EA040220B1 - SUBSTITUTED N-ARYLETHYL-2-AMINOQUINOLINE-4-CARBOXAMIDES, METHOD FOR THEIR PRODUCTION AND DRUG CONTAINING THE SPECIFIED COMPOUND - Google Patents

Description

with the values of the radicals Ar, Y, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ^7A , R ^7B , R ⁸ and R ⁹ specified in the description, as well as to the method of their preparation, biologically active a substance having the properties of an FP receptor antagonist, which is a compound of formula (I), and a drug for the treatment and/or prevention of diseases in which the FP receptor is involved in the course of an inflammatory process and/or remodeling of tissues or vessels, containing a compound of formula (I ).

The invention relates to new substituted derivatives of N-arylethyl-2-aminoquinoline-4carboxamide, a method for their preparation, a biologically active substance having the properties of an FP receptor antagonist, which is the above compound, and a drug for the treatment and/or prevention of diseases in which, during inflammatory the process and/or rearrangement of tissues or vessels involves the FP receptor.

Prostaglandin F2alpha (PGF2a) belongs to the family of bioactive prostaglandins, which are derivatives of arachidonic acid. After release from membrane phospholipids through A2-phospholipases, arachidonic acid is oxidized by cyclooxygenase to prostaglandin H2 (PGH2), which is further converted to PGF2a via PGF synthase. PGF2a can also be enzymatically formed from other prostaglandins, such as PGE2 or PGD2, in small amounts [Watanabe et al., J. Biol. Chem. 1985, 260, 7035-7041]. PGF2a does not accumulate, but is immediately released after synthesis, due to which it acts locally. PGF2a is an unstable molecule (t _1/2 < 1 min) that is rapidly enzymatically rearranged in the lung, liver and kidneys to an inactive metabolite, 15-ketodihydro-PGF2α [Basu et al., Acta Chem. Scand. 1992, 46, 108-110]. 15ketodihydro-PGF2α is found in high amounts in plasma and later also in urine, both under physiological and pathophysiological conditions.

The biological effect of PGF2a is mediated by the binding and activation of the permanent membrane receptor, the PGF2α receptor, or also the so-called FP receptor. The FP receptor refers to G-protein coupled receptors that are characterized by seven transmembrane domains. Along with the human FP receptor, mouse and rat FP receptors have also been 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. Compared to prostanoid receptors, the FP receptor is the least selective, since, in addition to PGF2a, PGD2 and PGE2 are also associated with it with nanomolar affinity [Woodward et al., Pharmacol. Rev. 2011, 63, 471-538]. Stimulation of the FP receptor primarily results in Gq-dependent activation of phospholipase C, which results from calcium release and activation of diacylglycerol-dependent protein kinase C (PKC). Elevated levels of intracellular calcium result in calmodulin-mediated stimulation of myosin light chain kinase (MLCK). In addition to binding to the G protein Gq, the FP receptor can also activate the Rho/Rho kinase signal transduction cascade via G12/G13 and alternatively stimulate the Raf/MEK/MAP signaling pathway via the Gi junction [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 uterine mucosa, uterine contractions, luteolysis, and in the induction of labor and delivery. PGF2a is also synthesized in the endometrium in epithelial cells, where it stimulates cell proliferation [Woodward et al., Pharmacol. Rev. 2011, 63, 471-538]. In addition, PGF2a is a potential stimulator of smooth muscle, vascular, and bronchial contraction and is present in both acute and chronic inflammatory processes. [Basu, Mol. Cells 2010, 30, 383-391]. We were able to show that 15-keto-dihydro-PGF2α, a stable metabolite of PGF2a, can be systemically detected in patients with rheumatoid arthritis, psoriatic arthritis and osteoarthritis. In the kidney, PGF2a is involved in water absorption, natriuresis, and diuresis. In the eyes, PGF2a regulates intraocular pressure. PGF2a also plays an important role in bone metabolism: prostaglandin stimulates sodium-dependent transport of inorganic phosphate in osteoblasts and increases the release of interleukin-6 and vascular endothelial growth factor (VEGF) in osteoblasts; in addition, PGF2a is a strong mitogen and survival factor for osteoblasts [Agas et al., J. Cell Physiol. 2013, 228, 25-29].

Increased PGF2a/FP receptor activity also results in upregulation of tumor and angiogenic genes like COX-2 [Sales et al., 2007, Endocrinology 148:3635-44], FGF-2 and VEGF [Sales et al., 2010 Am JPathol 176:431], indicating that the FP receptor stimulates endometrial tumor growth by regulating vascular functions. In addition, the FP receptor is involved in the regulation of endometrial epithelial cell proliferation and, due to its adhesion, can affect the extracellular matrix and motility. Studies indicate that the PGF2a/FP receptor plays a multifactorial role in endometrial adenocarcinoma [Yang et al., 2013 J Recept Signal Transduct, 33(1): 14-27].

Increased expression of the FP receptor in oligodendrocyte progenitor cells (ORCs) may be a marker for damage to oligodendrocytes and active myelin [Soldan et al., Neurology 2015, 84]. After autopsy, tissues from patients with multiple sclerosis (MS) could observe expression of the FP receptor on the ORF near the edges of the MS plaques. In the control samples of the white matter of the brain, the expression of the FP receptor was not detected. This indicates that the FP receptor plays a role in multiple sclerosis [Carlson et al., 2015, Mult. Sclerosis. 23 (11) 467-468].

Brain damage results in upregulation of prostaglandins, primarily pro-inflammatory PGF2a, and hyperactivation of the FP receptor. So with the help of mice with a missing prescription

- 1 040220 rum FP and through treatment with an FP agonist, AL-8810 has a significant neuroprotective effect after cerebral artery occlusion [Kim et al., 2012, Neurobiol Disease 48, 58-65].

In addition, it was possible to show that PGF2α-FP receptor activation is involved in various cardiovascular dysfunctions such as myocardial fibrosis, myocardial infarction and hypertension ist [Zhang et al., Frontiers in Pharmacol. 2010, 1, 1-7; Ding et al., Int. J Biochem. cell. Biol, 2012, 44, 1031-1039; Ding etal, J. Mol. Med, 2014, 6, 629-640].

Thus, the main metabolite of PGF2a, 15-keto-dihydro-PGF2α, is elevated in humans under conditions of increased cardiovascular risk [Helmersson-Karlquist et al., Eur Heart J 2015, 36, 238-243], such as also when smoking [Helmersson et al., 2005 Atherosclerosis 181, 201-207), obesity [Sinaiko et al., 2005 Circulation 111, 1985-1991], type I diabetes [Basu et al., 2005, 28, 1371-1375], and type II diabetes [Helmersson et al., 2004, Circulation 109, 1729-1734]. [Zhang et al., Frontiers in Pharmacol 2010, 1:1-7]. They were also able to show that genetic polymorphism in the Chinese subpopulation leads to increased FP gene transcription and increased vascular contraction [Xiao et al., 2015, Arterioscler Thromb Vasc Biol. 35:1687-1695].

In addition, the PGF2a (FP) receptor is involved in joint inflammation and regulation of the bone morphogenetic protein (BMP) signaling cascade and accelerates chondrocyte differentiation [Kim et al., Biochim. Biophys. Acta, 2015, 1853, 500-512]. Stabilizing analogues of PGF2a are used for ovarian synchronization and human reproductive function, and are also used to reduce intraocular pressure for the treatment of glaucoma [Basu, Mol. Cells 2010, 30, 383-391]. During the last application, stimulation of hair growth, such as eyelashes, was observed as a side effect due to a chemically stable analogue of PGF2a, for example, latanoprost. [Johnston et al., Am J Ophthalmol 1997, 124-544-547]. FP receptor genes are also expressed in human scalp hair follicles [Khidhir et al., J Invest Dermatol, 2009, Abstr 607]. These studies suggest that the FP receptor may be involved in the regulation of hair growth and also diseases such as hirsutism.

The role of the FP receptor in the signaling cascade in the occurrence of visceral pain (dysmenorrhea) is well described. Thus, dysmenorrhea pain is best correlated with the rate of PGF release during menstruation (vgl. Powell et al., Prostaglandins 1985, 29, 273-290; Dawood and Khan-Dawood, Am. J. Obstet. Gynecol. 2007, 196, 35. el-35.e5; Hsia et al., Endocrinology 2011, 152, 2090-2099). The association of the FP receptor signaling pathway in peripherally mediated inflammatory pain has not yet been described. In doing so, the presented data show this unexpected relationship for the first time.

In patients with idiopathic pulmonary fibrosis (IPF), a stable PGF2a metabolite appears to significantly increase plasma 15-ketodihydro-PGF2α and 15-ketodihydro-PGF2α levels are associated with functional parameters such as forced vital capacity (FVC), diffusive carbon monoxide lung capacity (DLCO) and the 6-minute walk test. In addition, an association between elevated plasma-15ketodihydro-PGF2α and patient mortality was able to be established [Aihara et al., PLoS One 2013, 8, 1-6]. In line with this, it has also been shown that stimulation of human lung fibroblasts with naturally occurring silicate dust, which can lead to silicosis in humans with chronic inhalation and consequent pulmonary fibrosis, causes a strong upregulation of PGF2α synthesis [O'Reilly et al., Am. J Physiol. lung cell. Mol. physiol. 2005, 288, L1010-L1016]. In mice with a bleomycin-induced pulmonary fibrosis model, knockout of the FP receptor (FP-/-) resulted in significant reductions in pulmonary fibrosis compared to wild-type mice [Oga et al., Nat. Med. 2009, 75, 1426-1430]. In FP-/- mice after administration of bleomycin, a significant decrease in the content of hydroxyproline was observed, as well as a reduced induction of profibrotic genes in the lung tissue. In addition, lung function was significantly improved in FP-/- mice compared to wild-type mice. In human lung fibroblasts, PGF2a stimulates the proliferation and production of collagen by FP receptors. Since this occurs independently of the profibrotic mediator TGFe, the PGF2α/FP receptor signaling cascade represents an independent pathway in the onset of pulmonary fibrosis [Oga et al., Nat. Med. 2009, 15, 1426-1430]. Studies show that the FP receptor is a therapeutic target protein for the treatment of IPF ist [Olman, Nat. Med. 2009, 75, 1360-1361]. The involvement of PGF2a in the induction of fibrosing changes has also been shown 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 on synoviocytes in patients with arthrosis of the knee [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, the occurrence and/or progression of which is associated with an inflammatory process and/or proliferative and fibroproliferative transformation of tissues and vessels. In particular, it can be diseases and/or damage to the lungs, cardiovascular system or kidneys, or it can mean a blood disease, cancer or other inflammatory diseases.

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In this regard, inflammatory and fibrosing lung diseases and injuries should be mentioned, in particular, idiopathic pulmonary fibrosis, interstitial lung diseases associated with rheumatoid arthritis, pulmonary hypertension, bronchiolitis obliterans syndrome (BOS), chronic obstructive pulmonary disease (COPD), asthma and cystic fibrosis. Diseases and injuries of the cardiovascular system in which the FP receptor is involved are, for example, tissue changes after myocardial infarction and in heart failure. Kidney diseases are, for example, kidney failure. Blood disease is, for example, drepanocytosis. Examples of tissue breakdown and reorganization during oncological processes are the migration of cancer cells (formation of metastases) and the formation of a network of capillaries from endothelial cells lining small venules (neoangiogenesis). Other inflammatory diseases in which the FP receptor plays an important role are, for example, arthrosis and multiple sclerosis.

Idiopathic pulmonary fibrosis or idiopathic pulmonary fibrosis (IPF) is a progressive lung disease that, if left untreated, leads to death approximately 2.5 to 3.5 years after diagnosis. Most often at the time of diagnosis, patients over 60 years of age, men get sick more often than women. The onset of IPF is latent and is characterized by increased dyspnoea and dry cough due to irritation of the respiratory tract. IPF belongs to the group of idiopathic interstitial pneumonias (IIP), a heterogeneous group of lung diseases that are characterized by fibrosis and inflammation of varying degrees and are recognized by clinical, limited, and histological criteria. Within this group, idiopathic pulmonary fibrosis is of particular importance because of its frequency and aggressive course of the disease [Ley et al., Am. J. Respir. Crit. Care Med. 2011, 183, 431-440]. IPF can occur either as a single case or with concomitant diseases. The reasons are currently unknown. In recent years, many studies have been conducted that chronic damage to the alveolar epithelium leads to the release of profibrotic cytokines / mediators, accompanied by increased fibroblast proliferation and increased collagen fiber formation, due to which patchy fibrosis occurs and a typical cellular structure of the lungs is formed [Strieter et al ., Chest 2009, 136, 1364-1370]. The clinical consequences of fibrosis are a decrease in the elasticity of the lung tissue, a decrease in diffusion capacity, and the development of severe hypoxia. Due to impaired lung function, respectively, a deterioration in forced vital capacity (FVC) and diffusive capacity (DLCO) can occur. The main and most significant predicted comorbidities of IPF are acute exacerbation and pulmonary hypertension [Beck et al., Der Pneumologe 2013, 10(2), 105111]. The prevalence of pulmonary hypertension among interstitial lung diseases is 10-40% [Lettieri et al., Chest 2006, 129, 746-752; Behr et al., Em. Respir. J. 2008, 31, 1357-1367]. There is currently no medical treatment for IPF other than lung transplantation.

Rheumatoid arthritis (RA) is a progressive, systemic autoimmune disease characterized by chronic erosive synovitis. Interstitial lung disease (ILD) is one of the most common extra-articular manifestations of PA [Wells et al. Nat Rev Rheumatol 2014, 10, 728-739]. Approximately 10% of RA patients have clinically proven interstitial lung disease (PA-ILD), another third show subclinical ILD on chest CT scans. The mortality rate in patients with PA-ILD is three times higher than in patients with RA without ILD, with a median life expectancy of only 2.6 years after diagnosis of ILD [Olson et al. Am J Respir Crit Care Med 2011 183, 372-378; Doyle et al. Chest 2014, 145(3), 454-463].

Inflammatory and autoimmune changes in the lungs, together with various environmental mediating factors (including smoking, fine dust, chemical irritants) and genetic predisposition, play an important role in the development and progression of PAILD [Catrina et al. Nat Rev Rheumatol 2014, 10(11), 645-653].

Pulmonary hypertension (PH) is a progressive lung disease that, if left untreated, is fatal within about 2.8 years of diagnosis. In chronic pulmonary hypertension, mean pulmonary arterial pressure (mPAP) is defined as > 25 mmHg at rest or > 30 mmHg during exercise (normal < 20 mmHg). The pathological physiology of pulmonary hypertension is characterized by vasoconstriction and pulmonary vascular remodeling. In chronic PH, neomuscularization of the primarily nonmuscularized pulmonary vessels occurs, and the muscles of such already muscularized vessels increase in volume. This increase in obliteration in the pulmonary circulation leads to a gradual increase in the load on the right heart, which leads to a decrease in right heart output and ultimately ends in right ventricular failure [M. Humbert et al., J. Am. Coll. cardiol. 2004, 43, 13S-24S]. While idiopathic (or primary) pulmonary arterial hypertension (IPAH) is a very rare disorder, secondary pulmonary hypertension (pop-RAN PH, NPAHPH) is very common, and PH is now thought to be the third most common group of cardiovascular disorders. after coronary heart disease and systemic hypertension [Naeije, in: A. J. Peacock et al. (Eds.), Pulmonary Circulation. Diseases and their treatment, 3rd edition, Hodder Arnold Publ., 2011, 3]. Since 2008, pulmonary hypertension has been classified according to the Dana Point classification into various

- 3 040220 subgroups according to the respective etiology [D. Montana und G. Simonneau, in: A. J. Peacock et al. (Eds.), Pulmonary Circulation. Diseases and their treatment, 3rd edition, Hodder Arnold Publ., 2011, 197-206].

