithium, sodium, potassium, calcium or cesium carbonate, alkali metal hydrides such as sodium or potassium hydride, amides such as lithium or potassium bis (trimethylsilyl ) - amide or lithium diisopropylamide, or organic amines such as triethylamine, N-methylmorpholine, N-methylpiperidine, N, N-diisopropylethylamine, pyridine, 4-N, N-dimethylaminopyridine, 1, 5-diazabicyclo [4.3.0] non- 5-ene (DBN), 1, 4-diazabicyclo [2.2.2] octane (DABCO ^®) or 1, 8- diazabicyclo [5.4.0] undec-7-ene (DBU). For the process step (VI) -> (lH) are suitable organic amines such as triethylamine, N-methylmorpholine, N-methylpiperidine, N, N-diisopropyl-ethylamine, pyridine, 4-N, N-dimethylaminopyridine, 1, 5-diazabicyclo [ 4.3.0] non-5-ene (DBN), 1, 4- diazabicyclo [2.2.2] octane (DABCO ^®) or 1, 8-diazabicyclo [5.4.0] undec-7-ene (DBU). Preference is given to pyridine for process step (III) -> (IB), DBU for process steps (III) -> (I-C) and (III) -> (IE) and triethylamine for process step (VI) -> (lH ) used.

 The reactions mentioned are generally carried out, depending on the reactivity of the participating reactants, in a temperature range of 0Ό bi s + 140Ό. Process steps (II) -> (I-A) and (V) -> (I-G) are preferably carried out in a temperature range from 80 ° to 140 °. Process steps (III) -> (IB), (III) -> (IC), (III) -> (ID), (III) -> (I-E), (IV) -> (IF) and ( VI) -> (lH) are preferably carried out in a temperature range from 0Ό to 50 Ό. The reactions may be at normal, elevated or reduced pressure (e.g., from 0.5 to 5 bar). Generally, one works at normal pressure. Depending on the reactivity of the compounds used, some process steps may preferably be carried out under an argon atmosphere.

In process step (II) -> (IA) suitable azide compounds are used. Suitable azide compounds are, for example, sodium azide, trimethylsilyl azide, dialkylaluminum azide and hydrazoic acid. The reaction can be carried out with the addition of an additive or catalyst such as tributyltin oxide, tributyltin chloride, ammonium halide, copper sulfate, nickel ferrite (NiFe204) or other metal compounds such as copper, zinc, zirconium, scandium salts or with addition of acetic acid. The reaction can be carried out, for example, in solvents such as N, / V-dimethylformamide (DMF), N-methylpyrrolidone (NMP), dimethyl sulfoxide (DMSO) or toluene. Process step (II) -> (IA) is preferably carried out either with sodium azide and ammonium chloride in DMF or with trimethylsilyl azide and di-butyltin oxide in toluene.

 In process step (III) -> (I-C) and (III) -> (I-D), the constitution of the resulting product can be influenced by the choice of a suitable additive. Suitable additives for process step (III) -> (I-C) are DBU or other amine bases, such as triethylamine or diisopropylethylamine. Suitable additives for process step (III) -> (I-D) are Lewis acids such as, for example, silica gel or boron trifluoride diethyl etherate. In process step (III) -> (I-D), Λ /, Λ / '- thiocarbonyldiimidazole can alternatively be replaced by chlorocarbonyl sulfenyl chloride.

 In the process steps (III) -> (l-E) and (IV) -> (l-F) N, / V-carbonyldiimidazole, phosgene or suitable phosgene analogues are used. Suitable phosgen analogues for process steps (III) -> (IE) and (IV) -> (IF) are, for example, diphosgene, phenyl chloroformate, methyl chloroformate, ethyl chloroformate, isobutyl chloroformate, 2-ethylhexyl chloroformate, 2-ethylcyclohexyl chloroformate, triphosgene, diphenyl carbonate, Dimethyl carbonate or diethyl carbonate.

 The process step (V) -> (l-G) is preferably carried out with (phenylsulfonyl) acetonitrile in DMF and a solution of sodium azide in water, [see. Tetrahedron Letters 2012, 53 (1), 59-63].

 For process step (VI) -> (1-H), instead of the acid chloride of formula (VI), it is also possible to react a corresponding carboxylic acid ester or a corresponding carboxylic acid orthoester with the semicarbazide. Alternatively, for the preparation of a compound of the formula (1H) from a cyano compound of the formula (II) by reaction with hydrazine hydrate, a hydrazonamide can be generated, which is converted to the desired triazolone by reaction with Λ /, Λ / '- carbonyldiimidazole or a phosgene analogue can be.

Compounds of the formula (II) and (VI) can be prepared from quinolinecarboxylic acids of the formula (VII) (Scheme 1 a). Upon activation of the carboxylic acid function and coupling with an amine compound of the formula (X), ester compounds of the formula (XI) are obtained which are transformed by the person skilled in the art into the corresponding carboxylic acid chloride compound of the formula (VI) or cyano compound of the formula (II ) can be converted:

The coupling reaction (VII) + (X) -> (XI) [amide formation] can be carried out with the aid of a condensation or activating agent or via the intermediate of a carboxylic acid chloride or carboxylic acid imidazolide obtainable from (VII).

Carbodiimides such as Λ /, Λ / '- diethyl, Λ /, Λ /' - dipropyl, Λ /, Λ / '- diisopropyl-, Λ /, Λ /' - dicyclohexylcarbodiimide are suitable as such condensation or activating agents. DCC) or Λ / - (3-dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride (EDC), phosgene derivatives such as Λ /, Λ / '- car- bonyldiimidazole (CDI) or isobutyl chloroformate, 1,2-oxazolium compounds such as 2-ethyl-5-phenyl-1,2-oxazolium-3-sulfate or 2-tert-butyl-5-methylisoxazolium perchlorate, acylamino compounds such as 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline, α-chloroeneamines such as 1-chloro-N, N, 2-trimethylprop-1 -ene-1-amine, 1, 3,5-triazine derivatives, such as 4- (4,6-dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholinium chloride, phosphorus compounds such as n-propanephosphonic anhydride (PPA), cyanophosphonic acid diethyl ester, diphenylphosphoryl azide (DPPA), bis (2-oxo-3 -oxazolidinyl) -phosphoryl chloride, benzotriazole-1-ynyloxy-tris (dimethylamino) phosphonium hexafluorophosphate or benzotriazole-1-ynyloxy-tris (pyrrolidino) phosphonium hexafluorophosphate (PyBOP), or uronium compounds such as 0- (benzotriazole -1 -yl) - / V, / V, / V '/ \ / - tetramethyluronium tetrafluoroborate (TBTU), 0- (benzotriazol-1-yl) -N, N, / \ /', / \ / tetramethyluronium hexafluorophosphate (HBTU), 0- (1H-6-chlorobenzotriazol-1-yl) -1, 1, 3,3-tetramethyluroni tetrafluoroborate (TCTU), O- (7-azabenzo-triazol-1-yl) -N, N, \ / ', / \ / tetramethyluronium hexafluorophosphate (HATU) or 2- (2-oxo-1 - (2H) -pyridyl) -1,3,3-tetramethyluronium tetrafluoroborate (TPTU), if appropriate in combination with other auxiliaries, such as 1-hydroxybenzotriazole (HOBt) or N-hydroxysuccinimide (HOSu), and as bases, alkali metal carbonates, for example, sodium or potassium carbonate, or tertiary amine bases such as triethylamine, N-methylmorpholine (NMM), N-methylpiperidine (NMP), N, N-diisopropylethylamine (DIPEA), pyridine or 4-N, N-dimethylaminopyridine (DMAP).

 In the case of a two-stage reaction procedure via the carboxylic acid chlorides of the formula (IX) or carboxylic acid imidazolides of the formula (VIII) obtainable from (VII), the coupling with the amine component of the formula (X) is carried out in the presence of a customary base, for example sodium or Potassium carbonate, triethylamine, N, / V-diisopropylethylamine (DIPEA), N-methylmorpholine (NMM), N-methylpiperidine (NMP), pyridine, 2,6-dimethylpyridine, 4-N, N-dimethylaminopyridine (DMAP), 1, 8 Diazabicyclo [5.4.0] undec-7-ene (DBU), 1, 5-diazabicyclo [4.3.0] non-5-ene (DBN), sodium or potassium methoxide, sodium or potassium ethanolate, sodium or potassium tert-butoxide or sodium or potassium hydride. In process step (VIII) + (X) -> (XI) it is preferred to use potassium tert-butoxide. In process step (IX) + (X) -> (XI) pyridine is preferably used.

Depending on the process used, inert solvents for the stated coupling reactions are, for example, ethers, such as diethyl ether, diisopropyl ether, methyl tert-butyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane or bis (2-methoxyethyl) ether , Hydrocarbons such as benzene, toluene, xylene, pentane, hexane or cyclohexane, halogenated hydrocarbons such as dichloromethane, trichloromethane, carbon tetrachloride, 1, 2-dichloroethane, trichlorethylene or chlorobenzene, or polar aprotic solvents such as acetone, methyl ethyl ketone, ethyl acetate, acetonitrile, butyronitrile , Pyridine, dimethyl sulfoxide (DMSO), N, N-dimethylformamide (DMF), Ν, Ν'-dimethylpropyleneurea (DMPU) or N-methylpyrrolidinone (NMP). It is also possible to use mixtures of such solvents. Preferably, N, / V-dimethylformamide is used. The couplings are generally carried out in a temperature range from 0Ό to +1 10Ό, preferably at + 20Ό to + 80Ό. The carboxylic acid imidazolides themselves are obtainable by known methods by reacting (VII) with Λ /, Λ / '- carbonyldiimidazole (CDI) at elevated temperature (+ 60Ό to + 150Ό) in a correspondingly higher-boiling solvent such as N, N-dimethylformamide (DMF) , The carboxylic acid chlorides are prepared in the usual way by treatment of (VII) with thionyl chloride or oxalyl chloride in an inert solvent such as dichloromethane.

 The cleavage of the ester in process step (XI) -> (XII) is carried out by customary methods by treating the ester in an inert solvent with an acid or base, wherein in the latter variant, the initially formed salt of the carboxylic acid by subsequent treatment with acid is converted into the free carboxylic acid. In the case of tert-butyl esters, the ester cleavage is preferably carried out with an acid. Methyl and ethyl esters are preferably cleaved by means of a base. Benzyl esters can alternatively also be removed by hydrogenation (hydrogenolysis) in the presence of a suitable catalyst, for example palladium on activated carbon. Silyl esters may be obtained by treatment with acids or fluorides, e.g. Tetrabutylammonium fluoride are cleaved.

Suitable solvents are, depending on the process used, water and the organic solvents customary for ester cleavage. These include in particular alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol or tert-butanol, ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane or 1,2-dimethoxyethane, or other solvents such as dichloromethane, acetonitrile, N, / V-dimethylformamide or dimethylsulfoxide. It is also possible to use mixtures of these solvents. In the case of basic ester hydrolysis, preference is given to using mixtures of water with tetrahydrofuran, 1,4-dioxane, methanol and / or ethanol. In the case of the reaction with trifluoroacetic acid, preference is given to using dichloromethane and, in the case of reaction with hydrogen chloride, preferably 1,4-dioxane, in each case under anhydrous conditions.

Suitable bases are the inorganic bases customary for a hydrolysis reaction. These include in particular alkali metal or alkaline earth metal hydroxides such as lithium, sodium, potassium or barium hydroxide, or alkali metal or alkaline earth metal carbonates such as sodium, potassium or calcium carbonate. Preference is given to using aqueous lithium hydroxide solution or sodium hydroxide solution (sodium hydroxide solution).

Suitable acids for the ester cleavage are generally sulfuric acid, hydrochloric acid / hydrochloric acid, hydrobromic / hydrobromic acid, phosphoric acid, acetic acid, trifluoroacetic acid, toluenesulfonic acid, methanesulfonic acid or trifluoromethanesulfonic acid or mixtures thereof, optionally with the addition of water. Hydrogen chloride or trifluoroacetic acid are preferably used.

The ester cleavage is usually carried out in a temperature range from -20Ό to + 100Ό, preferably at 0 ^< C to +80 ^< C. The preparation of the acid chloride (XII) -> (VI) is carried out in a conventional manner by treating a carboxylic acid of formula (XII) with oxalyl chloride or thionyl chloride in an inert solvent such as dichloromethane, trichloromethane or 1,2-dichloroethane, optionally with a small amount on N, / V-dimethylformamide as a catalyst. The reaction is generally carried out at a temperature of 0Ό to + 30 "C.

 The amide formation in process step (VI) -> (XIII) is usually carried out in the presence of a larger excess of the amine component, optionally with the addition of a conventional tertiary amine base as auxiliary base, such as triethylamine, DIPEA, N-methylmorpholine (NMM), N-methylpiperidine (NMP), pyridine, 2,6-dimethylpyridine or 4-N, N-dimethylaminopyridine (DMAP). Inert solvents for this reaction are - depending on the process used - for example, ethers such as diethyl ether, diisopropyl ether, methyl tert-butyl ether, tetrahydrofuran, 1, 4-dioxane, 1, 2-dimethoxyethane or bis (2-methoxyethyl) ether, hydrocarbons such Benzene, toluene, xylene, pentane, hexane or cyclohexane, halogenated hydrocarbons such as dichloromethane, trichloromethane, tetrachloromethane, 1, 2-dichloroethane, trichlorethylene or chlorobenzene, polar aprotic solvents such as acetone, methyl ethyl ketone, ethyl acetate, acetonitrile, butyronitrile, pyridine, dime - Thylsulfoxid (DMSO), Ν, Ν-dimethylformamide (DMF), Λ /, Λ / '- dimethylpropyleneurea (DMPU) or N-methylpyrrolidinone (NMP), or water. Likewise, mixtures of such solvents can be used. Preferably, water or a mixture of water with tetrahydrofuran, 1, 4-dioxane, 1, 2-dimethoxyethane or acetone is used. The reaction is usually carried out at a temperature of 0Ό to + 40Ό.

Alternatively, compounds of formula (II) may be prepared under similar reaction conditions directly via an amide coupling of a compound of formula (VII) with a compound of formula (XIV) (Scheme 1 b).

Alternatively, compounds of the formula (II-A) or (VA) can be prepared via a nucleophilic substitution reaction of a haloaromatic of the formula (XVII) or via a palladium-catalyzed coupling reaction of a haloaromatic of the formula (XVIII) with a quinolinecarboxamide of the formula (XVI) Scheme 2).

 (II-A) (V-A)

[(X ¹ ): F, Cl; (X ² ): Br, I].

 Process step (XVI) + (XVIII) -> (V-A) takes place in a solvent which is inert under the reaction conditions. Suitable solvents are, for example, ethers such as 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, diethyl ether, di-n-butyl ether, glycol dimethyl ether or diethylene glycol dimethyl ether, alcohols such as tert-butanol or amyl alcohols or other solvents such as dimethylformamide (DMF). , Dimethyl sulfoxide (DMSO), dimethylacetamide (DMA), toluene or acetonitrile. It is likewise possible to use mixtures of the solvents mentioned. For process step (XVI) + (XVIII) -> (V-A), preference is given to the use of 1,4-dioxane.

The process step (XVI) + (XVIII) -> (VA) is carried out in the presence of a suitable palladium catalyst. As the palladium catalyst, for example, palladium on activated carbon, palladium (II) acetate, bis (dibenzylideneacetone) palladium (0), tetrakis (triphenylphosphine) palladium (0), bis (triphenylphosphine) palladium (II) chloride , Bis (acetonitrile) -palladium (II) chloride, [1, 1 '-bis (diphenylphosphino) ferrocene] dichloropalladium (II), optionally in combination with additional phosphine ligands such as, for example, 2,2'-bis ( diphenylphosphino) -1,1'-binaphthyl (BINAP), (2-biphenyl) nyl) di-tert-butylphosphine, dicyclohexyl [2 ', 4', 6'-tris (1-methylethyl) biphenyl-2-yl] phosphine (XPhos), bis (2-phenylphosphinophenyl) ether (DPEphos) or 4, 5-bis (diphenylphosphino) -9,9-dimethylxanthene (xantphos), 2- (dicyclohexylphosphine) -3,6-dimethoxy-2 ', 4', 6'-triisopropyl-1,1'-biphenyl (BrettPhos), 2 -Dicyclohexylphosphino-2 ', 6'-dimethoxybiphenyl (SPhos), 2-dicyclohexylphosphino-2', 6'-diisopropoxybiphenyl (RuPhos), 2- (di-t-butylphosphino) -3-methoxy-6-methyl-2 ', 4', 6'-tri-i-propyl-1, 1'-biphenyl (RockPhos) and 2-di-tert-butylphosphino-2 ', 4', 6'-triisopropylbiphenyl (fert-ButylXPhos) suitable [see. eg Hassan J. et al., Chem. Rev. 2002, 102, 1359-1469]. Furthermore, it is possible corresponding precatalysts such as chloro- [2- (dicyclohexylphosphine) -3,6-dimethoxy-2 ', 4', 6'-triisopropyl-1, 1'-biphenyl] [2- (2-aminoethyl) phenyl ] palladium (II) (BrettPhos precatalyst) optionally in conjunction with additional phosphine ligands such as 2- (di-cyclohexylphosphine) -3,6-dimethoxy-2 ', 4', 6'-triisopropyl-1,1'-biphenyl (BrettPhos) to use [cf. eg SL Buchwald et al., Chem. 2013, 4, 916]. For process step (XVI) + (XVIII) → (VA), preference is given to using tris (dibenzylideneacetone) dipalladium in combination with 4,5-bis (diphenylphosphino) -9,9-dimethylxanthene.

The process step (XVI) + (XVIII) -> (V-A) is carried out in the presence of a suitable base. Suitable bases for this reaction are the usual inorganic or organic bases. These include preferably alkali metal or alkaline earth metal carbonates such as lithium, sodium, potassium, calcium or cesium carbonate, alkali metal or alkaline earth metal hydroxides such as sodium, potassium or barium hydroxide, alkali metal or alkaline earth metal phosphates such as potassium phosphate, alkali metal alcoholates such as sodium or potassium ferric butylate and sodium methoxide, alkali phenolates such as sodium phenolate, amides such as sodium amide, lithium, sodium or potassium bis (trimethylsilyl) amide or lithium diisopropylamide or organic amines such as 1, 5-diazabicyclo [4.3.0] non -5-ene (DBN), 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU). For the process step (XVI) + (XVIII) -> (V-A), cesium carbonate is preferably used.

The process step (XVI) + (XVIII) -> (V-A) is generally carried out in a temperature range from 0Ό to + 200Ό, preferably at + 10Ό to + 150Ό. The reactions can also be carried out in closed vessels (microwave tubes) in a microwave apparatus. The reaction may be carried out at normal, elevated or reduced pressure (e.g., from 0.5 to 5 bar). In general, working at atmospheric pressure or in closed vessels (microwave tubes) below or above the boiling point of the solvent used.

Process step (XVI) + (XVII) -> (II-A) takes place in a solvent which is inert under the reaction conditions. Suitable solvents are, for example, ethers such as diethyl ether, methyl tert-butyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, hydrocarbons such as benzene, toluene, xylene, hexane, cyclohexane or petroleum fractions or other solvents such as dimethyl sulfoxide (DMSO), dimethylformamide (DMF ) Λ /, Λ / '- dimethylpropyleneurea (DMPU), N-methyl-pyrrolidone (NMP) or acetonitrile. It is likewise possible to use mixtures of the solvents mentioned. The process step (XVI) + (XVII) -> (II-A) is carried out in the presence of a suitable base, for example sodium hydride, and generally runs in a temperature range from -20 Ό to 50 Ό. The subsequent substitution step is generally carried out in a temperature range of 20 Ό to 150 ^<C.

 Compounds of the formula (III) can be prepared by reacting compounds of the formula (II) with hydroxylammonium chloride in the presence of bicarbonate, compounds of the formula (V) can be prepared by reacting compounds of the formula (II) with diisobutylaluminum hydride (Scheme 3).

 Scheme 3:

Compounds of the formula (IV) can be prepared by reacting compounds of the formula (VI) with aqueous hydrazine hydrate solution (Scheme 4). Scheme 4:

 Depending on the respective substitution pattern, the compounds of the formula (VII) (see Scheme 1 a) can be prepared by reacting either an isatin derivative of the formula (XIX) in an acid- or base-mediated condensation reaction analogously to processes known from the literature a ketomethylene compound of formula (XX) to the compound of formula (VII) is reacted (Scheme 5a) or ortfro-Aminophenylessigsäureester the formula

(XXI) in an acid-induced condensation reaction with a diketo compound of the formula

(XXII) to give a compound of formula (VII-A) (Scheme 5b).

Scheme 5a:

(XXI) (VII-A) The condensation of the isatin derivative of formula (XIX) with the ketomethylene compound of formula (XX) to the quinoline-4-carboxylic acid of formula (VII) (Scheme 5a) can be carried out by heating the reactants in the presence of an aqueous acid such as sulfuric acid or concentrated hydrochloric acid, or in the presence of an aqueous base, such as sodium or potassium hydroxide, can be achieved. When using an acid, acetic acid is preferably used as the solvent for the reaction; in basic reaction, an alcoholic solvent such as methanol or ethanol is preferably used. The condensation is generally carried out in a temperature range from + 70Ό to + 120Ό [cf. eg. K. Lackey and DD Sternbach, Synthesis, 1993, 993-997; AN Boa et al., Bioorg. Med. Chem. 2005, 13 (6), 1945-1967].

The condensation reaction to the quinoline-4-carboxylic acid of formula (VII-A) (Scheme 5b) is carried out in an analogous manner by heating the ortfro-Aminophenylessigsäureesters of formula (XXI) and the diketone of formula (XXII) with aqueous acid, in particular concentrated hydrochloric acid. As the inert solvent for the reaction, acetic acid is also preferably used here.

 The site / 70-aminophenylacetic acid ester of the formula (XXI), in turn, can be prepared by a base-mediated reaction of the α-chloroacetic acid ester of the formula (XXIII) with a nitrophenyl derivative of the formula (XXIV) Nitrophenylacetic acid ester of the formula (XXV) are reacted (Scheme 6). The subsequent reduction of the nitro group to a compound of the formula (XXI) can be obtained, for example, by catalytic hydrogenation [cf. Beier et al., J. Org. Chem. 2011, 76, 4781-4786]. Scheme 6:

The compounds of the formula (X) are commercially available or their preparation is described in the literature, or they can, starting from other commercially available compounds, be prepared by methods known to those skilled in the literature.

The amine functionality of the compounds of formula (X) may also be represented by known Curtius rearrangement from the corresponding carboxylic acid azide (Scheme 7). After activation of the acid functionality, for example as carboxylic acid chloride or anhydride, the carboxylic acid is first reacted with sodium azide to form the acid azide. Alternatively, the carboxylic acid can be reacted with diphenylphosphoryl azidate (DPPA) under basic conditions, for example with triethylamine as base, and in the presence of an alcohol such as butanol or benzyl alcohol at elevated temperatures (see J. Am Chem. Soc, 1972 , 94 (17), 6203-6205). The resulting protected amines can then be deprotected, usually in the case of a Boc protecting group by acid hydrolysis with addition of e.g. Hydrochloric acid or trifluoroacetic acid or in the case of a Z-protecting group by hydrogenation to the corresponding amine. The temperature range in the Curtius rearrangement is typically in the range + 40Ό bi s + 120Ό. Inert solvents such as toluene or THF may be added. Other variants of the rearrangement of carboxylic acid to the amine are readily available to those skilled in the relevant literature.

 Scheme 7:

 (XXVII) (XXVIII)

(XXIX) (X)

The compounds of formulas (XIV), (XVII), (XVIII), (XIX), (XX), (XXII), (XXIII), (XXIV) and (XXVI) are also commercially available or described as such in the literature , or they can, starting from other commercially available compounds, be prepared in a simple manner in analogy to literature methods.

 Detailed instructions and further references can also be found in the Experimental Section in the section on the Preparation of Starting Compounds and Intermediates.

Further compounds of the formula (I) according to the invention can, if appropriate, also be prepared by conversions of functional groups of individual radicals and substituents, in particular those listed under R ¹ and R ⁵ , whereby other compounds of the formula (I ) or their precursors is assumed. These transformations are carried out by customary methods known to the person skilled in the art and include, for example, reactions such as nucleophilic or electrophilic substitution reactions, transition metal-mediated coupling reactions, preparation and addition reactions of organometallic compounds (eg Grignard compounds or lithium organyls), oxidation and reduction reactions, hydrogenation, halogenation ( For example, fluorination, bromination), dehalogenation, amination, alkylation and acylation, the formation of carboxylic acid esters, carboxylic acid amides and sulfonamides, the ester cleavage and hydrolysis and the introduction and removal of temporary protecting groups.

 The compounds according to the invention have valuable pharmacological properties and can be used for the treatment and / or prophylaxis of diseases in humans and animals.

The compounds according to the invention are potent, chemically and metabolically stable antagonists of the FP receptor and are therefore suitable for the treatment and / or prevention of diseases and pathological processes, in particular those in which in the course of an inflammatory event and / or a tissue or vascular remodeling FP receptor is involved.

For the purposes of the present invention, these include, in particular, diseases such as the group of interstitial idiopathic pneumonia, including idiopathic pulmonary fibrosis (IPF), acute interstitial pneumonia, non-specific interstitial pneumonia, lymphoid interstitial pneumonia, respiratory bronchiolitis with interstitial lung disease, cryptogenic organizing pneumonia Pneumonia, desquamative interstitial pneumonia and non-classifiable idiopathic interstitial pneumonia, granulomatous interstitial lung disease, interstitial lung disease of known cause and other unknown interstitial lung diseases, pulmonary arterial hypertension (PAH) and other forms of pulmonary hypertension (PH), bronchiolitis obliterans - Syndrome (BOS), chronic obstructive pulmonary disease (COPD), pulmonary sarcoidosis, acute respiratory tract syndrome (ARDS), acute lung injury (ALI), alpha-1-antitrypsin De (AATD), pulmonary emphysema (eg, cigarette smoke-induced lung emphysema). sem), cystic fibrosis (CF), inflammatory and fibrotic kidney diseases, chronic enteritis (IBD, Crohn's disease, ulcerative colitis), peritonitis, peritoneal fibrosis, rheumatoid diseases, multiple sclerosis, inflammatory and fibrotic skin diseases, sickle cell anemia and inflammatory and fibrotic eye diseases.

The compounds of the present invention may further be used for the treatment and / or prevention of asthmatic disorders of varying severity with intermittent or persistent history (refractory asthma, bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma, medication or dust-induced asthma) of various types Forms of bronchitis (chronic bronchitis, infectious bronchitis, eosinophilic bronchitis), bronchiectasis, pneumonia, farmer's lung and related diseases, cough and cold sores (chronic inflammatory cough, iatrogenic cough), nasal mucosal inflammation (including medicinal rhinitis, vasomotor rhinitis and seasonal, allergic rhinitis, eg hay fever) and of polyps.