Despite all the advances in the treatment of PH, there is still no hope of a cure for this serious disorder. Marketed therapies (eg, prostacyclin analogues, endothelin receptor antagonists, phosphodiesterase inhibitors) can improve quality of life, exercise capacity, and patient prognosis. They are systemically accepted, primarily hemodynamically acting principles of treatment that affect vascular tone. The applicability of these drugs is limited due to serious side effects and/or difficult to use dosage forms. The period during which the clinical condition of patients can be improved or stabilized with a specific monotherapy is limited (for example, due to the development of tolerance). Ultimately, the therapy is increased, thereby using combination therapy, in which several drugs must be administered simultaneously. Currently, these standard therapeutic agents are only approved for the treatment of pulmonary arterial hypertension (PAH). In the case of secondary forms of PH such as PHCOPD, these therapeutic agents (eg, sildenafil, bosentan) have been unsatisfactory in clinical trials because, as a result of non-selective vasodilation, they lead to a decrease in arterial oxygen content (decrease in saturation) in patients. A possible reason for this is the adverse effect on the coordination of ventilation-perfusion processes in the lungs in heterogeneous pulmonary disorders due to the systemic administration of non-selective 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 among the most promising possible treatments for pulmonary hypertension. In this regard, of particular interest is the identification of new pharmacological mechanisms for the treatment of PH [Ghofrani et al., Herz 2005, 30, 296-302; E. B. Rosenzweig, Expert Opin. Emerging Drugs 2006, 11, 609-619; T. Ito et al., Curr. Med. Chem. 2007, 14, 719-733]. In particular, new therapeutic approaches that can be combined with therapeutic concepts already on the market can form the basis for more effective treatments and thus be very beneficial to patients.

For the purposes of this invention, pulmonary hypertension includes the subforms of both primary and secondary hypertension (NPAHPH), as defined by the Dana Point classification, according to the respective etiology [D. Montana und G. Simonneau, in: A. J. Peacock et al. (Eds.), Pulmonary Circulation. Diseases and their treatment, 3rd edition, Hodder Arnold Publ., 2011, 197-206; Hoeper et al., J. Am. Coll. Cardiol, 2009, 54 (1), Suppl. S, S85-S96]. These include, in particular, in group 1, pulmonary arterial hypertension (PAH), which, among others, covers idiopathic and hereditary forms (IPAH or FPAH). In addition, the RAH also covers persistent pulmonary hypertension of the newborn and associated pulmonary arterial hypertension (APH), such as that associated with collagenoses, congenital systemic pulmonary shunts, portal hypertension, HIV infections, certain drugs and medications (eg, drugs to suppress appetite), with disorders that have a significant venous/capillary component, such as pulmonary veno-occlusive disorder and pulmonary capillary hemangiomatosis, or with other disorders, such as thyroid disorders, glycogen storage disease, Gaucher disease, hereditary telangiectasia, hemoglobinopathies, myeloproliferative disorders, and splenectomy . Group 2, according to the Dana Point classification, includes PH patients with causative left heart disorders such as ventricular, atrial, or valvular disorders. Group 3 contains forms of pulmonary hypertension that are associated with lung diseases such as chronic obstructive pulmonary disease (COPD), interstitial lung disease (ILD), pulmonary fibrosis (IPF), and/or hypoxemia (eg, obstructive sleep apnea syndrome, alveolar hypoventilation, chronic altitude sickness, congenital malformations). Group 4 includes PH patients suffering from chronic thrombotic and/or embolic disorders, for example, in the case of thromboembolic obstruction of the proximal and distal pulmonary arteries (STERN) or non-thrombotic emboli (for example, as a result of neoplastic diseases, parasites, foreign bodies). Less common forms of pulmonary hypertension, such as in patients suffering from sarcoidosis, histiocytosis X, or lymphangiomatosis, are summarized in Group 5.

Bronchiolitis obliterans syndrome (BOS) is a chronic rejection reaction after lung transplantation. During the first five years after lung transplantation, approximately 50-60% of all patients, and during the first nine years, more than 90% of patients suffer from this disease [Estenne et al., Am. J. Respir. Crit. Care Med. 2003, 166, 440-444]. The causes of the disease have not been elucidated. Despite numerous improvements in the treatment of transplant patients, the incidence of BOS has hardly changed in recent years. BOS is the most important long-term complication after lung transplantation and is considered to be the main reason why the percentage of survivors is still markedly lower than in other organ transplants. BOS means inflamed

- 4 040220 a serious event that is associated with changes in the lung tissue, affecting primarily the small airways. Damage and inflammatory changes in the epithelial cells and subepithelial structures of the smaller airways lead, due to inefficient epithelial regeneration and repair of aberrant tissue, to excessive fibroproliferation. There is scarring and, finally, destruction of the bronchi, as well as the growth of granulation tissue in the small airways and alveoli, sometimes with vascular involvement. Diagnosis is based on lung function. In BOS, there is a deterioration in FEV1 compared to the mean of the two best values measured in the postoperative period. There is currently no curative treatment for BOS. Some patients show improvement with more intensive immunosuppression, however, patients who do not show any response experience a constant deterioration, as a result of which they are indicated for repeated transplantation (retransplantation).

Chronic obstructive pulmonary disease (COPD) is a slowly progressive lung disease characterized by impaired respiratory flow caused by pulmonary emphysema and/or chronic bronchitis. The first symptoms of the disease usually appear during the fourth or fifth decade of life. In subsequent years of life, shortness of breath often worsens and a cough appears, associated with profuse, and in some cases purulent sputum, and respiratory stenosis up to suffocation (dyspnea). COPD is primarily a disease of smokers: smoking is responsible for 90% of all COPD cases and 80-90% of COPD-related deaths. COPD is a major medical problem and is considered the sixth most common cause of death worldwide. Of people over the age of 45, approximately 4-6% suffer from this condition. Although airflow obstruction may be only partial and temporary, COPD cannot be cured. Accordingly, the goal of treatment is to improve quality of life, relieve symptoms, prevent acute deterioration, and slow the development of progressive impairment of lung function. Existing medical therapies that have hardly changed over the past two to three decades include the use of bronchodilators to open blocked airways and, in certain situations, corticosteroids to fight pneumonia [P. J. Barnes, N. Engl. J. Med. 2000, 343, 269-280]. 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, during the lung inflammatory response, release proteases and various cytokines that cause pulmonary emphysema and bronchial remodeling.

It is an object of the present invention to provide and prepare novel substances which are potent, chemically and metabolically stable, non-prostanoid FP receptor antagonists and which may be suitable for the treatment and/or prevention, in particular of fibrosing and inflammatory diseases.

Among other things, 2-arylquinoline-4-carboxamides are known from WO 95/32948-A1, WO 96/02509-A1, WO 97/19926-A1 and WO 2000/031038-A1 as NK3- or dual NK ₂ /NK ₃ -antagonists that are suitable for the treatment of diseases of the lungs and central nervous system. WO 2016/004035 discloses 2-arylquinoline-4-carboxamides as TSH receptor agonists that can be used to treat thyroid disorders and malignancies. WO 2000/064877 discloses quinoline-4-carboxamide derivatives that can be used as NK3 antagonists in the treatment of various diseases, including diseases of the lungs and central nervous system. WO 2004/045614-A1 describes certain quinoline carboxamides as a glucokinase ligand for the treatment of diabetes. WO 2006/094237-A2 discloses quinoline derivatives as sirtuin modulators which can be used in the treatment of various diseases. WO 2011/153553-A2 presents various bicyclic heteroaryl compounds as kinase inhibitors for the treatment of, in particular, oncological diseases. EP2 415 755-A1 describes, inter alia, quinoline derivatives which are suitable for the treatment of diseases associated with plasminogen activator inhibitor 1 (PAI-1) activity. WO 2013/074059-A2 discloses various quinoline-4-carboxamide derivatives that can be used as inhibitors of cytosine deaminase to enhance the transfection of DNA cells. WO 2013/164326-A1 presents N,3diphenylnaphthalene-1-carboxamides as EP2-prostaglandin receptor agonists for the treatment of respiratory diseases. WO 2014/117090-A1 describes various 2-arylquinoline derivatives as metalloenzyme inhibitors. WO 2012/122370-A2 discloses quinoline-4carboxamide derivatives which can be used in the treatment of autoimmune and oncological diseases. WO 2015/094912-A1, inter alia, presents substituted N,2-diphenylquinoline4-carboxamide derivatives which are suitable as prostaglandin EP4 receptor antagonists for the treatment of arthritis and associated pain. WO 2016/061280 discloses protein tyrosine phosphatase modulators with a 4-amino-2-arylquinoline base substance, which can be used in the treatment of fat metabolism disorders, diabetes and cardiovascular diseases, among other things.

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

in which Ar means phenyl, and phenyl can be substituted up to three times, in each case equally or differently, by fluorine, chlorine, up to three times substituted by fluorine (C1-C ₄ )alkyl, up to three times substituted by fluorine (C1C ₂ )alkoxy,

Y means a bond or a group of the formula #1-X-(CR ^10A R ^10B ) _k -# ² , where #1 means the place of attachment to the carbon atom, #2 means the place of attachment to the carboxy group, X means the bond or -CH2-, and

R ^10a and R ^10B are independently hydrogen, k is 1 or 2,

R ¹ means bromine,

R ² , R ³ and R ⁴ are independently hydrogen,

R ⁵ means (C1-C ₄ )alkyl,

R ⁶ means -NR ¹² R ¹³ , and R ¹² means hydrogen or (C 1 -C ₃ )alkyl, and

R ¹³ means (C 1 -C ₄ )alkyl or (C ₃ -C ₇ )cycloalkyl, and (C 1 -C ₄ ) alkyl can be substituted up to three times with fluorine or once with (C ₃ -C ₆ ) cycloalkyl, methoxy or phenyl , or means a saturated or partially unsaturated 4-8-membered monocyclic or 6-10-membered bicyclic heterocycle linked to a nitrogen atom, which may contain an additional, identical or different heteroatom from the series N, O, S, SO or SO2 as a ring member , and 4-8-membered monocyclic and 6-10-membered bicyclic heterocycle, respectively, can be substituted by 1-2 substituents independently selected from the group (C1C ₄ )alkyl, hydroxy, oxo, (C1-C ₃ )alkoxy, cyano, amino, aminocarbonyl, and further up to four times by fluorine, and (C 1 -C ₄ ) alkyl can be substituted up to three times by fluorine or once by hydroxy or methoxy,

R ^7A and R ^7B are independently hydrogen or methyl, R ⁸ is hydrogen, R ⁹ is hydrogen, and salts thereof.

Compounds according to the invention are compounds of formula (I) and their salts containing formula (I) compounds of the following named formulas and their salts, as well as containing formula (I) named in the following as exemplary embodiments of the compounds and their salts, if named in the following, containing the formula (I) compounds no longer mean salts.

As salts within the scope of the present invention, physiologically unquestionable salts according to the invention are preferred. Also salts, which are not themselves suitable for pharmaceutical use, but they can be used, for example, for isolating, purifying or storing the compounds according to the invention.

The physiologically undoubted salts of the compounds according to the invention, in particular, contain salts derived from common bases, such as, for example and preferably, alkali metal salts (e.g. sodium and potassium salts), alkaline earth metal salts (e.g. calcium salts and magnesium salts) , zinc salts, as well as ammonium salts derived from ammonia of organic amines with 1-16 carbon atoms, such as, for example and preferably, ethylamine, diethylamine, triethylamine, DIPEA, monoethanolamine, diethanolamine, triethanolamine, dimethylaminoethanol, diethylaminoethanol, tris(hydroxymethyl)aminomethane , choline (2-hydroxy-N,N,N-trimethylethanamine), procaine, dicyclohexylamine, dibenzylamine, N-methylmorpholine, N-methylpiperidine, arginine, lysine, and 1,2-ethylenediamine.

In addition, the physiologically unquestionable salts according to the invention also contain added salts of mineral acids, carboxylic and sulfonic acids, for example salts of hydrochloric, hydrobromic, sulfuric, phosphoric, methanesulfonic, ethanesulfonic, toluenesulfonic, benzenesulfonic, naphthalenedisulfonic, formic, acetic, trifluoroacetic, propionic, succinic, fumaric, maleic, lactic, tartaric, malic, citric, glyconic, benzoic and embonic acids.

Solvates are those forms of compounds that, in the solid or liquid state, form a complex with solvent molecules. Hydrates are a special form of solvates in which

- 6 040220 agreement with water.

The compounds according to the invention, depending on their structure, can exist in various stereoisomeric forms, i.e. in the form of configurational isomers or, if appropriate, also in the form of conformational isomers (enantiomers and/or diastereomers, including atropical isomers). Therefore, this invention includes enantiomers and diastereomers and mixtures thereof. From such mixtures of enantiomers and/or diastereomers, the stereoisomeric single components can be isolated in a manner known per se. For this, a chromatographic method is preferably used, in particular HPLC chromatography of achiral or chiral separation phases. In the case of using a carboxylic acid as an intermediate or final product, it is also alternatively possible to carry out the separation via the diastereometric salt using chiral amine bases.

Within the scope of the present invention, the term without enantiomers is to be understood in such a way that said compound is present in an enantiomeric excess of more than 95%, preferably more than 98% relative to the absolute configuration of the chiral center. Enantiomeric excess (eng. enantiomeric excess, its value) is calculated by deciphering the HPLC analysis chromatogram in the chiral phase according to the following formula:

I Enantiomer 1 (Area Percent) - Enantiomer 2 (Area Percent) I , _z ee = -----------thet;--------------;--- t----------thet--------------g x 100%.

| Enantiomer 1 (Area Percentage) + Enantiomer 2 (Area Percentage) |

Since the compounds of the invention may occur in tautomeric forms, this invention includes all tautomeric forms.

This invention also includes all suitable isotopic variants of the compounds of the invention. An isotopic variant of a compound according to the invention is here understood to mean a compound in which at least one atom within the compound according to the invention is exchanged for another atom with the same atomic number, but with a different atomic mass with the usual or naturally occurring predominant atomic mass. Examples of isotopes that can be included in the compound according to the invention are 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 O ^{, 18} O ^, 32 P, ³³ P, ³³ S, 34 S, 35 S, ³⁶ S, ¹⁸ F, ³⁶ Cl, ⁸² Br, ¹²³ I, ¹²⁴ I, ¹²⁹ I and ^{131 I} Certain isotopic variants of the compound according to the invention, such as in particular those in which one or more radioactive isotopes are attached, may be useful, for example, for studying the mechanism of action or distribution of the biologically active substance in the body; because of the relatively easy preparation and detection, compounds marked with ³ H or ¹⁴ C isotopes are suitable for this. On this basis, the introduction of isotopes, such as deuterium, can lead to certain therapeutic advantages due to the greater metabolic stability of the compound, such as an increase in the half-life in the body or a reduction in the required effective dose; therefore, such modifications of the compounds according to the invention, if necessary, may also represent a preferred embodiment of the present invention. Isotopic variants of the compounds according to the invention can also be obtained by conventional methods known to the person skilled in the art, for example, by the methods described below and further demonstrated in the described exemplary embodiments, while using the appropriate isotopic modifications of the reagents and/or starting compounds.

In addition, this invention also includes prodrugs of the compounds according to the invention. The term "prodrug" here refers to compounds which themselves may be biologically active or inactive, but which, during their exposure in the body, for example, are converted metabolically or hydrolytically into the compounds according to the invention.

Particularly preferably, the present invention contains, as a prodrug, the hydrolyzable carboxylic acid ester derivatives according to the invention of formula (I). These are to be understood as meaning esters which, in a physiological environment, under the conditions of the biological test described below, and in particular in an in vivo test, can be enzymatically or chemically hydrolyzed both to free carboxylic acids and to biologically active compounds. As such an ester, a (CrC ₄ )alkyl ester of formula (IV) is preferred, in which the alkyl group may be straight chain or branched. Especially preferred are methyl, ethyl or tert-butyl ether.

Within the scope of this invention, the substituents, unless otherwise provided, have the following meanings.

The term halogen or halogen atom means a fluorine, chlorine, bromine or iodine atom.

The term C1- _C4 alkyl means a straight chain or branched saturated monovalent hydrocarbon group with 1, 2, 3 or 4 carbon atoms, for example a methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl or tert-butyl group or its isomer.

The term C ₃ -C ₇ -cycloalkyl refers to a saturated monovalent mono - or bicyclic hydrocarbon ring with 3, 4, 5, 6 or 7 carbon atoms (C ₃ -C ₇ -cycloalkyl). A C ₃ -C ₇ cycloalkyl group means, for example, a monocyclic hydrocarbon ring, for example a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl group.