The compounds of the invention may also be used for the treatment and / or prevention of cardiovascular diseases, such as hypertension, heart failure, coronary heart disease, stable and unstable angina, renal hypertension, peripheral and cardial vascular diseases, arrhythmias, atrial arrhythmia and of the ventricles as well as conduction disturbances such as atrio-ventricular blockades of grade l-lll, supraventricular tachyarrhythmia, atrial fibrillation, atrial flutter, ventricular fibrillation, ventricular flutter, ventricular tachyarrhythmia, torsades de pointes tachycardia, atrial and ventricular extrasystoles, atrioventricular extrasystoles, nodules Sinus syndrome, syncope, AV node reentry tachycardia, Wolff-Parkinson-White syndrome, acute coronary syndrome (ACS), autoimmune heart disease (pericarditis, endocarditis, valvolitis, aortitis, cardiomyopathy), boxer cardiomyopathy, aneurysms, Schoc k, such as cardiogenic shock, septic shock and anaphylactic shock, and for the treatment and / or prevention of thromboembolic disorders and ischaemias, such as myocardial ischemia, myocardial infarction, stroke, cardiac hypertrophy, transitory and ischemic attacks, preeclampsia, inflammatory cardiovascular diseases, coronary artery spasm and peripheral arteries, edema such as pulmonary edema, cerebral edema, renal edema or congestive heart failure edema, peripheral circulatory disorders, reperfusion injury, arterial and venous thrombosis, microalbuminuria, myocardial insufficiency, endothelial dysfunction, microvascular and macrovascular lesions (vasculitis), and prevention of Restenoses, for example, after thrombolytic therapies, percutaneous transluminal angioplasties (PTA), percutaneous trans luminal coronary angioplasties (PTCA), heart transplants, and bypass surgeries. For the purposes of the present invention, the term cardiac failure encompasses both acute and chronic manifestations of cardiac insufficiency as well as specific or related forms of disease thereof, such as acute decompensated heart failure, right heart failure, left heart failure, global insufficiency, ischemic cardiomyopathy, dilated cardiomyopathy, hypertrophic cardiomyopathy, idiopathic cardiomyopathy, diabetic cardiomyopathy, congenital heart defects, heart valve defects, heart failure in heart valve defects, mitral valve stenosis, mitral valve insufficiency, aortic valve stenosis, aortic valve insufficiency, tricuspid stenosis, tricuspid insufficiency, pulmonary valve stenosis, pulmonary valve insufficiency, combined valvular heart failure, myocarditis, chronic myocarditis, acute myocarditis, viral myocarditis , diabetic cardiac insufficiency, alcoholic cardiomyopathy, cardiac storage disorders as well as diastolic and s ystolic heart failure.

The compounds according to the invention are also suitable for the treatment and / or prevention of kidney diseases, in particular renal insufficiency and kidney failure. For the purposes of the present invention, the terms renal insufficiency and kidney failure include both acute and chronic manifestations thereof as well as underlying or related renal diseases such as renal hypoperfusion, intradialytic hypotension, obstructive uropathy, glomerulopathies, glomerulonephritis, acute glomerulonephritis, glomerulosclerosis, tubulointerstitial Diseases, nephropathic diseases such as primary and congenital kidney disease, nephritis, immunological kidney diseases such as renal transplant rejection and immune complex-induced renal disease, toxic-induced nephropathy, contrast-induced nephropathy, diabetic and non-diabetic nephropathy, pyelonephritis, renal cysts, nephrosclerosis, hypertensive nephrosclerosis and nephrotic Syndrome, which can be diagnosed, for example, by abnormally reduced creatinine and / or water excretion, abnormally elevated blood levels urea, nitrogen, potassium and / or creatinine, altered activity of renal enzymes, e.g. Glutamyl synthetase, altered urinary or urinary output, increased microalbuminuria, macroalbuminuria, glomerular and arteriolar lesions, tubular dilation, hyperphosphatemia, and / or the need for dialysis. The present invention also encompasses the use of the compounds according to the invention for the treatment and / or prevention of sequelae of renal insufficiency, such as hypertension, pulmonary edema, cardiac insufficiency, uremia, anemia, electrolyte disorders (eg hyperkalemia, hyponatremia) and disorders in the bone and carbohydrate. Metabolism.

Moreover, the compounds according to the invention are suitable for the treatment and / or prevention of diseases of the urogenital system, such as, for example, benign prostate syndrome (BPS), benign prostatic hyperplasia (BPH), benign prostate enlargement (BPE), bladder emptying disorders (BOO), lower urinary tract syndromes ( LUTS), neurogenic overacti- bladder incontinence (MUI, UUI, SUI, OUI), pelvic pain, and erectile dysfunction and female sexual dysfunction.

 The compounds of the invention may also be used to treat disorders of the female reproductive system, such as uterine fibroids, endometriosis, dysmenorrhea, and premature labor pains. Furthermore, they are suitable for the prophylaxis or treatment of hirsutism and hypertrichosis.

 In addition, the compounds of the invention have anti-inflammatory activity and can therefore be used as anti-inflammatory agents for the treatment and / or prevention of sepsis (SIRS), multiple organ failure (MODS, MOF), inflammatory diseases of the kidney, chronic intestinal inflammation (IBD, Crohn's disease, ulcerative colitis ), Pancreatitis, peritonitis, cystitis, urethritis, prostatitis, epidymitis, oophoritis, salpingitis, vulvovaginitis, rheumatoid diseases, osteoarthritis, inflammatory diseases of the central nervous system, multiple sclerosis, inflammatory skin diseases and inflammatory eye diseases.

 The compounds according to the invention are furthermore suitable for the treatment and / or prevention of fibrotic disorders of the internal organs such as, for example, the lung, the heart, the kidney, the bone marrow and in particular the liver, as well as dermatological fibroses and fibrotic disorders of the eye. For the purposes of the present invention, the term fibrotic disorders includes in particular such diseases as liver fibrosis, liver cirrhosis, pulmonary fibrosis, endomyocardial fibrosis, nephropathy, glomerulonephritis, interstitial renal fibrosis, fibrotic damage as a consequence of diabetes, bone marrow fibrosis, peritoneal fibrosis and similar fibrotic disorders, Scleroderma, morphea, keloids, hypertrophic scarring, nevi, diabetic retinopathy, proliferative vitororetinopathy and connective tissue disorders (eg sarcoidosis). The compounds of the invention may also be used to promote wound healing, to combat postoperative scarring, e.g. after glaucoma surgery, and for cosmetic purposes on aging or keratinizing skin.

 Also, the compounds of the invention may be used for the treatment and / or prevention of anemias, such as hemolytic anemias, especially hemoglobinopathies such as sickle cell anemia and thalassemias, megaloblastic anemias, iron deficiency anemias, acute blood loss anemia, crowding anaemias and aplastic anemias.

The compounds according to the invention are furthermore suitable for the treatment of cancers, such as, for example, skin cancer, brain tumors, breast cancer, bone marrow tumors, leukemias, liposarcomas, carcinomas of the gastrointestinal tract, liver, pancreas. gland, lung, kidney, ureter, prostate and genital tract, and malignant tumors of the lymphoproliferative system, such as Hodgkin's and Non-Hodgkin's Lymphoma.

In addition, the compounds according to the invention can be used for the treatment and / or prevention of arteriosclerosis, lipid metabolism disorders and dyslipidemias (hypolipoproteinemia, hypertriglyceridemia, hyperlipidemia, combined hyperlipidemias, hypercholesterolemia, abetalipoproteinemia, sitosterolemia), xanthomatosis, Tangier's disease, obesity (adiposity), Obesity, metabolic disorders (metabolic syndrome, hyperglycemia, insulin-dependent diabetes, non-insulin-dependent diabetes, gestational diabetes, hyperinsulinemia, insulin resistance, glucose intolerance and diabetic sequelae such as retinopathy, nephropathy and neuropathy), gastrointestinal disorders and abdomen (glossitis, gingivitis, periodontitis, esophagitis, eosinophilic gastroenteritis, mastocytosis, Crohn's disease, colitis, proctitis, pruritis ani, diarrhea, celiac disease, hepatitis, liver fibrosis, cirrhosis, pancreatitis and chol ecystitis), diseases of the central nervous system and neurodegenerative disorders (stroke, Alzheimer's disease, Parkinson's disease, dementia, epilepsy, depression, multiple sclerosis), immune diseases, thyroid disorders (hyperthyroidism), skin diseases (psoriasis, acne, Eczema, atopic dermatitis, various forms of dermatitis such as abacribus dermatitis, dermatitis actinica, dermatitis allergica, ammoniacal dermatitis, dermatitis artefacta, autogenica dermatitis, dermatitis atrophicans, dermatitis calorica, dermatitis bustopus, dermatitis congelationis, dermatitis cosmetica, dermatitis escharotica, dermatitis exfoliativa , Dermatitis gangrenosis, Dermatitis haemostatica, Dermatitis herpetiformis, Dermatitis lichenoides, Dermatitis linearis, Malignant dermatitis, Medimencatosa dermatitis, Palmaris et plantaris dermatitis, Dermatitis parasitaria, Dermatitis photoallergica, Dermatitis phototoxica, Dermatitis pustularis, Seborrhoic dermatitis ca, dermatitis solaris, dermatitis toxica, ulcerative colitis, dermatitis veneata, infectious dermatitis, pyogenic dermatitis and rosacea-like dermatitis, as well as keratitis, bullosis, vasculitis, cellulitis, panniculitis, lupus erythematosus, erythema, lymphoma, skin cancer, sweet syndrome, Weber -Christian syndrome, scarring, wart formation, frostbite), inflammatory eye diseases (saccoidosis, blepharitis, conjunctivitis, iritis, uveitis, choroiditis, ophthalmitis), viral diseases (by influenza, adeno and coronaviruses, such as HPV, HCMV, HIV , SARS), diseases of skeletal bone and joints and skeletal muscle (various forms of arthritis such as arthritis alcaptonurica, arthritis ankylosans, arthritis dysenterica, arthritis exsudativa, arthritis fungosa, arthritis gonorrhoica, arthritis mutilans, arthritis psoriatica, arthritis purulenta, arthritis rheumatica , Arthritis serosa, Arthritis syphilitica, Arthritis tuberculosa, Arthritis urica, Arthritis villonodularis pigmentosa, atypical arthritis, haemophilic arthritis, juvenile chronic arthritis, rheumatoid arthritis and metastatic arthritis, furthermore the Sti II syndrome, Felty syndrome, Sjörgen syndrome, Clutton syndrome, Poncet syndrome, potty syndrome Syndrome and Reiter's syndrome, various forms of arthropathies such as arthropathy deformatans, arthropathy neuropathica, ovarian arthroprostics, arthropathy psoriatica and arthropathy tabica, systemic sclerosis, multiple forms of inflammatory myopathies such as myopathy epidemica, myopathy fibrosa, myopathy myoglobinurica, myopathy ossi - ficans, myopathy ossificans neurotica, myopathy ossificans progressiva multiplex, myopathy purulenta, myopathy rheumatica, myopathy trichinosa, myopathy tropica and myopathy typosa, as well as the Günther syndrome and the Münchmeyer syndrome), of inflammatory arterial changes (various forms of arteritis such as eg, endarteritis, mesarteritis, periarteritis, panarteritis, rheumatoid arthritis, deformity of the arteritis, temporal arteritis, cranial arteritis, gigantocellular arteritis and granulomatous arteritis, as well as Horton's syndrome, Churg-Strauss syndrome and Takayasu's arteritis) Muckle-Well's syndrome s, Kikuchi's disease, polychondritis, scleroderma and other diseases with an inflammatory or immunological component, such as cataract, cachexia, osteoporosis, gout, incontinence, leprosy, Sezary syndrome and paraneoplastic syndrome, in organ transplant rejection and wound healing and angiogenesis especially in chronic wounds.

 Because of their biochemical and pharmacological properties profile, the compounds of the invention are particularly suitable for the treatment and / or prevention of interstitial lung diseases, especially idiopathic pulmonary fibrosis (IPF), as well as pulmonary hypertension (PH), bronchiolitis obliterans syndrome (BOS), inflammatory and fibro - skin and eye diseases and fibrotic diseases of the internal organs.

The aforementioned well-characterized human diseases of similar etiology may also be present in other mammals and also be treated there with the compounds of the present invention.

For the purposes of the present invention, the term "treatment" or "treating" includes inhibiting, delaying, arresting, alleviating, attenuating, restraining, reducing, suppressing, restraining or curing a disease, a disease, a disease, an injury or a medical condition , the unfolding, the course or progression of such conditions and / or the symptoms of such conditions. The term "therapy" is understood to be synonymous with the term "treatment".

The terms "prevention", "prophylaxis" or "prevention" are used interchangeably in the context of the present invention and denote the avoidance or reduction of the risk, a disease, a disease, a disease, an injury or a health disorder, a development or a The progression of such conditions and / or the symptoms may be to get, to experience, to suffer or to have states. The treatment or the prevention of a disease, a disease, a disease, an injury or a health disorder can be partial or complete.

Another object of the present invention is therefore the use of the compounds of the invention for the treatment and / or prevention of diseases, in particular the aforementioned diseases.

 Another object of the present invention is the use of the compounds of the invention for the manufacture of a medicament for the treatment and / or prevention of diseases, in particular the aforementioned diseases.

 Another object of the present invention is a pharmaceutical composition containing at least one of the compounds of the invention, for the treatment and / or prevention of diseases, in particular the aforementioned diseases.

 Another object of the present invention is the use of the compounds of the invention in a method for the treatment and / or prevention of diseases, in particular the aforementioned diseases.

Another object of the present invention is a method for the treatment and / or prevention of diseases, in particular the aforementioned diseases, using an effective amount of at least one of the compounds of the invention.

The compounds according to the invention can be used alone or as needed in combination with one or more other pharmacologically active substances, as long as this combination does not lead to undesired and unacceptable side effects. Another object of the present invention are therefore pharmaceutical compositions containing at least one of the compounds of the invention and one or more other active ingredients, in particular for the treatment and / or prevention of the aforementioned diseases. Suitable combination active ingredients for this purpose are by way of example and preferably mentioned:

organic nitrates and NO donors such as sodium nitroprusside, nitroglycerin, isosorbide mononitrate, isosorbide dinitrate, molsidomine or SIN-1, and inhaled NO;

 Compounds which inhibit the degradation of cyclic guanosine monophosphate (cGMP) and / or cyclic adenosine monophosphate (cAMP), such as inhibitors of phosphodiesterases (PDE) 1, 2, 3, 4 and / or 5, in particular PDE 5 inhibitors such as sildenafil , Vardenafil, Tadalafil, Udenafil, Dasantafil, Avanafil, Mirodenafil or Lodenafil;

NO and heme-independent activators of soluble guanylate cyclase (sGC), in particular the compounds described in WO 01/19355, WO 01/19776, WO 01/19778, WO 01/19780, WO 02/070462 and WO 02/070510; NO-independent, but heme-dependent stimulators of soluble guanylate cyclase (sGC), in particular riociguat, as well as those described in WO 00/06568, WO 00/06569, WO 02/42301, WO 03/095451, WO 201 1/147809, WO 2012 / 004258, WO 2012/028647 and WO 2012/059549;

Prostacyclin analogs and IP receptor agonists such as, for example, and preferably louprost, beraprost, treprostinil, epoprostenol, or selexipag;

 Endothelin receptor antagonists, such as by way of example and preferably bosentan, darusentan, ambrisentan or sitaxsentan;

 Compounds which inhibit human neutrophil elastase (HNE), such as by way of example and preferably Sivelestat or DX-890 (Reltran);

the signal transduction cascade inhibiting compounds, by way of example and preferably from the group of kinase inhibitors, in particular from the group of tyrosine kinase and / or serine / threonine kinase inhibitors, such as by way of example and preferably Ninte-danib, dasatinib, nilotinib, bosutinib, regorafenib, sorafenib, Sunitinib, cediranib, axitinib, telatinib, imatinib, brivanib, pazopanib, vatalanib, gefitinib, erlotinib, lapatinib, canertinib, lestaurtinib, pelitinib, semaxanib or tandutinib;

 Compounds which inhibit the removal and remodeling of the extracellular matrix, by way of example and preferably inhibitors of the matrix metalloproteases (MMPs), in particular inhibitors of stroelysin, collagenases, gelatinases and aggrecanases (here in particular of MMP-1, MMP-3, MMP -8, MMP-9, MMP-10, MMP-1 1 and MMP-13) and metallo-elastase (MMP-12);

Compounds which block the binding of serotonin to its receptor, by way of example and preferably antagonists of the 5-HT ₂ B receptor such as PRX-08066;

 Antagonists of growth factors, cytokines and chemokines, by way of example and preferably antagonists of TGF-β, CTGF, IL-1, IL-4, IL-5, IL-6, IL-8, IL-13 and integrins;

the Rho kinase inhibiting compounds, such as exemplified and preferably Fasudil, Y-27632, SLx-21 19, BF-66851, BF-66852, BF-66853, KI-23095 or BA-1049;

 Compounds which inhibit the soluble epoxide hydrolase (sEH), such as Λ /, Λ / '- dicyclohexylurea, 12- (3-adamantan-1-yl-ureido) -dodecanoic acid or 1-adamantan-1-yl-3 {5- [2- (2-ethoxyethoxy) ethoxy] pentyl} urea;

the energy metabolism of the heart affecting compounds, such as by way of example and preferably etomoxir, dichloroacetate, ranolazine or trimetazidine;

anti-obstructive agents, such as those used for the treatment of chronic obstructive pulmonary disease (COPD) or bronchial asthma, by way of example and with preferably from the group of inhaled or systemically applied β-adrenergic receptor agonists (β-mimetics) and the inhaled anti-muscarcinogenic substances; anti-inflammatory, immunomodulatory, immunosuppressive and / or cytotoxic agents, by way of example and preferably from the group of systemic or inhaled corticosteroids, and acetylcysteine, montelukast, azathioprine, cyclophosphamide, hydroxycarbamide, azithromycin, pirfenidone or etanercept;

antifibrotic agents, such as, by way of example and by way of illustration, adenosine A2b receptor antagonists, sphingosine 1-phosphate receptor 3 (S1 P3) antagonists, autotaxine inhibitors, lysophosphatidic acid receptor 1 (LPA-1) and lysophosphatidic acid Receptor 2 (LPA-2) antagonists, lysyl oxidase (LOX) inhibitors, lysyl oxidase-like 2 inhibitors, CTGF inhibitors, IL-4 antagonists, IL-13 antagonists, overe-integrin antagonists, TGF β antagonists, Wnt signaling inhibitors or CCR2 antagonists;

antithrombotic agents, by way of example and preferably from the group of platelet aggregation inhibitors, anticoagulants and profibrinolytic substances; antihypertensive agents, by way of example and preferably from the group of calcium antagonists, angiotensin all-antagonists, ACE inhibitors, vasopeptidase inhibitors, endothelin antagonists, renin inhibitors, α-receptor blockers, β-receptor blockers, Mi - Neralocorticoid receptor antagonists and diuretics;

lipid metabolism-altering agents, by way of example and preferably from the group of thyroid receptor agonists, cholesterol synthesis inhibitors such as by way of example and preferably HMG-CoA reductase or squalene synthesis inhibitors, ACAT inhibitors, CETP inhibitors, MTP inhibitors, PPAR-a , PPAR-γ and / or PPAR-8 agonists, cholesterol absorption inhibitors, lipase inhibitors, polymeric bile acid adsorbents, bile acid reabsorption inhibitors and lipoprotein (a) antagonists; and or

Chemotherapeutic agents, as described e.g. used for the treatment of neoplasms of the lungs or other organs.

 In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a β-adrenergic receptor agonist such as, by way of example and by way of preference, albuterol, isoproterenol, metaproterenol, terbutaline, fenoterol, formoterol, repro sterol, salbutamol or salmeterol.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with an anti-muscarinergic substance, such as by way of example and preferably ipratropium bromide, tiotropium bromide or oxitropium bromide. In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a corticosteroid, such as by way of example and preferably prednisone, prednisolone, methylprednisolone, triamcinolone, dexamethasone, beclomethasone, betamethasone, flunisolide, budesonide or fluticasone.

Antithrombotic agents are preferably understood as meaning compounds from the group of platelet aggregation inhibitors, anticoagulants and profibrinolytic substances.

 In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a platelet aggregation inhibitor, such as, by way of example and by way of preference, aspirin, clopidogrel, ticlopidine or dipyridamole.

 In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a thrombin inhibitor, such as, by way of example and by way of preference, ximagatran, melagatran, dabigatran, bivalirudin or clexane.

 In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a GPIIb / IIIa antagonist, by way of example and with preference tirofiban or abciximab.

 In a preferred embodiment of the invention, the compounds according to the invention are used in combination with a factor Xa inhibitor, such as by way of example and preferably rivaraban, apixaban, fidexaban, razaxaban, fondaparinux, idraparinux, DU-176b, PMD-31 12, YM-150, KFA-1982, EMD-503982, MCM-17, MLN-1021, DX 9065a, DPC 906, JTV 803, SSR-126512 or SSR-128428.

 In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with heparin or a low molecular weight (LMW) heparin derivative.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a vitamin K antagonist, such as by way of example and preferably coumarin.

 Among the antihypertensive agents are preferably compounds from the group of calcium antagonists, angiotensin all-antagonists, ACE inhibitors, endothelin antagonists, renin inhibitors, α-receptor blocker, ß-receptor blocker, mineralocorticoid receptor Antagonists and diuretics understood.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a calcium antagonist, such as, by way of example and by way of preference, nifedipine, amlodipine, verapamil or diltiazem. In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a cti receptor blocker, such as by way of example and preferably prazosin.

 In a preferred embodiment of the invention, the compounds according to the invention are used in combination with a β-receptor blocker such as, by way of example and by way of preference, propranolol, atenolol, timolol, pindolol, alprenolol, oxprenolol, penbutolol, bupranolol, metipropanol, nadolol, mepindolol, Caroteneol, sotalol, metoprolol, betaxolol, celiprolol, bisoprolol, carteolol, esmolol, labetalol, carvedilol, adaprolol, landiolol, nebivolol, epanolol or bucinolol.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with an angiotensin all-antagonist, such as by way of example and preferably losartan, candesartan, valsartan, telmisartan or embursatan.

 In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with an ACE inhibitor such as, by way of example and by way of preference, enalapril, captopril, lisinopril, ramipril, delapril, fosinopril, quinopril, perindopril or trandopril.

 In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with an endothelin antagonist such as, by way of example and by way of preference, bosentan, darusentan, ambrisentan or sitaxsentan.

In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a renin inhibitor, such as by way of example and preferably aliskiren, SPP-600 or SPP-800.

 In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a mineralocorticoid receptor antagonist, such as by way of example and preferably spironolactone, eplerenone or finerenone.

 In a preferred embodiment of the invention, the compounds according to the invention are used in combination with a diuretic, such as by way of example and preferably furosemide, bumetanide, torsemide, bendroflumethiazide, chlorothiazide, hydrochlorothiazide, hydroflumethiazide, methyclothiazide, polythiazide, trichloromethiazide, chlorthalidone, indapamide, metolazone, quinethazone, Acetazolamide, dichlorophenamide, methazolamide, glycerol, isosorbide, mannitol, amiloride or triamterene.

Among the lipid metabolizing agents are preferably compounds from the group of CETP inhibitors, thyroid receptor agonists, cholesterol synthesis inhibitors such as HMG-CoA reductase or squalene synthesis inhibitors, the ACAT inhibitors, MTP inhibitors, PPAR-a- , PPAR-γ and / or PPAR-8 agonists, cholesterol absorption inhibitors, poly- bile acid adsorbers, bile acid reabsorption inhibitors, lipase inhibitors and lipoprotein (a) antagonists.

 In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a CETP inhibitor such as, by way of example and by way of preference, Torcetrapib (CP-529 414), JJT-705 or CETP-vaccine (Avant).

 In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a thyroid receptor agonist such as, by way of example and by way of preference, D-thyroxine, 3,5,3'-triiodothyronine (T3), CGS 23425 or axitirome (CGS 26214).

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with an HMG-CoA reductase inhibitor from the class of statins, such as by way of example and preferably lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rosuvastatin or pitavastatin.

 In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a squalene synthesis inhibitor, such as by way of example and preferably BMS-188494 or TAK-475.

 In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with an ACAT inhibitor, such as by way of example and preferably avasimibe, melinamide, pactimibe, eflucimibe or SMP-797.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with an MTP inhibitor, such as by way of example and preferably implants, BMS-201038, R-103757 or JTT-130.

 In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a PPAR-.gamma.-agonist, by way of example and preferably pioglitazone or rosiglitazone.

 In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a PPAR-8 agonist, such as by way of example and preferably GW 501516 or BAY 68-5042.

 In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a cholesterol absorption inhibitor such as, for example and preferably, ezetimibe, tiqueside or pamaqueside.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a lipase inhibitor, such as, for example and preferably, orlistat. In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a polymeric bile acid adsorbent such as, by way of example and by way of preference, cholestyramine, colestipol, colesolvam, cholesta gel or colestimide.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a bile acid reabsorption inhibitor, such as by way of example and preferably AS BT (= IBAT) inhibitors, such as e.g. AZD-7806, S-8921, AK-105, BARI-1741, SC-435 or SC-635.

 In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a lipoprotein (a) antagonist, such as by way of example and preferably gemcabene calcium (CI-1027) or nicotinic acid.

 Particularly preferred are combinations of the compounds according to the invention with one or more further active compounds selected from the group consisting of PDE 5 inhibitors, sGC activators, sGC stimulators, prostacyclin analogs, IP receptor agonists, endothelin antagonists, the signal transduction cascade inhibiting compounds and pirfenidone.

 Another object of the present invention are pharmaceutical compositions containing at least one compound of the invention, usually together with one or more inert, non-toxic, pharmaceutically suitable excipients, and their use for the purposes mentioned above.

The compounds according to the invention can act systemically and / or locally. For this purpose, they may be applied in a suitable manner, e.g. oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, dermal, transdermal, conjunctival, otic or as an implant or stent.

 For these administration routes, the compounds according to the invention can be administered in suitable forms of administration.

For oral administration are according to the prior art functioning, the compounds of the invention rapidly and / or modified donating application forms containing the compounds of the invention in crystalline and / or amorphized and / or dissolved form, such as tablets (uncoated or coated Tablets, for example with enteric or delayed-release or insoluble coatings, which control the release of the compound according to the invention), tablets or films / wafers, films / lyophilisates, capsules (for example hard or soft gelatin capsules) which break quickly in the oral cavity, dragees, Granules, pellets, powders, emulsions, suspensions, aerosols or solutions. Parenteral administration can be done bypassing a resorption step (eg intravenously, intraarterially, intracardially, intraspinally or intralumbarly) or using absorption (for example by inhalation, intramuscularly, subcutaneously, intracutaneously, percutaneously or intraperitoneally). For parenteral administration, suitable application forms include injection and infusion preparations in the form of solutions, suspensions, emulsions, lyophilisates or sterile powders.

 For the other routes of administration are suitable, for example Inhalation medicaments (including powder inhalers, nebulizers, metered dose aerosols), nasal drops, solutions or sprays, lingual, sublingual or buccal tablets, films / wafers or capsules, suppositories, ear or ophthalmic preparations, vaginal capsules, aqueous suspensions (lotions, shake mixtures), lipophilic suspensions, ointments, creams, transdermal therapeutic systems (eg plasters), milk, pastes, foams, powdered powders, implants or stents.

 Preference is given to oral and parenteral administration, in particular oral, intravenous and intrapulmonary (inhalative) administration.

The compounds according to the invention can be converted into the stated administration forms. This can be done in a conventional manner by mixing with inert, non-toxic, pharmaceutically suitable excipients. These adjuvants include, among others. Excipients (for example microcrystalline cellulose, lactose, mannitol), solvents (for example liquid polyethylene glycols), emulsifiers and dispersants or wetting agents (for example sodium dodecyl sulfate, polyoxysorbitanoleate), binders (for example polyvinylpyrrolidone), synthetic and natural polymers (for example albumin), stabilizers ( For example, antioxidants such as ascorbic acid), dyes (eg, inorganic pigments such as iron oxides) and flavor and / or odoriferous.

 In general, it has proven to be advantageous, when administered parenterally, to administer amounts of about 0.001 to 1 mg / kg, preferably about 0.01 to 0.5 mg / kg of body weight, in order to achieve effective results. When administered orally, the dosage is about 0.01 to 100 mg / kg, preferably about 0.01 to 20 mg / kg and most preferably 0.1 to 10 mg / kg of body weight. For intrapulmonary administration, the amount is generally about 0.1 to 50 mg per inhalation.

Nevertheless, it may be necessary to deviate from the stated amounts, depending on body weight, route of administration, individual behavior towards the active ingredient, type of preparation and time or interval at which the application is carried out. Thus, in some cases it may be sufficient to manage with less than the aforementioned minimum amount, while in other cases, the said upper limit must be exceeded. In the case of the application of larger quantities, it may be advisable to distribute these in several single doses throughout the day. The following embodiments illustrate the invention. The invention is not limited to the examples.

A. Examples

Abbreviations and acronyms:

br. wide (at NMR signal)

about circa, about

 CDI Λ /, Λ / '- carbonyldiimidazole

d doublet (by NMR)

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

dd doublet of doublet (by NMR)

 DIBAL-H Diisobutylaluminum hydride

 DIPEA N, N-diisopropylethylamine

 DMF N, N-dimethylformamide

 DMSO dimethyl sulfoxide

dt doublet of triplet (by NMR)

d. Th. Of theory (in chemical yield)

 ESI electrospray ionization (in MS)

h hour (s)

 HATU 0- (7-azabenzotriazol-1-yl) -N, N, N ', N-tetramethyluronium hexafluorophosphate

 HPLC high pressure, high performance liquid chromatography

conc. concentrated (at solution)

 LC / MS liquid chromatography-coupled mass spectrometry

 Literature (position)

 M molar

m multiplet (by NMR)

min minute (s)

 MS mass spectrometry

 NMR nuclear magnetic resonance spectrometry

q (or quart) quartet (by NMR)

qd Quartet by Dublett (by NMR)

quint quintet (by NMR)

 RP reverse phase (reversed phase, for HPLC)

 RT room temperature

R _t retention time (for HPLC, LC / MS)

s singlet (by NMR) sept septet (by NMR)

 SFC Supercritical Fluid Chromatography

t triplet (by NMR)

td triplet of doublet (by NMR)

tert. tertiary

 TFA trifluoroacetic acid

 THF tetrahydrofuran

 UV ultraviolet spectrometry

 Xanthophos (9,9-dimethyl-9 / - / - xanthene-4,5-diyl) bis (diphenylphosphine)

 Other abbreviations have their meanings known to those skilled in the art.

HPLC and LC / MS methods:

Method 1 (LC / MS):

Instrument: Waters Acquity SQD UPLC System; Column: Waters Acquity UPLC HSS T3 1 .8 μ, 50 x 1 mm; Eluent A: 1 l of water + 0.25 ml of 99% formic acid, eluent B: 1 l of acetonitrile + 0.25 ml of 99% formic acid; Gradient: 0.0 min 90% A -> 1 .2 min 5% A -> 2.0 min 5% A; Oven: 50 ^< C; Flow: 0.40 ml / min; UV detection: 208-400 nm.

 Method 2 (LC / MS):

 Instrument: Thermo Scientific FT-MS; Device type UHPLC +: Thermo Scientific UltiMate 3000; Column: Waters, HSST3, 2.1 x 75 mm, C18 1 .8 mm; Eluent A: 1 liter of water + 0.01% of formic acid; Eluent B: 1 L acetonitrile + 0.01% formic acid; Gradient: 0.0 min 10% B-> 2.5 min 95% B -> 3.5 min 95% B; Oven: 50 ° C; Flow: 0.90 ml / min; UV detection: 210 nm / Optimum Integration Path 210-300 nm.

 Method 3 (LC / MS):

Instrument: Micromass Quattro Premier with Waters UPLC Acquity; Column: Thermo Hypersil GOLD 1 .9 μ 50 x 1 mm; Eluent A: 1 l of water + 0.5 ml of 50% formic acid, eluent B: 1 l of acetonitrile + 0.5 ml of 50% formic acid; Gradient: 0.0 min 97% A -> 0.5 min 97% A -> 3.2 min 5% A -> 4.0 min 5% A; Oven: 50Ό; Flow: 0.3 ml / min; UV detection: 210 nm.

 Method 4 (LC / MS):

Instrument Waters (Micromass) Quattro Micro; Instrument Waters UPLC Acquity; Column: Waters BEH C18 1 .7 μ 50 x 2.1 mm; Eluent A: 1 l of water + 0.01 mol of ammonium formate, eluent B: 1 l of acetonitrile; Gradient: 0.0 min 95% A -> 0.1 min 95% A -> 2.0 min 15% A -> 2.5 min 15% A ^ 2.51 min 10% A ^ 3.0 min 10% A; Oven: 40 ° C; Flow: 0.5 ml / min; UV detection: 210 nm.

Method 5 (LC / MS): Instrument: Agilent MS Quad 6150; HPLC: Agilent 1290; Column: Waters Acquity UPLC HSS T3 1 .8 μ 50 x 2.1 mm; Eluent A: 1 l of water + 0.25 ml of 99% formic acid, eluent B: 1 l of acetonitrile + 0.25 ml of 99% formic acid; Gradient: 0.0 min 90% A -> 0.3 min 90% A -> 1 .7 min 5% A 3.0 min 5% A; Oven: 50 ^< C; Flow: 1, 20 ml / min; UV-D delivery: 205-305 nm.

Method 6 (LC / MS):

Instrument: Waters ACQUITY SQD UPLC System; Column: Waters Acquity UPLC HSS T3 1 .8 μ 50 x 1 mm; Eluent A: 1 l of water + 0.25 ml of 99% formic acid, eluent B: 1 l of acetonitrile + 0.25 ml of 99% formic acid; Gradient: 0.0 min 95% A -> 6.0 min 5% A -> 7.5 min 5% A; Oven: 50 ^< C; Flow: 0.35 ml / min; UV detection: 210-4 00 nm.

Method 7 (preparative HPLC):

 Column: Reprosil C18, 10 [in, 125 x 30 mm; Eluent A: water + 0.1% TFA, eluent B: acetonitrile; Injection at 3 min; Gradient: 0.0 min 10% B 5.5 min 10% B 17.65 min 95% B 19.48 min 95% B 19.66 min 10% B 20.51 min 10% B; Flow: 75 ml / min. UV detection: 210 nm.

Method 8 (preparative HPLC):

 Column: Chromatorex C18, 10 [in, 125 x 30 mm; Eluent: acetonitrile / water with 0.1% TFA; Flow: 75 ml / min; Gradient: 0-5.50 min 10:90, sample injection at 3.00 min, 5.50-17.65 min to 95: 5, 17.65-19.48 min 95: 5, 19.48-19.66 min to 10:90, 19.66-20.72 min 10:90.

 Method 9 (preparative HPLC):

Column: Chromatorex C18, 10 μm, 125 x 40 mm; Eluent A: water + 0.05% TFA, eluent B: acetonitrile; Gradient: 0.0 min 20% B 4.0 min 20% B ^ 30 min 95% B ^ 35 min 95% B 36 min 20% B; Flow: 50 ml / min.

 Method 10 (preparative HPLC):

 Column: Chromatorex C18, 10 μm, 250 × 30 mm; Eluent A: water, eluent B: acetonitrile; Gradient: 0.0 min 40% B 4.5 min 60% B -> 1 1 .5 min 80% B -> 12 min 100% B -> 14.75 min 40% B; Flow: 50 ml / min.

 More information:

 The percentages in the following example and test descriptions are by weight unless otherwise indicated; Parts are parts by weight. Solvent ratios, dilution ratios and concentration data of liquid / liquid solutions are based on the volume.

In purifications of compounds according to the invention by preparative HPLC according to the methods described, in which the eluent additives such as trifluoro- contain acetic acid, formic acid or ammonia, the compounds of the invention may be obtained in salt form, for example as trifluoroacetate, formate or ammonium salt, provided that the compounds of the invention contain sufficiently basic or acidic functionalities. Such a salt can be converted into the corresponding free base or acid by various methods known to the person skilled in the art.

Purity specifications usually refer to corresponding peak integrations in the LC / MS chromatogram, but may additionally have been determined with the aid of the ¹ H NMR spectrum. Compounds may still contain residual solvents, which was not necessarily taken into account in the indication of purity. If no purity is specified, it is either a 100% purity according to automatic peak integration in the LC / MS chromatogram or the purity was not explicitly determined.

Data on yields in% d. Th. Are purity-corrected as a rule, provided that a purity of <100% is specified. For solvent-containing or contaminated batches, the yield may be formally "> 100%"; in these cases, the yield is not solvent or purity corrected.

The following descriptions of the coupling patterns of ¹ H NMR signals have been taken in part directly from the suggestions of the ACD SpecManager (ACD / Labs Release 12.00, Product version 12.5) or ACD / Spectrus Processor 2014 (File Version S20S41, Build 72444, 21 Aug 2014) and not necessarily rigorously questioned. In some cases, the suggestions of the SpecManager were adapted manually. Manually customized descriptions are usually based on the visual appearance of the signals in question and do not necessarily correspond to a rigorous, physically correct interpretation. As a rule, the indication of the chemical shift refers to the center of the relevant signal. For wide multiplets, an interval is specified. Solvent or water concealed or partially obscured signals were either tentatively assigned or are not listed. Strongly broadened signals-caused, for example, by rapid rotation of moieties or by exchanging protons-have also been tentatively assigned (often referred to as broad multiplet or broad singlet) or are not listed.

The ¹ H NMR data of selected examples are noted in part in the form of ¹ H NMR peaks. For each signal peak, first the δ value in ppm and then the signal intensity in round brackets are listed. The δ value signal intensity number pairs of different signal peaks are listed separated by commas. The peak list of an example therefore has the form: δι (intensity i), 02 (intensity 2), ..., δ, (intensity), ..., δ _η (intensity).

The intensity of sharp signals correlates with the height of the signals in a printed example of an NMR spectrum in cm and, in comparison with other signals, shows the true ratios of the signal intensities. For broad signals, multiple peaks or the center of the signal and their relative intensity can be shown compared to the most intense signal in the spectrum. The lists of the ¹ H NMR peaks are similar to the classical ¹ H NMR prints and thus usually contain all the peaks listed in a classical NMR interpretation. Moreover, like classical ¹ H NMR prints, they can show solvent signals, signals from stereoisomers of the target compounds, which are also the subject of the invention, and / or peaks of impurities. The peaks of stereoisomers of the target compounds and / or peaks of impurities usually have on average a lower intensity than the peaks of the target compounds (for example with a purity of> 90%). Such stereoisomers and / or impurities may be typical of the particular preparation process. Their peaks can thus help identify the reproduction of our manufacturing process by "by-product fingerprints." An expert calculating the peaks of the target compounds by known methods (MestreC, ACD simulation, or using empirically evaluated expectancy values) can isolate the peaks of the target compounds as needed, using additional intensity filters if necessary. This isolation would be similar to peak-picking in the classical ¹ H NMR interpretation. A detailed description of the representation of NMR data in the form of peak lists can be found in the publication "Citation of NMR Peak Data within Patent Applications" (see Research Disclosure Database Number 605005, 2014, August 1, 2014 or Error! Hyperlink Reference invalid. http://www.researchdisclosure.com/searching-disclosures). In the Peak Picking Routine described in Research Disclosure Database Number 605005, the MinimumHeight parameter can be set between 1% and 4%. Depending on the type of chemical structure and / or depending on the concentration of the compound to be measured, it may be useful to set the parameter "MinimumHeight" to values <1%.

 Melting points and melting ranges, where indicated, are not corrected.

 For all reactants or reagents, the preparation of which is not explicitly described below, it is true that they were obtained commercially from generally available sources. For all other reactants or reagents, the preparation of which is also not described below and which were not commercially available or obtained from sources that are not generally available, reference is made to the published literature describing their preparation.

Starting compounds and intermediates:

Example 1 A

6-bromo-3-methyl-2-phenylquinoline-4-carboxylic acid

100.0 g (purity 90%, 398.16 mmol) of 5-bromo-1 / - / - indole-2,3-dione and 59.4 g (442.41 mmol) of 1-phenylpropan-1-one were admixed with acetic acid (1 .2 liter) and stirred at 75 Ό for 20 min. Thereafter, the reaction mixture was concentrated. Hydrochloric acid (400 ml) and the mixture was further stirred overnight at 105 °. The reaction solution was then added with stirring to a mixture of 1M hydrochloric acid (10 liters), water (9.2 liters) and conc. Hydrochloric acid (840 ml). Ice water (1 liter) was added to the mixture and the precipitate was filtered off with the aid of a frit. The filter residue was washed twice with water (500 ml), then twice with a 3: 1 mixture of tert-butyl methyl ether and acetone (150 ml each) stirred and filtered again. The residue was stirred three more times with tert-butyl methyl ether (100 ml in each case), filtered off again and finally dried in vacuo. There were obtained 1 17.96 g (purity 100%, 78% of theory) of the title compound.

LC-MS (Method 1): R _t = 0.76 min; MS (ESIpos): m / z = 342/344 [M + H] ⁺

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: 14.39 (br.s, 1H), 8.01 (d, 1H), 7.94-7.90 (m, 2H), 7.63-7.61 (m, 2H), 7.56-7.49 (m, 3H), 2.40 (s, 3H).

Example 2A

 6-bromo-3-chloro-2-phenylquinoline-4-carboxylic acid

5-Bromo-1 / - / - indole-2,3-dione (10.00 g, 44.24 mmol) was initially charged in acetic acid (120 ml) and 2-chloro-1-phenylethanone (6.84 g, 44.24 mmol) was added. The reaction mixture was stirred for 5 min at 75 °. Subsequently, conc. Hydrochloric acid (5 ml) was added and the mixture was stirred further at 105 ° overnight. After cooling to RT, the reaction mixture was added to 1 M hydrochloric acid (200 ml). The precipitated solid was filtered off, washed twice with water and dried in vacuo. The solid was then stirred in acetonitrile (50 ml), filtered again and dried again in vacuo. There were obtained 5.60 g (purity 82%, 29% of theory) of the title compound. LC-MS (Method 1): R _t = 0.88 min; MS (ESIpos): m / z = 362/364 [M + H] ⁺ Example 3A

 6-bromo-3-cyclopropyl-2-phenylquinoline-4-carboxylic acid

Method A:

 5-Bromo-1 / - / - indole-2,3-dione (1.75 g, purity 90%, 6.97 mmol) was initially charged in acetic acid (15 mL) and treated with 2-cyclopropyl-1-phenyl-ethanone (1 .12 g, 6.97 mmol) [representation described in WO 2009/143049-A1, p. 182, compound 99A]. The reaction mixture was stirred at 75 ° C. for 5 minutes, then concentrated hydrochloric acid (5 ml) was added and the mixture was stirred at 110 ° C. for 2.5 hours and then at RT overnight. The reaction mixture was then added to 1 M hydrochloric acid (100 ml). The precipitated solid was filtered off, washed twice with water (10 ml) and dried in vacuo. 2.23 g of a crude product were obtained. 200 mg of this crude product were purified by preparative HPLC (Method 7). From this, 43 mg (1 .5% of theory, based on 6.97 mmol starting material, purity 93%) of the title compound were obtained.

 Method B:

 To a solution of 5-bromo-1 / - / - indole-2,3-dione (2.03 g, purity 90%, 8.12 mmol) in ethanol (20 mL) at RT was added 2-cyclopropyl-1-phenyl-ethanone (1.95 g , 12.18 mmol) [representation described in WO 2009/143049-A1, p. 182, compound 99A] and potassium hydroxide (2.05 g, 36.56 mmol). The reaction mixture was stirred for 1 h at a bath temperature of 100 ° C. After cooling to RT, the mixture was admixed with water (300 ml) and adjusted to pH 2 with concentrated hydrochloric acid, extracted twice with ethyl acetate (20 ml each time) The residue was suspended in a mixture of DMSO (30 ml) and acetonitrile (10 ml), and the remaining solid was filtered off and dried in vacuo to give 107 mg (purity 100%) %, 4% of theory) of a first batch of the title compound The filtrate was concentrated and the residue was purified by preparative HPLC (Method 7) to give 750 mg (purity 100%, 25% of theory) of a second batch of the title compound.

LC-MS (Method 1): R _t = 0.91 min; MS (ESIpos): m / z = 368/370 [M + H] ^{+ 1} H-NMR (400 MHz, DMSO-d6) δ [ppm]: 14.22 (br.s, 1H), 8.01 (d, 1H), 7.97 (d, 1H), 7.93 (dd, 1H) , 7.76-7.71 (m, 2H), 7.54-7.46 (m, 3H), 2.38-2.28 (m, 1H), 0.76-0.66 (m, 2H), 0.33-0.25 (m, 2H).

Example 4A

 6-iodo-3-methyl-2-phenylquinoline-4-carboxylic acid

Method A:

To a mixture of 1-phenylpropan-1-one (3.5 mL, 27 mmol) in ethanol (44 mL, 751 mmol) was added 5-iodo-1 / - / - indole-2,3-dione (5.00 g, 97%). Purity, 17.8 mmol). Then potassium hydroxide (4.48 g, 79.9 mmol) was added and the mixture was stirred for 2 h at 100 Ό. After cooling to RT, the mixture was mixed with water (300 ml) and concentrated with conc. Hydrochloric acid adjusted to pH 2. The formed precipitate was filtered off, washed with water (75 ml) and dried in vacuo. Filter residues were dissolved in ethyl acetate, the ethyl acetate was removed, and the residue was combined with the resulting precipitate. There was obtained 6.25 g (purity 96%, 87% of theory) of the title compound. LC-MS (Method 1): R _t = 0.75 min; MS (ESIpos): m / z = 390 [M + H] ⁺

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (4.85), 0.008 (4.06), 0.146 (0.60), 1 .069 (0.76), 1 .087 (1 .39), 1 .105 (0.76), 2.366 (1.23), 2.385 (16.00), 2.670 (0.82), 2.710 (1.07), 3.041 (0.66), 3.059 (0.72), 7.502 (1.13), 7.512 (4.25 ), 7,515 (4.66), 7,520 (2.71), 7,530 (3.40), 7,543 (1 .32), 7,599 (3.40), 7,603 (3.75), 7,618 (2.05), 7,623 (2.33), 7,824 (2.80), 7,846 (3.56), 8,033 (1 .86), 8,038 (2.1 1), 8,055 (1.48), 8,060 (1.70), 8,126 (3.40), 8,131 (3.09).

 Method B:

 5-iodo-1 / - / - indole-2,3-dione (20.0 g, 73.25 mmol) was initially charged in acetic acid (200 ml) and 1-phenylpropan-1-one (9.83 g, 73.25 mmol) was added. The reaction mixture was stirred for 5 min at 75 °. Thereafter, conc. Hydrochloric acid (66 ml) was added and the mixture was stirred further at 105 ° overnight. Subsequently, the reaction solution was carefully added with stirring in water. The resulting precipitate was filtered off and washed twice with water and twice with a little butyl ferric butyl ether. After drying overnight in vacuo, 11.1 g (32% of theory, purity 82%) of the title compound were obtained.

LC-MS (Method 1): R _t = 0.78 min, m / z = 390 [M + H] ^{+ 1} H-NMR (400 MHz, DMSO-d6) δ [ppm]: 14.36 (br.s, 1H), 8.13 (d, 1H), 8.05 (dd, 1H), 7.84 (d, 1H) , 7.66-7.57 (m, 2H), 7.57-7.41 (m, 3H), 2.39 (s, 3H).

Example 5A

 3-chloro-6-iodo-2-phenylquinoline-4-carboxylic acid

5-iodo-1 / - / - indole-2,3-dione (10.00 g, 36.63 mmol) was initially charged in acetic acid (100 ml) and washed with

Added 2-chloro-1-phenylethanone (5.66 g, 36.63 mmol). The reaction mixture was stirred for 5 min at 75 °. Subsequently, conc. Hydrochloric acid (5 ml), and the mixture was further stirred at 105 ° overnight. After cooling to RT, the reaction mixture was added to 1 M hydrochloric acid (200 ml). The precipitated solid was filtered off, washed twice with water and dried in vacuo. The solid was then stirred in acetonitrile (50 ml), filtered again and dried again in vacuo. There were obtained 4.45 g (purity 54%, 16% of theory) of the title compound in which the dechlorinated compound was by-produced (m / z = 376 [M + H] ⁺ ).

LC-MS (Method 1): R _t = 0.94 min, m / z = 410 [M + H] ⁺ Example 6A

 3-Cyclopropyl-6-iodo-2-phenylquinoline-4-carboxylic acid

To a mixture of 2-cyclopropyl-1-phenylethanone (5.17 g, 90% purity, 29.2 mmol) [representation described in WO 2009/143049-A1, p. 182, compound 99A] in ethanol (48 ml) at RT became 5 -lod-1 / - / - indole-2,3-dione (5.47 g, 97% purity, 19.4 mmol). Then potassium hydroxide (4.91 g, 87.5 mmol) was added and the mixture was stirred for 1 h at 100 Ό. After cooling to RT, the mixture was treated with water (300 ml) and acidified with conc. Hydrochloric acid adjusted to pH 2. The formed precipitate was filtered off, washed with water (50 ml) and dried in vacuo. It became a first fraction of Title compound obtained (1 .06 g, 100% purity, 13% of theory, see analysis). Filter residues were dissolved in ethyl acetate, combined with the aqueous phase and shaken. After phase separation, the aqueous phase was extracted once with ethyl acetate (50 ml). The combined organic phases were dried over sodium sulfate, filtered and concentrated. This gave a second fraction of the title compound (2.88 g, 97% purity, 35% of theory).

LC-MS (Method 1): R _t = 0.96 min; MS (ESIpos): m / z = 416 [M + H] ⁺

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (2.72), 0.008 (2.37), 0.265 (2.19), 0.277 (7.13), 0.280 (8.19), 0.291 (8.74), 0.295 ( 7.08), 0.306 (2.42), 0.683 (2.29), 0.695 (6.59), 0.699 (6.20), 0.705 (3.49), 0.71 1 (3.58), 0.716 (6.54), 0.720 (6.29), 0.732 (2.04), 1 .743 (1.15), 1.751 (1.29), 1 .760 (3.39), 1 .769 (1 .27), 1 .776 (1.18), 2.283 (0.90), 2.297 (1.94), 2.304 ( 2.08), 2.31 1 (1.47), 2.319 (3.78), 2.326 (1.68), 2.333 (2.19), 2.340 (1.88), 2.355 (0.81), 2.367 (0.73), 2.71 1 (0.72) , 3,585 (1 .1 1), 3,591 (0.77), 3,595 (1.09), 3,601 (2.69), 3,607 (1.04), 3,612 (0.77), 3,618 (1 .09), 7,475 (1 .79), 7,480 ( 3.62), 7.487 (16.00), 7.491 (15.07), 7.498 (6.07), 7.506 (9.78), 7.514 (2.56), 7.518 (2.88), 7.524 (1.15), 7.528 (1.45), 7.709 (1 .04), 7,717 (8.28), 7,721 (10.09), 7,730 (4.66), 7,735 (6.59), 7,741 (7.76), 7,827 (9.32), 7,849 (1 1 .43), 8,038 (6.22), 8,043 (6.70 ), 8,060 (5.12), 8,065 (5.61), 8,166 (10.14), 8,170 (9.51), 14,208 (1 .54).

Example 7A

 6-bromo-3-methyl-2-phenylquinoline-4-carbonyl chloride

A suspension of 6-bromo-3-methyl-2-phenylquinoline-4-carboxylic acid (10.0 g, 29.2 mmol, Example 1 A) in dichloromethane (100 ml) was treated with a few drops of DMF. Subsequently, oxalichloride (5.1 ml, 58 mmol) was added dropwise slowly. It was stirred until the evolution of gas subsided and the mixture was then concentrated and dried in vacuo. The residue obtained was used directly (without further workup) for subsequent chemistry. Example 8A

6-bromo-3-methyl-2-phenylquinoline-4-carboxamide

The compound of 6-bromo-3-methyl-2-phenylquinoline-4-carbonyl chloride (10.5 g, 29.0 mmol, Example 7A) was added with 35% ammonia solution (100 ml) and the resulting suspension was allowed to stand for 30 minutes RT and then allowed to stand overnight at RT. The resulting solid was filtered off, washed with water, taken up in a dichloromethane-methanol mixture and prepurified by column chromatography (400 g of silica gel, Buchi, dichloromethane / methanol 100: 3). Recrystallization of the prepurified product from methanol gave a first fraction of the title compound (6.19 g, 97% purity, 61% of theory). The resulting mother liquor was concentrated and the residue was stirred in dichloromethane. The resulting solid was filtered off, washed once with dichloromethane and once with pentane and dried. There was thus obtained a second fraction of the title compound (1.72 g, 93% purity, 16% of theory).

LC-MS (Method 3): R _t = 1 .93 min; MS (ESIpos): m / z = 341/343 [M + H] ⁺

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (0.51), 0.008 (0.49), 2.374 (16.00), 7.504 (0.97), 7.514 (1.52), 7.519 (4.36), 7,524 (2.59), 7,538 (3.59), 7,549 (0.71), 7,553 (1.35), 7,560 (0.94), 7,570 (0.70), 7,576 (3.72), 7,580 (3.59), 7,591 (0.94), 7,595 (1 .87 ), 7.600 (1.53), 7.875 (1.17), 7.880 (1.40), 7.897 (1.71), 7.902 (2.30), 7.927 (3.35), 7.932 (2.58), 7.975 (3.61), 7.997 ( 2.33), 8.1 19 (1.63), 8.287 (1.64).

Example 9A

 (6-Bromo-3-methyl-2-phenyl-quinolin-4-yl) (1 / - / - imidazol-1-yl) methanone

6-Bromo-3-methyl-2-phenylquinoline-4-carboxylic acid (100.0 g, 292.23 mmol, Example 1 A) was suspended in DMF (1 .5 liter) and treated at RT with CDI (95.0 g, 584.45 mmol). The reaction mixture was first stirred for 4 h at 60 ° and then overnight at RT. With ice bath cooling, ice water (1.5 liters) was added slowly and the mixture was then left for three days put in the fridge. The precipitated solid was filtered through a frit, washed three times with water (250 ml) and dried in vacuo. There were obtained 103.41 g (purity 94%, 85% of theory) of the title compound.

LC-MS (Method 1): R _t = 1 .16 min; MS (ESIpos): m / z = 392/394 [M + H] ⁺

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 8.6-8.0 (br, m, 1H), 8.09 (d, 1H), 8.0-7.5 (br, m, 1H), 7.97 ( dd, 1H), 7.82 (s, 1H), 7.72-7.66 (m, 2H), 7.59-7.48 (m, 3H), 7.22 (br, s, 1H), 2.25 (s, 3H).

Example 10A

 (6-Bromo-3-chloro-2-phenyl-quinolin-4-yl) (1 / - / - imidazol-1-yl) methanone

To a solution of 6-bromo-3-chloro-2-phenylquinoline-4-carboxylic acid (500 mg, purity 82%, 1.13 mmol, Example 2A) in DMF (5 ml) was added CDI (202 mg, 1.24 mmol) at RT, and the mixture was stirred for 2 h at 60 ° C. CDI (202 mg, 1.24 mmol) was added again and the mixture was stirred for another 4 h at 60 ° C. After cooling to RT The resulting solid was filtered off, washed twice with water (2 ml each time) and dried in vacuo to give 553 mg (purity 80%, 95% of theory) of water. ) of the title compound.

LC-MS (Method 1): R _t = 1 .14 min; MS (ESIpos): m / z = 412/414 [M + H] ⁺ Example 11 A

 (6-bromo-3-cyclopropyl-2-phenyl-quinolin-4-yl) (1 / - / - imidazol-1-yl) methanone

To a solution of 6-bromo-3-cyclopropyl-2-phenylquinoline-4-carboxylic acid (2.55 g, 6.92 mmol, Example 3A) in DMF (31 ml) was added CDI (1.24 g, 7.62 mmol) at RT, and the Mixture was stirred for 20.5 h at 60 Ό. Subsequently, CDI (620 mg, 3.81 mmol) was added again, and the mixture was stirred for a further 5.5 h at 60 °. Then CDI (620 mg, 3.81 mmol) was added again, and the mixture was stirred again for 2 h at 6 ° C and then allowed to stand at RT for four days. The reaction mixture was then added to a mixture of water and ethyl acetate (400 ml each time), shaken and the phases were separated. The aqueous phase was extracted once with ethyl acetate (200 ml). The combined organic phases were dried over sodium sulfate, filtered and concentrated. The residue was taken up in dichloromethane and purified by column chromatography (300 g of silica gel, Biotage, cyclohexane / ethyl acetate first 9: 1, then 3: 1). There were obtained 1 .64 g (purity 100%, 57% of theory) of the title compound.