- 7 040220

The term C ₁ -C ₃ -alkoxy means a straight chain or branched saturated univalent group of the formula (C1-C ₃ -alkyl)-O-, in which the term C ₁ -C ₃ -alkyl has the above meanings, for example, means methoxy-, an ethoxy, p propoxy or isopropoxy group, or isomers thereof.

The term 4-8-membered monocyclic heterocycle within the meaning of the invention means a monocyclic saturated or partially unsaturated heterocycle with 4-8 ring atoms, which may contain one other ring heteroatom from the group N, O, S, SO or SO2 and which is connected via a ring atom nitrogen. Preferred is a 5- to 7-membered heterocycloalkyl with one nitrogen ring and optionally one other ring heteroatom from the group N, O and S. Especially preferred is a 5-, 6- or 7-membered heterocycloalkyl with one nitrogen ring. For example, the following may be mentioned: azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrofuranyl, thiolanyl, 1,1-dioxidothiolanyl, 1,2oxazolidinyl, 1,3-oxazolidinyl, 1,3-thiazolidinyl, piperidinyl, piperazinyl, tetrahydropyranyl , tetrahydrothiopyranyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,2-oxazinanyl, morpholinyl, thiomorpholinyl, 1,1-dioxidothiomorpholinyl, azepanil, 1,4-diazepanil, 1,4-oxazepanyl, 2,5-dihydro -III-pyrrol-1-yl, 3,6-dihydropyridin-1(2H)-yl and 3,6-dihydro-2H-1,2-oxazin-2-yl. Preferred are azetidinyl, pyrrolidinyl, imidazolidinyl, 1,2-oxazolidinyl, piperidinyl, piperazinyl, 1,2oxazinanil, morpholinyl, thiomorpholinyl, 2,5-dihydro-III-pyrrol-1-yl, 3,6-dihydropyridin-1(2H) -yl and 3,6-dihydro-2H-1,2-oxazin-2-yl. Especially preferred are pyrrolidinyl, piperidinyl and azepanil.

The term 6-10-membered bicyclic heterocycle in the context of the invention means a bicyclic saturated or partially unsaturated heterocycle with 6-10 ring atoms, which may contain one other ring heteroatom from the group N, O, S, SO or SO2 and which is connected via a ring atom nitrogen. Preferred is a 7- to 10-membered heterocycloalkyl with one ring nitrogen atom and optionally one other ring heteroatom from the group N, O and S. Bicyclic spirocyclic heterocyclic residues within the meaning of this invention are to be encompassed by the definition of a bicyclic heterocycle. For example and preferably, the following may be mentioned: azabicyclo[3.1.1]hept-3-yl, 3-azabicyclo[3.2.1]oct-3-yl, 3,4-dihydroisoquinolin-2(1H)-yl, octahydro- 2H-isoindol-2-yl and 5-azaspiro[2.5]oct-5-yl.

The term C ₁ -C ₂ alkylsulfanyl means a straight chain or branched saturated monovalent group of the formula (C1-C2 alkyl)-8-, in which the term C 1 -C ₂ -alkyl has the above meanings, for example, means a methylsulfanyl or ethylsulfanyl group.

Oxo substituent in the context of the invention means oxygen which is double bonded to a carbon atom.

Within the scope of this invention, it is valid for all residues that occur several times, the value of which is independent of each other. If residues in the compounds according to the invention are substituted, they may, unless otherwise indicated, be singly or multiply substituted. Substitution with one or two or three identical or different substituents is preferred. Particular preference is given to substitution with one substituent.

Preferred within the scope of the present invention are compounds of formula (I) in which

Ar is phenyl, where phenyl may be substituted up to three times, equally or differently, with fluorine, chlorine, methyl, trifluoromethyl, methoxy, difluoromethoxy or trifluoromethoxy,

Y means a bond or a group of the formula # ¹ -(CH ₂ ) _p - # ² , where # ¹ means the place of attachment to the carbon atom, # ² means the place of attachment to the carboxy group, n means 1 or 2, R ¹ means bromine,

R ² , R ³ and R ⁴ respectively are hydrogen, R ⁵ is methyl, and

R ⁶ means -NR12R ¹³ , and

R ¹² is hydrogen or methyl, and R ¹³ is (C1-C ₄ )alkyl, wherein (C1-C ₄ )alkyl can be substituted up to three times by fluorine or once by phenyl, or is nitrogen bonded, saturated or partially unsaturated , 5-7-membered monocyclic or 7-10-membered bicyclic heterocycle, which may contain an additional, identical or different heteroatom from the series N, O or S as a ring member, and 5-7-membered monocyclic and 7-10-membered the bicyclic heterocycle can respectively be substituted with 1-2 substituents independently selected from the group of methyl, difluoromethyl, trifluoromethyl, ethyl, isopropyl, and further up to four times with fluorine,

R ^7A , R ^7B , R ⁸ and R ⁹ are respectively hydrogen and their salts.

Particularly preferred within the scope of the present invention are compounds of formula (I) in which

Ar means phenyl, and phenyl can be substituted up to three times, equally or differently, by fluorine, chlorine, methyl,

- 8 040220 trifluoromethyl, difluoromethoxy or trifluoromethoxy,

Y means a group of the formula # ¹ -CH ₂ CH ₂ -# ² , where #1 means the place of attachment to the carbon atom, #2 means the place of attachment to the carboxy group,

R ¹ means bromine,

R ² , R ³ , R ⁴ are respectively hydrogen,

R ⁵ means methyl,

R ⁶ means a group of the formula where # ³ means the place of attachment to the rest of the molecule,

R ¹⁴ means fluorine or methyl,

R ¹⁵ means fluorine, methyl or ethyl,

R ^7A , r ⁷ b, r8 and R9 are respectively hydrogen and their salts.

A particular embodiment of the present invention includes compounds of formula (I) wherein

R ¹ means bromine and

R ² , R ³ and R ⁴ are respectively hydrogen and their salts.

Another particular form of implementation of the present invention includes compounds of formula (I), in which R ⁵ means methyl, as well as their salts.

Another particular embodiment of the present invention includes compounds of formula (I) wherein

R ⁶ means a group of the formula where # ³ means the place of attachment to the rest of the molecule,

R ¹⁴ means fluorine or methyl,

R ¹⁵ means fluorine, methyl or ethyl, as well as their salts.

Another particular form of implementation of the present invention includes compounds of formula (I), in which R ⁶ means pyrrolidine, as well as their salts.

Another particular embodiment of the present invention includes compounds of formula (I) wherein

Y means a group of formula # ¹ -CH ₂ -# ² where # ¹ means the place of attachment to the carbon atom, # ² means the place of attachment to the carboxy group, as well as their salts.

Another particular embodiment of the present invention includes compounds of formula (I) wherein

Y means a group of the formula # ¹ -CH ₂ CH ₂ -# ² where # ¹ means the place of attachment to the carbon atom, # ² means the place of attachment to the carboxy group, as well as salts thereof.

Another particular embodiment of the present invention includes compounds of formula (I) wherein

Ar means phenyl, and phenyl may be substituted up to three times, equally or differently, with fluorine, chlorine, methyl, trifluoromethyl, difluoromethoxy or trifluoromethoxy, as well as their salts.

Another particular embodiment of the present invention includes compounds of formula (I),

- 9 040220 in which

R ¹ means bromine,

R ² , R ³ , R ⁴ are respectively hydrogen,

R ⁵ means methyl, as well as their salts.

Another particular form of implementation of the present invention includes compounds of formula (I), in which R ^7A , R ^7B , R ⁸ and R ⁹ respectively denote hydrogen, as well as their salts.

The residue definitions specified in these or preferred combinations of residues individually apply independently of the residue combinations mentioned, also arbitrarily with the aid of the residue definitions of other combinations.

Most preferred are combinations of two or more of the above preferred areas.

The definitions of residues mentioned as preferred, particularly preferred and highly preferred apply both to the compounds of formula (I) and, accordingly, to all intermediates.

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

in which R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ^7A , R ^7B , R ⁸ , R ⁹ and Ag have the above meanings, and

T means the protective group of esters, which is (Ci-CDalkyl in the first step

[A] is reacted with an amine compound of formula (III) ^R - ^H (III) in which R ⁶ has the above meanings, and in the next step

[B] isolate the ester residue of the compound of formula (IV) obtained in step [A] after reaction with the amine compound (III) o

in which R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ^7A , R ^7B , R ⁸ , R ⁹ and Ag have the above meanings, and T means a protective group of esters, representing ((D -CDalkyl, and in this way compounds of formula (I) are obtained o

in which R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ^7A , R ^7B , R ⁸ , R ⁹ and Ag have the above meanings, if necessary with the appropriate bases or acids are converted into their salts. The transformation in step [A]: (II) + (III) -> (IV) can be carried out using a nucleophilic substitution reaction.

- 10040220

The nucleophilic substitution reaction is preferably carried out with an excess of the amine compound and optionally in the presence of a base. Suitable bases are all conventional inorganic or organic bases. These preferably include alkali metal hydroxides such as lithium, sodium or potassium hydroxide, alkali or alkaline earth metal carbonates such as lithium, sodium, potassium or cesium carbonate, alkali metal alcoholates such as lithium, sodium or potassium tert-butoxide, alkali hydrides metals such as sodium or potassium hydride, or organic amides such as N,N-diisopropylethylamine (DIPEA), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN) and 1,8diazabicyclo[5.4.0]undec -7-ene (DBU). Preferably, N,N-diisopropylethylamine (DIPEA) is used. The reaction is generally carried out at temperatures of 30-130°C, preferably 90-110°C.

Inert solvents for process step [A] are, for example, ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, alcohols such as methanol, ethanol, propanol, butanol, isopropyl alcohol and tert-butanol, hydrocarbons such as benzene, toluene, xylene, hexane, cyclohexane or petroleum fractions, halocarbons such as dichloromethane, trichloromethane, carbon tetrachloride, 1,2-dichloroethane, trichloroethylene or chlorobenzene, or other solvents such as acetone, ethyl acetate, acetonitrile, pyridine, dimethyl sulfoxide, N, N-dimethylformamide (DMF), N,N'-dimethylpropylene urea (DMPU), or Nmethylpyrrolidone (NMP). It is also possible to use mixtures of the named solvents. Preferably, butanol or N-methylpyrrolidone (NMP) is used.

The separation of the ester protecting group at the stage of the technological step [B]: (IV) ^ (I) is carried out by conventional methods, when the ester is treated in an inert solvent with an acid or base, and in the latter case, the carboxylic acid salt formed first is transferred by subsequent treatment with acid into a free carboxylic acid. In the case of the tert-butyl ester, the cleavage of the esters is preferably carried out with an acid. The methyl and ethyl esters are preferably cleaved off with a base. The benzyl ester can also alternatively be cleaved off by hydrogenation (destructive hydrogenation) in the presence of a suitable catalyst, such as palladium on active carbon. The silyl ether can be cleaved off by treatment with acids or fluorides, for example tetrabutylammonium fluorine.

Suitable inert solvents for this reaction are water and the usual organic solvents for ester cleavage. These include in particular alcohols such as methanol, ethanol, p-propanol, isopropanol, p-butanol or tert-butanol, styrene ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane or 1,2-dimethoxyethane, or other solvents. such as dichloromethane, acetonitrile, N,N-dimethylformamide or dimethyl sulfoxide. Mixtures of these solvents can also be used. In the case of basic hydrolysis of esters, mixtures of water with tetrahydrofuran, 1,4-dioxane, methanol and/or ethanol are preferred. In the case of conversion with trifluoroacetic acid, dichloromethane is preferably used, and in the case of conversion with hydrogen chloride, 1,4-dioxane is preferably used, respectively under anhydrous conditions.

Suitable bases are conventional inorganic bases for the hydrolysis reaction. These preferably include alkali or alkaline earth metal hydroxides such as sodium, lithium, potassium or barium hydroxide, or alkali or alkaline earth metal carbonates such as sodium, potassium or calcium carbonate. Preferably, an aqueous solution of lithium hydroxide or sodium hydroxide (soda lye) is used.

Suitable acids for ester removal are generally sulfuric acid, hydrogen chloride/hydrochloric acid, hydrogen bromide/hydrobromic acid, phosphoric acid, acetic acid, trifluoroacetic acid, toluenesulfonic acid, methanesulfonic acid or trifluoromethanesulfonic acid, or mixtures thereof, optionally with the addition of water. Preferably, hydrogen chloride or trifluoroacetic acid is used.

The splitting of the complex ester is carried out, in General, at temperatures of -20-100°C., preferably 080°C.

The compounds of formula (I) can be converted by conventional methods into their corresponding, as well as derived from bases, and acid salts. Acid salts (acid addition salts) can, for example, be converted into the compounds of formula (I) into the corresponding acid addition salts, for example by adding strong acids such as mineral acids, hydrochloric acid or sulfuric acid. Preferred acid salts are hydrochloric acid salts. Preferably, solutions of hydrochloric acid in dioxane are used. The corresponding acid salts can also be formed by adding strong acids, such as the mineral acids of hydrochloric acid or sulfuric acid, to the ester compounds of formula (IV), while separation of the ester group T first occurs and the corresponding salt is formed in situ, i.e. without isolating the free carboxylic acid. The preferred ester group T with respect to separation with acids is the tert-butyl group.

Commonly base-derived salts of a compound of formula (I) can be obtained, for example, by adding bases, such as solutions of alkali and alkaline earth metal hydroxides, to compounds of formula (I). Preferably, aqueous hydroxide solutions are used (eg sodium hydroxide solution). Aqueous hydroxide solutions (eg, potassium hydroxide solution) can also be produced in situ by mixing an organometallic compound dissolved in an organic solvent (eg, a solution of potassium tert-butylate in THF) with water or an aqueous solution. The corresponding salt base derivatives can also be formed by adding bases, such as solutions of alkali and alkaline earth metals, to the ether compounds of formula (IV), while separation of the ester group T first occurs and the corresponding salt is formed in situ, i.e. without isolating the free carboxylic acid. The preferred ester groups of T with respect to base separation are methyl and ethyl groups.

Compounds of formula (II) can be obtained if the carboxylic acid chloride of formula (V)

in which R ¹ , R ² , R ³ , R ⁴ and R ⁵ have the above meanings, are converted using an amine compound of formula (VI)

in which R ^7A , R ^7B , R ⁸ , R ⁹ and Ar have the above meanings, and

T is an ester protecting group which is (C1-C ₄ )alkyl and, optionally using an auxiliary base, to a compound of formula (II) according to the invention

in which R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ^7A , R ^7B , R ⁸ , R ⁹ and Ar have the above meanings,

T is an ester protecting group which is (C1- _C4 )alkyl.

The conversion (V) + (VI) ^ (II) is preferably carried out in the presence of conventional auxiliary bases, such as sodium or potassium carbonate, sodium or potassium hydrogen carbonate, triethylamine, DIPEA, N-methylmorpholine (NMM), N-methylpiperidine (NMP) , pyridine, 2,6-dimethylpyridine, 4-N,Ndimethylaminopyridine (DMAP), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,5-diazabicyclo[4.3.0]non5-ene (DBN), sodium or potassium ethanolate, sodium or potassium tert-butoxide, sodium or potassium hydride, or sodium or potassium bicarbonate. Preferably, DIPEA is used as the base.

Inert solvents for these coupling reactions, depending on the method used, are, for example, ethers such as diethyl, diisopropyl, methyl tert-butyl ethers, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane or bis(2- methoxyethyl) ether, hydrocarbons such as benzene, toluene, xylene, pentane, hexane or cyclohexane, halocarbons such as dichloromethane, trichloromethane, carbon tetrachloride, 1,2-dichloroethane, trichloroethylene or chlorobenzene, or polar aprotic solvents such as acetone, methyl ethyl ketone , ethyl acetate, acetonitrile, butyronitrile, pyridine, dimethyl sulfoxide (DMSO), N,N-dimethylformamide (DMF), N,N'-dimethylpropyleneurea (DMPU) or N-methylpyrrolidinone (NMP) or alcohols such as methanol, ethanol and isopropyl alcohol. Mixtures of these solvents can also be used. Preferably dichloromethane is used. The coupling reaction is generally carried out at temperatures of 0-130°C, preferably 20-80°C.