LC-MS (Method 1): R _t = 1 .17 min; MS (ESIpos): m / z = 418/420 [M + H] ⁺

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.068 (0.82), -0.054 (1.96), -0.043 (2.77), -0.030 (2.83), -0.019 (2.29), 0.352 (0.82), 0.366 (2.13), 0.377 (2.98), 0.390 (2.77), 0.401 (2.10), 0.415 (1 .08), 0.437 (0.89), 0.459 (2.37), 0.470 (2.63), 0.482 (2.26) , 0.492 (1.71), 0.506 (0.92), 0.549 (1 .10), 0.571 (2.32), 0.582 (2.57), 0.595 (2.03), 0.617 (0.64), 1 .148 (0.42), 1 .397 (0.90), 2.045 (0.92), 2.060 (2.06), 2.067 (2.20), 2.081 (3.71), 2.096 (2.03), 2.102 (1.94), 2.1.17 (0.81), 3.286 (2.88), 5.754 (0.43 ), 7.219 (4.21), 7.477 (0.64), 7.494 (3.75), 7.502 (15.81), 7.505 (16.00), 7.520 (10.66), 7.529 (2.65), 7.533 (2.89), 7.542 (1.62), 7.790 (8.93), 7.794 (10.80), 7.808 (8.03), 7.814 (8.85), 7.850 (7.65), 7.855 (8.24), 7.965 (4.77), 7.970 (4.36), 7.988 (6.74), 7.993 (6.43), 8.085 (12.01), 8.107 (8.41), 8.402 (0.63).

Example 12A

 1 / - / - imidazol-1-yl (6-iodo-3-methyl-2-phenylquinolin-4-yl) -methanone

Method A:

To a solution of 6-iodo-3-methyl-2-phenylquinoline-4-carboxylic acid (1.20 g, 95% pure, 2.93 mmol, Example 4A) in DMF (12 mL) at RT was CDI (951 mg, 5.86 mmol) and the mixture was stirred for 2 h at 60 ° C. After cooling to RT, the reaction mixture was poured into a mixture of water and ethyl acetate (100 ml each), shaken and the phases were separated with ethyl acetate (100 ml) extracted. The combined organic phases were dried over sodium sulfate, filtered and concentrated, and the residue was dried in vacuo. There were obtained 1 .35 g (purity 87%, 91% of theory) of the title compound.

LC-MS (Method 1): R _t = 1 .16 min; MS (ESIpos): m / z = 440 [M + H] ⁺

Method B:

 The compound from 6-iodo-3-methyl-2-phenylquinoline-4-carboxylic acid (600mg, purity 80%, 1.23mmol, Example 4A) was dissolved in DMF (5.5ml) and extracted at RT with CDI (400mg , 2.47 mmol). The reaction mixture was stirred overnight at 60 ° and then after cooling to RT with water and ethyl acetate. The phases were separated and the aqueous phase was extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (80 g silica gel, eluent cyclohexane / ethyl acetate 5: 1, Biotage). After removal of the solvent in vacuo, the residue was dried in vacuo overnight. 568 mg (purity 94%, 98% of theory) of the title compound were obtained.

LC-MS (Method 1): R _t = 1 .13 min, m / z = 440 [M + H] ⁺

¹ H NMR (400 MHz, DMSO-d6) δ [ppm]: 9.50-6.00 (br, m, 2H), 8.10 (dd, 1H), 7.95 (s, 1H), 7.91 (d, 1H ), 7.72-7.65 (m, 2H), 7.60-7.42 (m, 3H), 7.22 (br, s, 1H), 2.24 (s, 3H).

Example 13A

 (3-chloro-6-iodo-2-phenylquinolin-4-yl) (1 / - / - imidazol-1-yl) methanone

To a solution of 3-chloro-6-iodo-2-phenylquinoline-4-carboxylic acid (700 mg, purity 54%, 0.92 mmol, Example 5A) in DMF (6 mL) at RT was CDI (165 mg, 1.02 mmol). The mixture was stirred for 2 h at 60 ° C. CDI (165 mg, 1.02 mmol) was then added again, and the mixture was stirred for a further 4 h at 60 ° C. After cooling to RT, the mixture was stirred with stirring The resulting solid was filtered off, washed twice with water (2 ml each time) and dried in vacuo to give 699 mg (still solvent-containing, purity 81% according to LC / MS, (">100%" d Th.) Of the title compound. LC-MS (Method 1): R _t = 1 .17 min; MS (ESIpos): m / z = 460 [M + H] ⁺

Example 14A

 (3-Cyclopropyl-6-iodo-2-phenylquinolin-4-yl) (1 / - / - imidazol-1-yl) methanone

To a solution of 3-cyclopropyl-6-iodo-2-phenylquinoline-4-carboxylic acid (3.90 g, 9.39 mmol, Example 6A) in DMF (60 mL) at RT was added CDI (1.68 g, 10.3 mmol), and the mixture was stirred for 2 h at 60 °. Subsequently, CDI (1.68 g, 10.3 mmol) was added again, and the mixture was again stirred for 2 h at 60 °. After cooling to RT, the mixture was introduced with stirring into a 10% citric acid solution (100 ml). The resulting precipitate was filtered off, washed twice with water (2 ml each time) and dried in vacuo. There were obtained 4.68 g (91% purity, 97% of theory) of the title compound.

LC-MS (Method 1): R _t = 1 .20 min; MS (ESIpos): m / z = 466 [M + H] ⁺ Example 15A

6-bromo- / V- (4-cyano-2-fluorophenyl) -3-methyl-2-phenylquinoline-4-carboxamide

To a mixture of (6-bromo-3-methyl-2-phenylquinolin-4-yl) (1 / - / - imidazol-1-yl) methanone (2.50 g, 6.37 mmol, Example 9A) in DMF (24 mL). At RT, 4-amino-3-fluorobenzonitrile (91 1 mg, 6.69 mmol) was added. Then, with stirring, a 1 M solution of Potassium tert-butoxide in THF (13 ml, 13.00 mmol) was slowly added dropwise and the mixture was stirred at RT for 3 h. Then the mixture was poured into a 10% citric acid solution (300 ml) and the precipitate was filtered off, washed twice with water (20 ml) and dried in vacuo. There were obtained 2.95 g (93% purity, 94% of theory) of the title compound.

LC-MS (Method 4): R, = 2.14 min; MS (ESIpos): m / z = 460/462 [M + H] ⁺

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1 .665 (0.79), 2,408 (1 .57), 2,418 (16,00), 7,522 (1 .31), 7,533 (1 .98), 7,539 (4.66), 7,558 (4.06), 7,573 (1 .35), 7,580 (1.02), 7,616 (3.98), 7,619 (4.17), 7,635 (2.60), 7,639 (2.17), 7,803 (1.74), 7,823 (1 .89), 7,920 (1.33), 7,926 (1: 54), 7,943 (1,93), 7,948 (2.37), 7,984 (3.99), 7,989 (3.42), 8,000 (1 .82), 8,004 (1.77), 8,026 (1,98), 8,032 (5.36), 8,054 (2.67), 8,336 (1.58), 8,356 (2.66), 8,376 (1 .48), 1 1 .193 (3.39).

Example 16A

 6-bromo-3-chloro- / V- (4-cyano-2-fluorophenyl) -2-phenylquinoline-4-carboxamide

To a mixture of (6-bromo-3-chloro-2-phenylquinolin-4-yl) (1 / - / - imidazol-1-yl) methanone (553 mg, 80% purity, 1.07 mmol, Example 10A) in DMF (5.5 mL) at RT was added 4-amino-3-fluorobenzonitrile (153 mg, 1.13 mmol). Then, while stirring, a 1 M solution of potassium tert-butoxide in THF (2.1 ml, 2.10 mmol) was added dropwise thereto, and the mixture was stirred at RT for 1 h. Then, the mixture was added with water and ethyl acetate (each 100 ml), shaken, and the phases were separated. The aqueous phase was extracted with ethyl acetate (once 100 ml and once 50 ml). The combined organic phases were dried over sodium sulfate, filtered and concentrated, and the residue was purified by column chromatography (50 g silica gel, Biotage, ethyl acetate / cyclohexane 85:15). 270 mg (99% purity, 52% of theory) of the title compound were obtained.

LC-MS (Method 1): R _t = 1 .28 min; MS (ESIpos): m / z = 480/482 [M + H] ^{+ 1} H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (4.26), 0.008 (3.81), 2.366 (0.90), 2.670 (0.61) 2.710 (0.98), 5.754 (0.95), 7.556 (1.82 ), 7,562 (11:56), 7,567 (12/1), 7,575 (7.75), 7,580 (7.51) 7,590 (2.35), 7,744 (6.19), 7,749 (7.14), 7,757 (5.63), 7,760 (4.47), 7,768 (4.95) , 7,805 (2.94) 7,809 (3,07), 7,826 (3.15), 7,830 (3.33), 8,000 (3.62), 8,004 (3.49), 8,026 (4.18), 8,029 (4.79) 8,031 (4.52), 8,034 (4.68), 8,050 (2.49), 8,055 (16:00), 8,060 (5.90), 8,097 (1 .22), 8,102 (6.98) 8,105 (6.1 1), 8,124 (3.52), 8,126 (3.76), 8,438 (3.36), 8,458 (5.40) , 8.479 (3.15), 11.343 (6.61).

Example 17A

 6-bromo- / V- (4-cyano-2-fluorophenyl) -3-cyclopropyl-2-phenylquinoline-4-carboxamide

To a mixture of (6-bromo-3-cyclopropyl-2-phenylquinolin-4-yl) (1 / - / - imidazol-1-yl) methanone (502 mg, 1.20 mmol, Example 11A) in DMF ( 5.0 mL) at RT was added 4-amino-3-fluorobenzonitrile (172 mg, 1.26 mmol). Then, while stirring, a 1 M solution of potassium tert-butoxide in THF (2.4 ml, 2.40 mmol) was slowly added dropwise, and the mixture was stirred at RT for 2 h. Then, the mixture was poured into water (100 ml) and extracted twice with ethyl acetate (100 ml each). The combined organic phases were dried over sodium sulfate, filtered and concentrated, and the residue was purified by column chromatography (50 g silica gel, Biotage, ethyl acetate / cyclohexane 85:15). 450 mg (100% purity, 77% of theory) of the title compound were obtained.

LC-MS (Method 1): R _t = 1 .29 min; MS (ESIpos): m / z = 486/488 [M + H] ⁺

1 H-NMR (500 MHz, DMSO-d 6) δ [ppm]: 0.303 (3.20), 0.313 (3.14), 0.658 (3.13), 0.675 (3.09), 1 .162 (4.36), 1 .176 (8.73), 1 .191 (4.36), 1.396 (1.48), 1 .990 (16.00), 2.359 (1.30), 2.365 (1.43), 2.376 (2.27), 2.388 (1.23), 2.393 (1.15 ), 4,010 (1 .27), 4,024 (3.72), 4,039 (3.66), 4,053 (1 .19), 7,485 (1,00), 7,499 (3.24), 7,505 (1.66), 7,510 (2.94), 7,513 ( 4.73), 7.516 (3.66), 7.521 (6.38), 7.524 (3.31), 7.532 (3.76), 7.535 (7.23), 7.540 (1.84), 7.545 (1.44), 7.549 (2.40), 7.553 (1.70 ), 7,743 (1 .32), 7,748 (6/17), 7,750 (7 .37), 7,754 (3 .72), 7,759 (2.49), 7,764 (6,21), 7,767 (4.93), 7,812 (2. 87), 7,815 (2. 86), 7,829 (2.96), 7.832 (3.00), 7.928 (3.32), 7.933 (3.28), 7.946 (4.16), 7,951 (4.57), 8,010 (3.46), 8,014 (3.35), 8,031 (4.29), 8,035 (10.69), 8,047 (7.39), 8,052 (10.50), 8,366 (2.79), 8,383 (4.47), 8,399 (2.53), 11.146 (5.92).

Example 18A

 6-bromo-N- [4-cyano-2- (methylsulfonyl) phenyl] -3-methyl-2-phenylquinoline-4-carboxamide

6-Bromo-3-methyl-2-phenylquinoline-4-carboxamide (200 mg, 586 μmol, Example 8A ) and the mixture was stirred at RT for 1 h. Then 4-fluoro-3- (methylsulfonyl) benzonitrile (1 17 mg, 586 μιηοΙ) was added and the mixture was stirred for 3 h at 80 °. The mixture was then purified by means of preparative HPLC (method 7). The combined product fractions were concentrated and the residue was taken up in dichloromethane, concentrated again and dried in vacuo. There was obtained 132 mg (100% purity, 43% of theory) of the title compound.

LC-MS (Method 1): R _t = 1 .20 min; MS (ESIpos): m / z = 520/522 [M + H] ⁺

1H-NMR (500 MHz, DMSO-d6) δ [ppm]: 10.85 (s, 1H), 8.46 (d, 1H), 8.41 (d, 1H), 8.30 (dd, 1H), 8.24 ( d, 1H), 8.04 (d, 1H), 7.94 (dd, 1H), 7.66-7.60 (m, 2H), 7.59-7.50 (m, 3H), 3.45 (s, 3H, obscured), 2.47 (s, 3H).

Example 19A

N- (4-cyano-2-fluorophenyl) -6-iodo-3-methyl-2-phenylquinoline-4-carboxamide

To a mixture of 1 / - / - imidazol-1-yl (6-iodo-3-methyl-2-phenyl-quinolin-4-yl) -methanone (1.35 g, 87% purity, 2.66 mmol, Example 12A) in DMF (10.0 ml) at RT 4-amino-3-fluorobenzonitrile (380 mg, 2.79 mmol) was added. Then, while stirring, a 1 M solution of potassium tert-butylate in THF (5.3 ml, 5.3 mmol) was added dropwise thereto, and the mixture was stirred at RT for 2 h. Then, the mixture was poured into water (200 ml) and extracted twice with ethyl acetate (100 ml each). Due to poor phase separation, it was filtered once through diatomaceous earth. The combined organic phases were dried over sodium sulfate, filtered and concentrated and the residue was stirred in dichloromethane (8 ml). The resulting solid was filtered off and washed twice with dichloromethane (1 ml). A first fraction of the title compound (175 mg, 99% purity, 13% of theory, see analysis) was obtained. The mother liquor obtained was concentrated, taken up in dichloromethane and purified by column chromatography (100 g of silica gel, Biotage, cyclohexane / ethyl acetate 85:15). There was thus obtained a second fraction of the title compound (605 mg, 98% purity, 44% of theory).

LC-MS (Method 1): R _t = 1 .24 min; MS (ESIpos): m / z = 508 [M + H] ⁺

¹ H NMR (400 MHz, DMSO-d6) δ [ppm]: 2,407 (16:00), 3,287 (0.82), 7,516 (1.26), 7,528 (1, 79), 7,533 (4.70), 7,553 (4.14), 7,568 (1.35), 7,574 (1 .01), 7,609 (3.74), 7,613 (4.14), 7,628 (2.53), 7,633 (2.24), 7,804 (1 .61), 7,825 (1.77), 7,856 (2.98), 7,878 ( 3.70), 8,005 (1 .57), 8,009 (1 .58), 8,031 (1 .60), 8,036 (1 .62), 8,049 (1.97), 8,054 (2.1 1), 8,071 (1.59), 8.076 (1 .78), 8,166 (3.39), 8,171 (3.30), 8.31 1 (1.48), 8,332 (2.54), 8,352 (1 .43), 1 1 .181 (3.58).

Example 20A

3-chloro- / V- (4-cyano-2-fluorophenyl) -6-iodo-2-phenylquinoline-4-carboxamide

To a mixture of (3-chloro-6-iodo-2-phenylquinolin-4-yl) (1 / - / - imidazol-1-yl) methanone (690 mg, 81% purity, 1.22 mmol, Example 13A) in DMF (5.0 mL) at RT was added 4-amino-3-fluoro-benzonitrile (174 mg, 1.28 mmol). Then, while stirring, a 1 M solution of potassium tert-butoxide in THF (2.4 ml, 2.4 mmol) was added dropwise, and the mixture was stirred at RT for 2 h. Then the mixture was poured into water (100 ml) and extracted three times with ethyl acetate (100 ml each). Due to poor phase separation, it was filtered once through diatomaceous earth. The combined organic phases were dried over sodium sulfate, filtered and concentrated, and the residue was purified by column chromatography (50 g silica gel, Biotage, cyclohexane / ethyl acetate 85:15). 285 mg (86% purity, 38% of theory) of the title compound were obtained.

LC-MS (Method 1): R _t = 1 .30 min; MS (ESIpos): m / z = 528 [M + H] ⁺

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (4.92), 0.008 (4.25), 2.366 (0.79), 2.669 (0.62), 2.710 (0.82), 3.287 (5.06), 7.551 ( 2.62), 7.557 (15.58), 7.562 (16.00), 7.570 (10.60), 7.574 (10.77), 7.584 (3.57), 7.599 (1.60), 7.739 (8.27), 7.744 (9.56), 7.752 (7.56), 7,755 (6.07), 7,763 (6.55), 7,805 (4.41), 7,809 (4.61), 7,830 (4.92), 7,922 (8.91), 7,944 (1 1 .14), 7,965 (1.32), 8,005 (5.06), 8,010 ( 5.23), 8.032 (5.09), 8.037 (5.12), 8.1 1 1 (0.76), 8.1 16 (0.76), 8.138 (0.65), 8.158 (6.36), 8.163 (7.14), 8.180 (4.84), 8.185 (6.30) , 8,215 (1 1 .22), 8,219 (9.67), 8,346 (1.04), 8,362 (0.96), 8,416 (4.39), 8,436 (7:00), 8,446 (2.22), 8,457 (4.08), 8,565 (1 .01) , 8,569 (1 .07), 1 1 .077 (0.87), 1 1 .336 (8.52).

Example 21A

N- (4-cyano-2-fluorophenyl) -3-cyclopropyl-6-iodo-2-phenylquinoline-4-carboxamide

To a mixture of (3-cyclopropyl-6-iodo-2-phenylquinolin-4-yl) (1 / - / - imidazol-1-yl) methanone (616 mg, 91% purity, 1.20 mmol, Example 14A) in DMF (5.0 mL) at RT was added 4-amino-3-fluorobenzonitrile (172 mg, 1.26 mmol). Then, while stirring, a 1 M solution of potassium tert-butylate in THF (2.4 ml, 2.4 mmol) was added dropwise thereto, and the mixture was stirred at RT for 2 h. Then, the mixture was poured into water (100 ml) and extracted twice with ethyl acetate (100 ml each). Due to poor phase separation, it was filtered once through diatomaceous earth. The combined organic phases were dried over sodium sulfate, filtered and concentrated, and the residue was taken up in dichloromethane and purified by column chromatography (50 g of silica gel, Biotage, cyclohexane / ethyl acetate 85:15). 303 mg (100% purity, 47% of theory) of the title compound were obtained.

LC-MS (Method 1): R _t = 1 .31 min; MS (ESIpos): m / z = 534 [M + H] ⁺

¹ H-NMR (500 MHz, DMSO-d6) δ [ppm]: 0.297 (2.58), 0.307 (2.54), 0.654 (2.56), 0.671 (2.53), 2.350 (1.10), 2.356 (1.18), 2.367 (1.98), 2.379 (1.05), 2.385 (0.99), 5.755 (16.00), 7.480 (0.86), 7.495 (2.88), 7.500 (1.34), 7.505 (2.49), 7.508 (4.14), 7,512 (3.04), 7,516 (5.66), 7,519 (2.63), 7,527 (2.80), 7,531 (6.39), 7,541 (1.15), 7,544 (2.07), 7,548 (1.48), 7,744 (5.47), 7,747 (6.53), 7,750 (3.07), 7,756 (2,00), 7,760 (5.52), 7,763 (4.23), 7,814 (2.55), 7,817 (2.46), 7,831 (2.65), 7,834 (2.60), 7,862 (5.60), 7,880 (6.47), 8,014 (3.02), 8,018 (2.86), 8,036 (2.98), 8,039 (2.80), 8,056 (3.97), 8,060 (3.86), 8,074 (3.17), 8,078 (3.21), 8,241 (6.37), 8,245 (5.93), 8,352 (2.57), 8,368 (4.06), 8,385 (2.33), 1 1 .133 (5.39). Example 22A

 6-bromo-N- [2-fluoro-4- (N'-hydroxycarbamimidoyl) phenyl] -3-methyl-2-phenylquinone

carboxamide

A mixture of hydroxylammonium chloride (540 mg, 7.77 mmol) and sodium bicarbonate (751 mg, 8.94 mmol) in DMSO (10 mL) was stirred at 40 ^° C. for 30 min. Subsequently, 6-bromo / V- (4-cyano-2-fluorophenyl) -3-methyl-2-phenylquinoline-4-carboxamide (358 mg, 777 μιηοΙ, Example 15A) was added and the reaction mixture was for 1 h at 100 ° touched. After cooling to RT, the mixture was treated with water (50 ml). The precipitate formed was filtered off and washed three times with 10 ml of water. Thereafter, the precipitate was dissolved in ethyl acetate (100 ml) and the solution was washed once with saturated aqueous sodium chloride solution (100 ml), dried over sodium sulfate, filtered and concentrated. 365 mg (96% purity, 91% of theory, solvent-containing) of the title compound were obtained.

LC-MS (Method 1): R _t = 0.85 min; MS (ESIpos): m / z = 493/495 [M + H] ⁺

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (0.96), 1 .157 (3.29), 1 .175 (6.48), 1 .193 (3.24), 1 .665 (0.85) , 1,988 (12,666), 2,445 (16:00), 3,291 (1: 58), 4,002 (1,10), 4,021 (3.11), 4,038 (3.05), 4,056 (0.98), 5,926 (4.12), 7,523 (1 .56), 7,535 (2.13), 7,540 (4.46), 7,560 (4.29), 7,576 (1 .50), 7,582 (1 .16), 7,606 (2.04), 7.61 1 (3.77), 7,619 (5.36), 7,623 (4.86), 7.637 (7.7), 7.890 (1.65), 7.910 (2.83), 7.921 (1.74), 7.927 (2.1.1), 7.943 (2.18), 7.949 (2.44), 8.000 (4.10), 8.006 (3.47), 8,030 (4.26), 8,053 (2.81), 9.794 (8.25), 10.835 (3.98). Example 23A

 Methyl 4 - {[(6-bromo-3-methyl-2-phenylquinoline-4-yl) carbonyl] amino} -3-fluorobenzoate

(6-Bromo-3-methyl-2-phenylquinolin-4-yl) (1 / - / - imidazol-1-yl) methanone (1, 00 g, 2.55 mmol, Example 9A) was dissolved in DMF (10 mL ) solved. To the solution was added methyl 4-amino-3-fluorobenzoate (474 mg, 2.80 mmol) and potassium tert-butylate (429 mg, 3.82 mmol). The reaction mixture was stirred at RT for 1 h and then stirred into a mixture of ice-water (50 ml), saturated ammonium chloride solution (50 ml) and ethyl acetate (100 ml). The organic phase was separated, washed twice with water and once with saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solvent was removed in vacuo and the residue purified by column chromatography (silica gel, eluent: 5% ethyl acetate / 95% cyclohexane -> 15% ethyl acetate / 85% cyclohexane -> 45% ethyl acetate / 55% cyclohexane, Biotage). The product-containing fractions were concentrated and the residue was stirred in tert-butyl methyl ether (10 ml). The solid was filtered off, washed twice with tert-butyl methyl ether (5 ml) and then stirred in ethyl acetate (4 ml) for three days. The solid was then filtered off again and dried in vacuo. 810 mg (purity 99%, 64% of theory) of the title compound were obtained.

LC-MS (Method 1): R _t = 1 .27 min; MS (ESIpos): m / z = 493/495 [M + H] ⁺

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1 1.10 (s, 1H), 8.27 (t, 1H), 8.05 (d, 1H), 7.99 (d, 1H), 7.95-7.90 (m, 2H), 7.85 (dd, 1H), 7.64-7.62 (m, 2H), 7.58-7.51 (m, 3H), 3.89 (s, 3H), 2.43 (s, 3H).

Example 24A

4 - {[(6-bromo-3-methyl-2-phenylquinoline-4-yl) carbonyl] amino} -3-fluorobenzoic acid

Methyl 4 - {[(6-bromo-3-methyl-2-phenylquinolin-4-yl) carbonyl] amino} -3-fluorobenzoate (100 mg, 0.20 mmol, Example 23A) was dissolved in THF (2.5 mL) and methanol (0.5 ml) dissolved. To the solution was added 1 M sodium hydroxide solution (0.61 ml, 0.61 mmol). The reaction mixture was stirred for 1 h under reflux. The volume of the solution was then reduced on a rotary evaporator and the concentrated solution was adjusted to pH 3 with 1 M hydrochloric acid (0.6 ml). It was diluted with water (5 ml) and the precipitated solid was filtered off. The solid was washed with water and dried in vacuo. There were obtained 94 mg (purity 100%, 97% of theory) of the title compound.

LC-MS (Method 1): R _t = 1 .08 min; MS (ESIpos): m / z = 479/481 [M + H] ⁺

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: 13.27 (br.s, 1H), 1.04 (s, 1H), 8.17 (t, 1H), 8.05 (d, 1H ), 7.99 (d, 1H), 7.94 (dd, 1H), 7.88 (dd, 1H), 7.80 (dd, 1H), 7.65-7.61 (m, 2H), 7.58-7.50 (m, 3H ), 2.44 (s, 3H).

Example 25A

4 - {[(6-bromo-3-methyl-2-phenylquinoline-4-yl) carbonyl] amino} -3-fluorobenzoyl chloride

To a suspension of 4 - {[(6-bromo-3-methyl-2-phenylquinolin-4-yl) carbonyl] amino} -3-fluorobenzoic acid (250 mg, 0.52 mmol, Example 24A) in dichloromethane (2.5 ml ) were added successively a drop of DMF and slowly oxalyl chloride (1 10 mg, 0.87 mmol). After dilution with further dichloromethane (2.5 ml) and stirring at RT for 1 h, the mixture was concentrated and the residue was dried in vacuo. The title compound was obtained in 94% purity by LC / MS (the analytical sample was quenched with methanol).

LC-MS (Method 5): R _t = 1 .55 min; MS (ESIpos): m / z = 493/495 [M-CI + OCH ₃ + H] ⁺ Example 26A

 6-bromo- / V- [2-fluoro-4- (hydrazinocarbonyl) phenyl] -3-methyl-2-phenylquinoline-4-carboxamide

A mixture of 4 - {[(6-bromo-3-methyl-2-phenylquinolin-4-yl) carbonyl] amino} -3-fluorobenzoyl chloride (500 mg, 1 .00 mmol, Example 25A) in THF (10 ml) was treated at 0 ° with 80% aqueous hydrazine hydrate solution (2.0 ml, 40 mmol) and stirred after warming to RT overnight at RT. It was stirred under reflux for a further 24 h. After cooling to RT, the mixture was poured into ethyl acetate (100 ml) and washed with 1 M sodium hydroxide solution (80 ml) and saturated aqueous sodium chloride solution (80 ml). After removal of the solvent, the residue was purified by preparative HPLC (Method 8). 422 mg (purity 96%, 85% of theory) of the title compound were obtained.