As a protecting group of the esters T, in general, all protecting groups known to the person skilled in the art are suitable, for example, substituted methyl, such as methylthiomethyl (MTM), tetrahydropyranyl (THP), 2-(trimethylsilyl)ethoxymethyl (SEM), benziooxymethyl (BOM), phenacyl and N-phthalimidomethyl, suitable 2-substituted ethyl, such as 4-methylphenylsulfonylethyl (TSE), 2,2,2-trichloroethyl, 2(trimethylsilyl)ethyl and 2-(2'-pyridyl)ethyl (PET), allyl, benzyl , suitable substituted benzyl, such as diphenylmethyl (DPM), bis(ortho-nitrophenyl)methyl, 9-antrylmethyl, 2,4,6-trimethylbenzyl, 4-bromobenzyl, 4

- 12 040220 methoxybenzyl (PMB), piperonyl and suitable substituted silyl, such as triethylsilyl (TES), tert-butyldimethylsilyl (TBDMS) and di-tert-butylmethylsilyl (DTBMS), in particular in the process according to the invention (C ₁ -C ₄ )alkyl in as an ether protecting group T.

Compounds of formula (V) can be obtained, depending on the appropriate substituent reference, when, analogously to known methods in the literature (J. Med. Chem. 2005, 48 (10), 3564-3575), the isatin derivative of formula (VII) is converted during the acylation reaction with an acid anhydride (VIII) to a compound of formula (IX) and then converted during a rearrangement reaction with sodium hydroxide to a carboxylic acid of formula (X). Alternatively, it is also possible to convert the isatin derivative of the formula (VII) without isolating the intermediate step (IX) during the reaction with the acid anhydride (VIII) directly into the carboxylic acid of the formula (X). Chlorides of the acid of formula (XI) can then be prepared by methods known to the person skilled in the art, for example by reaction with phosphoroxychloride or thionyl chloride, from carboxylic acids of formula (X) (Scheme 1).

Scheme 1

[R ¹ , R ² , R ³ , R ⁴ and R ⁵ as above; a) ΔΤ, for example, during the night; b) ΔΤ, zB 1-3 h; c)

NaOH, ΔΤ; d) POCIS or SOCL ΔΤ].

Compounds of formula (VI) can be prepared depending on the appropriate substituent reference, for example, according to the synthetic routes described in the following Schemes 2-8 and the experimental part of the respective examples, and similarly to known methods of synthesis in the literature.

Scheme 2 (for Y = # ¹ - (CH2)n-# ² , where n = 0, 1, 2, 3 (VI-1))

[Alkyl = methyl, ethyl; Ar = subst. phenyl, subst. pyridyl; T = protecting group of esters, eg methyl, ethyl, t-butyl; n = 0, 1, 2, 3; a) for n = 0: di-tert-butyl dicarbonate, LDA, -78°C; for n=1: tert-butyl bromoacetate, LDA or LiHMDS, -78°C; for n = 2: tert-butyl-3-bromopropanoate, LDA or LiHMDS, -78°C; or tert-butyl acrylate, potassium carbonate or sodium hydride; for n = 3: tert-butyl-4-bromobutanoate, LDA, -78° C. b): H ₂ , Raney nickel or PtO ₂ . LDA = lithium diisopropylamide; LiHMDS = lithium bis(trimethylsilyl)amide].

Scheme 3 (for R8 = fluorine (VI-2), hydroxy (VI-3))

[Ar = substitute phenyl, subst. pyridyl; T = protecting group of esters, eg methyl, ethyl, t-butyl; n = 0, 1, 2, 3; a) for example, KCN or TMSCN; b) DAST; c) H ₂ , catalyst, eg Raney nickel or PtO ₂ . DAST = diethylaminosulfur trifluoride].

- 13 040220

Scheme 4 (for R7A/R7B = H, Me (VI-4))

[Ar = substitute phenyl, subst. pyridyl; T = protecting group of esters, eg methyl, ethyl, mpem-butyl; a) nitroethane, a base, for example 2-tert-butyl-1,1,3,3-tetramethylguanidine; b) zinc dust, hydrochloric acid].

Scheme 5 (for R10A/R10B = Me, Me (VI-5) or F, F (VI-6))

[Ar = substitute phenyl, subst. pyridyl; T = protecting group of esters, eg methyl, ethyl, t-butyl; a) LDA, -78°C; b) zinc; c) H2, Raney nickel; d) H ₂ , PtO ₂ . LDA = lithium diisopropylamide].

Scheme 6 (for X = NH (VI-7) or NMe (VI-8))

[Ar = substitute phenyl, subst. pyridyl; T = protecting group of esters, eg methyl, ethyl, t-butyl; a) TMS-CN; b) H ₂ , Raney nickel].

Scheme 7 (for X = S (VI-9) or SO2 (VI-10))

(XVIII) (XXVI) (VI-9) (VI-10)

[Ar = substitute phenyl, subst. pyridyl; T = protecting group of esters, eg methyl, ethyl, mpem-butyl; a) for example, in DCM; b) SnCl ₂ ; c) protection of amine functionality, for example as NH-Boc: di-tert-butyl dicarbonate, triethylamine; d) mCPBA; f) deprotection of the amine functionality, eg HCl/dioxane. Boc = tert-butyloxycarbonyl; DCM = dichloromethane].

Scheme 8 (for X = O (VI-11))

Ag Ag

ΝΗ o NH ₂ O (XVII) (XXVIII) (VI-11)

[Ar = substitute phenyl, subst. pyridyl; T = protecting group of esters, eg methyl, ethyl, t-butyl; PG = protecting group, eg Boc; a) Rh ₂ (OAc) ₄ ; b) deprotection of the amine functionality, eg HCl/dioxane. Boc = tert-butyloxycarbonyl].

The separation of the compounds according to the invention into the respective enantiomers and/or diastereomers can, if necessary, also take place, depending on the purpose, even already in the step of the individual intermediates (II), (IV), or (VI), these intermediates in the separated form can then be converted further according to the previously described processing steps. It may also be advantageous if the amine functionality of intermediates (III-A) and (III-B) is protected before such separation, for example Boc, and then removed again after separation. For this separation of stereoisomers from intermediates, a chromatographic method of achiral or chiral separation phases is preferably used simultaneously.

A compound of formulas (VII), (VIII), (XII), (XIV), (XVI), (XVIII), (XIX), (XXI), (XXIII), (XXIV), (XXVI),

- 14 040220 (XVII) and (XXVIII) are commercially available or can be obtained according to the methods described in the literature, or they can be obtained from other commercially available compounds, by conventional methods, similar to the methods described in the literature.

Detailed prescriptions and other bibliographic references are also found in the experimental part in the section on preparation of starting and intermediate compounds.

Other compounds of formula (I) according to the invention can also be obtained, if appropriate, by converting the functional groups of the individual residues and substituents, in particular those named among R ¹ and R ⁵ , starting from others obtained by the above methods or in appropriate steps, compounds of the formula. The transformations are carried out by conventional methods known to those skilled in the art and include, for example, reactions such as nucleophilic or electrophilic substitution reactions, transition metal-mediated coupling reactions, reactions for the production and addition of metal organyls (for example, Grignard reagents or lithium organyls), oxidation reactions, or reduction, hydrogenation, halogenation (eg fluorination, bromination), dehalogenation, amination, alkylation and acylation, formation of carboxylic acid esters, carboxylic acid amides and sulfonamides, ester cleavage and hydrolysis, and the introduction and removal of temporary protective groups.

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

The compounds according to the invention are potent, chemically and metabolically stable FP receptor antagonists (FP antagonists) and are therefore suitable for the treatment and/or prevention of diseases and pathological processes, in particular those in which inflammation and/or tissue remodeling or vascular involvement of the FP receptor.

These in the meaning of this invention, in particular, include diseases such as the group of interstitial idiopathic pneumonia, which include idiopathic pulmonary fibrosis (IPF), acute interstitial pneumonia, non-specific interstitial pneumonia, lymphoid and interstitial pneumonia, respiratory bronchiolitis with interstitial lung diseases, pneumonias of unknown origin, desquamative interstitial pneumonias and unclassified idiopathic interstitial pneumonias, further, granulomatous interstitial lung diseases, rheumatoid arthritis with interstitial lung diseases, interstitial lung diseases with known causes and other interstitial lung diseases with unknown causes, pulmonary arterial hypertension (PAH) and others forms of pulmonary hypertension (PH), bronchiolitis obliterans syndrome (BOS), chronic obstructive pulmonary disease (COPD), pulmonary sarcoidosis, acute respiratory distress NDROME (ARDS), Acute Lung Injury Syndrome (ALIT), alpha-1 antitrypsin deficiency (AATD), pulmonary emphysema (eg, cigarette smoke-induced pulmonary emphysema), cystic fibrosis (CF), inflammatory and fibrosing kidney disease, chronic inflammation bowel disease (IBD, Crohn's disease, ulcerative colitis), peritonitis, peritoneal fibrosis, rheumatoid diseases, multiple sclerosis, inflammatory and fibrosing skin diseases, drepanocytosis, and inflammatory and fibrosing eye diseases.

The compounds according to the invention can also be used for the treatment and/or prevention of asthmatic diseases of varying severity with intermittent or persistent course (refractive asthma, bronchial asthma, allergic asthma, internal asthma, external asthma, asthma caused by drugs or dust), various forms of bronchitis ( chronic bronchitis, infectious bronchitis, eosinophilic bronchitis), bronchiectasis, pneumonia, farmer's lung and related diseases, coughs and colds (chronic inflammatory cough, iatrogenic cough), inflammation of the nasal mucosa (including drug-induced, vasomotor and seasonal, allergic rhinitis, for example, hay runny nose) and polyps.

In addition, the compounds according to the invention can be used for the treatment and/or prevention of cardiovascular diseases, such as hypertension (hypertension), heart failure, vascular disease of the heart, stable and unstable angina, renal hypertension, peripheral and cardiac angiopathy, arrhythmias, arrhythmias atrial and ventricular fibrillation, as well as impulse conduction disorders, such as atrioventricular blockade of degree I-III, supraventricular tachyarrhythmia, atrial fibrillation, atrial flutter, ventricular fibrillation, ventricular flutter, ventricular tachyarrhythmia, drug torsades de pointes, ventricular and atrial extrasystole, atrial atrioventricular extrasystole, sick sinus syndrome, syncope, atrioventricular nodal reciprocal tachycardia, Wolff-Parkinson-White syndrome, acute coronary syndrome (ACS), autoimmune heart diseases (pericarditis, endocarditis, valvulitis, aortitis, cardiomyopathies), ka boxer's rdiomyopathy, aneurysm, shock, cardiogenic shock, septic and anaphylactic shock, further for the treatment and / or prevention of thromboembolic diseases and ischemia, such as myocardial ischemia, myocardial infarction, apoplexy, cardiac hypertrophy, transistor ischemic attack, preeclampsia, inflammatory cardiovascular diseases , spasms of the coronary and peripheral arteries, formation of edema, such as pulmonary edema, edema

- 15 040220 brain, renal edema or edema caused by heart failure, peripheral circulatory disorders, repercussion damage, arterial and venous thrombosis, microalbuminuria, cardiac weakness, endothelial dysfunction, micro- and macrovascular damage (vasculitis), as well as to prevent restenosis, for example, after treatment for thrombosis, percutaneous transluminal angioplasty (PTA), percutaneous transluminal coronary angioplasty (PTCA), heart transplantation, and coronary bypass surgery.

In the meaning of this invention, the concept of heart failure includes both acute and chronic manifestations of heart failure, as well as specific or related forms of diseases, such as acute decompensated heart failure, right ventricular failure of the heart, left ventricular failure, complete heart failure, ischemic cardiomyopathy, dilated cardiomyopathy, hypertrophic cardiomyopathy, idiopathic cardiomyopathy, diabetic cardiomyopathy, congenital heart disease, valvular heart disease, mitral valve stenosis, mitral valve insufficiency, aortic valve stenosis, aortic valve insufficiency, tricuspid valve stenosis, tricuspid valve insufficiency, pulmonary valve stenosis, valve insufficiency pulmonary artery, combined mitral heart disease, myocarditis (inflammation of the myocardium), chronic myocarditis, acute myocarditis, viral myocarditis, cardiac failure insufficiency in diabetes mellitus, toxic alcoholic cardiomyopathy, storage diseases, diastolic and systolic heart failure.

The compounds according to the invention are also suitable for the treatment and/or prevention of kidney diseases, in particular renal insufficiency. Within the meaning of this invention, the concepts of renal insufficiency cover both acute and chronic manifestations of renal insufficiency, as well as their underlying or related diseases, such as renal hypoperfusion, intradialytic hypotension, obstructive uropathy, glomerulopathy, glomerulonephritis, acute glomerulonephritis, glomerulosclerosis, tubulointerstitial diseases, nephropathy such as primary and congenital kidney diseases, nephritis, immunological kidney diseases, such as kidney transplant rejection and immune complex-induced kidney diseases, nephropathy caused by the action of poisonous substances, nephropathy caused by the use of contrast agents, diabetic and non-diabetic nephropathy, pyelonephritis, kidney cyst, nephrosclerosis, hypertensive nephrosclerosis and nephrotic syndrome, which can be diagnostically characterized, for example, by abnormally low excretion of creatinine and/or water, abnormally high concentrations of urea, nitrogen, potassium in the blood I and / or creatinine, altered activity of enzymes in the kidneys, such as glutamine synthetase, altered molarity or amount of urine, increased microalbuminuria, macroalbuminuria, glomerular and arteriole lesions, tubular dilatation, hyperphosphatemia and / or the need for dialysis. It is also possible to use the compounds according to the invention for the treatment and/or prevention of the consequences of renal insufficiency, such as hypertension, pulmonary edema, heart failure, uremia, anemia, electrolyte disorders (eg hyperkalemia, hyponatremia), bone metabolism disorder and carbohydrate metabolism disorder. .

In addition, the compounds according to the invention are suitable for the treatment and/or prevention of diseases of the genitourinary system, such as benign prostate syndrome (BPS), benign prostatic hyperplasia (BPH), benign prostatic hyperplasia (BPH), bladder procreation disorder, syndrome lower urinary tract (LUTS), neurogenic overactive bladder (NAB), incontinence such as mixed, urge incontinence, stress or overflow incontinence (MUI, UUI, SUI, OUI), pelvic pain, and erectile dysfunction in men and sexual dysfunction in women.

The compounds of the invention can also be used in the treatment of diseases of the female reproductive system such as uterine fibroids, endometriosis, dysmenorrhea and preterm labour, as well as peripherally mediated inflammatory pain (eg in symptomatic endometriosis). Further, they are also suitable for the prevention or treatment of hirsutism and hypertrichosis.

In addition, the compounds according to the invention have an anti-inflammatory effect and can therefore be used as an anti-inflammatory agent for the treatment and/or prevention of sepsis (SIRS), multiple organ failure (MODS, MOF), inflammatory lung diseases, chronic inflammatory bowel disease (IBD, Crohn's disease, ulcerative colitis), pancreatitis, peritonitis, inflammation of the bladder, urethritis, prostatitis, epidymitis, oophoritis, salpingitis, vulvovaginitis, rheumatoid diseases, arthrosis, inflammatory diseases of the central nervous system, multiple sclerosis, inflammatory diseases of the skin and fibrotic eye diseases.

Further, the compounds according to the invention are suitable for the treatment and/or prevention of inflammatory diseases of the internal organs, such as lung, heart, kidney, bone marrow and in particular the liver, as well as dermatological fibrosis and fibrotic diseases of the eye. Within the meaning of the present invention, fibrotic diseases specifically encompasses such terms as hepatic fibrosis, hepatic cirrhosis, pulmonary fibrosis, endomyocardial fibrosis, nephropathy, glomerulonephritis, renal interstitial fibrosis, fibrotic lesions due to diabetes, bone marrow fibrosis, pericardial

- 16 040220 tonal fibrosis and similar fibrotic diseases, scleroderma, limited scleroderma, keloids, hypertrophic scarring, nevus, diabetic retinopathy, proliferative vitreoretinopathy and connective tissue diseases (eg sarcoidosis). The compounds according to the invention are also suitable for promoting wound healing, for combating postoperative wound healing, for example after glaucoma surgery, and for cosmetic purposes after removal of aging and keratinized skin.