LC-MS (Method 2): R _t = 1.64 min; MS (ESIpos): m / z = 493/495 [M + H] ⁺ Example 27 A

6-bromo- / V- (2-fluoro-4-formylphenyl) -3-methyl-2-phenylquinoline-4-carboxamide

A solution of 6-bromo-3-methyl-2-phenylquinoline-4-carboxamide (150 mg, 440 μιηοΙ, Example 8A) in dioxane (5 ml) under argon was successively at RT with 4-bromo-3-fluoro-benzaldehyde (107 mg, 528 μιηοΙ), cesium carbonate (201 mg, 615 μιηοΙ), xantphos (38 mg, 66 μιηοΙ) and tris (dibenzylidenaceton) dipalladium (20 mg, 22 μιηοΙ) were added, and the mixture was then 24 h at 1 10th Ό stirred. After cooling to RT, the mixture was filtered once through a frit, filter residue was washed with ethyl acetate, and the filtrate was washed with saturated aqueous sodium chloride solution and concentrated. The residue was prepurified by preparative HPLC (Method 8). The combined product-containing fractions were concentrated and the residue was taken up in acetonitrile, filtered and re-purified by column chromatography (50 g silica gel, cyclohexane / ethyl acetate 97: 3 → 8: 2). There were obtained 89 mg (purity 80%, 44% of theory) of the title compound.

LC-MS (Method 2): R, = 2.21 min; MS (ESIpos): m / z = 463/465 [M + H] ⁺ Example 28A

Methyl 4 - {[(6-bromo-3-methyl-2-phenylquinolin-4-yl) carbonyl] amino} bicyclo [2.2.2] octane-1-carboxylate

To a solution of 6-bromo-3-methyl-2-phenylquinoline-4-carboxylic acid (Example 1A, 200 mg, 0.58 mmol) in DMF (3 ml) was added methyl 4-amino-nicyclo [2.2.2] octane-1-carboxylate (214 mg, 1.17 mmol), HATU (333 mg, 0.88 mmol) and DIPEA (0.20 mL, 1.17 mmol). The mixture was then stirred at 60 ° C overnight. After cooling to RT, the mixture was purified directly (without further work-up) by preparative HPLC (Method 9). There were obtained 269 mg (purity 99%, 90% of theory) of the title compound.

LC-MS (Method 1): R _t = 1 .20 min; MS (ESIpos): m / z = 507/509 [M + H] ⁺

¹ H-NMR (500 MHz, DMSO-d6) δ [ppm]: 8.48 (s, 1H), 7.97 (d, 1H), 7.88 (dd, 1H), 7.83 (d, 1H), 7.65 -7.42 (m, 5H), 3.59 (s, 3H), 2.32 (s, 3H), 2.12-1 .95 (m, 6H), 1.94-1.76 (m, 6H). Example 29A

 Methyl 4 - {[(3-chloro-6-iodo-2-phenylquinolin-4-yl) carbonyl] amino} bicyclo [2.2.2] octane-1-carboxylate

Method A:

To a solution of 3-chloro-6-iodo-2-phenylquinoline-4-carboxylic acid (914mg, 54% purity, 1.20mmol, Example 5A) in DMF (6mL) was added methyl 4-aminobicyclo sequentially at RT - [2.2.2] octane-1-carboxylate hydrochloride (265 mg, 1 .20 mmol), HATU (687 mg, 1 .81 mmol) and DIPEA (630 μΙ, 3.6 mmol). The mixture was then stirred at 60 ° C. for 3 hours. Then again DIPEA (630 μΙ, 3.6 mmol) was added and the mixture was stirred for a further hour at 60 Ό. After cooling to RT, the mixture was poured into 10% citric acid (50 ml) and extracted twice with ethyl acetate (30 ml each). The combined organic phases were dried over sodium sulfate, filtered and concentrated. Upon dissolution of the residue with ethyl acetate, a precipitate formed, which was filtered off and washed with ethyl acetate. The filtrate was concentrated and the residue was taken up in dichloromethane and purified by column chromatography (silica gel, 100 g, Biotage, cyclohexane / ethyl acetate 85:15). 309 mg (purity 60%, 27% of theory) of the title compound were obtained. Method B:

 To a solution of 3-chloro-6-iodo-2-phenylquinoline-4-carboxylic acid (500 mg, 54% purity, 0.66 mmol, Example 5A) in DMF (4 mL) at RT was HATU (376 mg, 0.99 mmol). and DIPEA (256 mg, 1 .98 mmol) and the mixture was stirred at RT for 30 min. Subsequently, methyl 4-aminobicyclo [2.2.2] octane-1-carboxylate hydrochloride (145 mg (0.66 mmol) dissolved in 1 ml of DMF was added and the mixture was stirred overnight at 60 ° C. After cooling to RT, the mixture was purified twice by preparative HPLC (Method 7) to give 74 mg (purity 98%, 19% of theory) of the title compound.

¹ H-NMR (500 MHz, DMSO-d6) δ [ppm]: 8.60 (s, 1H), 8.1 1 (dd, 1H), 8.06 (d, 1H), 7.87 (d, 1H), 7.73-7.66 (m, 2H), 7.57-7.51 (m, 3H), 3.59 (s, 3H), 2.07-1 .99 (m, 6H), 1.91 -1 .83 (m, 6H).

LC-MS (Method 1): R _t = 1 .33 min; MS (ESIpos): m / z = 575 [M + H] ⁺ Example 30A

 4 - {[(6-Bromo-3-methyl-2-phenylquinolin-4-yl) carbonyl] amino} bicyclo [2.2.2] octane-1-carboxylic acid

Method A:

 To a solution of methyl 4 - {[(6-bromo-3-methyl-2-phenylquinolin-4-yl) carbonyl] amino} bicyclo [2.2.2] octane-1-carboxylate (260 mg, 0.51 mmol Example 28A) in THF / methanol (5: 1, 7.7 ml) was added at RT 1M sodium hydroxide solution (2.6 ml, 2.6 mmol) and the mixture was stirred at reflux for 1 h. After cooling to RT, the mixture was purified directly (without further work-up) by preparative HPLC (Method 9). There were obtained 134 mg (purity 100%, 53% of theory) of the title compound.

LC-MS (Method 1): R _t = 1 .03 min; MS (ESIpos): m / z = 493/495 [M + H] ⁺

¹ H-NMR (500 MHz, DMSO-d6) δ [ppm]: 8.33 (s, 1H), 7.97 (d, 1H), 7.87 (dd, 1H), 7.84 (d, 1H), 7.60 -7.46 (m, 5H), 2.32 (s, 3H), 2.00-1.91 (m, 6H), 1.79-1.70 (m, 6H).

Method B: To a solution of methyl 4 - {[(6-bromo-3-methyl-2-phenylquinolin-4-yl) carbonyl] amino} bicyclo [2.2.2] octane-1-carboxylate (15.23 g, 30.01 mmol Example 28A) in THF (444 mL) and methanol (88 mL) at RT was added 1 M sodium hydroxide solution (150 mL, 150 mmol) and the mixture was stirred at reflux for 2.5 h. After cooling to RT, the mixture was added with water (200 ml) and adjusted to pH 2 with concentrated hydrochloric acid to precipitate a solid. The mixture was extracted three times with ethyl acetate (without the solid previously separated) and the combined organic phases were then washed twice with saturated aqueous sodium chloride solution and concentrated in vacuo. The residue was then suspended in water (200 ml) and stirred at 120 ° C. for 2 hours. After cooling to RT, the solid was filtered off, then resuspended in water (200 ml) and the mixture was stirred for a further 1 h at 120 ° C. The resulting Fes material was then filtered off directly from the non-cooled reaction solution and then dried in vacuo. 13.48 g (purity 99%, 90% of theory) of the title compound were obtained.

Example 31A

4 - {[(3-Chloro-6-iodo-2-phenylquinolin-4-yl) carbonyl] amino} bicyclo [2.2.2] octane-1-carboxylic acid

Method A:

 To a solution of methyl 4 - {[(3-chloro-6-iodo-2-phenylquinolin-4-yl) carbonyl] amino} bicyclo [2.2.2] octane-1-carboxylate (309 mg, purity 60%). , 323 mmol, Example 29A) in a mixture of THF (16 ml) and methanol (3.3 ml) was added at RT 1 M sodium hydroxide solution (3.2 ml, 3.2 mmol) and the mixture was allowed to stand for 22 h at RT. Subsequently, the mixture was concentrated. The residue was added with water (20 ml), and the mixture was adjusted to pH 2 with 1 M hydrochloric acid. The resulting precipitate was filtered off, washed twice with water (2 ml) and dried. 290 mg (purity 60%, 96% of theory) of the title compound were obtained.

LC-MS (Method 1): R _t = 1 .12 min; MS (ESIpos): m / z = 561 [M + H] ⁺ Method B:

 To a solution of methyl 4 - {[(3-chloro-6-iodo-2-phenylquinolin-4-yl) carbonyl] amino} bicyclo [2.2.2] octane-1-carboxylate (70 mg, purity 98%). , 0.12 mmol, Example 29A) in a mixture of THF (4 ml) and methanol (0.7 ml) was added 1 M sodium hydroxide solution (0.73 ml, 0.73 mmol) and the mixture was stirred at RT overnight. The mixture was then adjusted to pH 3 by addition of TFA (0.07 ml, 0.85 mmol) and purified by preparative HPLC (Method 7). 50 mg (purity 96%, 70% of theory) of the title compound were obtained.

¹ H-NMR (500 MHz, DMSO-d6) δ [ppm]: 12.13 (br.s, 1H), 8.58 (s, 1H), 8.1 1 (dd, 1H), 8.06 (d, 1H ), 7.87 (d, 1H), 7.72-7.66 (m, 2H), 7.58-7.51 (m, 3H), 2.07-1.96 (m, 6H), 1 .89-1 .79 (m, 6H).

LC-MS (Method 1): R _t = 1 .12 min; MS (ESIpos): m / z = 561 [M + H] ⁺

Example 32A

 4 - {[(6-Bromo-3-methyl-2-phenylquinolin-4-yl) carbonyl] amino} bicyclo [2.2.2] octane-1-carbonyl chloride

To a suspension of 4 - {[(6-bromo-3-methyl-2-phenylquinolin-4-yl) carbonyl] amino} bicyclo [2.2.2] octane-1-carboxylic acid (395 mg, 0.80 mmol, Example 30A ) in dichloromethane (10 ml) at RT was added dropwise a drop of DMF and then slowly oxalyic chloride (0.14 ml, 1.60 mmol) and the mixture was then stirred at RT for 1 h. The mixture was then concentrated in vacuo, the residue was taken up again in dichloromethane and the mixture was then concentrated again in vacuo. This process was repeated several times. The residue was then dried in vacuo. There was obtained 410 mg (100% of theory) of the title compound, which was used directly (without analysis) for subsequent chemistry.

Example 33A

4 - {[(3-Chloro-6-iodo-2-phenylquinolin-4-yl) carbonyl] amino} bicyclo [2.2.2] octane-1-carbonyl chloride

To a suspension of 4 - {[(3-chloro-6-iodo-2-phenylquinolin-4-yl) carbonyl] amino} bicyclo [2.2.2] octane-1-carboxylic acid (290 mg, purity 60%, 310 μιηοΙ, Example 31 A) in dichloromethane (5 ml) at RT a drop of DMF and then slowly oxalyl chloride (90 μΙ, 1 .0 mmol) was added and the mixture was then stirred for 1 h at RT. The mixture was then concentrated in vacuo, the residue was taken up again in dichloromethane and the mixture was then concentrated again in vacuo. This process was repeated several times. The residue was then dried in vacuo. There were obtained 300 mg (about 100% of theory, assumption: purity 60%) of the title compound, which was used directly (without analysis) for subsequent chemistry.

Example 34A

 6-Bromo / V- (4-carbamoylbicyclo [2.2.2] oct-1-yl) -3-methyl-2-phenylquinoline-4-carboxamide

To a solution of 4 - {[(6-bromo-3-methyl-2-phenylquinolin-4-yl) carbonyl] amino} bicycle [2.2.2] octane-1-carbonyl chloride (300 mg, 0.59 mmol, Example 32A ) in THF (6 ml) was slowly added 33% aqueous ammonia solution (4.5 ml, 38.1 mmol) and the mixture was stirred at RT overnight. Then, water (50 ml) was added. The resulting solid was then filtered off, washed twice with water and washed in vacuo. dried under vacuum. 205 mg (purity 100%, 71% of theory, see analysis) of the title compound were obtained.

 In an experiment carried out analogously, 4.26 g (purity 98%, 95% of theory) of the title compound were obtained from 5.26 g (10.28 mmol) of the compound from Example 32A and 79 ml (668 mmol) of 33% aqueous ammonia solution.

LC-MS (Method 1): R _t = 0.87 min; MS (ESIpos): m / z = 492/494 [M + H] ⁺

¹ H-NMR (500 MHz, DMSO-d6) δ [ppm]: 8.43 (s, 1H), 7.97 (d, 1H), 7.91-7.79 (m, 2H), 7.61-7.44 (m, 5H) , 6.97 (brs s, 1H), 6.75 (brs s, 1H), 2.33 (s, 3H), 2.08-1 .93 (m, 6H), 1.89-1 .72 (m, 6H ).

Example 35A

N- (4-carbamoylbicyclo [2.2.2] oct-1-yl) -3-chloro-6-iodo-2-phenylquinoline-4-carboxamide

To a solution of 4 - {[(3-chloro-6-iodo-2-phenylquinolin-4-yl) carbonyl] amino} bicyclo [2.2.2] octane-1-carbonyl chloride (299 mg, 517 μιηοΙ, purity: Assumption: 60%, Example 33A) in THF (5 ml) was slowly added 33% aqueous ammonia solution (3.0 ml, 25.4 mmol) and the mixture was stirred at RT for two days. Then, water (50 ml) was added. The resulting solid was then filtered off, washed four times with water (2 ml each time) and dried in vacuo. 286 mg (purity 59%, 97% of theory) of the title compound were obtained.

LC-MS (Method 1): R _t = 1 .02 min; MS (ESIpos): m / z = 560 [M + H] ⁺ Example 36A

6-Bromo / V- (4-cyanobicyclo [2.2.2] oct-1-yl) -3-methyl-2-phenylquinoline-4-carboxamide

 To a suspension of 6-bromo / V- (4-carbamoylbicyclo [2.2.2] oct-1-yl) -3-methyl-2-phenylquinoline-4-carboxamide (500 mg, 1.02 mmol, Example 34A). in dichloromethane (20 ml) under argon, methoxycarbonylsulfamoyl) triethylammonium hydroxide (Burgess reagent, 968 mg, 4.06 mmol) was added at RT and the mixture was stirred at RT for 18 h. Then, the mixture was added with dichloromethane and 1 M hydrochloric acid (50 ml each), shaken, and the phases were separated. The aqueous phase was extracted once with dichloromethane (30 ml). The combined organic phases were dried over sodium sulfate, filtered and concentrated and the residue was taken up in dichloromethane and purified by column chromatography (50 g of silica gel, Biotage, cyclohexane / ethyl acetate 4: 1). 314 mg (purity 67%, 43% of theory) of the title compound were obtained.

LC-MS (Method 6): R _t = 3.73 min; MS (ESIpos): m / z = 474/476 [M + H] ⁺ Example 37A

 3-Chloro- / V- (4-cyanobicyclo [2.2.2] oct-1-yl) -6-iodo-2-phenylquinoline-4-carboxamide

To a suspension of /V- (4-carbamoylbicyclo [2.2.2] octo-1-yl) -3-chloro-6-iodo-2-phenylquinoline-4-carboxamide (286 mg, 51 μl, purity 59%, Example 35A) in dichloromethane (10 ml) under argon, methoxycarbonylsulfamoyl) triethylammonium hydroxide (183 mg, 766 μιηοΙ, Burge's reagent) was added at RT and the mixture was stirred at RT for 31 h. Subsequently, methoxycarbonylsulfamoyl) triethylammonium hydroxide (61 mg, 255 μιηοΙ, Burgess reagent) was added again and the mixture was stirred at RT for a further 1.5 days. Then, the mixture was added with dichloromethane and 1 M hydrochloric acid (each 40 ml), shaken, and the phases were separated. The aqueous phase was extracted once with dichloromethane (30 ml). The combined organic phases were dried over sodium sulfate, filtered and concentrated. 258 mg (purity 56%, 88% of theory) of the title compound were obtained.

LC-MS (Method 1): R _t = 1 .23 min; MS (ESIpos): m / z = 542 [M + H] ⁺ Example 38A

 6-Bromo / V- [4 - (/ V -hydroxycarbamimidoyl) bicyclo [2.2.2] oct-1-yl] -3-methyl-2-phenylquinoline-4-carboxamide

A mixture of hydroxylammonium chloride (2.78 g, 40.0 mmol) and sodium bicarbonate (3.86 g, 46.0 mmol) in DMSO (50 ml) was stirred at 40 ° C. for 30 min. Subsequently, 6-bromo-N- (4-cyanobicyclo [2.2.2] oct-1-yl) -3-methyl-2-phenylquinoline-4-carboxamide (2.30 g, 82% purity, 4.00 mmol, Example 36A) was added The reaction mixture was stirred at 100 ° C. for 6 h followed by 1 h at RT, then water (50 ml) was added and the precipitate formed was filtered off and washed three times with water (10 ml) the precipitate was dissolved in ethyl acetate (100 ml) and the solution was washed once with saturated aqueous sodium chloride solution (100 ml), dried over sodium sulfate, filtered and concentrated to give 1.30 g (72% purity, 46%). d. Th.) of the title compound. LC-MS (Method 1): R _t = 0.71 min; MS (ESIpos): m / z = 507/509 [M + H] ⁺ Example 39A

 6-Bromo / V- [4- (hydrazinocarbonyl) bicyclo [2.2.2] oct-1-yl] -3-methyl-2-phenylquinoline-4-carboxamide

A mixture of 4 - {[(6-bromo-3-methyl-2-phenylquinolin-4-yl) carbonyl] amino} bicyclo [2.2.2] octane-1-carbonyl chloride (474 mg, 926 μιηοΙ, Example 32A). in THF (5 ml) was added dropwise at 0 Ό with 80% aqueous hydrazine hydrate solution (180 μΙ, 3.7 mmol) and stirred after warming to RT overnight at RT. Subsequently, 80% hydrazine hydrate solution (90 .mu.l, 1 .9 mmol) was again added and the mixture was stirred at RT for a further 3 hours. Subsequently, again 80% hydrazine hydrate solution (90 μΙ, 1.9 mmol) was added and the mixture was stirred for a further 18 h at 40 °. Then again 80% hydrazine hydrate solution (90 μΙ, 1 .9 mmol) was added and the mixture was stirred for a further three days at 40 °. Thereafter THF (5 ml) and again 80% aqueous hydrazine hydrate solution (1.35 ml, 28 mmol) were added and the mixture was stirred overnight at 75 ° C. bath temperature. After cooling to RT, the mixture was poured into ethyl acetate (100 ml) and washed with 1 M sodium hydroxide solution (100 ml) and saturated aqueous sodium chloride solution (50 ml). After removal of the solvent, the residue was purified by preparative HPLC (Method 8). 126 mg (purity 95%, 25% of theory) of the title compound were obtained.

LC-MS (Method 2): R _t = 1 .53 min; MS (ESIpos): m / z = 507/509 [M + H] ⁺ Example 40A

6-Bromo / V- (4-formylbicyclo [2.2.2] oct-1-yl) -3-methyl-2-phenylquinoline-4-carboxamide

 To a solution of 6-bromo / V- (4-cyanobicyclo [2.2.2] oct-1-yl) -3-methyl-2-phenylquinoline-4-carboxamide (150 mg, 316 μιηοΙ, Example 36A) in dichloromethane (6 ml) under argon, a 1 .2 M solution of Diisobutylaluminiumhydri d (580 μΙ, 700 μιηοΙ) was added dropwise in toluene at 0 Ό, and the mixture was stirred for 10 min at 0 Ό and then overnight at RT. Then, the mixture was added with 1 M hydrochloric acid (2 ml). After stirring for 10 min at RT, the precipitate formed was filtered off and washed with saturated aqueous sodium chloride solution. The filtrate was concentrated and the residue was purified by preparative HPLC (Method 8). 54 mg (85% purity, 30% of theory) were obtained.

LC-MS (Method 2): R, = 2.18 min; MS (ESIpos): m / z = 477/479 [M + H] ⁺

Exemplary embodiments: Example 1

 6-Bromo / V- [2-fluoro-4- (1 / - / - tetrazol-5-yl) phenyl] -3-methyl-2-phenylquinoline-4-carboxamide

To a mixture of 6-bromo / V- (4-cyano-2-fluorophenyl) -3-methyl-2-phenylquinoline-4-carboxamide (299 mg, 650 μιηοΙ, Example 15A) in DMF (2.9 ml). Sodium azide (51 mg, 779 μιηοΙ) and ammonium chloride (42 mg, 779 μιηοΙ) were added and the mixture was stirred for 8 h at 120 Ό. Then again sodium iumazide (51 mg, 779 μιηοΙ) and ammonium chloride (42 mg, 779 μιηοΙ) were added and the mixture was stirred for a further 6 h at 120 Ό. After cooling to RT, water was added to the mixture and extracted with ethyl acetate. The organic phase was washed with water and saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated. The residue was purified by preparative HPLC (Method 10). 214 mg (purity 100%, 65% of theory) of the title compound were obtained.

LC-MS (Method 2): R _t = 1 .89 min; MS (ESIpos): m / z = 503/505 [M + H] ⁺

¹ H-NMR (500 MHz, DMSO-d6) δ [ppm]: 2.463 (16.00), 5.754 (2.21), 7.516 (0.49), 7.530 (1.72), 7.536 (0.76), 7.541 (1.39) , 7,544 (2.41), 7,548 (1 .77), 7,552 (3.07), 7,567 (4.18), 7,577 (0.81), 7,580 (1 .52), 7,584 (1 .14), 7,634 (3.74), 7,637 (4.20 ), 7.650 (3.01), 7.653 (2.34), 7.932 (1.61), 7.936 (1.71), 7.950 (2.10), 7.954 (2.33), 7.985 (1.40), 7.988 (2.37), 7.992 ( 2.1 1), 8,009 (4.92), 8,025 (3.72), 8,029 (3.42), 8,045 (3.97), 8,063 (2.88), 8,251 (1.40), 8,268 (2.15), 8,284 (0.97), 1 1 .057 (3.65 ).

Example 2

 6-bromo-3-chloro- / V- [2-fluoro-4- (2 / - / - tetrazol-5-yl) phenyl] -2-phenylquinoline-4-carboxamide

To a mixture of 6-bromo-3-chloro / V- (4-cyano-2-fluorophenyl) -2-phenylquinoline-4-carboxamide (125 mg, 260 μιηοΙ, Example 16A) in toluene (2.5 ml). Under argon, trimethylsilyl azide (140 μΙ, 1 .0 mmol) and dibutyltin oxide (13 mg, 52.0 μιηοΙ) were added and the mixture was stirred for 16.5 h at 120 Ό. T rimethylsilyl azide (140 μΙ, 1.0 mmol) and dibutyltin oxide (13 mg, 52.0 μιηοΙ) were added again and the mixture was stirred at 120 ° C. for a further 24 h. After cooling to RT, the mixture was washed with water and ethyl acetate (each because 50 ml), shaken and the phases were separated. The aqueous phase was extracted once with ethyl acetate (30 ml). The combined organic phases were dried over sodium sulfate, filtered and concentrated, and the residue was taken up in DMSO and purified by preparative HPLC (Method 7). 1 12 mg (purity 100%, 83% of theory) of the title compound were obtained.

LC-MS (Method 1): R _t = 1 .09 min; MS (ESIpos): m / z = 523/525 [M + H] ⁺

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (0.88), 7.559 (1.05), 7.563 (1.68), 7.566 (2.45), 7.570 (9.01), 7.575 (9.42 ), 7,583 (5.38), 7,588 (5.65), 7,595 (1.30), 7,599 (1 .63), 7,758 (4.74), 7,763 (5.52), 7,767 (2.16), 7,772 (3.85), 7,775 (3.58), 7,783 (3.89), 7,979 (2.42), 7,984 (3.31), 7,997 (3.01), 8,008 (2.86), 8,012 (4.08), 8,016 (3.99), 8,021 (2.06), 8,040 (1 .94), 8,045 (2.95) , 8,062 (5.85), 8,066 (16:00), 8.1 14 (5.19), 8.1 18 (3.20), 8,135 (1,98), 8,138 (2.64), 8,372 (1 .83), 8,392 (2.89), 8,413 (1.54 ), 1 1 .225 (5.06).

Example 3

 6-bromo-3-cyclopropyl-N- [2-fluoro-4- (2 / - / - tetrazol-5-yl) phenyl] -2-phenylquinoline-4-carboxamide

To a mixture of 6-bromo / V- (4-cyano-2-fluorophenyl) -3-cyclopropyl-2-phenylquinoline-4-carboxamide (395 mg, 813 μιηοΙ, Example 17A) in toluene (15 ml) under argon Trimethylsilylazide (220 μΙ, 1 .6 mmol) and dibutyltin oxide (20 mg, 81. 3 μιηοΙ) were added and the mixture was stirred for 3 h at 120 Ό. Nuclear trimethylsilyl azide (220 μΙ, 1 .6 mmol) and dibutyltin oxide (20 mg, 81 .3 μιηοΙ) were added and the mixture was stirred for a further hour at 120 Ό. It again Trimeth were ylsilylazid (220 μΙ, 1 .6 mmol) and dibutyltin oxide (20 mg, 81.3 μιηοΙ) was added and the mixture was stirred for a further 16 h at 120 Ό. After cooling to RT, the mixture was treated with water and ethyl acetate (50 ml each), shaken and the phases were separated. The aqueous phase was extracted once with ethyl acetate (50 ml). The combined organic phases were dried over sodium sulfate, filtered and concentrated, and the residue was taken up in DMSO and purified by preparative HPLC (Method 7). 379 mg (purity 100%, 88% of theory) of the title compound were obtained.

LC-MS (Method 1): R _t = 1 .1 1 min; MS (ESIpos): m / z = 529/531 [M + H] ⁺

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.008 (1.76), 0.338 (7.25), 0.350 (7.23), 0.693 (6.68), 0.715 (6.73), 2.370 (1.25) , 2.385 (2.32), 2.392 (2.51), 2.406 (4.1 1), 2.421 (2.36), 2.428 (2.14), 2.442 (0.97), 3.169 (7.06), 3.563 (1.97), 5.754 (0.99), 7.485 (1.38 ), 7.493 (0.98), 7.504 (4.58), 7.51 1 (2.90), 7.520 (10.72), 7.525 (15.06), 7.543 (12.40), 7.559 (3.82), 7.565 (2.68), 7.755 (1 1.22) , 7,758 (12.84), 7,774 (10:43), 7,779 (8.89), 7,935 (4.82), 7,940 (4.97), 7,957 (7.31), 7,963 (7.67), 7,989 (5.17), 7,994 (8.52), 7,999 (7.01) , 8,020 (16:00), 8,041 (13:23), 8,063 (8.74), 8,082 (1 1.98), 8,087 (1 1.28), 8,296 (3.63), 8,317 (5.88), 8,337 (2.85), 1 1,013 (10.53).

Example 4

 6-Bromo-3-methyl-N- [2- (methylsulfonyl) -4- (1 / - / - tetrazol-5-yl) phenyl] -2-phenylquinoline-4-carboxamide

To a mixture of 6-bromo-N- [4-cyano-2- (methylsulfonyl) phenyl] -3-methyl-2-phenylquinoline-4-carboxamide (100 mg, 192 μιηοΙ, Example 18A) in DMF (1 .0 ml) sodium azide (15 mg, 230 μιηοΙ) and ammonium chloride (12 mg, 230 μιηοΙ) were added and the mixture was stirred for 8 h at 120 Ό. Sodium azide (15 mg, 230 μmol) and ammonium chloride (12 mg, 230 μmol) were then added again, and the mixture was stirred at 120 ° C. for a further hour and then allowed to stand at RT over N 8. The mixture was filtered and the product was filtered Filtrate was purified by preparative HPLC (Method 7) to give 60 mg (100% purity, 56% of theory) of the title compound.