Also, the compounds according to the invention can be used for the treatment and/or prevention of anemia, such as hemolytic anemia, in particular hemoglobinopathies, such as drepanocytosis and thalassemia, megaloblastoma anemia, anemia caused by iron deficiency, anemia caused by acute blood loss, excising anemia and aplastic anemia.

In addition, the compounds according to the invention are suitable for the treatment of oncological diseases, such as skin cancer, brain tumor, breast cancer, bone marrow tumors, leukemia, liposarcoma, carcinoma of the gastrointestinal tract, liver, pancreas, lung, kidney, ureter, prostate and genital tract, as well as malignant tumors of the lymphatic system, such as Hodgkin's lymphoma 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 disorders and dyslipidemia (hyperlipoproteinemia, hypertriglyceridemia, hyperlipidemia, combined hyperlipidemia, hypercholesterolemia, abetalipoproteinemia, sitosterolemia), xanthomatosis, Tangier's disease, obesity, obesity, metabolic diseases ( metabolic syndrome, hyperglycemia, insulin-dependent diabetes, non-insulin-dependent diabetes, gestational diabetes, hyperinsulinemia, insulin resistance, glucose intolerance and diabetic consequences of retinopathy, nephropathy and neuropathy), diseases of the gastrointestinal tract and abdominal cavity (glossitis, gingivitis, periodontitis, esophagitis, eosinophilic gastroenteritis, mastocytosis, Crohn's disease, colitis, proctitis, itching of the anus, diarrhea, celiac disease, hepatitis, liver fibrosis, cirrhosis, pancreatitis and cholecystitis), diseases of the central nervous system and neurodegenerative diseases diseases (apoplexy, Alzheimer's disease, Parkinson's disease, dementia, epilepsy, depression, multiple sclerosis), immune diseases, thyroid diseases (hyperthyroidism), skin diseases (psoriasis, acne, eczema, neurodermatitis, various forms of dermatitis, such as Dermatitis abacribus , actinic dermatitis, allergic dermatitis, ammonia dermatitis, self-induced dermatitis, autogenous dermatitis, atopic dermatitis, dermatitis caused by vasodilation in heated areas, burn dermatitis, frostbite dermatitis, Dermatitis cosmetica, Dermatitis escharotica, exfoliative dermatitis, Dermatitis dermatitis gangraenose, congestive dermatitis , Dermatitis herpetiformis, lichenoid dermatitis, Dermatitis linearis, drug-induced dermatitis, Dermatitis maligna, Dermatitis palmaris et plantaris, parasitic dermatitis, photoallergic contact dermatitis, phototoxic dermatitis, Dermatitis pustularis, seborrheic dermatitis, sunburn , toxic dermatitis, Meleney's ulcers, Dermatitis veneata, infectious dermatitis, pyogenic dermatitis and perioral dermatitis, as well as keratitis, epidermolysis bullosa, vasculitis, cellulitis, panniculitis, systemic lupus erythematosus, erythema, lymphoma, skin cancer, Sweet's syndrome, Weber-Christian syndrome , scarring, wart formation, frostbite), inflammatory diseases of the eye (saccoidosis, blepharitis, conjunctivitis, iritis, choroiditis uveitis, ophthalmitis), viral diseases (caused by group viruses, adeno and coviruses, such as HPV, HCMV, HIV, SARS ), diseases of the bones of the skeleton, joints and skeletal muscles (various types 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 pigmento sa, atypical arthritis, hemophilic arthritis, juvenile chronic arthritis, rheumatoid arthritis and metastatic arthritis, in addition, Still's syndrome, Felty's syndrome, Sjögren's syndrome, Clatton's syndrome, Poncet's syndrome, Pott's syndrome and Reiter's syndrome, various forms of arthropathies, such as, for example , Arthropathie deformans, Arthropathie neuropathica, Arthropathie ovaripriva, Arthropathie psoriatica and Arthropathie tabica, systemic scleroses, various forms of inflammatory myopathies, such as, for example, Myopathie epidemica, Myopathie fibrosa, Myopathie myoglobinurica, Myopathie ossificans, Myopathie ossificans neurotica, Myopathie ossx, Myopathie purulenta, Myopathie rheumatica, Myopathie trichinosa, Myopathie tropica and Myopathie typhosa, as well as Günther's syndrome and Münchmeier's syndrome), inflammatory changes in the arteries (various forms of arteritis, such as endarteritis, mesarteritis, periarteritis, panarteritis, rheumatoid arteritis, arteritis deformans a, temporal arteritis, temporal arteritis, giant cell arteritis and granulomatous arteritis, as well as Horton's syndrome, Cherg-Strauss syndrome and Takayasu's arteritis), Muckle-Wells syndrome, Kikuchi disease, polychondritis, scleroderma, as well as other diseases with inflammatory and immunological components, such as , cataracts, cachexia, osteoporosis, gout, incontinence, leprosy, Cesari syndrome and tumor syndrome, in rejection reactions after organ transplantation and for wound healing and angiogenesis, in particular in chronic wounds.

- 17 040220

Due to their biochemical and pharmacological profile of action, the medicinal substances are particularly suitable for the treatment and/or prevention of interstitial lung diseases, especially idiopathic pulmonary fibrosis (IPF), pulmonary hypertension (PH), bronchiolitis obliterans syndrome (BOS), inflammatory and fibrosing diseases of the skin and eyes; and fibrosing diseases of the internal organs.

Previously named, well-described human diseases of comparable etiology may also occur in other mammals and may also be treated with the compounds of this invention.

In the present invention, the term "treatment" or "treatment" includes curbing, slowing down, delaying, alleviating, attenuating, reducing, reducing, suppressing, suppressing or curing a disease, ailment, disease, injury or disorder related to health, development, course or the progression of such a condition and/or the symptoms of such a condition. The concept of therapy is synonymous with the concept of treatment.

The terms prevention or prophylaxis within the scope of this invention may be used interchangeably and mean preventing or reducing the risk of acquiring, getting, experiencing or having a disease, disease, illness, injury or health-related disorder, development, course or progression of such a condition and/or symptoms. such a state.

The treatment or prevention of a disease, ailment, illness, injury or health-related disorder may be total or partial.

Thus, the compounds according to the invention can be used for the treatment and/or prevention of diseases, in particular the diseases mentioned above.

The compounds according to the invention can be used for the manufacture of drugs for the treatment and/or prevention of diseases, in particular the above diseases.

Thus, the subject of the present invention is a medicinal product containing at least one compound according to the invention for the treatment and/or prevention of diseases, in particular the above-mentioned diseases.

Another object of the present invention is a biologically active substance having the properties of an FP receptor antagonist, which is a compound of formula (I).

The compounds according to the invention can be used alone or, if necessary, in combination with one or more other pharmacologically active substances as long as these combinations do not lead to undesirable and unacceptable side effects. Therefore, another subject of the present invention are medicinal substances which contain at least one compound according to the invention for the treatment and/or prevention of diseases in which the FP receptor is involved in the inflammatory process and/or tissue or vascular remodeling, in particular for the treatment and /or prevention of previously named diseases. As these suitable combinations of biologically active substances, for example, and preferably should be mentioned:

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

compounds that prevent the degradation of cyclic guanosine monophosphate (cGMP) and/or cyclic adenosine monophosphate (cAMP), such as phosphodiesterase (PDE) 1, 2, 3, 4 and/or 5 inhibitors, in particular PDE 5 inhibitors such as sildenafil, vardenafil, tadalafil, udenafil, dasantafil, avanafil, mirodenafil, or lodenafil;

NO- and heme-independent soluble guanylate cyclase (sGC) activators, as in particular those described in WO 01/19355, WO 01/19776, WO 01/19778, WO 01/19780, WO 02/070462 and WO 02/070510 compounds ;

NO-independent but also heme-dependent stimulators of soluble guanylate cyclase (sGC), such as those described in WO 00/06568, WO 00/06569, WO 02/42301, WO 03/095451, WO 2011/147809, WO 2012 /004258, WO 2012/028647 and WO 2012/059549 compounds;

prostacyclin analogs and IP receptor agonists, such as and preferably iloprost, beraprost, treprostinil, epoprostenol or selexipag;

endothelin receptor antagonists such as, for example and preferably, bosentan, darusentan, ambrisentan or sitaxsentan;

compounds which inhibit human neurophilic elastase (HNE), such as, for example and preferably, sivelestat or DX-890 (reltran);

compounds inhibiting the signal transduction cascade, for 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 for example and preferably nintedanib, 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 breakdown and rearrangement of the extracellular matrix, for example, and preferably matrix metalloprotease (MMP) inhibitors, in particular stromelysin inhibitors,

- 18 040220 collagenases, gelatinases and agrecanases (especially mmP-1, mmP-3, mmP-8, mmP-9, mmP-10, mmP-11 and mmP-13), as well as metal elastase (MMP-12);

compounds which block the binding of serotonin to its receptors, for example and preferably 5-HT _2B receptor antagonists, such as PRX-08066;

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

Rho kinase inhibitory compounds such as, for example and preferably, fasudil, Y-27632, SLx2119, BF-66851, BF-66852, BF-66853, KI-23095 or BA-1049;

compounds inhibiting soluble epoxide hydrolase (sEH), such as N,N'dicyclohexylurea, 12-(3-adamantan-1-yl-ureido)dodecanoic acid or 1-adamantan-1-yl-3-{5[2- (2-ethoxyethoxy)ethoxy]pentyl}urea;

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

anti-obstructive agents which are used, for example, in the treatment of chronic obstructive pulmonary disease (COPD) or bronchial asthma, for example and preferably from the group of inhaled or systemically used β-adrenergic receptor agonists (β-mimetics) and inhaled antimuscarinic substances;

anti-inflammatory, immunomodulatory, immunosuppressive and/or cytotoxic agents, for example and preferably from the group of systemically or inhaled corticosteroids, as well as acetylcysteine, montelukast, azathioprine, cyclophosphamide, hydroxyurea, azithromycin, pirfenidone or etanercept;

antifibrotic agents, such as, for example and preferably, the multikinase inhibitor nintedanib, adenosine A2b receptor antagonists, sphingosine-1-phosphate receptor 3 (S1P3) antagonists, autotaxin inhibitors, lysophosphatidic acid receptor 1 (LPA-1) antagonists, and receptor 2 (LPA-) antagonists 2) lysophosphatidic acid, lysyl oxidase (LOX) inhibitors, 2-lysyl oxidase-like inhibitors, CTGF inhibitors, IL-4 antagonists, IL-13 antagonists, α _γ β ₆ integrin antagonist, TGF-β antagonist, Wnt signaling pathway inhibitors or a CCR2 antagonist;

antithrombotic agents, for example and preferably from the group of blockers of platelet aggregation, anticoagulants and profibrinolytic substances;

biologically active substances that lower blood pressure, for example and preferably from the group of calcium antagonists, angiotensin AII antagonists, ACE blockers, vasopeptidase inhibitors, endothelin antagonists, renin inhibitors, α-receptor blockers, β-receptor blockers, mineralocorticoid receptor antagonists, as well as diuretics;

biologically active substances affecting fat metabolism, for example and preferably from the group of thyroid receptor antagonists, inhibitors of cholesterol synthesis, such as and preferably inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A reductase or squalene synthase, inhibitors of acyl-CoA-cholesterol- acyltransferases, cholesteryl ester transfer inhibitors, microsomal triglyceride transfer protein inhibitors, peroxisome proliferator-activated PPAR-α, PPAR-γ and/or PPAR-δ antagonists, cholesterol uptake blockers, lipase inhibitors, polymeric bile acid adsorbers, blockers reabsorption of bile acids and lipoprotein(s) antagonists; and/or chemotherapeutic agents, which are used, for example, for the treatment of neoplasms (neoplasia) of the lungs or other organs.

The compounds of the invention may be administered in combination with β-adrenergic receptor agonists, such as, for example and preferably, albuterol, isoproterenol, metaproterenol, terbutaline, fenoterol, formoterol, reproterol, salbutamol or salmeterol.

The compounds of the invention may be administered in combination with antimuscarinic agents, such as, for example, and preferably with ipratropium bromide, tiotropium bromide or oxitropium bromide.

The compounds of the invention may be administered in combination with a corticosteroid, such as, for example and preferably, prednisone, prednisolone, methylprednisolone, triamcinolone, dexamethasone, betamethasone, beclomethasone, flunisolide, budesonide or fluticasone.

Antithrombotic agents are understood to mean, for example, compounds from the group of blockers of platelet aggregation, anticoagulants or profibrinolytic substances.

The compounds of the invention may be administered in combination with an antithrombotic agent such as, for example and preferably, aspirin, clopidogrel, ticlopidine or dipyridamole.

The compounds of the invention may be administered in combination with a thrombin inhibitor such as, for example and preferably, xymelagatran, melagatran, dabigatran, bivalirudin or clexane.

The compounds of the invention are formulated in combination with a glycoprotein (GP) IIb-IIIa antagonist, such as, for example and preferably, tirofiban or abciximab.

- 19 040220

The compounds of the invention may be administered in combination with a factor Xa inhibitor, such as, for example and preferably, rivaroxaban, apixaban, fidexaban, razaxaban, fondaparinux, idraparinux, PMD-3112, YM-150, KFA-1982, EMD-503982, MCM-17, MLN -1021, DX 9065a, DPC 906, JTV 803, SSR-126512 or SSR-128428.

The compounds of the invention may be administered in combination with heparin or a low molecular weight heparin (LMW) derivative.

The compounds of the invention may be administered in combination with a vitamin K antagonist, such as, for example, and preferably with coumarin.

Preferably, blood pressure lowering agents are compounds from the group of calcium antagonists, angiotensin AII antagonists, ACE blockers, endothelin antagonists, renin inhibitors, α-receptor blockers, β-receptor blockers, mineralocorticoid receptor antagonists, as well as diuretics.

The compounds of the invention may be administered in combination with a calcium antagonist such as, for example and preferably, nifedipine, amlodipine, verapamil or diltiazem.

The compounds of the invention may be administered in combination with an a1 receptor blocker, such as, for example, and preferably with prazosin.

The compounds of the invention may be administered in combination with a β-receptor blocker, such as, for example and preferably, propranolol, atenolol, timolol, pindolol, alprenolol, oxprenolol, penbutolol, bupranolol, metipranolol, nadolol, mepindolol, carazalol, sotalol, metoprolol, betaxolol, celiprolol, bisoprolol, carteolol, esmolol, labetalol, carvedilol, adaprolol, landiolol, nebivolol, epanolol, or bucindolol.

The compounds of the invention may be administered in combination with an angiotensin AII antagonist, such as, for example, and preferably with losartan, candesartan, valsartan, telmisartan or embusartan.

The compounds of the invention may be administered in combination with a calcium antagonist such as, for example and preferably, enalapril, captorpril, lisinopril, ramipril, delapril, fosinopril, quinopril, perindopril or trandopril.

The compounds of the invention may be administered in combination with an endothelin antagonist such as, for example and preferably, bosentan, darusentan, ambrisentan or sitaxsentan.

The compounds of the invention may be administered in combination with a renin inhibitor, such as, for example and preferably, aliskiren, SPP-600 or SPP-800.

The compounds of the invention may be administered in combination with a mineralocorticoid receptor antagonist, such as, for example and preferably, spironolactone, eplerenone or finerenon.

The compounds according to the invention can be administered in combination with a diuretic, such as, for example and preferably, furosemide, bumetanide, torsemide, bendroflumethiazide, chlorthiazide, hydrochlorothiazide, hydroflumethiazide, methiclothiazide, polythiazide, trichloromethiazil, chlorthalidone, indapamide, metolazone, quinetasone, chloracetazolamide, metacerazine glidomamide , isosorbide, mannitol, amiloride or triamterene.

Substances affecting fat metabolism are preferably understood to mean compounds from the group of cholesteryl ester transfer inhibitors, thyroid receptor antagonists, inhibitors of cholesterol synthesis, such as inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A reductase or squalene synthase, inhibitors of acyl-CoA- cholesterol acyltransferase, microsomal triglyceride transfer protein inhibitors, PPAR-alpha, PPAR-gamma and/or PPAR-delta agonists, cholesterol uptake blockers, polymeric bile acid adsorbers, bile acid reabsorption blockers, lipase inhibitors, and lipoprotein(s) antagonists.