LC-MS (Method 1): R _t = 1 .07 min; MS (ESIpos): m / z = 563/565 [M + H] ^{+ 1} H-NMR (400 MHz, DMSO-d6) δ [ppm]: 10.77 (s, 1H), 8.71 (d, 1H), 8.49 (dd, 1H), 8.34 (d, 1H), 8.30 (d, 1H), 8.04 (d, 1H), 7.95 (dd, 1H), 7.70-7.61 (m, 2H), 7.61-7.50 (m, 3H), 3.44 (s, 3H), 2.52 ( s, 3H).

Example 5

N- [2-fluoro-4- (2 / - / - tetrazol-5-yl) phenyl] -6-iodo-3-methyl-2-phenylquinoline-4-carboxamide

To a mixture of N- (4-cyano-2-fluorophenyl) -6-iodo-3-methyl-2-phenylquinoline-4-carboxamide (167mg, 329μιηοΙ, Example 19A) in toluene (3.1ml) under argon Trimethylsilylazid (175 μΙ, 1 .3 mmol) and dibutyltin oxide (16 mg, 66 μιηοΙ) was added and the mixture was stirred for 17 h at 120 Ό. After cooling to RT, the mixture was treated with water and ethyl acetate (50 ml each), shaken and the phases were separated. The aqueous phase was extracted once with ethyl acetate (30 ml). The combined organic phases were dried over sodium sulfate, filtered and concentrated, and the residue was taken up in DMSO and purified by preparative HPLC (Method 7). 160 mg (100% purity, 88% of theory) of the title compound were obtained.

LC-MS (Method 1): R _t = 1 .07 min; MS (ESIpos): m / z = 551 [M + H] ⁺

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: 2.086 (9.25), 2.447 (16.00), 3.170 (0.77), 5.754 (1.72), 7.525 (1.38), 7.532 (0.95) , 7,536 (1.81), 7,540 (3.67), 7,544 (4.32), 7,557 (1 .84), 7,562 (4.19), 7,577 (1 .34), 7,583 (1 .03), 7,624 (3.89), 7,627 (4.21 ), 7,638 (1.18), 7,643 (2.66), 7,648 (2.23), 7,867 (3.24), 7,889 (3.99), 7,992 (4.03), 8,015 (4.08), 8,060 (2.22), 8,065 (2.28), 8,082 (1 .74), 8,087 (1 .87), 8,213 (3.73), 8,217 (3.54), 8,237 (1 .07), 8,257 (1.92), 8,277 (0.90), 1 1,057 (3.31).

Example 6

3-chloro- / V- [2-fluoro-4- (2 / - / - tetrazol-5-yl) phenyl] -6-iodo-2-phenylquinoline-4-carboxamide

To a mixture of 3-chloro- / V- (4-cyano-2-fluorophenyl) -6-iodo-2-phenylquinoline-4-carboxamide (100 mg, 189 μιηοΙ, Example 20A) in toluene (1 .8 ml) Under argon, trimethylsilyl azide (100 μΙ, 760 μιηοΙ) and dibutyltin oxide (9.4 mg, 38 μιηοΙ) were added and the mixture was stirred for 8 h at 120 Ό. After cooling to RT, the mixture was treated with water and ethyl acetate (50 ml each), shaken and the phases were separated. The aqueous phase was extracted once with ethyl acetate (30 ml). The combined organic phases were dried over sodium sulfate, filtered and concentrated, and the residue was taken up in DMSO and purified by preparative HPLC (Method 7). There were obtained 80 mg (100% purity, 74% of theory) of the title compound.

LC-MS (Method 1): R _t = 1 .08 min; MS (ESIpos): m / z = 571 [M + H] ⁺

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (1.58), 1 .232 (0.95), 7.554 (1.88), 7.558 (3.10), 7.565 (14.70), 7.570 (16.00), 7.578 (9.23), 7.583 (9.68), 7.590 (2.38), 7.594 (2.72), 7.606 (0.91), 7.745 (1.18), 7.754 (7.83), 7.758 (9.23), 7.766 (6.68) , 7.770 (6.34), 7.778 (6.56), 7.783 (1.44), 7.934 (8.00), 7.956 (9.74), 7.985 (3.98), 7.989 (5.76), 8.000 (5.1.1), 8.013 (4.76), 8.018 (9.75), 8,024 (3.61), 8,167 (5.61), 8,172 (6.16), 8,189 (4.50), 8,194 (5.40), 8,239 (9.97), 8,243 (9/09), 8,353 (2.99), 8,373 (4.76), 8,394 (2.46), 1 1 .217 (8.78).

Example 7

3-cyclopropyl-N- [2-fluoro-4- (2 / - / - tetrazol-5-yl) phenyl] -6-iodo-2-phenylquinoline-4-carboxamide

To a mixture of N- (4-cyano-2-fluorophenyl) -3-cyclopropyl-6-iodo-2-phenylquinoline-4-carboxamide (275 mg, 515 μιηοΙ, Example 21A) in toluene (5 ml) under argon Trimethylsilyl azide (140 μΙ, 1 .0 mmol) and dibutyltin oxide (13 mg, 52 μιηοΙ) were added and the mixture was stirred for 3 h at 120 Ό. Renew t trimethylsilyl azide (140 μΙ, 1 .0 mmol) and dibutyltin oxide (13 mg, 52 μιηοΙ) were added and the mixture was stirred for an additional hour at 120 Ό. There were again trimeth ylsilylazid (140 μΙ, 1 .0 mmol) and dibutyltin oxide (13 mg, 52 μιηοΙ) was added and the mixture was stirred for a further 16 h at 120 Ό. After cooling to RT, the mixture was treated with water and ethyl acetate (50 ml each), shaken and the phases were separated. The aqueous phase was extracted once with ethyl acetate (50 ml). The combined organic phases were dried over sodium sulfate, filtered and concentrated, and the residue was taken up in DMSO and purified by preparative HPLC (Method 7). 247 mg (95% pure, 79% of theory) of the title compound were obtained.

LC-MS (Method 1): R _t = 1 .13 min; MS (ESIpos): m / z = 577 [M + H] ⁺

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (1.96), 0.008 (1.42), 0.331 (6.65), 0.344 (6.65), 0.689 (6.17), 0.710 (6.24 ), 0.859 (1.57), 0.877 (3.56), 0.896 (1.82), 1 .232 (1 .41), 1.301 (0.88), 1 .318 (0.80), 1 .493 (0.71), 1, 500 (1.18 ), 1 .504 (1 .13), 2,361 (1.06), 2,368 (0.94), 2,375 (2.20), 2,382 (2.39), 2,396 (3.97), 2,404 (1.81), 2.41 1 (2.21), 2,418 (2.08 ), 2,432 (0.91), 3,170 (3.30), 3,966 (1 .18), 7,481 (1 .28), 7,485 (0.99), 7,489 (0.86), 7,500 (4.41), 7,507 (2.70), 7,512 (5.74) , 7,516 (10.24), 7,520 (14.96), 7,532 (4.43), 7,539 (12:30), 7,550 (2.39), 7,554 (3.78), 7,560 (2.73), 7,744 (1.71), 7,751 (10.77), 7,754 (12:59) , 7,765 (4.17), 7,770 (10.08), 7,775 (8.64), 7,866 (10.17), 7,888 (12:52), 7,993 (4.79), 7,998 (8.97), 8,003 (6.91), 8,023 (16:00), 8,063 (7.30) , 8,068 (7.17), 8,085 (5.83), 8,090 (6:00), 8,283 (15.39), 8,287 (12.69), 8,304 (6.24), 8,324 (2.90), 1 1,001 (10.61). Example 8

 6-Bromo-N- [2-fluoro-4- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) -phenyl] -3-methyl-2-phenyl-4-carboxamide

To a solution of 6-bromo / V- [2-fluoro-4 - (/ V-hydroxycarbamimidoyl) phenyl] -3-methyl-2-phenyl-quinoline-4-carboxamide (368 mg, 745 μιηοΙ, Example 22A). in THF (5 ml) were added CDI (181 mg, 1.12 mmol) and DBU (170 μΙ, 1.1 mmol) and the mixture was stirred at RT for 30 min. Then, the mixture was added with ethyl acetate (30 ml) and washed with 1 M hydrochloric acid and saturated sodium chloride aqueous solution (each 30 ml). The organic phase was dried over sodium sulfate, filtered and concentrated, and the residue was purified by preparative HPLC (Method 7). 246 mg (100% pure, 64% of theory) of the title compound were obtained.

LC-MS (Method 2): R, = 2.02 min; MS (ESIpos): m / z = 519/521 [M + H] ⁺

¹ H-NMR (500 MHz, DMSO-d6) δ [ppm]: 2,439 (16,00), 7,527 (1 .64), 7,532 (0.81), 7,537 (1 .45), 7,540 (2:63), 7,544 (2.29) , 7,547 (3.39), 7,559 (2.08), 7,562 (4.22), 7,575 (1: 49), 7,579 (1,20), 7,624 (3.74), 7,627 (4.64), 7,636 (1.27), 7,640 (3.02), 7.643 (2.58), 7.765 (1.40), 7.769 (2.10), 7.776 (1.93), 7.780 (2.51), 7.784 (2.51), 7.799 (1.90), 7.802 (1.60), 7.930 (1. 53), 7,934 (1 .73), 7,948 (2.05), 7,952 (2.42), 7,998 (3.73), 8,002 (3.46), 8,039 (3.84), 8,057 (2.78), 8,258 (1 .32), 8,275 (2.29 ), 8,291 (1.34), 1 1,103 (3.94), 13,070 (0.91). Example 9

6-Bromo- / V- [2-fluoro-4- (5-oxo-4,5-dihydro-1,2,4-thiadiazol-3-yl) -phenyl] -3-methyl-2-phenylquinoline-4 carboxamide

A mixture of 6-bromo / V- [2-fluoro-4 - (/ V-hydroxycarbamimidoyl) phenyl] -3-methyl-2-phenyl-quinoline-4-carboxamide (274 mg, 556 μιηοΙ, Example 22A) and N, W-thiocarbonyldiimidazole (198 mg, 1 .1 1 mmol) in THF (8.0 ml) was stirred at RT for 1 h. Subsequently, the mixture was admixed with a suspension of silica gel in a dichloromethane / methanol mixture (9: 1, 15 ml) and stirred at RT overnight. The silica gel was filtered off and washed with dichloromethane-methanol mixture (9: 1). The filtrate was concentrated and the residue was dried in vacuo. The residue was purified by preparative HPLC (Method 7). 15 mg (90% purity, 5% of theory) of the title compound were obtained.

LC-MS (Method 2): R, = 2.13 min; MS (ESIpos): m / z = 535/537 [M + H] ⁺

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1 .234 (1 .05), 1 .336 (0.78), 2,074 (3.42), 2,317 (0.83), 2,441 (4:00 pm), 3,830 ( 0.82), 4,098 (0.64), 7,525 (1 .46), 7,533 (1 .13), 7,537 (2,08), 7,543 (4.77), 7,562 (4.52), 7,573 (0.94), 7,577 (1.50), 7,584 (1 .1 1), 7,622 (4.27), 7,626 (4.56), 7,636 (1 .43), 7,641 (2.96), 7,646 (2.48), 7,898 (4.33), 7,924 (3.74), 7,931 (2.18), 7,948 (2.19 ), 7,953 (2.49), 7,999 (3.70), 8,004 (3.01), 8,036 (3.97), 8,059 (2.70), 8,182 (1.21), 8,202 (2.33), 8,223 (1 .21), 1 1 .046 (3.61 ).

Example 10

6-Bromo-V- [2-fluoro-4- (5-thioxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) -phenyl] -3-methyl-2-phenyl-quinoline 4-carboxamide

To a solution of 6-bromo / V- [2-fluoro-4 - (/ V-hydroxycarbamimidoyl) phenyl] -3-methyl-2-phenyl-quinoline-4-carboxamide (133 mg, 270 μιηοΙ, Example 22A) in THF (5 ml) were added N, N-thiocarbonyldiimidazole (72 mg, 404 μιηοΙ) and then DBU (60 μΙ, 400 μιηοΙ) and the mixture was stirred for 30 min at RT. Then the mixture was poured into ethyl acetate (30 ml) and washed once with 1 M hydrochloric acid (30 ml) and once with saturated aqueous sodium chloride solution (30 ml). The organic phase was dried over magnesium sulfate, filtered and concentrated, and the residue was purified by preparative HPLC (Method 7). 46 mg (98% purity, 31% of theory) of the title compound were obtained.

LC-MS (Method 2): R, = 1 .99 min; MS (ESIpos): m / z = 535/537 [M + H] ⁺

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: 2.442 (16.00), 7.527 (1.22), 7.534 (0.83), 7.538 (1.69), 7.545 (4.21), 7.559 (1. 79), 7,564 (4.06), 7,579 (1 .32), 7,585 (1.01), 7,624 (3.75), 7,628 (4.12), 7,638 (1 .14), 7,643 (2.61), 7,648 (2.22), 7,840 (1 .32), 7.845 (1.96), 7.853 (2.02), 7.858 (2.57), 7.864 (2.29), 7.882 (2.03), 7.886 (1.58), 7.928 (1.46), 7.934 (1.61), 7.950 (2.04) , 7,956 (2.45), 8,004 (3.82), 8,009 (3.30), 8,039 (4.19), 8,061 (2.83), 8,262 (1.47), 8,284 (2.28), 8,304 (1 .41), 1 1 .1 16 (3.77 ).

Example 11

6-Bromo-N- [2-fluoro-4- (2-oxido-3 / - / - 1, 2,3,5-oxathiadiazol-l-4-yl) -phenyl] -3-methyl-2-phenylquinoline-4 -carboxamide

A solution of 6-bromo / V- [2-fluoro-4 - (/ V -hydroxycarbamimidoyl) phenyl] -3-methyl-2-phenyl-quinoline-4-carboxamide (199 mg, 403 μmol, Example 22A) in THF (4 ml) was treated with pyridine (65 μΙ, 810 μιηοΙ). Then a solution of thionyl chloride (32 μΙ, 440 μιηοΙ) in dichloromethane (1 .0 ml) was added at 0 und and the mixture after heating to RT for 2 h at RT. Thereafter, the mixture was concentrated and the residue was taken up several times in dichloromethane and concentrated again. The residue was then purified by preparative HPLC (Method 7). 82 mg (98% purity, 37% of theory) of the title compound were obtained.

LC-MS (Method 2): R, = 2.09 min; MS (ESIpos): m / z = 539/541 [M + H] ⁺

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: 2.446 (16.00), 7.525 (1.23), 7.534 (0.91), 7.538 (1.78), 7.543 (3.76), 7.545 (4.12) , 7,560 (1.89), 7,564 (4.02), 7,579 (1.31), 7,586 (0.96), 7,625 (3.91), 7,629 (4.05), 7,639 (1 .18), 7,645 (2.57), 7,649 (2.12), 7,802 ( 1.46), 7.807 (1.61), 7.823 (1.46), 7.828 (2.09), 7.837 (2.14), 7.841 (1.38), 7.864 (1.83), 7.869 (1.54), 7.928 (1.44) , 7,934 (1 .57), 7,950 (2,07), 7,956 (2.40), 8,005 (3.74), 8,010 (3.17), 8,039 (4.06), 8,062 (2.74), 8,260 (1 .52), 8,280 (2.65), 8,301 (1.41), 1 1 .098 (3.78).

Example 12

6-Bromo- / V- [2-fluoro-4- (5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl) -phenyl] -3-methyl-2-phenyl-quinoline-4 carboxamide

A solution of 6-bromo / V- [2-fluoro-4- (hydrazinocarbonyl) phenyl] -3-methyl-2-phenylquinoline-4-carboxamide (422 mg, 855 mmol, Example 26A) in THF (6 ml). was added CDI (208 mg, 1 .28 mmol) and stirred at RT for 10 min. The mixture was then concentrated and the residue was purified by preparative HPLC (Method 8). There were obtained 106 mg (96% purity, 23% of theory) of the title compound.

LC-MS (Method 2): R, = 2.01 min; MS (ESIpos): m / z = 519/521 [M + H] ⁺

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: 2.432 (1.92), 2.440 (16.00), 2.891 (0.66), 7.525 (1 .37), 7.533 (1.09), 7.536 ( 1,92), 7,543 (4.30), 7,555 (1 .21), 7,558 (2.02), 7,562 (4.03), 7,577 (1 .33), 7,584 (0.99), 7,622 (3.87), 7,626 (4.09), 7,637 (1 .32), 7,642 (2.70), 7,647 (2.21), 7,735 (3.96), 7,757 (4.02), 7,925 (1 .41), 7,930 (1.54), 7,947 (2:03), 7,953 (2.45), 7,995 ( 3.76), 8,000 (3.13), 8,037 (3.95), 8,059 (2.68), 8,208 (1 .37), 8,228 (2.51), 8,248 (1 .24), 1 1,059 (3.91), 12,706 (1 .23).

Example 13

6-Bromo-N- [4- (5-cyano-2 / - / - 1, 2,3-triazol-4-yl) -2-fluorophenyl] -3-methyl-2-phenylquinoline-4-carboxamide

To a solution of 6-bromo / V- (2-fluoro-4-formylphenyl) -3-methyl-2-phenylquinoline-4-carboxamide (89 mg, 192 μιηοΙ, Example 27A) and (phenylsulfonyl) acetonitrile (35 mg , 192 μιηοΙ) in DMF (4 ml) was added dropwise at RT a solution of sodium azide (19 mg, 287 μιηοΙ) in water (1 ml) at RT, and the mixture was then stirred for 1 h under reflux. After cooling to RT, to the mixture was added ethyl acetate (50 ml) and washed with water (100 ml). The aqueous phase was extracted once with ethyl acetate (30 ml) and the combined organic phases were washed with saturated aqueous sodium chloride solution, filtered and dried. The residue was purified by preparative HPLC (Method 8). 50 mg (98% purity, 48% of theory) of the title compound were obtained.

LC-MS (Method 2): R, = 2.10 min; MS (ESIpos): m / z = 527/529 [M + H] ⁺

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: 2,458 (16:00), 3,920 (1 .18), 7,528 (1.38), 7,529 (1 .44), 7,536 (1 .12), 7,541 ( 1 .94), 7,545 (3.56), 7,548 (4.15), 7,559 (1.26), 7,562 (1 .91), 7,566 (4,01), 7,582 (1 .35), 7,588 (1 .06), 7,630 (3.90) , 7.633 (4.13), 7.638 (2.17), 7.644 (1.23), 7.649 (2.59), 7.654 (2.23), 7.823 (1.26), 7.828 (1.76), 7.837 (2.05), 7.842 (2.55), 7,847 (1 .99), 7,865 (1 .89), 7,870 (1 .47), 7,931 (1 .54), 7,937 (1.65), 7,954 (2.15), 7,959 (2.43), 8,022 (3.66), 8,027 ( 3.30), 8,042 (4.06), 8,064 (2.71), 8,231 (0.98), 8,252 (1 .67), 8,272 (0.89), 1 1,059 (2.97).

Example 14

6-Bromo-3-methyl- / V- [4- (5-oxo-4,5-dihydro-1H, 2,4-triazol-3-yl) phenyl] -2-phenylquinoline-4-carboxamide

To a suspension of semicarbazide hydrochloride (157 mg, 1.41 mmol) in dichloromethane (3 ml) was added triethylamine (430 μΙ, 3.1 mmol) under ice-acetone cooling and the mixture was stirred for 30 min. Subsequently, a suspension of 4 - {[(6-bromo-3-methyl-2-phenylquinolin-4-yl) carbonyl] amino} -3-fluorobenzoyl chloride (585 mg, 1.18 mmol, Example 25A) in dichloromethane (1 1 ml) and the mixture was stirred for a further 1 h at RT after warming to RT. The mixture was then concentrated, treated with a solution of sodium hydroxide (423 mg, 10.6 mmol) in 7.2 ml of water and stirred at 120 ° for 20 h. After cooling to RT, the mixture was treated with water (20 ml) and acidified with conc. Hydrochloric acid adjusted to pH 1. The precipitate formed was washed twice with water (10 ml each time) and then purified by preparative HPLC (Method 7). 165 mg (100% purity, 28% of theory) of the title compound were obtained.

LC-MS (Method 1): R _t = 0.89 min; MS (ESIpos): m / z = 500/502 [M + H] ⁺

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1 1 .99 (s, 1 H), 1 1 .63 (s, 1 H), 11 .10 (s, 1 H), 8.05 (d, 1H), 7.97-7.78 (m, 6H), 7.67-7.49 (m, 5H), 2.41 (s, 3H).

Example 15

6-Bromo-3-methyl-2-phenyl- / V- [4- (2 / - / - tetrazol-5-yl) bicyclo [2.2.2] oct-1-yl] quinoline-4-carboxamide

To a mixture of 6-bromo / V- (4-cyanobicyclo [2.2.2] oct-1-yl) -3-methyl-2-phenylquinoline-4-carboxamide (127 mg, 67% purity, 178 μιηοΙ, Example 36A) in toluene (1.7 ml) under argon, trimethylsilyl azide (95 μM, 710 μιηοΙ) and dibutyltin oxide (9 mg, 36 μιηοΙ) were added and the mixture was stirred for 21 h at 120 Ό. Trimethylsilyl azide (95 μΙ, 710 μιηοΙ) was added again and the mixture was stirred at 120 ° C. for a further 3 h. There were again trimethylsilyl azide (95 μΙ, 710 μιηοΙ) and dibutyltin oxide (9 mg, 36 μιηοΙ) was added and the mixture was stirred for a further 12 h at 120 Ό. Again, trimethylsilyl azide (95 μΙ, 710 μιηοΙ) and dibutyltin oxide (9 mg, 36 μιηοΙ) were added. After every 3 hours, trimethylsilyl azide (95 μM, 710 μιηοΙ) and dibutyltin oxide (9 mg, 36 μιηοΙ) were added two more times with stirring at 120 Ό. After stirring at 120 ° C. for a total of 3 days, the mixture was cooled and combined with 30 ml each of water and ethyl acetate, shaken and the phases were separated. The aqueous phase was extracted once with ethyl acetate (30 ml). The combined organic phases were dried over sodium sulfate, filtered and concentrated, and the residue was taken up in DMSO and purified by preparative HPLC (Method 7). 48 mg (100% purity, 52% of theory) of the title compound were obtained.

LC-MS (Method 1): R _t = 0.94 min; MS (ESIpos): m / z = 517/519 [M + H] ⁺

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.874 (0.77), 1 .988 (0.84), 2.027 (2.73), 2.043 (4.76), 2.056 (4.41), 2.066 (5.77), 2.148 (5.45), 2.157 (4.38), 2.172 (4.74), 2.188 (2.94), 2.351 (16.00), 7.507 (1.13), 7.516 (1.69), 7.522 (4.90), 7.526 (3.06), 7.536 ( 1.70), 7.541 (4.19), 7.551 (0.95), 7.555 (1.57), 7.562 (1.15), 7.575 (4.07), 7.579 (4.08), 7.583 (2.35), 7.590 (1.12), 7.595 (2.07), 7.599 (1.74), 7.856 (2.86), 7.861 (3.95), 7.877 (1.87), 7.883 (1.13), 7.900 (2.53), 7.905 (2.1.1), 7.976 (4.05), 7.998 (2.64), 8.558 (4.04).

Example 16

3-Chloro-6-iodo-2-phenyl-N- [4- (2 / - / - tetrazol-5-yl) -bicyclo [2.2.2] oct-1-yl] quinoline-4-carboxamide

To a mixture of 3-chloro-N- (4-cyanobicyclo [2.2.2] oct-1-yl) -6-iodo-2-phenylquinoline-4-carboxamide (255 mg, purity 56%, 471 μιηοΙ, Example 37A in toluene (4.5 ml) under argon, trimethylsilyl azide (120 μM, 940 μιηοΙ) and dibutyltin oxide (24 mg, 94 μιηοΙ) were added and the mixture was stirred for 4 h at 120 ° C. Trimethylsilyl azide (120 μΙ, 940 g) was again obtained μιηοΙ) and dibutyltin oxide (24 mg, 94 μιηοΙ) was added and the mixture was stirred for a further 17 h at 120 "C. Trimethylsilyl azide (120 μΙ, 940 μιηοΙ) and dibutyltin oxide (24 mg, 94 μιηοΙ) were added again and the mixture was stirred for a further 5 h at 120 ° C. Trimethylsilyl azide (120 μΙ, 940 μιηοΙ) and dibutyltin oxide (24 Mg, 94 μιηοΙ) was added and the mixture was stirred for a further 3 hours at 120 ° C. Trimethylsilyl azide (120 μΙ, 940 μιηοΙ) and dibutyltin oxide (24 mg, 94 μιηοΙ) were added again and the mixture was allowed to remain for a further 16 h 120 "C stirred. After stirring for a total of about 2 days at 120 ° C., the mixture was cooled and combined with water and ethyl acetate (50 ml each), shaken, and the phases separated The aqueous phase was extracted once with ethyl acetate (50 ml) dried organic phases were dried over sodium sulfate, filtered and concentrated and the residue was taken up in DMSO and prepurified by preparative HPLC (Method 7.) Three product-containing fractions were obtained, the first by column chromatography (silica gel 10 g Biotage, dichloromethane / methanol 95 From this, 60 mg of a first batch of the title compound (purity 100%, 37% of theory, see analysis) were obtained, and the second and third fractions from the HPLC separation were combined and purified by preparative SFC ( Column: Chiralpak AD-H, 5 μιη, 250 mm x 20 mm, flow: 80 ml / min, detection: 210 nm, injection volume 4.5 ml, temperature: 40Ό, 70% C0 ₂ /30% ethanol isocratic, running time 23 min). 30 mg of a second batch of the title compound (purity 90%, 18% of theory) were obtained therefrom.

LC-MS (Method 1): R _t = 1 .06 min; MS (ESIpos): m / z = 585 [M + H] ⁺

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (5.95), 0.008 (4.36), 1 .234 (1 .56), 2.029 (7.95), 2.045 (13.39), 2.058 (12.85 ), 2,067 (15:42), 2,093 (1: 86), 2,138 (16:00), 2,146 (12:82), 2,162 (12.72), 2.176 (7.43), 2.366 (0.61), 2.710 (0.66), 5.754 (3.23), 7.530 (2.74), 7.534 (3.72), 7.539 (14.96), 7.544 (15.50), 7.552 (10.03), 7.556 (9.94), 7,566 (2.87), 7,580 (0.71), 7,689 (1.73), 7,698 (8.22), 7,703 (8.94), 7.71 1 (7.56), 7,722 (5.76), 7,870 (7.92), 7,892 (9.39), 8,085 (8.80), 8,089 (10.66), 8.1 10 (7.01), 8.1 15 (5.04), 8.132 (5.37), 8.137 (4.46), 8.674 (10.00). Example 17

 6-Bromo-3-methyl-N- [4- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl] -2 -phenyl quinoline-4-carboxamide

 To a solution of 6-bromo / V- [4 - (/ V -hydroxycarbamimidoyl) bicyclo [2.2.2] oct-1-yl] -3-methyl-2-phenylquinoline-4-carboxamide (1 .30 g, 72% purity, 1.85mmol, Example 38A) in THF (15ml) was added CDI (450mg, 2.77mmol) and DBU (410μΙ, 2.8mmol) and the mixture was stirred at RT for 1 day. Then, the mixture was added with ethyl acetate (100 ml) and washed with 1 M hydrochloric acid (75 ml each) and saturated sodium chloride solution. The organic phase was dried over sodium sulfate, filtered and concentrated and the residue was taken up in a mixture of DMSO, acetonitrile and a drop of 1 M sodium hydroxide solution and purified by preparative HPLC (Method 17). 274 mg (100% purity, 28% of theory) of the title compound were obtained.