The compounds of the invention may be administered in combination with a cholesteryl ester transfer inhibitor such as, for example, and preferably Torcetrapib (CP-529 414), JJT-705 or the CETP vaccine (Avant).

According to the invention, it can be administered in combination with a thyroid receptor antagonist, such as, for example and preferably, D-thyroxine, 3,5,3'-triiodothyronine (T3), CGS 23425 or axithyrom (CGS 26214).

The compounds of the invention may be administered in combination with a 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor from the class of statins, as for example and preferably with lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rosuvastatin or pitavastatin.

The compounds of the invention may be administered in combination with a squalene synthase inhibitor, such as, for example, and preferably with BMS-188494 or TAK-475.

The compounds of the invention may be administered in combination with an acyl-CoAcholesterol acyltransferase inhibitor, such as, for example and preferably, avasimib, melinamide, pactimib, efflucimib or SMP-797.

The compounds of the invention may be administered in combination with an inhibitor of microsomal

- 20 040220 triglyceride transfer protein, as for example and preferably with implitapid, BMC-201038, R-103757 or JTT-130.

The compounds of the invention may be administered in combination with a PPAR-gamma agonist, such as, for example and preferably, with pioglitazone or rosiglitazone.

The compounds of the invention may be administered in combination with a PPAR delta agonist, as for example and preferably with GW 501516 or BAY 68-5042.

The compounds of the invention may be administered in combination with a cholesterol uptake blocker, such as, for example and preferably, ezetimibe, tikveside or pamaqueside.

The compounds of the invention may be administered in combination with a lipase inhibitor, such as, for example, and preferably with orlistat.

The compounds of the invention may be administered in combination with a polymeric bile acid adsorber, such as, for example, and preferably with cholestyramine, cholestyrol, colesolvam, cholestagel or colestimide.

The compounds according to the invention can be administered in combination with a bile acid reabsorption blocker, such as, and preferably with, ASBT (=IBAT) inhibitors, such as, for example, AZD-7806, S-8921, AK-105, BARI-1741, SC-435 or SC- 635.

The compounds of the invention may be administered in combination with a lipoprotein antagonist, such as, for example, and preferably with gemcaben calcium (CI-1027) or nicotinic acid.

Particularly preferred are combinations of the compounds of the invention with one or more other active ingredients selected from the group consisting of PDE5 inhibitors, sGC activators, sGC stimulants, prostacyclin analogs, IP receptor agonists, endothelin antagonists, compounds that inhibit the signaling cascade, and pirfenidone.

Another subject of the present invention is medicinal substances which contain at least one compound according to the invention, usually together with one or more inert, non-toxic, pharmaceutically acceptable excipients, and their use for the previously mentioned purposes.

The compounds according to the invention can act systemically and/or locally. For this purpose, they may be administered by any suitable route, such as, for example, oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, vaginal, dermal, transdermal, by instillation of drugs into the eyes, ear canal, or as an implant. or a stent.

For these uses, the compounds of the invention can be administered in a suitable application form.

For oral administration according to the technical regulation, fast-acting and/or modified compounds are suitable in administration forms which contain the compounds according to the invention in crystalline and/or amorphous and/or dissolved form, such as tablets (coated or non-coated tablets, e.g. resistant to the action of gastric juice or slowly soluble or insoluble shells that control the release of the compound according to the invention), rapidly dissolving tablets or films/wafers, films/lyophilisates, capsules (e.g. hard or soft gelatin capsules), dragees, substance in granules, granules, powder, emulsions, suspensions, aerosols or solutions.

Parenteral administration can occur without depending on the stage of absorption (for example, intravenously, intraarterially, intracardiac, intravertebral or intralumbar), or including the stage of absorption (for example, intramuscularly, by subcutaneous injection, intradermal injection, transdermal, intravenous or intraperitoneal injection). Suitable forms of administration and other preparations for injection and infusion in the form of solutions, suspensions, emulsions, lyophilisates or sterile powders are suitable for parenteral use.

Suitable for other uses are, for example, inhalation formulations (and other powder inhalers, nebulizers), nasal drops, solutions or sprays, tablets, films/wafers or capsules, lingual, sublingual, or buccal sprays, suppositories, eye drops and ointments, solutions for rinsing eyes, eyepieces, ear drops, sprays, powders, preparations for the ears or eyes, vaginal capsules, aqueous suspensions (regular lotions, suspensions or lotions with a low fat content), fat-soluble suspensions, emulsions, microemulsions, ointments, creams, transdermal therapeutic systems (eg patches), milks, pastes, foams, powders, implants or stents.

Preferred is oral or parenteral administration, in particular oral, intravenous administration and pulmonary administration (by inhalation).

The compounds according to the invention can be converted into the indicated application forms. This can be done in a known manner by mixing with pharmaceutically acceptable excipients. These excipients also include aggregates and fillers (eg cellulose, microcrystalline cellulose, such as Avicel®, lactose, mannitol, starch, calcium phosphates, such as Di-Cafos®);

- 21 040220 ointment bases (eg petrolatum, paraffin, triglyceride, wax, wool wax, wool wax alcohols, lanolin, hydrophilic ointment, polyethylene glycol);

suppository bases (eg polyethylene glycol, cocoa butter, hydrogenated fat), solvents (eg water, ethanol, isopropanol, glycerol, propylene glycol, medium chain triglycerides, fatty oils, liquid polyethylene glycols, paraffins);

Surfactants, emulsifiers, dispersants or wetting agents (e.g. sodium dodecyl sulfate, lecithin, phospholipids, fatty alcohols such as Lanette®, fatty acid sorbitan ester such as Span®, polyoxyethylene sorbitan fatty acid ester such as , Tween®, polyoxyethylene fatty acid glyceride, such as Cremophor®, polyoxyethylene fatty ester, polyoxyethylene fatty alcohol ester, fatty alcohol glycerol ester, poloxamers, such as Pluronic®);

buffer substances, as well as acids and bases (eg phosphates, carbonates, citric acid, acetic acid, hydrochloric acid, sodium hydroxide, ammonium carbonate, trometamol, triethanolamine);

isotonizing agents (eg glucose, sodium chloride);

adsorbent substances (for example, highly dispersed silicon dioxide);

viscosifying agents, gelling agents, thickeners or binders (eg polyvinylpyrrolidone, methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, starch, carbomers, polyacrylic acids such as Carbopol®, alginates, gelatin);

explosives (eg modified starch, sodium carboxymethylcellulose, sodium starch glycolate such as Explotab®, cross-linked polyvinylpyrrolidone, croscarmellose sodium such as AcDiSol®);

flow control agents, internal lubricants, lubricants, lubricants (eg magnesium stearate, stearic acids, talc, highly dispersed silica such as Aerosil®);

coating compositions (e.g. sugar, shellac), as well as film formers for fast or modified dissolving films or diffusion membranes (e.g. polyvinylpyrrolidones, such as Kollidon®, polyvinyl alcohol, ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl methyl cellulose phthalate, cellulose acetate, acetate -cellulose phthalate, polyacrylates, polymethacrylates, such as Eudragit®);

encapsulating materials (eg gelatins, hydroxypropyl methylcellulose);

synthetic polymers (eg polylactides, polyglycolides, polyacrylates, polymethacrylates such as Eudragit®, polyvinyl pyrrolidones such as Kollidon®, polyvinyl alcohol, polyvinyl acetate, polyethylene oxides, polyethylene glycols and their copolymers and block copolymers);

emollients (eg, polyethylene glycols, propylene glycol, glycol, triacetin, triacetyl citrate, dibutyl phthalate);

penetration enhancers;

stabilizers (eg antioxidants such as ascorbic acid, ascorbul palmitate, sodium ascorbate, butylhydroxyanisole, butylhydroxytoluene, propylgallate);

preservatives (eg parabens, sorbic acid, sodium benzoate, thiomersal, benzalkonium chloride, chlorhexidine acetate);

dyes (eg inorganic pigments such as iron oxides, titanium dioxide);

flavorings, sweet substances, taste and/or smell improvers.

Preferably, for parenteral administration, an amount of about 0.001-1 mg/kg, particularly preferably 0.01-0.5 mg/kg body weight, is used to achieve the desired result. For oral administration, the dosage is about 0.01-100 mg/kg, preferably about 0.01-20 mg/kg, and very preferably 0.1-10 mg/kg of human weight. With the intrapulmonary route of administration, the amount is generally about 0.1-50 mg per inhalation.

Despite this, it is sometimes necessary to deviate from the indicated dosage, namely, depending on the body weight, the method of application, the individual relationship to the biologically active substance, the method of preparation and the time or intervals in which the application is carried out. So in some cases it may be sufficient to apply less than the specified minimum amount, while in other cases it is necessary to exceed the specified upper limit. In case of using a larger amount, it may be recommended to divide it into more single doses per day.

Also applicable are pharmaceutical compositions which contain at least one compound according to the invention, usually together with one or more inert, non-toxic, pharmaceutically acceptable excipients, as well as their use for the previously mentioned purposes.

The following examples clarify the invention. The invention is not limited to the examples.

- 22 040220

A. Examples

Abbreviations and abbreviations:

[a]o ²⁰ special angle of rotation (for polarometry) atm Atm; pressure unit

br. lat. (at NMR) with the concentration of ca. approximately d doublet (at NMR)

DAD Diode Array Photometric Detector (High Performance Liquid Chromatography)

DBU 1,8-d iazabicyclo[5.4.0]und ec-7-ene dd doublet doublet (by NMR)

DIPEA A,A-diisopropylethylamine

DMF Ν,Ν-dimethylformamide

DMSO dimethyl sulfoxide

AT Heating, temperature increase (in the reaction scheme)

d. th. theor. yield (during chemical yield) its enantiomeric excess

EI electron impact ionization (at MS) eq. Equivalent(s)

ESI electrospray ionization (at MS)

Et ethyl

wt. % mass percent h hour(s)

HPLC HPLC, HPLC, HPLC:

iPr isopropyl

LC LC Liquid Chromatography

LC-MS LC-MS liquid chromatography coupled with mass spectrometry

LDA lithium diisopropylamide m multiplet (by NMR)

M Molar

Me methyl

- 23 040220 min minute(s)

MS MS Mass Spectrometry

MWD multi-wavelength spectrophotometric detector (HPLC, UV detector)

NMP Y-methyl-2-pyrrolidone

NMR NMR nuclear magnetic resonance spectroscopy

MTB-ether / ireot-butyl-methyl ether

MTP microtiter plate q quartet (for NMR) qd doublet quartet (for NMR)

RP reverse phase (reverse phase, HPLC)

CT room temperature

Rt retention time (for HPLC, LC/MS) s singlet (for NMR)

SLC SLC t triplet (at NMR) td triplet doublet (at NMR)

TFA Trifluoroacetic acid tertiary

THF Tetrahydrofuran

ULC Ultra-Liquid Chromatography

UHPLC Ultra High Performance Liquid Chromatography

UV ultraviolet spectrometry

Vol.% Vol.%

Other abbreviations have meanings known to the skilled person.

HPLC and LC/MS methods.

Method 1 (LC-MS):

MS device type: Thermo Scientific FT-MS; device type UHPLC+: Thermo Scientific UltiMate 3000; column: Waters, HSST3, 2.1x75 mm, C18, 1.8 µm; eluent A: 1 l water + 0.01% 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 2 (LC-MS):

instrument: Waters ACQUITY SQD UPLC System; column: Waters Acquity UPLC HSS T3 1.8 µm 50x1 mm; eluent A: 1 l water + 0.25 ml 99% formic acid, eluent B: 1 l acetonitrile + 0.25 ml 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 3 (LC-MS):

instrument: Waters Single Quad MS System; Waters UPLC Acquity; column: Waters VEN C18, 1.7 µm, 50x2.1 mm; eluent A: 1 l water + 1.0 ml (25% ammonia)/L, eluent B: 1 l acetonitrile; gradient: 0.0 min 92% A ^ 0.1 min 92% A ^ 1.8 min 5% A ^ 3.5 min 5% A; oven: 50°C; flow: 0.45 ml/min; UV detection: 210 nm (208-400 nm).

Method 4 (LC-MS):

instrument: Agilent MS Quad 6150; HPLC: Agilent 1290; column: Waters Acquity UPLC HSS T3, 1.8 µm, 50x2.1 mm; eluent A: 1 l water + 0.25 ml 99% formic acid, eluent B: 1 l acetonitrile + 0.25 ml 99% formic acid; gradient: 0.0 min 90% A ^ 0.3 min 90% A ^ 1.7 min 5% A ^ 3.0

- 24 040220 min 5% A oven: 50°C; flow: 1.20 ml/min; UV detection: 205-305 nm.

Method 5 (GC-MS):

instrument: Thermo Scientific DSQII, Thermo Scientific Trace GC Ultra; column: Restek RTX-35MS, 15 mx200 µmx0.33 µm; constant flow with helium: 1.20 ml/min; oven: 60°C; sample injection: 220°C; gradient: 60°C, 30°C/min ^ 300°C (3.33 min exposure).

Method 6 (preparative HPLC):

column: Chromatorex C18, 10 µm, 250x40 mm; eluent A: water; eluent B: acetonitrile; sample injection at 3 min; gradient: 0.0 min 30% B ^ 6.0 min 30% B ^ 27 min 95% B ^ 38 min 95% B ^ 39 min 30% B ^ 40.2 min 30% B; flow: 50 ml/min. UV detection: 210 nm.

Method 7 (preparative HPLC):

column: Chromatorex C18, 10 µm, 125x30 mm; eluent A: water; eluent B: acetonitrile; sample injection at 3 min; gradient: 0.0 min 30% B ^ 5.5 min 30% B ^ 17.65 min 95% B ^ 19.48 min 95% B ^ 19.66 min 30% B ^ 20.51 min 30% B; flow: 75 ml/min. UV detection: 210 nm.

Method 8 (preparative HPLC):

column: Chromatorex C18, 10 µm, 250x40 mm; eluent A: water; eluent B: acetonitrile; sample injection at 3 min; gradient: 0.0 min 10% B ^ 6.0 min 10% B ^ 27 min 95% B ^ 38 min 95% B ^ 39 min 10% B ^ 40.2 min 10% B; flow: 50 ml/min. UV detection: 210 nm.

Method 9 (preparative HPLC):

column: Chromatorex C18, 10 µm, 250x40 mm; eluent A: water + 0.1% TFA, eluent B: acetonitrile; sample injection at 3 min; gradient: 0.0 min 10% B ^ 6.0 min 10% B ^ 27 min 95% B ^ 38 min 95% B ^ 39 min 10% B ^ 40.2 min 10% B; flow: 50 ml/min. UV detection: 210 nm.

Method 10 (preparative HPLC):

column: Chromatorex C18, 10 µm, 125x30 mm; eluent A: water + 0.1% TFA, eluent B: acetonitrile; sample 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 11 (preparative HPLC):

column: Chromatorex C18, 10 µm, 125x30 mm; eluent A: water; eluent B: acetonitrile; sample 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 12 (preparative HPLC):

column: Chromatorex C18, 10 µm, 250x40 mm; eluent A: water + 0.1% TFA, eluent B: acetonitrile; sample injection at 3 min; gradient: 0.0 min 30% B ^ 6.0 min 30% B ^ 27 min 95% B ^ 38 min 95% B ^ 39 min 30% B ^ 40.2 min 30% B; flow: 50 ml/min. UV detection: 210 nm.

Method 13 (preparative HPLC):

column: Chromatorex C18, 10 µm, 125 mmx30 mm; eluent A: water + 0.1% formic acid, eluent B: acetonitrile + 0.1% formic acid; sample injection at 3 min; gradient: 0.0 min 10% B ^ 6.0 min 10% B ^ 27 min 95% B ^ 38 min 95% B ^ 39 min 10% B ^ 40 min 10% B; flow: 75 ml/min, UV detection: 210 nm.

Method 14 (preparative HPLC):

column: Chromatorex C18, 10 µm, 250 mmx40 mm; eluent A: water + 0.1% formic acid, eluent B: acetonitrile + 0.1% formic acid; gradient: 0.0 min 10% B ^ 6.0 min 10% B ^ 27 min 95% B ^ 38 min 95% B ^ 39 min 10% B ^ 40 min 10% B; flow: 75 ml/min, UV detection: 210 nm.