LC-MS (Method 2): R _t = 1 .89 min; MS (ESIpos): m / z = 533/535 [M + H] ⁺

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1 .890 (4.90), 1 .908 (7.67), 1 .927 (7.1 1), 2,073 (6.97), 2,096 (7.33), 2,336 (16.00), 7.501 (1.60), 7.516 (5.64), 7.535 (5.13), 7.548 (2.31), 7.568 (5.41), 7.586 (2.77), 7.835 (3.72), 7.839 (4.34), 7.868 (1. 86), 7,890 (2.71), 7,967 (3.97), 7,990 (2.57), 8,535 (4.30).

Example 18 6-Bromo-3-methyl-N- [4- (5-oxo-4,5-dihydro-1,2,4-thiadiazol-3-yl) bicyclo [2.2.2] oct-

quinoline-4-carboxamide

A mixture of 6-bromo / V- [4 - (/ V -hydroxycarbamimidoyl) bicyclo [2.2.2] oct-1-yl] -3-methyl-2-phenylquinoline-4-carboxamide (216 mg, 425 μιηοΙ, Example 38A) and N, / V-thiocarbonyldiimidazole (152 mg, 851 μιηοΙ) in THF (4.0 ml) was stirred at RT for 1 h. Subsequently, the mixture was mixed with a suspension of silica gel in dichloromethane (2 ml) and stirred at RT for three days. The silica gel was filtered off and washed with dichloromethane. The filtrate was concentrated and the residue was purified by preparative HPLC (Method 8). 19 mg (95% purity, 8% of theory) of the title compound were obtained.

LC-MS (Method 1): R _t = 1 .07 min; MS (ESIpos): m / z = 549/551 [M + H] ⁺

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.149 (0.93), -0.008 (8.89), 0.008 (8.24), 0.146 (0.91), 1 .235 (1 .43), 1. 928 (2.83), 1,943 (4.74), 1,966 (5.17), 1,988 (0.76), 2,062 (4.76), 2,073 (5.13), 2,086 (4.76), 2,101 (3.09), 2,335 (4:00 pm), 2,366 (0.76), 2,710 (0.72), 3,613 (1,20), 7,499 (1 .13), 7,502 (1 .26), 7:51 1 (2:00), 7,516 (5:41), 7,521 (3.28), 7,530 (1.91) , 7,535 (4.39), 7,544 (1:30), 7,549 (1: 80), 7,556 (1: 57), 7,561 (1.09), 7,567 (4.57), 7,571 (4.28), 7,586 (2.02), 7,592 (1 .78), 7.834 (3.02), 7.839 (3.80), 7.868 (1.96), 7.874 (1.48), 7.891 (2.72), 7.896 (2.39), 7.967 (4.37), 7.990 (2.85), 8.520 (3.57) , 12.702 (2.50).

Example 19

6-Bromo-3-methyl-2-phenyl-N- [4- (5-thioxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl ] quinoline-4-carboxamide

To a solution of 6-bromo / V- [4 - (/ V -hydroxycarbamimidoyl) bicyclo [2.2.2] oct-1-yl] -3-methyl-2-phenylquinoline-4-carboxamide (1 13 mg, 223 μιηοΙ, Example 38A) in THF (3 ml) DBU (130 μΙ, 890 μιηοΙ) and N, W-thiocarbonyldiimidazole (60 mg, 335 μιηοΙ) were added and the mixture was stirred for 1 h at RT. The mixture was then poured into ethyl acetate (30 ml), shaken, and after phase separation, the organic phase was washed once with 1 M hydrochloric acid (20 ml) and once with saturated sodium chloride solution (20 ml). The organic phase was dried over magnesium sulfate, filtered and concentrated and the residue was taken up in a mixture of DMSO and 1 M sodium hydroxide solution and pre-purified by preparative HPLC (Method 8) and then purified (Method 8). There were obtained 27 mg (83% purity, 18% of theory) of the title compound.

LC-MS (Method 2): R, = 2.01 min; MS (ESIpos): m / z = 549/551 [M + H] ⁺

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1 .235 (3.22), 1 .989 (8.47), 2,050 (8.80), 2,073 (7.1 1), 2,125 (7.95), 2,318 (5.51 ), 2,337 (14.75), 3,365 (16:00), 7,514 (7.1 1), 7,534 (6.33), 7,569 (6.70), 7,842 (4.14), 7,868 (2.46), 7,891 (3.41), 7,968 (3.93), 7,990 ( 2.70), 8.551 (3.96).

Example 20

6-Bromo-3-methyl-N- [4- (2-oxido-3 / - / - 1, 2,3,5-oxathiadiazol-4-yl) bicyclo [2.2.2] oct-1-yl] - 2-phenylquinoline-4-carboxamide

A solution of 6-bromo / V- [4 - (/ V -hydroxycarbamimidoyl) bicyclo [2.2.2] oct-1-yl] -3-methyl-2-phenylquinoline-4-carboxamide (146 mg, 288 μmol, Example 38A) in THF (4 ml) was treated with pyridine (47 μΙ, 580 μιηοΙ). Subsequently, a solution of thionyl chloride (23 μΙ, 320 μιηοΙ) in dichloromethane (1 .0 ml) was added at 0 und and the mixture stirred after warming to RT overnight at RT. Thereafter, the mixture was concentrated and the residue was purified by preparative HPLC (Method 8). There were obtained 79 mg (98% purity, 49% of theory) of the title compound.

LC-MS (Method 2): R _t = 1 .97 min; MS (ESIpos): m / z = 553/555 [M + H] ⁺

1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (0.76), 0.008 (0.63), 1 .179 (0.43), 1 .234 (0.41), 1 .956 (3.63), 1 .977 (4.44), 1,994 (2.14), 2,026 (0.65), 2,101 (4.91), 2,120 (6.99), 2,140 (2.94), 2,341 (4:00 pm), 7,502 (1.12), 7,513 (1 .84), 7,518 (4.97), 7,522 (2.96), 7,536 (4.13), 7,546 (1,10), 7,550 (1 .63), 7,558 (1 .31), 7,569 (4.32), 7,573 (4.03), 7,588 (1.91) , 7.593 (1.64), 7.840 (3.12), 7.845 (3.90), 7.871 (1.74), 7.876 (1.23), 7.893 (2.45), 7.898 (2.09), 7.970 (4.12), 7.993 (2.66), 8,547 (3.84), 1 1 .368 (3.68).

Example 21

6-Bromo-3-methyl-N- [4- (5-oxo-4,5-dihydro-1, 3,4-oxadiazol-2-yl) bicyclo [2.2.2] oct-1-yl] -2 - phenylquinoline-4-carboxamide

A solution of 6-bromo / V- [4- (hydrazinocarbonyl) bicyclo [2.2.2] oct-1-yl] -3-methyl-2-phenylquinoline-4-carboxamide (126 mg, 249 mmol, example 39A) in THF (3 ml) was added CDI (61 mg, 373 mmol) and stirred at RT for 1 h. The mixture was then concentrated and the residue was purified by preparative HPLC (Method 8). There were obtained 80 mg (98% purity, 59% of theory) of the title compound.

LC-MS (Method 2): R, = 1 .88 min; MS (ESIpos): m / z = 533/535 [M + H] ⁺

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1 .175 (1 .39), 1 .234 (0.90), 1 .896 (3.78), 1 .913 (5.81), 1 .935 (5.78), 2,073 (4.05), 2,081 (5.70), 2,092 (5.07), 2,104 (5.66), 2,121 (3.69), 2,335 (4:00 pm), 7,499 (1: 26), 7,515 (4.96), 7,534 (4.49) , 7,548 (1 .74), 7,554 (1.40), 7,567 (4.51), 7,571 (4.41), 7,585 (2.24), 7,590 (1 .88), 7,833 (3.35), 7,839 (4.15), 7,867 (1.61), 7,873 (1,20), 7,890 (2.35), 7,894 (2,07), 7,967 (4,02), 7,989 (2.60), 8,533 (4.18), 12,081 (4.38).

Example 22

6-Bromo-N- [4- (5-cyano-2 / - / - 1, 2,3-triazol-4-yl) bicyclo [2.2.2] oct-1-yl] -3-methyl-2- phenylquinoline-4-carboxamide

To a mixture of 6-bromo- / V- (4-formylbicyclo [2.2.2] oct-1-yl) -3-methyl-2-phenylquinoline-4-carboxamide (54 mg, purity 85%, 12 μιηοΙ, Example 40A) and (phenylsulfonyl) acetonitrile (20 mg, 1 12 μιηοΙ) in water (3 ml) was added dropwise at RT a solution of sodium azide (1 1 mg, 168 μιηοΙ) in water (1 ml) at RT, and the mixture was then stirred for 1 h under reflux. After cooling to RT, the mixture was allowed to stand overnight. Then, DMF (3 ml) was added and the mixture was stirred at 120 ° C. for 1 h. After cooling to RT, the mixture was lyophilized and the residue was purified by preparative HPLC (Method 8). 41 mg (98% purity, 78% of theory) of the title compound were obtained.

LC-MS (method 2): R _t = 2.02 min; MS (ESIpos): m / z = 541/543 [M + H] ⁺

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: 2.063 (3.30), 2.075 (6.83), 2.099 (7.93), 2.156 (7.57), 2.178 (6.11), 2.348 (16.00), 2.731 (0.78 ), 2.891 (0.90), 7.503 (1.40), 7.521 (5.40), 7.539 (4.80), 7.554 (1.85), 7.574 (5.37), 7.594 (2.44), 7.856 (4.03), 7.872 (1.82) , 7,896 (2.62), 7,972 (3.74), 7,995 (2.43), 8,556 (3.59).

Example 23

6-Bromo-3-methyl-N- [4- (5-oxo-4,5-dihydro-1 / - / - 1, 2,4-triazol-3-yl) bicyclo [2.2.2] oct-1 -yl] -2-phenyl-quinoline-4-carboxamide

To a suspension of semicarbazide hydrochloride (134 mg, 1.20 mmol) in dichloromethane (2 ml) was added triethylamine (360 μΙ, 2.6 mmol) under ice-acetone cooling, and the mixture was stirred for 30 min. A suspension of 4 - {[(6-bromo-3-methyl-2-phenylquinolin-4-yl) carbonyl] amino} bicyclo [2.2.2] octane-1-carbonyl chloride (512 mg,

I .00 mmol, Example 32A) in dichloromethane (10 ml) and the mixture was stirred for a further 18 h at RT after warming to RT. The mixture was then concentrated, treated with a solution of sodium hydroxide (180 mg, 4.50 mmol) in water (3 ml) and stirred at 100 ° C. for 4 h. A solution of sodium hydroxide (180 mg, 4.50 mmol) in 3 ml of water was added again, and the mixture was stirred at 100 ° C. for a further 20 h. After cooling to RT, the mixture was treated with conc. Hydrochloric acid adjusted to pH 1 and treated successively with acetonitrile (4 ml), water (first 15 ml, then 100 ml) and ethyl acetate (100 ml) and shaken. The precipitate formed was filtered off, washed twice with water (3 ml each time) and then purified by preparative HPLC (Method 7). There were obtained 268 mg (100% purity, 50% of theory) of the title compound.

LC-MS (Method 1): R _t = 0.86 min; MS (ESIpos): m / z = 532/534 [M + H] ⁺

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1 .847 (3.24), 1 .865 (4.87), 1 .886 (4.83), 2,052 (4.67), 2,063 (4.16), 2,074 ( 4.76), 2,091 (3.19), 2,334 (16:00), 7,500 (1 .13), 7.51 1 (1 .84), 7,516 (4.96), 7,521 (2.83), 7,530 (1 .79), 7,535 (4.18), 7,545 (1 .02), 7,549 (1,52), 7,556 (1,20), 7,568 (4.31), 7,572 (3.93), 7,576 (2.22), 7,582 (1.1 1), 7,587 (1,991), 7,592 (1.60 ), 7,838 (3.18), 7,844 (3.96), 7,868 (1,774), 7,873 (1: 15), 7,890 (2.45), 7,896 (2.02), 7,967 (4.12), 7,989 (2.67), 8,495 (3.92) .

I I .090 (2.63), 1 .094 (2.66), 1 1 .240 (2.38).

B. Evaluation of Pharmacological Activity

The pharmacological activity of the compounds of the invention can be demonstrated by in vitro and in vivo studies as known to those skilled in the art. The The following application examples describe the biological action of the compounds according to the invention without restricting the invention to these examples.

Abbreviations and acronyms:

 CRTH2 chemoattractant receptor-homologous molecule expressed

 on T-Helper type 2 cells

 DMEM Dulbecco's modified Eagle's medium

 DMSO dimethyl sulfoxide

 DP PGD2 receptor

 EC50 half maximum effective concentration

 Em emission

 EP PGE2 receptor

 Ex excitation

 Company (source of supply)

 FCS fetal calf serum

 FP PGF2a receptor

 HEPES 2- [4- (2-hydroxyethyl) piperazine-1-yl] ethanesulfonic acid

 IC50 half-maximal inhibitory concentration

 IP PGI2 receptor

 Literature (position)

 MES 2 - (/ V-morpholino) ethanesulfonic acid

 Pen / Strep penicillin / streptomycin

 PGD2 prostaglandin D2

 PGE2 prostaglandin E2

 PGF2a prostaglandin F2a

 PGI2 prostaglandin 12

 TC tissue culture

 TP thromboxane A2 receptor

 Tris tris (hydroxymethyl) aminomethane

v / v volume to volume ratio (of a solution)

w / w weight to weight ratio (of a solution)

B-1. In vitro test for inhibition of human FP receptor activity

For the characterization of test substances for FP antagonism, the PGF2a-induced calcium flux was used in FP-expressing CHEM1 cells (Millipore, HTS093C). 3000 cells in 25 μM complete medium [DMEM F12, 10% FCS, 1 .35 mM sodium pyruvate, 20 mM HEPES, 4 mM GlutaMAX ™, 2% sodium bicarbonate, 1% Pen / Strep, 1% 100x nonessential amino acids] are added per well seeded a 384 multi-well plate (Greiner, TC plate, black with a clear bottom) and incubated at 37Ό / 5% CO ₂ for 24 hours. Prior to measurement, the medium is passed through 30 μM Fluo-8 AM loading buffer [calcium-free Tyrode (130 mM NaCl, 5 mM KCl, 20 mM HEPES, 1 mM MgCl ₂ , 4.8 mM NaHCO ₃ , pH 7.4), 2 mM CaCl 2 ₂ , 1 x SmartBlock (CANDOR Bioscience GmbH), 4.5 mM Probenecid, 5 μM Fluo-8 AM, 0.016% Pluronic®, 0.04% Brilliant black] and incubated at 37 ^< C / 5% C0 ₂ for 30 minutes. The test substance is prepared in DMSO in various concentrations as a dose-response curve (starting concentration 10 mM, dilution factor 3.16) and prediluted 1:50 with Caicium-free Tyrode / 2 mM CaCl ₂ . 10 μΙ of the prediluted substance solution are added to the Fluo-8-loaded cells and incubated at 37Ό / 5% C0 ₂ for 10 minutes. The FP receptor is activated by addition of 20 μΙ 3 nM (final concentration) of PGF2a in calcium-free Tyrode / 2 mM CaCl ₂ / 0.04% Brilliant black, and the calcium flux is determined by measuring the fluorescence at Ex. 470 nm / em. 525 nm for 120 seconds in a fluorescence meter (FLIPR Tetra®, Molecular Devices).

In the following Table 1, for individual embodiments of the invention, the IC ₅ o values from this assay are listed (in part as averages of several independent individual determinations):

Table 1

 Example FP receptor activity

No. IC ₅₀ [μπιοΙ / L]

 1 0.005

 2 0.004

 3 0.014

 4 0.009

 5 0.015

 6 0.002

 7 0.012

 8 0.006

 9 0.047

 10 0.012

 11 0.009

 12 0.036

 13 0.018

14 0.373 Example FP receptor activity

No. IC ₅₀ [μπιοΙ / L]

 15 0.015

 16 0.007

 17 0.281

 18 0.210

 19 0.101

 20 0.024

 21 0.285

 22 0.032

 23 0.594

B-2. In vitro FP receptor binding inhibition test

For the FP receptor binding assay, human recombinant prostanoid FP receptors expressed in HEK293 cells are used in modified MES buffer, pH 6.0. The performance of this test is commercially available (Eurofins Panlabs, catalog # 268510). 80 μg of membrane are incubated with 1 nM [ ³ H] -PGF2a for 60 minutes at 25 °. The amount of membrane protein can vary from lot to lot and is adjusted as needed. Non-specific binding is determined in the presence of 1 μΜ cloprostenol. The membranes are filtered, washed and then measured to determine the specific binding of [ ³ H] -PGF2a. Substances are tested for inhibitory activity at a concentration of 10 μΜ or in the form of a dose-response curve [Ref. : Abramovitz et al., J. Biol. Chem. 1994, 269 (4): 2632].

B-3. In vitro CRTH2 receptor binding inhibition test

For this assay, human recombinant prostanoid CRTH2 receptors expressed in CHO-K1 cells are used in modified Tris-HCl buffer, pH 7.4. The performance of this test is commercially available (Eurofins Panlabs, catalog # 268030). 4 μg of membrane are incubated with 1 nM [ ³ H] -PGD2 for 120 minutes at 25 °. The amount of membrane protein can vary from lot to lot and is adjusted as needed. Non-specific binding is determined in the presence of 1 μΜ PGD2. The membranes are filtered, washed and then measured to determine the specific binding of [ ³ H] PGD2. Substances are tested for inhibitory activity at a concentration of 10 μΜ or in the form of a dose-response curve [Lit .: Sugimoto et al., J. Pharmacol. Exp. Ther. 2003, 305 (1): 347].

B-4. In vitro DP receptor binding inhibition test For this assay, human recombinant prostanoid DP receptors expressed in Chem-1 cells are used in modified HEPES buffer, pH 7.4. The performance of this test is commercially available (Eurofins Panlabs, catalog # 268060). 10 μg of membrane are incubated with 2 nM [ ³ H] -PGD2 for 120 minutes at 25 °. The amount of membrane protein can vary from lot to lot and is adjusted as needed. Non-specific binding is determined in the presence of 1 μΜ PGD2. The membranes are filtered, washed and then measured to determine the specific binding of [ ³ H] PGD2. Substances are tested for inhibitory activity at a concentration of 10 μΜ or in the form of a dose-response curve [Ref. : Wright et al., Br. J. Pharmacol. 1998, 123 (7): 1317; Sharif et al., Br. J. Pharmacol. 2000, 131 (6): 1025].

B-fifth In vitro EP1 receptor binding inhibition assay

For this assay, human recombinant prostanoid EP1 receptors expressed in HEK293 cells are used in modified MES buffer, pH 6.0. The performance of this test is commercially available (Eurofins Panlabs, catalog # 2681 10). 14 μg of membrane are incubated with 1 nM [ ³ H] -PGE2 for 60 minutes at 25 °. The amount of membrane protein can vary from lot to lot and is adjusted as needed. Non-specific binding is determined in the presence of 10 μΜ PGE2. The membranes are filtered, washed and then measured to determine the specific binding of [ ³ H] -PGE2. Substances are tested for inhibitory activity at a concentration of 10 μΜ or in the form of a dose-response curve [Lit .: Abramovitz et al., Biochim. Biophys. Acta 2000, 1483 (2): 285; Funk et al., J. Biol. Chem. 1993, 268 (35): 26767].

B-sixth In vitro EP2 receptor binding inhibition assay

For this assay, human recombinant prostanoid EP2 receptors expressed in HEK293 cells are used in modified MES / KOH buffer, pH 6.0. The performance of this test is commercially available (Eurofins Panlabs, catalog # 268200). 25 mg / ml membrane are incubated with 4 nM [ ³ H] -PGE2 for 120 minutes at 25 °. The amount of membrane protein can vary from lot to lot and is adjusted as needed. Non-specific binding is determined in the presence of 10 μΜ PGE2. The membranes are filtered, washed and then measured to determine the specific binding of [ ³ H] -PGE2. Substances are tested for inhibitory activity at a concentration of 10 μΜ or in the form of a dose-response curve [Ref .: Bastien et al., J. Biol. Chem. 1994, 269 (16): 1873; Boie et al., Eur. J. Pharmacol. 1997, 340 (2-3): 227].

B. 7 In vitro EP3 receptor binding inhibition assay

For this assay, human recombinant prostanoid EP3 receptors expressed in HEK293 cells are used in modified MES buffer, pH 6.0. The implementation of this Tests are commercially available (Eurofins Panlabs, catalog # 268310). 3 μg of membrane are incubated with 0.5 nM [ ³ H] -PGE2 for 120 minutes at 25 °. The amount of membrane protein can vary from lot to lot and is adjusted as needed. Non-specific binding is determined in the presence of 10 μΜ PGE2. The membranes are filtered, washed and then measured to determine the specific binding of [ ³ H] -PGE2. Substances are tested for inhibitory activity at a concentration of 10 μΜ or in the form of a dose-response curve [Ref. : Schmidt et al., Eur. J. Biochem. 1995, 228 (1): 23].

B-eighth In vitro EP4 receptor binding inhibition test

For this assay, human recombinant prostanoid EP4 receptors expressed in Chem-1 cells are used in modified MES buffer, pH 6.0. The performance of this test is commercially available (Eurofins Panlabs, catalog # 268420). 3 μg of membrane are incubated with 1 nM [ ³ H] -PGE2 for 120 minutes at 25 °. The amount of membrane protein can vary from lot to lot and is adjusted as needed. Non-specific binding is determined in the presence of 10 μΜ PGE2. The membranes are filtered, washed and then measured to determine the specific binding of [ ³ H] -PGE2. Substances are tested for inhibitory activity at a concentration of 10 μΜ or in the form of a dose-response curve [Lit .: Davis et al., Br. J. Pharmacol. 2000, 130 (8): 1919].

B. 9 In vitro IP receptor binding inhibition test

For this assay, human recombinant prostanoid IP receptors expressed in HEK293 cells are used in modified HEPES buffer, pH 6.0. The performance of this test is commercially available (Eurofins Panlabs, catalog # 268600). 15 μg of membrane are incubated with 5 nM [ ³ H] -loprotect for 60 minutes at 25 °. The amount of membrane protein can vary from lot to lot and is adjusted as needed. Unspecific binding is determined in the presence of 10 μl of lloprost. The membranes are filtered, washed and then measured to determine the specific binding of [ ³ H] -loprostone. Substances are tested for inhibitory activity at a concentration of 10 μΜ or in the form of a dose-response curve [Lit .: Armstrong et al., Br. J. Pharmacol. 1989, 97 (3): 657; Boie et al., J. Biol. Chem. 1994, 269 (16): 12173].

B-tenth In vitro TP receptor binding inhibition test

For this assay, human recombinant prostanoid TP receptors expressed in HEK-293 EBNA cells are used in modified Tris / HCl buffer, pH 7.4. The performance of this test is commercially available (Eurofins Panlabs, catalog # 285510). 18.4 μg of membrane are incubated with 5 nM [ ³ H] -SQ-29,548 for 30 minutes at 25 °. The amount of membrane protein can vary from lot to lot and is adjusted as needed. Non-specific binding is determined in the presence of 1 μΜ SQ-29,548. The membranes are filtered, and then measured to determine the specific binding of [ ³ H] -SQ-29,548. Substances are tested for inhibitory activity at a concentration of 10 μΜ or in the form of a dose-response curve [Ref. : Saussy Jr. et al., J. Biol. Chem. 1986, 261: 3025; Hedberg et al., J. Pharmacol. Exp. Ther. 1988, 245: 786]. B. 11 In vitro test for DP agonism and antagonism

For the characterization of test substances for DP agonism and antagonism, PGD2-induced calcium flux was used in DP-expressing CHEM1 cells (Millipore, HTS091 C): 3000 cells in 25 μM complete medium [DMEM, 4.5 g / l glucose, 10% heat-inactivated FCS, 1% 100x non-essential amino acids, 10 mM HEPES, 0.25 mg / ml Geneticin (G418), 100 U / ml penicillin and streptomycin] are incubated per well of a 384 multititer plate (Greiner, Co.). Plate, black with a clear bottom) and incubated at 37Ό / 5% CO 2 for 24 hours. Prior to measurement, the medium is replaced with 30 μM Calcium Dye Loading Buffer (FLIPR Calcium Assay, Molecular Devices) and incubated at 37Ό / 5% C0 ₂ for 60 minutes. The test substance is prepared in DMSO in various concentrations as a dose response curve (starting concentration 10 mM, dilution factor 3.16) and 1:50 with, for example, calcium-free Tyrode (130 mM NaCl, 5 mM KCl, 20 mM HEPES, 1 mM MgCl ₂ , 4.8 mM NaHCO 3, pH 7.4) / 2 mM CaCl ₂ prediluted. For the DP agonism measurement in a fluorescence meter (FLI PR Tetra ^®, Molecular Devices) 10 μΙ the prediluted substance solution is added to the loaded with calcium dye cells and calcium flux by measuring the fluorescence at Ex. 470 nm / Em 525 nm for 120 seconds. Thereafter, the cells are incubated at 37Ό / 5% C0 ₂ for 10 minutes. For the antagonism DP measurement of the DP receptor in FLIPR Tetra ^® is prepared by adding 20 μΙ -76 nM (2 x EC50, final concentration) PGD2 activated in, for example, calcium-free Tyrode / 2 mM CaCl ₂ and the calcium Flux determined by measuring the fluorescence at Ex. 470 nm / Em. 525 nm for 120 seconds [Lit. : T. Matsuoka et al. (2000) Science 287: 2013-2017; S. Narumiya and GA Fitzgerald (2001) J. Clin. Invest. 108: 25-30].

B-12th In vitro test for EP1 activity and antagonism

For the characterization of test substances for EP1 agonism and antagonism, the PGE2-induced calcium flux was used in EP1-expressing CHEM1 cells (Millipore, HTS099C): 3000 cells in 25 μM complete medium [DMEM, 4.5 g / l glucose, 10 % Heat inactivated FCS, 1% 100x nonessential amino acids, 10mM HEPES, 0.25mg / ml Geneticin (G418), 100 U / ml penicillin, and streptomycin] are plated per well of a 384 multititer plate (Greiner, TC Plate , black with clear soil) seeded and incubated at 37Ό / 5% CO ₂ for 24 hours. Prior to measurement, the medium is replaced with 30 μM Calcium Dye Loading Buffer (FLIPR Calcium Assay, Molecular Devices) and incubated at 37Ό / 5% CO ₂ for 60 minutes. The test substance is in DMSO in various concentrations as a dose response curve prepared (starting concentration 10 mM, dilution factor 3.16) and 1:50 with, for example, calcium-free Tyrode (130 mM NaCl, 5 mM KCl, 20 mM HEPES, 1 mM MgCl ₂ , 4.8 mM NaHCO ₃ , pH 7.4) / 2 prediluted mM CaCl ₂ . For the EP1 agonism measurement in a fluorescence meter (FLIPR Tetra ^®, Molecular Devices) is added 10 μΙ the prediluted substance solution to the loaded Caicium dye cells and calcium flux by measuring the fluorescence at Ex. 470 nm / Em. 525 nm for 120 seconds. Thereafter, the cells are incubated at 37Ό / 5% C0 ₂ for 10 minutes. For the EP1 antagonism measurement of the EP1 receptor in FLIPR Tetra ^® is prepared by adding 20 μΙ ~ 6 nM (2 x EC50, final concentration) PGE2 activated in, for example, calcium-free Tyrode / 2 mM CaCl ₂ and the calcium Flux determined by measuring the fluorescence at Ex. 470 nm / Em. 525 nm for 120 seconds [Lit. : Y. Matsuoka et al. (2005) Proc. Natl. Acad. Be. USA 102: 16066-16071; S. Narumiya and GA Fitzgerald (2001) J. Clin. Invest. 108: 25-30; Watanabe et al. (1999) Cancer Res. 59: 5093-5096].