Method 15 (preparative HPLC):

column: Chromatorex C18, 10 µm, 250 mmx40 mm; eluent A: water + 0.1% formic acid, eluent B: methanol + formic acid; gradient: 0.0 min 20% B ^ 6.2 min 20% B ^ 6.5 min 40% B ^ 15.5 min 60% B ^ 16 min 100% B ^ 23 min 100% B ^ 23.6 min 20% B ^ 25.8 min 20% B; flow: 75 ml/min, UV detection: 210 nm.

Method 16 (preparative HPLC-MS):

MS instrument: Waters SQD; HPLC instrument: Waters UPLC; column: Zorbax SB-Aq (Agilent), 50 mmx2.1 mm, 1.8 µm; eluent A: water + 0.025% formic acid, eluent B: acetonitrile (ULC) + 0.025% formic acid; gradient: 0.0 min 98% A ^ 0.9 min 25% A ^ 1.0 min 5% A ^ 1.4 min 5% A ^ 1.41 min 98% A ^ 1.5 min 98% A; oven: 40°C; flow: 0.600 ml/min; UV detection: DAD; 210 nm.

Method 17 (preparative HPLC-MS):

MS instrument: Waters, HPLC instrument: Waters (Saule Phenomenex, Luna, 5µm, C18(2) 100A, AXIA Tech. 50x21.2 mm), eluent A: water + 0.0375% formic acid, eluent B: acetonitrile (ULC) + 0.0375% formic acid gradient; flow: 40 ml/min; UV detection: DAD; 210-400 nm.

Method 18 (preparative HPLC):

instrument: Waters Prep LC/MS System, column: Phenomenex Kinetex, C18, 5 µm, 100x30 mm; Input

- 25 040220 samples per column (full injection); eluent A: water, eluent B: acetonitrile, eluent C: 2% formic acid in water; flow for eluent (A + B): 65 ml/min, flow for eluent C: constant 5 ml/min; gradient (A/B): 0.0 min 20% B ^ 2 min 20% B ^ 7 min 92% B ^ 9 min 92% B ^ 20% B; UV detection: 210 nm.

Method 19 (preparative HPLC):

instrument: Waters Prep LC/MS System, column: Phenomenex Kinetex, C18, 5 µm, 100x30 mm; Injection of samples into the column (full injection of samples); eluent A: water, eluent B: acetonitrile, eluent C: 2% formic acid in water; flow for eluent (A + B): 65 ml/min, flow for eluent C: constant 5 ml/min; gradient (A/B): 0.0 min 30% B ^ 2 min 30% B ^ 2.2 min 50% B ^ 7 min 90% B ^ 7.5 min 92% B ^ 9 min 92% B ^ 30% B; UV detection: 200-400 nm.

Method 20 (preparative HPLC):

instrument: Waters Prep LC/MS System, column: Phenomenex Kinetex, C18, 5 µm, 100x30 mm; Injection of samples into the column (full injection of samples); eluent A: water, eluent B: acetonitrile, eluent C: 2% formic acid in water; flow for eluent (A + B): 65 ml/min, flow for eluent C: constant 5 ml/min; gradient (A/B): 0.0 min 10% B ^ 2 min 10% B ^ 2.2 min 30% B ^ 7 min 70% B ^ 7.5 min 92% B ^ 9 min 92% B ^ 10% B; UV detection: 200-400 nm.

Method 21 (preparative HPLC):

instrument: Waters Prep LC/MS System, column: Phenomenex Kinetex, C18, 5 µm, 100x30 mm; Injection of samples into the column (full injection of samples); eluent A: water, eluent B: acetonitrile, eluent C: 2% formic acid in water; flow for eluent (A + B): 65 ml/min, flow for eluent C: constant 5 ml/min; gradient (A/B): 0.0 min 10% B ^ 2 min 10% B ^ 2.2 min 20% B ^ 7 min 60% B ^ 7.5 min 92% B ^ 9 min 92% B ^ 10% B; UV detection: 200-400 nm.

Method 22 (preparative HPLC):

instrument: Waters Prep LC/MS System, column: Phenomenex Kinetex, C18, 5 µm, 100x30 mm; Injection of samples into the column (full injection of samples); eluent A: water, eluent B: acetonitrile, eluent C: 2% formic acid in water; flow for eluent (A + B): 65 ml/min, flow for eluent C: constant 5 ml/min; gradient (A/B): 0.0 min 7.5% B ^ 2 min 7.5% B ^ 7 min 35% B ^ 7.5 min 92% B ^ 9 min 92% B ^ 10% B; UV detection: 200-400 nm.

Method 23 (preparative HPLC):

instrument: Waters Prep LC/MS System, column: Phenomenex Kinetex, C18, 5 µm, 100x30 mm; Injection of samples into the column (full injection of samples); eluent A: water, eluent B: acetonitrile, eluent C: 2% formic acid in water; flow for eluent (A + B): 65 ml/min, flow for eluent C: constant 5 ml/min; gradient (A/B): 0.0 min 50% B ^ 2 min 50% B ^ 2.2 min 70% B ^ 7 min 92% B ^ 9 min 92% B ^ 10% B; UV detection: 200-400 nm.

Method 24 (preparative HPLC):

column: Chromatorex, C18, 10 µm, 125 mmx30 mm; eluent A: water; eluent B: acetonitrile; sample injection at 3 min; gradient: 0.0 min 10% B ^ 6 min 10% B ^ 27 min 95% B ^ 38 min 95% B ^ 39 min 10% B ^ 40 min 10% B; flow: 75 ml/min, UV detection: 210 nm.

Method 25 (LC-MS):

instrument: Waters Acquity UPLCMS SingleQuad; column: Acquity UPLC VEN C18 1.7 µm, 50x2.1 mm; eluent A: water + 0.1 vol.% formic acid (99%), eluent B: acetonitrile; gradient: 0-1.6 min 199% B, 1.6-2.0 min 99% B; flow 0.8 ml/min; temperature: 60°C; DAD scan: 210-400 nm.

Method 26 (LC-MS):

instrument: Waters Acquity UPLCMS SingleQuad; column: Acquity UPLC VEN C18 1.7 µm, 50x2.1mm; eluent A: water + 0.2 vol% aqueous ammonia (32%), eluent B: acetonitrile; gradient: 0-1.6 min 1-99% B, 1.6-2.0 min 99% B; flow 0.8 ml/min; temperature: 60°C; DAD scan: 210-400 nm.

Method 27 (preparative HPLC):

instrument: Waters Autopurification MS SingleQuad; column: Waters XBrigde C18 5 µm 100x30 mm; eluent A: water + 0.2 vol% aqueous ammonia (32%), eluent B: acetonitrile; gradient: 0-5.5 min 5-100% B; flow 70 ml/min; temperature: 25°C; DAD scan: 210-400 nm.

Method 28 (preparative HPLC):

Waters XBrigde C18 5µm 100x30mm; eluent A: water + 0.1% formic acid, eluent B: acetonitrile; gradient: 0 min 5% B ^ 5.5 min 100% B; flow 70 ml/min; DAD detection: 210-400 nm.

Method 29 (preparative HPLC):

column: Reprosil C18 10 µm; 250 mmx40 mm, flow: 75 ml/min, detection at 210 nm; eluent A: water; eluent B: acetonitrile; 0-6 min 10% B; 6-27 min: gradient to 95% B; 27-38 min 95% B; 38-39 min gradient to 10% B; 39-40 min 10% B.

Method 30 (preparative HPLC):

column: Reprosil C18 10 µm, 250 mmx40 mm; eluent A: water + 0.1% formic acid, eluent B: acetonitrile + 0.1% formic acid; 0-6 min 10% B; 6-27 min: gradient to 95% B; 27-38 min

- 26 040220

95% B; 38-39 min gradient to 10% B; 39-40 min 10% B; flow: 75 ml/min, UV detection: 210 nm.

Method 31 (preparative HPLC):

column: Chromatorex C18 10 µm; 125 mm x 30 mm, flow: 75 ml/min, detection at 210 nm; eluent A: water + 0.1% formic acid, eluent B: methanol + formic acid; 0-7.2 min 5% B; 7.2-7.45 min: gradient to 20% B; 7.45-14.5 min gradient to 40% B; 14.5-15 min gradient to 100% B; 1524.3 min 100% B; 24.2-24.5 min gradient to 5% B; 24.5-27.3 min 5% B.

Method 32 (preparative HPLC):

Reprosil C18, 10 µm, 205x50 mm; eluent A: water; eluent B: acetonitrile; sample injection at 3 min; gradient: 0.0 min 30% B ^ 5.5 min 30% B ^ 17.65 min 95% B ^ 20.79 min 95% B ^ 20.97 min 30% B ^ 22.65 min 30% B; flow: 150 ml/min. UV detection: 210 nm.

Method 33 (preparative HPLC):

Reprosil C18, 10 µm, 205x50 mm; eluent A: water; eluent B: acetonitrile; sample injection at 3 min; gradient: 0.0 min 10% B ^ 5.5 min 10% B ^ 17.65 min 95% B ^ 20.79 min 95% B ^ 20.97 min 10% B ^ 22.65 min 10% B; flow: 150 ml/min. UV detection: 210 nm.

Method 34 (quantitative ion chromatography):

determination of ions with external standards; instrument: Thermo Scientific ICS 5000+; Kapillar IC columns: IonPac AS11-HC and IonPac CS16; eluent: gradient eluent [H] ⁺ [OH] ^- detector: conductivity detection.

Other data.

The percentage readings in the following examples and tests are, unless otherwise stated, weight percent; parts are parts by weight. Solvent ratio, dilution ratio, and liquid concentration data for solutions refer to volume, respectively.

When purifying the compounds according to the invention by means of preparative HPLC using the methods described above, in which the eluents contain additives such as trifluoroacetic acid, formic acid or ammonia, the compounds according to the invention can be obtained in the form of a salt, for example in the form of trifluoroacetate, formate or ammonium salt, if the compounds according to the invention contain sufficient basic or acidic functionalities. Such a salt can be converted by various methods known to those skilled in the art to the corresponding free base or acid.

Purity data generally refers to the corresponding peak integration in the LC/MS chromatogram and can also be additionally determined using ¹ H-NMR spectrum. Compounds may contain solvent residues, which need not be taken into account when specifying purity. If purity is not specified, then either means 100% purity according to automatic peak integration in the LC/MS chromatogram, or purity is not determined.

Data to output in % theor. outputs are generally corrected for purity if <100% purity is reported. When loading substances containing solvent or contaminated substances, the yield can formally be >100%; in these cases, the yield is not corrected for solvent or purity.

The following 1H-NMR signal combination pattern descriptions are partly selected directly from ACD SpecManagers (ACD/Labs Release 12.00, Product version 12.5) or ACD/Spectrus Processor 2014 (File Version S20S41, Build 72444, 21 Aug 2014) or ACD/Spektrus Processor 2015 Pack 2 (File Version S40S41, Build 79720, 30 Jul 2015) and taken into account as needed. Part of the SpecManager data is reconciled manually. Manually negotiated or provided descriptions tend to focus on the external properties of these signals and, if necessary, do not fully comply with a strict, physically correct interpretation. Generally, the data refer to the chemical shift toward the center of said signal. For a wide multiplet, interval data are presented. Signals closed completely or partially by solvent or water are either compared empirically or not indicated. Very extended signals - for example, caused by the rapid rotation of parts of the molecules or due to substituted protons - are also empirically available (often indicated as a wide multiplet or wide singlet) or not indicated.

¹ H-NMR data of selected examples are partially recorded as an H-NMR wiki. Each signal peak is first given a δ-value in hours per thousand and then the signal intensity is given in parentheses. The data pair δ-value-signal intensity of the various signal peaks is separated from each other by commas. Therefore, the list of example peaks has the form: δ1 (intensity1), δ2 (intensities), ..., δ1 (intensity;), ..., δ _n (intensity,).

The intensity of clear signals is in correlation with the height of the signals in the printed example of the NMR spectrum in cm and shows in comparison with other signals the actual signal intensity ratio. In wide signals, there may be several peaks or the middle of the signal and its relative intensity compared to the most intense signal in the spectrum. The 1H-NMR peak lists are similar to the classic 1H-NMR printed lists and usually contain all the peaks that mention the classic NMR interpretations. In addition, they can, like the classic 1H-NMR printed lists, show signals of solvents, stereoisomers of desired compounds that are also the subject of the invention, and/or impurity peaks. Stereoisomer peaks

- 27 040220 target compounds and/or impurity peaks usually have a lower intensity than the peaks of the desired compounds (for example, >90% purity). Such stereoisomers and/or impurities may be representative of the respective preparation methods. Thus, their peaks can help in recognizing the reproduction of our by-product fingerprinting process. An expert who evaluates the peaks of the desired compounds using known methods (MestreC, ACD modeling, or empirically derived, analyzed expected values) can isolate the peaks of the desired compounds as needed, applying an additional intensity filter if necessary. Such an isolation would be similar to the aforementioned peak mapping in the classical ¹ H-NMR interpretation.

A detailed description of the presentation of NMR data as peak lists can be found in Citation of NMR Peaklist Data within Patent Applications (see Research Disclosure Database Number 605005, 2014, 1. August 2014 http://www.researchdisclosure.com/searching-disclosures) . In the Peak Picking Routine, which is described in Research Disclosure Database Number 605005, the MinimumHeight parameter can be set to 1-4%. Depending on the type of chemical structure and/or depending on the concentration of the measured compound, it is worth setting the MinimumHeight parameter to <1%.

Melting points and melting range, unless otherwise indicated, do not correct.

For all reactants and reagents, the preparation of which is not described in detail below, they are considered to be commercially available substances. For all other reactants and reagents, the preparation of which is also not described below, and which are not commercially available or refer to starting materials that are not generally available, there is a reference to the published literature, where their preparation is described.

parent compounds and intermediate compounds.

Example 1A.

-Bromo-1 -propionyl-1 H-indole-2,3-dione o

Vg L

A mixture of 5-bromo-1H-indole-2,3-dione (35.0 g, 155 mmol) and propionic anhydride (150 ml, 1.2 mol) was heated under reflux for 3 h with stirring. After cooling to RT, the solid present was filtered off, washed with t-butyl methyl ether and dried in vacuo. 16.20 g (60% pure according to 1H-NMR, 22% th. y.) of the title compound in product mixture were obtained. According to 1H-NMR of the product mixture, one part of the title compound was carried over to the next product 6-bromo-2-hydroxy-3-methylquinoline-4-carboxylic acid.

'H-NMR (400 MHz, DMSO-d6) δ [ppm]: 8.23 (d, 1H), 8.03-7.86 (m, 2H), 3.01 (q, 2H), 1.14 (t, 3H).

Example 2A.

6-Bromo-2-hydroxy-3-methylquinoline-4-carboxylic acid

Method A.

Sodium hydroxide (13.8 g, 345 mmol), and the mixture was stirred for 2 h under reflux. After cooling to RT, the mixture was acidified with 3M hydrochloric acid and the resulting solid was filtered off. The solid was dissolved in 1 M sodium hydroxide solution (400 ml) and the solution was washed five times with ethyl acetate (respectively 200 ml). The aqueous solution was then acidified with concentrated hydrochloric acid and the resulting solid was filtered off, washed with water and dried in vacuo. 8.30 g (95% pure, 49% th. y.) of the title compound were obtained.

LC-MS (method 1): R _t = 0.65 min; MS (ESIpos): m/z = 282/284 [M+H]+.

'H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 14.28 (br. s, 1H), 12.13 (br. s, 1H), 7.85-7.07 (m, 3H), 2.09 (br. s , 3H).

Purification by preparative HPLC.

From a similarly conducted preliminary test, a batch purified by prep HPLC was obtained as follows: the starting product (4.4 g, 9% pure according to LC-MS) was dissolved in 50 ml of a mixture of methanol, DMSO and THF at elevated temperature and purified by preparative HPLC [column : Chromatorex Spring Column, C18, 10 µm, 290 mmx100 mm; flow: 250 ml/min; detection: 210 nm; temperature: 22°C; sample injection: 30 ml; acetonitrile/water gradient 0:100 ^ 9:1; duration of action 41 minutes]. Received 248 mg (purity 100%) indicated

- 28 040220 in connection header.