B. 13 In vitro test for EP2 activity and antagonism

For the characterization of test substances for EP2 agonism and antagonism, the PGE2-induced calcium flux was used in EP2-expressing CHEM9 cells (Millipore, HTS185C): 3000 cells in 25 μl plating medium [DMEM, 4.5 g / l glucose, 4 mM glutamine, 10% heat-inactivated FCS, 1% 100x nonessential amino acids, 10 mM HEPES, 100 U / ml penicillin and streptomycin) are added to each well of a 384 multititer plate (Greiner, TC plate, black with clear bottom ) and incubated at 37Ό / 5% C0 ₂ for 24 hours. Prior to measurement, the medium is replaced with 30 μM calcium dye loading buffer (FLIPR Calcium Assay, Molecular Devices) and incubated at 37 ° / 5% C 0 ₂ for 60 minutes. The test substance is prepared in DMSO at various concentrations as a dose response curve (starting concentration 10 mM, dilution factor 3.16) and 1:50 with, for example, calcium-free Tyrode (130 mM NaCl, 5 mM KCl, 20 mM HEPES, 1 mM MgCl ₂ , 4.8 mM NaHCO ₃ , pH 7.4) / 2 mM CaCl ₂ prediluted. For the EP2 agonism measurement in a fluorescence meter (FLIPR Tetra ^®, Molecular Devices) is added 10 μΙ the prediluted substance solution to the loaded Caicium dye cells and calcium flux by measuring the fluorescence at Ex. 470 nm / Em. 525 nm for 120 seconds. Thereafter, the cells are incubated at 37Ό / 5% C0 ₂ for 10 minutes. For the EP2 antagonism measurement of the EP2 receptor in the FLIPR Tetra ^® is prepared by adding 20 μΙ -22 nM (2 x EC ₅ o, final concentration) PGE2 activated in, for example, calcium-free Tyrode / 2 mM CaCl ₂ and Calcium flux determined by measuring the fluorescence at Ex. 470 nm / Em. 525 nm for 120 seconds [Lit .: CR Kennedy et al. (1999) Nat. Med. 5: 217-220; S. Narumiya and GA Fitzgerald (2001) J. Clin. Invest. 108: 25-30; N. Yang et al. (2003) J. Clin. Invest. 1 11: 727-735]. B-14th In vitro test for EP3 activity and antagonism

For the characterization of test substances for EP3 agonism and antagonism, the PGE2-induced calcium flux was used in EP3 (splice variant 6) -expressing CHEM1 cells (Millipore, HTS092C): 3000 cells in 25 μl plating medium [DMEM, 4.5 g / l glucose, 4 mM glutamine, 10% heat-inactivated FCS, 1% 100x nonessential amino acids, 10 mM HEPES, 100 U / ml penicillin and streptomycin] are incubated per well of a 384 multititer plate (Greiner, Co.). Plate, black with a clear bottom) and incubated at 37Ό / 5% CO 2 for 24 hours. Prior to measurement, the medium is replaced with 30 μM Calcium Dye Loading Buffer (FLIPR Calcium Assay, Molecular Devices) and incubated at 37Ό / 5% C0 ₂ for 60 minutes. The test substance is prepared in DMSO at various concentrations as a dose response curve (starting concentration 10 mM, dilution factor 3.16) and 1:50 with, for example, calcium-free Tyrode (130 mM NaCl, 5 mM KCl, 20 mM HEPES, 1 mM MgCl ₂ , 4.8 mM NaHCO ₃ , pH 7.4) / 2 mM CaCl ₂ prediluted. For the EP3 agonism measurement in a fluorescence meter (FLIPR Tetra ^®, Molecular Devices) 10 μΙ the prediluted substance-solution is added to the loaded with calcium dye cells and calcium flux by measuring the fluorescence at Ex. 470 nm / Em. 525 nm for 120 seconds. Thereafter, the cells are incubated at 37Ό / 5% CO 2 for 10 minutes. For the EP3 Antagonismus- measurement of EP3 receptor in the FLIPR Tetra ^® is prepared by adding 20 μΙ ~ 2 nM (2 x EC50, final concentration) PGE2 in, for example, calcium-free Tyrode / 2 mM CaCl ₂ activated and the calcium Flux determined by measuring the fluorescence at Ex. 470 nm / Em. 525 nm for 120 seconds [Lit .: M. Kotani et al. (1995) Mol. Pharmacol. 48: 869-879; M. Kotani et al. (1997) Genomics 40: 425-434; T. Kunikata et al. (2005) Nat. Immunol. 6: 524-531; S. Narumiya and GA Fitzgerald (2001) J. Clin. Invest. 108: 25-30; F. Ushikubi et al. (1998) Nature 395: 281-284].

B-15 °. In vitro test for EP4 activity and antagonism

For the characterization of test substances for EP4 agonism and antagonism, the PGE2-induced calcium flux was used in EP4-expressing CHEM1 cells (Millipore, HTS142C): 3000 cells in 25 μl plating medium [DMEM, 4.5 g / l glucose, 4 mM glutamine, 10% heat-inactivated FCS, 1% 100x nonessential amino acids, 10 mM HEPES, 100 U / ml penicillin and streptomycin) are added to each well of a 384 multititer plate (Greiner, TC plate, black with clear bottom ) and incubated at 37Ό / 5% C0 ₂ for 24 hours. Prior to measurement, the medium is replaced with 30 μM Calcium Dye Loading Buffer (FLIPR Calcium Assay, Molecular Devices) and incubated at 37 ° C / 5% C 0 ₂ for 60 minutes. The test substance is prepared in DMSO at various concentrations as a dose response curve (starting concentration 10 mM, dilution factor 3.16) and 1:50 with, for example, calcium-free Tyrode (130 mM NaCl, 5 mM KCl, 20 mM HEPES, 1 mM MgCl ₂ , 4.8 mM NaHCOs, pH 7.4) / 2 mM CaCl ₂ prediluted. For the EP4 agonism measurement, in a fluorescence measuring device (FLIPR Tetra ^® , Molecular Devices) 10 μΙ the prediluted substance solution to the calcium dye-loaded cells and the calcium flux determined by measuring the fluorescence at Ex. 470 nm / Em. 525 nm for 120 seconds. Thereafter, the cells are incubated at 37Ό / 5% CO 2 for 10 minutes. For the EP4 antagonism measurement, the EP4 receptor in the FLIPR Tetra ^{® is} activated by addition of 20 μΙ -26 nM (2 x EC ₅ o, final concentration) PGE 2 in, for example, calcium-free Tyrode / 2 mM CaC and the calcium Flux determined by measuring the fluorescence at Ex. 470 nm / Em. 525 nm for 120 seconds [Lit. : S. Rumiya and GA Fitzgerald (2001) J. Clin. Invest. 108: 25-30; M. Nguyen et al. (1997) Nature 390: 78-81; K. Yoshida et al. (2002) Proc. Natl. Acad. Be. USA 99: 4580-4585]. B-sixteenth In Vitro Test for IP Aqonism and Antagonism

For the characterization of test substances for IP agonism and antagonism, the Iloprost-induced calcium flux was used in IP-expressing CHEM1 cells (Millipore, HTS131 C): 3000 cells in 25 μΙ plating medium [DMEM, 4.5 g / l glucose, 4 mM glutamine, 10% heat-inactivated FCS, 1% 100x nonessential amino acids, 10 mM HEPES, 100 U / ml penicillin and streptomycin) are incubated per well of a 384 multititer plate (Greiner, TC plate , black with a clear bottom) and incubated at 37Ό / 5% C0 ₂ for 24 hours. Prior to measurement, the medium is replaced with 30 μM calcium dye loading buffer (FLIPR Calcium Assay, Molecular Devices) and incubated at 37 ° C / 5% C O2 for 60 minutes. The test substance is prepared in DMSO at various concentrations as a dose response curve (starting concentration 10 mM, dilution factor 3.16) and 1:50 with, for example, calcium-free Tyrode (130 mM NaCl, 5 mM KCl, 20 mM HEPES, 1 mM MgCl ₂ , 4.8 mM NaHCO ₃ , pH 7.4) / 2 mM CaCl ₂ prediluted. For the IP agonism measurement in a fluorescence meter (FLIPR Tetra ^®, Molecular Devices) is added 10 μΙ the prediluted substance solution to the loaded with calcium dye cells and calcium flux by measuring the fluorescence zenz in Ex. 470 nm / Em. 525 nm for 120 seconds. Thereafter, the cells are incubated at 37Ό / 5% CO 2 for 10 minutes. For the IP antagonism measurement of IP receptor in the FLIPR Tetra ^® is prepared by adding 20 μΙ -106 nM (2 x EC50, final concentration) iloprost in, for example, calcium-free Tyrode / 2 mM CaCl ₂ activated and the calcium Flux determined by measuring the fluorescence at Ex. 470 nm / Em. 525 nm for 120 seconds [Lit. : S. Narumiya et al. (1999) Physiol. Rev. 79: 1 193-1226; T. Murata et al. (1997) Nature 388: 678-682; Cheng, Y. et al. (2002) Science 296: 539-541; CH Xiao et al. (2001) Circulation 104: 2210-2215; GA Fitzgerald (2004) N. Engl. J. Med. 351: 1709-171 1].

B-17th In vitro test for TP agonism and antagonism

For the characterization of test substances for TP agonism and antagonism, the U46619-induced calcium flux in TP-expressing CHEM1 cells (Millipore, HTS081 C) was determined. 3,000 cells in 25 μΙ plating medium [DMEM, 10% heat-inactivated FCS, 1% 100x nonessential amino acids, 10mM HEPES, 0.25mg / ml Geneticin (G418), 100 U / ml penicillin and streptomycin] are per well seeded from a 384-Mu Itititer plate (Greiner, TC plate, black with a clear bottom) and incubated at 37Ό / 5% C0 ₂ for 24 hours. Prior to measurement, the medium is replaced with 30 μM calcium dye loading buffer (FLIPR Calcium Assay, Molecular Devices) and incubated at 37 ° / 5% C 0 ₂ for 60 minutes. The test substance is prepared in DMSO at various concentrations as a dose response curve (starting concentration 10 mM, dilution factor 3.16) and 1:50 with, for example, calcium-free Tyrode (130 mM NaCl, 5 mM KCl, 20 mM HEPES, 1 mM MgCl ₂ , 4.8 mM NaHCOs, pH 7.4) / 2 mM CaCl ₂ prediluted. For the TP-agonism measurement in a fluorescence meter (FLIPR Tetra ^®, Molecular Devices) is added 10 μΙ the prediluted substance solution to the loaded with calcium dye cells and calcium flux by measuring the fluorescence at Ex. 470 nm / Em. 525 nm for 120 seconds. Thereafter, the cells are incubated at 37Ό / 5% C0 ₂ for 10 minutes. For the TP-antagonism measurement of the TP receptor in the FLIPR Tetra ^® by adding 20 μΙ -88 nM (2 x EC ₅ o, final concentration) U46619 activated, for example, in calcium-free Tyrode / 2 mM CaCl ₂ and Calcium flux determined by measuring the fluorescence at Ex. 470 nm / Em. 525 nm for 120 seconds [Lit. : S. Ali et al. (1993) J. Biol. Chem. 268: 17397-17403; K. Hanasaki et al. (1989) Biochem. Pharmacol. 38: 2967-2976; M. Hirata et al. (1991) Nature 349: 617-620]. B-18th Animal model of bleomycin-induced pulmonary fibrosis

 Bleomycin-induced lung fibrosis in the mouse or rat is a widely used animal model of pulmonary fibrosis. Bleomycin is a glycopeptide antibiotic used in oncology for the treatment of testicular tumors, Hodgkin's and non-Hodgkin's tumors. It is eliminated renally, has a half-life of about 3 hours and, as a cytostatic, influences different phases of the division cycle [Lazo et al., Cancer Chemother. Biol. Response Modif. 15, 44-50 (1994)]. Its anti-neoplastic effect is due to an oxidative damaging effect on DNA [Hay et al., Arch. Toxicol. 65, 81-94 (1991)]. The lung tissue is particularly endangered in comparison with bleomycin, since so-called cysteine hydrolases, which lead to inactivation of bleomycin in other tissues, are only present in small numbers. After administration of bleomycin, the animals develop an acute respiratory distress syndrome (ARDS) with subsequent development of pulmonary fibrosis.

Administration of bleomycin may be single or multiple intratracheal, inhalational, intravenous or intraperitoneal. Treatment of the animals with the test substance (by gavage, by addition in food or drinking water, by osmotic minipump, by subcutaneous or intraperitoneal injection or by inhalation) starts on the day of the first administration of bleomycin or therapeutically 3-14 days later and extends over a period of time νοη 2-6 weeks. At the end of the study, a bronchoalveolar lavage is performed to determine the cell content and the pro-inflammatory and pro-fibrotic markers as well as lung function measurements and histological assessment of pulmonary fibrosis.

B-19th Animal model of DQ12-quartz-induced pulmonary fibrosis

Mouse and rat DQ12 quartz induced lung fibrosis is a widely used animal model of pulmonary fibrosis [Shimbori et al., Exp. Lung Res. 36, 292-301 (2010)]. DQ12 quartz is a highly active quartz that breaks or grinds. Intratracheal or inhaled administration of DQ12-quartz leads to alveolar proteinosis in mice and rats followed by interstitial pulmonary fibrosis. The animals receive a single or multiple intratracheal or inhaled instillation of DQ12 quartz. The treatment of the animals with the test substance (by gavage, by addition in food or drinking water, by osmotic minipump, by subcutaneous or intraperitoneal injection or by inhalation) starts on the day of the first instillation of the silicate or therapeutically 3-14 days later and extends over a period of 3-12 weeks. At the end of the study, a bronchioalveolar lavage is performed to determine cell content and pro-inflammatory and pro-fibrotic markers as well as lung function measurements and histological assessment of pulmonary fibrosis.

B-twentieth Animal model of DQ12 quartz or FITC-induced pulmonary inflammation

 Intratracheal administration of DQ12-quartz or fluorescein isothiocyanate (FITC) to mouse and rat leads to lung inflammation [Shimbori et al., Exp. Lung Res. 36, 292-301 (2010)]. The animals are treated with the test substance on day of instillation of DQ12 quartz or FITC or one day later for a period of 24 h to 7 days (by gavage, by addition in food or drinking water, by osmotic minipump, by subcutaneous or intraperitoneal Injection or via inhalation). At the end of the experiment a bronchoalveolar lavage is performed to determine the cell content and the proinflammatory and pro-fibrotic markers.

C. Embodiments of Pharmaceutical Compositions

The compounds according to the invention can be converted into pharmaceutical preparations as follows:

Tablet:

Composition:

100 mg of the compound according to the invention, 50 mg of lactose (monohydrate), 50 mg of corn starch (native), 10 mg of polyvinylpyrrolidone (PVP 25) (BASF, Ludwigshafen, Germany) and 2 mg of magnesium stearate. Tablet weight 212 mg. Diameter 8 mm, radius of curvature 12 mm.

production:

 The mixture of compound of the invention, lactose and starch is granulated with a 5% solution (m / m) of the PVP in water. The granules are mixed after drying with the magnesium stearate for 5 minutes. This mixture is compressed with a conventional tablet press (for the tablet format see above). As a guideline for the compression, a pressing force of 15 kN is used.

Orally administrable suspension:

 Composition:

1000 mg of the compound of the invention, 1000 mg of ethanol (96%), 400 mg of Rhodigel ^® (xanthan gum of the firm FMC, Pennsylvania, USA) and 99 g of water.

 A single dose of 100 mg of the compound of the invention corresponds to 10 ml of oral suspension.

 production:

The rhodigel is suspended in ethanol, the compound according to the invention is added to the suspension. While stirring, the addition of water. Until the completion of the swelling of Rhodigels is stirred for about 6 h.

Orally administrable solution:

 Composition:

500 mg of the compound according to the invention, 2.5 g of polysorbate and 97 g of polyethylene glycol 400. A single dose of 100 mg of the compound according to the invention correspond to 20 g of oral solution.

production:

 The compound of the invention is suspended in the mixture of polyethylene glycol and polysorbate with stirring. The stirring is continued until complete dissolution of the compound according to the invention. i.v. Lösunq:

 The compound of the invention is dissolved in a concentration below the saturation solubility in a physiologically acceptable solvent (e.g., isotonic saline, 5% glucose solution, and / or 30% PEG 400 solution). The solution is sterile filtered and filled into sterile and pyrogen-free injection containers.

Claims

claims

Compounds of the formula (I)

 in which

 the ring Q for a group of the formula

i-C4) alkyl,

Hydroxy, (Ci-C ₄ ) -alkoxy, amino or a group of mel -NH-C (= 0) -R ⁷ , -NH-C (= 0) -NH-R ⁷ or -S (= 0) _n R ⁸ , where (C 1 -C ₄ ) -alkyl and (C 1 -C ₄ ) -alkoxy can be substituted up to three times by fluorine,

and in which R ^{7 is} hydrogen or (C 1 -C ₄ ) -alkyl which may be substituted up to three times by fluorine,

R ^{8 is} (C 1 -C ₄ ) -alkyl which may be substituted by hydroxyl, methoxy or ethoxy or up to three times by fluorine, and

 n is the number 0, 1 or 2,

D is CR ^D or N,

E is CR ^E or N,

G is CR ^G or N,

 wherein a maximum of two of the ring members D, E and G are also N, and wherein

R ^D and R ^E independently of one another are hydrogen, fluorine, chlorine, methyl, trifluoromethyl, methoxy or trifluoromethoxy

 and

R ^{G is} hydrogen, fluorine, chlorine, bromine, methyl or trifluoromethyl,

is halogen, up to five times fluorine-substituted (C 1 -C ₄ ) -alkyl, up to three times fluorine-substituted methoxy, (trifluoromethyl) sulfanyl, pentafluorosulfanyl, trimethylsilyl, ethynyl, cyclopropyl, or cyclobutyl,

 where cyclopropyl and cyclobutyl can be substituted up to fourfold by fluorine,

R ³ and R ⁴ independently of one another represent hydrogen, halogen or up to three times fluorine-substituted methyl,

is halogen, up to five times fluorine-substituted (C 1 -C ₄ ) -alkyl, up to three times fluorine-substituted methoxy, hydroxyl, methylsulfanyl, cyano, ethenyl, cyclopropyl or cyclobutyl,

 where cyclopropyl and cyclobutyl can be substituted up to fourfold by fluorine,

for a group of the formula

stands, where

^{* stands} for the point of attachment to the ring Q,

 and

 Ar is phenyl which may be substituted up to three times, identically or differently, by fluorine, chlorine, methyl substituted up to three times by fluorine and methoxy substituted up to three times by fluorine, or by thienyl which is mono- or di-methyl or monosubstituted may be substituted by chlorine or bromine, or represents thiazolyl or pyridyl,

 and their N-oxides, salts, solvates, salts of N-oxides and solvates of N-oxides and salts.

 2. Compounds of formula (I) according to claim 1, in which

 the ring Q for a group of the formula

stands, where

# ^{1 represents} the point of attachment to R ⁶ ,

# ^{2 represents} the point of attachment to the nitrogen atom,

Y is -C (H) (OH) - or -CHF-, R ^{A is} hydrogen, fluorine, chlorine, bromine, cyano, methyl, trifluoromethyl, methoxy, trifluoromethoxy or a group of the formula -S (= O) _n -R ⁸ , in which

R ^{8 is} methyl or trifluoromethyl

 and

 n is the number 0 or 2,

D is CR ^D or N, in which

R ^{D is} hydrogen or fluorine,

 E stands for C-H,

G is CR ^G or N, in which

R ^{G is} hydrogen, fluorine or chlorine,

R ^{1 is} chlorine, bromine, iodine, methyl, isopropyl, tert-butyl, difluoromethyl, trifluoromethyl, trifluoromethoxy, (trifluoromethyl) sulfanyl, trimethylsilyl, ethynyl, cyclopropyl or cyclobutyl,

R ^{2 is} hydrogen,

R ^{4 is} independently of one another hydrogen, chlorine or methyl, fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, monofluoromethyl, difluoromethyl, trifluoromethyl, methoxy, trifluoromethoxy, hydroxy, methylsulfanyl or cyclopropyl,

 for a group of the formula

stands, where

 *

 stands for the point of attachment to the ring Q,

and for phenyl which may be mono- or di-substituted by fluorine, thienyl which may be mono- or di-substituted by methyl or simply by chlorine or bromine, or a group of the formula

 stands, where

# ^{3 represents} the point of attachment to the quinoline ring,

R ^{9 is} chlorine or methyl, and

R ^{10 is} chlorine or methoxy,

 and their salts, solvates and solvates of the salts.

3. Compounds of formula (I) according to claim 1 or 2, in which

 the ring Q for a group of the formula

 stands, where

# ^{1 represents} the point of attachment to R ⁶ ,

# ^{2 represents} the point of attachment to the nitrogen atom,

R ^{A is} fluorine, chlorine, cyano, methyl, trifluoromethyl, methoxy, trifluoromethoxy or a group of the formula -S (= O) _n -R ⁸ , in which

R ^{8 is} methyl or trifluoromethyl

 and

 n is the number 0 or 2,

 D stands for C-H,

 E stands for C-H,

G is CR ^G or N, in which

R ^{G is} hydrogen, fluorine or chlorine, R ^{1 is} chlorine, bromine, iodine, methyl, tert-butyl, difluoromethyl, trifluoromethyl, trimethylsilyl, ethynyl or cyclopropyl,

R ^{2 is} hydrogen,

R ³ and R ⁴ independently of one another are hydrogen, chlorine or methyl, where at least one of the radicals R ³ and R ^{4 is} each hydrogen,

R ^{5 is} fluorine, chlorine, methyl, ethyl, methoxy, hydroxy, methylsulfanyl or cyclopropyl,

R ^{6 is} a group of the formula

stands, where

 * stands for the point of attachment to the ring Q,

and

 Ar represents phenyl, which may simply be substituted by fluorine,

and their salts, solvates and solvates of the salts.

 Compounds of formula (I) according to any one of claims 1 to 3, in which

the ring Q for a group of the formula

is the point of attachment to R ⁶ ,

represents the point of attachment to the nitrogen atom, R ^{A represents} hydrogen, fluorine or a group of the formula -S (= ^O ) 2CH ₃ ,

D stands for C-H,

 E stands for C-H,

 G stands for C-H,

R ^{1 is} bromine,

R ² , R ³ and R ^{4 are} hydrogen,

R ^{5 is} methyl, cyclopropyl or chlorine,

R ^{6 is} a group of the formula

stands, where

^{* stands} for the point of attachment to the ring Q,

 and

 Ar is phenyl,

 and their salts, solvates and solvates of the salts.

5. Compounds of formula (I) according to any one of claims 1 to 4, in which

 the ring Q for a group of the formula

 stands, where

# ^{1 represents} the point of attachment to R ⁶ , # ^{2 represents} the point of attachment to the nitrogen atom,

R ^{A represents} hydrogen, fluorine or a group of the formula -S (= ^O ) 2CH ₃ ,

D stands for C-H,

 E stands for C-H,

 G stands for C-H,

R ^{1 is} bromine,

R ² , R ³ and R ^{4 are} hydrogen,

R ^{5 is} methyl, cyclopropyl or chlorine,

R ^{6 is} a group of the formula

stands, where

 * stands for the point of attachment to the ring Q,

 and

 Ar is phenyl,

 and their salts, solvates and solvates of the salts.

 6. A process for the preparation of a compound as defined in claims 1 to 5, characterized in that either

 [A] a compound of the formula (II)

in which R ¹ , R ² , R ³ , R ⁴ , R ⁵ , Q and Ar have the abovementioned meanings, with a suitable azide compound to give a compound of the formula (I-A)

in which R ¹ , R ² , R ³ , R ⁴ , R ⁵ , Q and Ar have the meanings given above,

or

a compound of the formula (III)

in which R ¹ , R ² , R ³ , R ⁴ , R ⁵ , Q and Ar have the meanings given above,

[B-1] with thionyl chloride to give a compound of the formula (1B)

in which R ¹ , R ² , R ³ , R ⁴ , R ⁵ , Q and Ar have the meanings given above,

or

 [B-2] with Λ /, Λ / '- thiocarbonyldiimidazole and a suitable additive in each case to give a compound of the formula (I-C) or (I-D)

in which R ¹ , R ² , R ³ , R ⁴ , R ⁵ , Q and Ar have the meanings given above,

or

[B-3] with Λ /, Λ / '- carbonyldiimidazole, phosgene or a suitable phosgen analogue to give a compound of formula (IE)

in which R ¹ , R ² , R ³ , R ⁴ , R ⁵ , Q and Ar have the meanings given above,

or

 a compound of the formula (IV)

in which R ¹ , R ² , R ³ , R ⁴ , R ⁵ , Q and Ar have the meanings given above, with Λ /, Λ / '- carbonyldiimidazole, phosgene or a suitable phosgen genogonogen

to a compound of formula (IF)

in which R ¹ , R ² , R ³ , R ⁴ , R ⁵ , Q and Ar have the meanings given above,

or

[D] a compound of formula (V)

in which R ¹ , R ² , R ³ , R ⁴ , R ⁵ , Q and Ar have the abovementioned meanings, with (phenylsulfonyl) acetonitrile and sodium azide to give a compound of the formula (I)

in which R ¹ , R ² , R ³ , R ⁴ , R ⁵ , Q and Ar have the meanings given above,

or

 a compound of the formula (VI)

in which R ¹ , R ² , R ³ , R ⁴ , R ⁵ , Q and Ar have the abovementioned meanings, with semicarbazide hydrochloride to give a compound of the formula (1H)

(LH) in which R ¹ , R ² , R ³ , R ⁴ , R ⁵ , Q and Ar have the meanings given above, is reacted

and the compounds according to the invention thus obtained are optionally converted with the corresponding (i) solvents and / or (ii) acids or bases into their solvates, salts and / or solvates of the salts.

 A compound as defined in any one of claims 1 to 5 for the treatment and / or prevention of diseases.

 A compound as defined in any one of claims 1 to 5 for use in a method for the treatment and / or prevention of idiopathic pulmonary fibrosis, pulmonary hypertension, bronchiolitis obliterans syndrome, inflammatory and fibrotic skin and ophthalmic disorders, and fibrotic disorders of the internal organs.

Use of a compound as defined in any one of claims 1 to 5 for the manufacture of a medicament for the treatment and / or prevention of idiopathic pulmonary fibrosis, pulmonary hypertension, bronchiolitis obliterans syndrome, inflammatory and fibrotic skin and ophthalmic disorders and fibrotic disorders of the internal organs.

 A pharmaceutical composition comprising a compound as defined in any one of claims 1 to 5 in combination with one or more inert non-toxic pharmaceutically acceptable excipients.

 A pharmaceutical composition comprising a compound as defined in any one of claims 1 to 5 in combination with one or more further active ingredients selected from the group consisting of PDE 5 inhibitors, sGC activators, sGC stimulators, prostacyclin analogs, IP receptor Agonists, endothelin antagonists, signal transduction cascade inhibiting compounds and pirfenidone.

 Medicament according to claim 10 or 11 for the treatment and / or prevention of idiopathic pulmonary fibrosis, pulmonary hypertension, bronchiolitis obliterans syndrome, inflammatory and fibrotic skin and eye diseases and fibrotic disorders of the internal organs.

 A method for the treatment and / or prevention of idiopathic pulmonary fibrosis, pulmonary hypertension, bronchiolitis obliterans syndrome, inflammatory and fibrotic skin and eye diseases and fibrotic disorders of the internal organs in humans and animals by administering an effective amount of at least one compound as claimed in any one of the claims 1 to 5, or a drug as defined in any one of claims 10 to 12.