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 14.26 (br. s, 1H), 12.13 (s, 1H), 7.67 (dd, 1H), 7.50 (d, 1H), 7.30 (d, 1H), 2.09 (s, 3H).

Method B.

A mixture of 5-bromo-1-propionyl-1H-indole-2,3-dione (99.3 g, 352 mmol, example 1A), water (615 ml) and sodium hydroxide (84.5 g, 2.11 mol) was stirred for 2 h at 100 °C. After cooling to RT, the mixture was mixed with water (1400 ml) and washed with ethyl acetate (1400 ml). The aqueous phase was acidified with concentrated hydrochloric acid and the resulting solid was drawn out and dried in vacuo. 74.4 g (100% pure by LC-MS, 75% th. y.) of the title compound were obtained.

LC-MS (method 1): R _t = 0.65 min; MS (ESIpos): m/z = 282/284 [M+H]+. Method C:

A mixture of 5-bromo-1H-indole-2,3-dione (58.8 g, 260.2 mmol) and propionic acid anhydride (250 ml, 1.95 mol) in argon was refluxed overnight with stirring (160°C internal temperature ). The mixture was then cooled to 0°C, mixed with MTB-ether (500 ml) and stirred 1 h at 0°C. The solid present was filtered off, washed further with MTBether and air dried. 43.0 g (100% pure, 59% th. y.) of the title compound were obtained.

LC-MS (method 1): R _t = 0.69 min; MS (ESIpos): m/z = 282/284 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 14.26 (br. s, 1H), 12.13 (s, 1H), 7.67 (dd, 1H), 7.50 (d, 1H), 7.30 (d, 1H), 2.09 (s, 3H).

Example 3A.

6-Bromo-2-chloro-3-methylquinoline-4-carbonyl chloride

Method A.

A mixture of 6-bromo-2-hydroxy-3-methylquinoline-4-carboxylic acid (8.30 g, 29.4 mmol, example 2A) and phosphorus oxychloride (60 ml, 641 mmol) in argon was stirred for 3 h at reflux. After cooling to RT, the mixture was slowly poured into ice water (600 ml). The resulting solution was extracted three times with dichloromethane (respectively 300 ml). The combined organic phases were dried over sodium sulfate, filtered and concentrated, and the residue was purified by flash column chromatography (320 g silica gel, first cyclohexane, then cyclohexane/ethyl acetate 98:2, then cyclohexane/ethyl acetate 96:4, Isolera). The combined desired fractions were concentrated and the residue was dried in vacuo. 3.74 g (83% pure, 33% theoretical) of the first batch of the title compound and 1.90 g (88% pure, 18% of theor. y., see Analysis) of the second batch of the title compound were obtained.

LC-MS (method 2): R _t = 1.35 min; MS (ESIpos): m/z = 320 [M+H] ⁺ .

Method B.

Thionyl chloride (52 ml, 710 mmol) and DMF (11 ml , 140 mmol). The mixture was heated under reflux slowly with stirring, and gas formation was observed. After approximately 1 hour of stirring at reflux, the mixture was allowed to cool to RT and the volatiles were removed on a rotary evaporator. The resulting residue was purified by flash column chromatography (200 g silica gel, dichloromethane). The combined desired fractions were concentrated and the residue was dried in vacuo. 16.4 g (97% pure, 70% th. y.) of the title compound were obtained.

LC-MS (method 4): R _t = 1.66 min; MS (ESIpos): m/z = 320 [M+H] ⁺ .

Example 4A.

(6-Chloro-2,3-difluorophenyl)methanol

G t no

A solution of 6-chloro-2,3-difluorobenzaldehyde (5.00 g, 28.3 mmol) in THF (20 mL) was mixed portionwise with sodium borohydride (1.39 g, 36.8 mmol) at RT (gas formation). An additional 20 ml of THF was then added and the mixture was stirred for 45 minutes at RT. Thereafter, the mixture was mixed with dichloromethane (100 ml), water (100 ml) and saturated aqueous ammonium chloride solution (50 ml) and shaken. The aqueous phase was simultaneously acidified with concentrated acetic acid. After phase separation, the organic phase was washed once with saturated aqueous sodium chloride, dried over sodium sulfate, filtered and concentrated, and the residue was quickly dried in vacuo. 5.35 g (100% pure, >106% th. y., not quite dry) of the title compound was obtained.

- 29 040220

GC-MS (method 5): Rt = 3.23 min, MS (EIpos): m/z = 178 [M] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 7.45 (dd, 1H), 7.36 (ddd, 1H), 5.36 (t, 1H), 4.59 (dd, 3H).

Example 5A.

2-(Bromomethyl)-1-chloro-3,4-difluorobenzene

Phosphorus tribromide (1.6 ml, 16 mmol) was added dropwise to a solution of (6-chloro-2,3-difluorophenyl)methanol (5.34 g, 29.9 mmol, example 4A) in dichloromethane (30 ml) at -15° C. with stirring. Then the cold bath was removed and the mixture was stirred for an additional 2 hours. After that, the mixture was slowly mixed with saturated aqueous sodium hydrogen carbonate solution, water and dichloromethane (respectively 50 ml) and shaken. After phase separation, the organic phase was washed with saturated aqueous sodium chloride solution (100 ml), dried over sodium sulfate, filtered and concentrated, and the residue was dried quickly in vacuo. 3.88 g (94% pure according to GC-MS, 51% theoretical yield) of the title compound were obtained.

GC-MS (method 5): Rt = 3.57 min, MS (EIpos): m/z = 240 [M] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 7.55 (dd, 1H), 7.45 (ddd, 1H), 4.71 (d, 3H).

Example 6A.

2-(Bromomethyl)-1-(difluoromethoxy)-3-fluorobenzene

A solution of from phosphorus tribromide (1.6 ml, 16 mmol) in dichloromethane (20 ml). Then the cold bath was removed and the mixture was stirred for an additional 2 hours. After that, the mixture was slowly mixed with saturated aqueous sodium hydrogen carbonate solution, water and dichloromethane (respectively 100 ml) and shaken. After phase separation, the organic phase was washed with saturated aqueous sodium chloride solution (200 ml), dried over sodium sulfate, filtered and concentrated, and the residue was quickly dried in vacuo. 9.60 g (95% pure, 69% th. y.) of the title compound were obtained.

GC-MS (method 5): Rt = 3.38 min, MS (EIpos): m/z = 254/256 [M] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 1.238 (0.57), 1.255 (1.12), 1.273 (0.58), 4.610 (15.58), 4.614 (16.00), 7.105 (3.32), 7.126 (3.80 ), 7.161 (2.02), 7.184 (8.39), 7.205 (2.57), 7.366 (8.46), 7.470 (2.03), 7.487 (2.27), 7.491 (3.74), 7.508 (3.68), 7.512 (2.00), 7.529 (1.66 ), 7.549 (4.14).

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 7.60-7.03 (m, 4H), 4.61 (d, 2H).

Example 7A.

(2-Chloro-3-fluorophenyl)acetonitrile

Water (60 ml) and tetrabutylammonium bromide (1.00 g, 3.11 mmol) were added to a solution of 1-(bromomethyl)-2-chloro-3-fluorobenzene (6.96 g, 31.1 mmol) in dichloromethane (60 ml) with stirring. Then a solution of potassium cyanide (6.08 g, 93.4 mmol) in water (60 ml) was added and the mixture was stirred for 2.5 h at RT. The phases were then separated and the organic phase was washed three times with saturated aqueous sodium hydrogen carbonate, dried over sodium sulfate, filtered and concentrated, and the residue was dried quickly in vacuo. 4.98 g (100% pure, 94% th. y.) of the title compound was obtained.

GC-MS (method 5): Rt = 4.03 min, MS (EIpos): m/z = 169 [M] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 4.175 (16.00), 7.400 (0.90), 7.408 (1.10), 7.414 (1.15), 7.417 (1.13), 7.424 (2.60), 7.440 (2.84) , 7.443 (2.99), 7.459 (5.37), 7.468 (1.52), 7.474 (1.39).

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 7.50-7.37 (m, 3H), 4.18 (s, 2H).

Example 8A.

(6-Chloro-2,3-difluorophenyl)acetonitrile

To a solution of 2-(bromomethyl)-1-chloro-3,4-difluorobenzene (3.87 g, 16.0 mmol, example 5A) in acetonite

Trimethylsilyl cyanide (2.5 ml, 18 mmol) and a 1 M solution of tetrabutylammonium fluoride in THF (19 ml, 19 mmol) were added with stirring, and the mixture was stirred for 30 min at 80°C. After cooling to RT, the solvent was removed on a rotary evaporator. The residue was adsorbed into ethyl acetate (80 ml) and the solution was washed with water and saturated aqueous sodium chloride solution (respectively 80 ml), dried over sodium sulfate, filtered and concentrated. The residue was adsorbed into dichloromethane and purified by flash column chromatography (100 g silica gel

Biotage Snap-Cartridge KP-Sil, cyclohexane/ethyl acetate gradient 93:7 ^ 7:3, Isolera One). The combined desired fractions were concentrated and the residue was dried in vacuo. 2.24 g (71% pure by GC-MS, 96% th. y.) of the title compound were obtained.

GC-MS (method 5): R _t = 3.92 min, MS (EIpos): m/z = 187 [M] ⁺ .

LC-MS (method 1): R _t = 1.57 min; MS (ESIneg): m/z = 186 [MH] ^- .

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 7.58 (dd, 1H), 7.49 (ddd, 1H), 4.16 (d, 2H).

Example 9A.

(2-Chloro-3,6-difluorophenyl)acetonitrile

Water (40 ml ) and tetrabutylammonium bromide (641 mg, 1.99 mmol). Then a solution of potassium cyanide (3.88 g, 59.6 mmol) in water (40 ml) was added and the mixture was stirred for 2.5 h at RT. The phases were then separated and the organic phase was washed three times with saturated aqueous sodium hydrogen carbonate, dried over sodium sulfate, filtered and concentrated, and the residue was dried quickly in vacuo. 3.80 g (94% pure, 96% th. y.) of the title compound were obtained.

LC-MS (method 1): R _t = 1.59 min; MS (ESIneg): m/z = 186 [M-H] ^- .

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 7.57 (td, 1H), 7.44 (td, 1H), 4.15 (d, 2H).

Example 10A.

[2-(Difluoromethoxy)-6-fluorophenyl]acetonitrile

II jQi F^O'^r^F

Water (60 ml) and tetrabutylammonium bromide (1.21 g, 3.76 mmol). Then a solution of potassium cyanide (7.35 g, 113 mmol) in water (120 ml) was added and the mixture was stirred for 2.5 h at RT. The phases were then separated and the organic phase was washed twice with saturated aqueous sodium hydrogen carbonate solution (respectively 100 ml), dried over sodium sulfate, filtered and concentrated, and the residue was quickly dried in vacuo. 7.26 g (98% pure, 94% theoretical) of the title compound were obtained.

GC-MS (method 5): Rt = 3.70 min, MS (EIpos): m/z = 201 [M] ⁺ .

LC-MS (method 1): R _t = 1.56 min.

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.937 (0.68), 3.164 (0.78), 3.177 (0.77), 3.952 (16.00), 7.152 (3.20), 7.171 (6.16), 7.215 (2.00) , 7.237 (3.89), 7.259 (2.35), 7.353 (6.55), 7.489 (1.60), 7.509 (2.98), 7.526 (3.04), 7.531 (1.93), 7.535 (3.48), 7.547 (1.32).

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 7.58-7.43 (m, 1H), 7.39-7.05 (m, 3H), 3.95 (s, 2H).

Example 11A.

(+/-)-tert-Butyl-3 -(2-chloro-6-fluorophenyl)-3-cyanopropanoate (racemate) jOl

CI^Y^F

0^0 n ₃ s—|—sn ₃ CH ₃

To a solution of (2-chloro-5-fluorophenyl)acetonitrile (25.0 g, 147 mmol) in THF (200 ml) in argon at -78°C was added a 2 M solution of LDA in THF (110 ml, 220 mmol ). The mixture was brought to 0°C and after 15 min re-cooled to -78°C. Then, tert-butyl bromoacetate (33 ml, 220 mmol) was added slowly with stirring at -78° C. dropwise. The mixture was brought to RT over 3 hours and then mixed with water (100 ml) and stirred at RT for 10 minutes. Water (200 ml) was added again and then ethyl acetate (200 ml) and the phases were separated. The aqueous phase was extracted with ethyl acetate (200 ml). Volume

- 31 040220 the dinyne organic phases were washed once with saturated aqueous sodium chloride solution (300 ml), dried over sodium sulfate, filtered and concentrated, and the residue was adsorbed in dichloromethane and purified by flash column chromatography (1 kg silica gel, cyclohexane/ethyl acetate 9: 1). The combined desired fractions were concentrated and the residue was dried in vacuo. 15.2 g (64% pure, 23% theoretical) of the first batch of the title compound and 28.6 g (87% pure, 59% of theor. y., see Analysis) of the second batch of the title compound were obtained.

LC-MS (method 2): Rt = 1.09 min; MS (ESIpos): m/z = 284 [M+H]+.

1H-NMR (500 MHz, DMSO-d6) δ [ppm]: 0.934 (1.18), 0.947 (1.27), 1.343 (16.00), 1.392 (1.87), 1.401 (1.18), 2.976 (0.49), 2.991 (0.48) , 3.081 (0.60), 3.316 (0.94), 4.854 (0.42), 7.452 (0.69), 7.500 (0.48), 7.512 (0.47).

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 7.55-7.47 (m, 1H), 7.47-7.42 (m, 1H), 7.40-7.33 (m, 1H), 4.85 (td, 1H), 3.10 (dd, 1H), 2.97 (dd, 1H), 1.34 (s, 9H).

Example 12A.

(+/-)-tert-Butyl-4-(2-chloro-5-fluorophenyl)-4-cyanobutanoate (racemate)

To a solution of (2-chloro-5-fluorophenyl)acetonitrile (10.0 g, 59.0 mmol) in THF (75 ml) in argon at -78°C was added a 2 M solution of LDA in THF (44 ml, 88 mmol ). The mixture was brought to 0°C and after 15 min re-cooled to -78°C. Then, tert-butyl-3-bromopropanoate (11 ml, 71 mmol) was slowly added dropwise with stirring at -78°C. The mixture was further stirred overnight while the cooling bath (dry ice/acetone) was slowly brought to RT. The mixture was then slowly mixed with water and extracted twice with ethyl acetate. The combined organic phases were washed once with saturated aqueous sodium chloride, dried over sodium sulfate, filtered and concentrated, and the residue was purified by flash column chromatography (340 g Biotage Snap-Cartridge KP-Sil, cyclohexane/ethyl acetate gradient 93:7^3: 7, Isolera One). The combined desired fractions were concentrated and the residue was dried in vacuo. 14.8 g (93% pure, 78% th. y.) of the title compound were obtained.

LC-MS (method 1): Rt = 2.22 min; MS (ESIpos): m/z = 298 [M+H]+.

Example 13A.

(+/-)-tert-Butyl-4-(2-chlorophenyl)-4-cyanobutanoate (racemate)

To a solution of (2-chlorophenyl)acetonitrile (5.00 g, 33.0 mmol) in THF (46 ml) in argon at -78°C was added a 2 M solution of LDA in THF (25 ml, 49 mmol) slowly with stirring. The mixture was brought to 0°C and after 15 min re-cooled to -78°C. Then, tert-butyl-3-bromopropanoate (8.28 g, 39.6 mmol) was slowly added dropwise with stirring at -78°C. The mixture was further stirred overnight while the cooling bath (dry ice/acetone) was slowly brought to RT. The mixture was then slowly mixed with water and extracted twice with ethyl acetate. The combined organic phases were washed once with saturated aqueous sodium chloride, dried over sodium sulfate, filtered and concentrated, and the residue was purified by preparative HPLC (method 8). The combined desired fractions were concentrated and the residue was dried in vacuo. 5.20 g (75% pure, 42% th. y.) of the title compound was obtained.

LC-MS (method 1): Rt = 2.22 min; MS (ESIpos): m/z=280 [M+H]+.

Example 14A.

(+/-)-tert-Butyl-4-cyano-4-[2-(trifluoromethyl)phenyl]butanoate (racemate)

To a solution of [2-(trifluoromethyl)phenyl]acetonitrile (14.8 g, 79.8 mmol, CAS-RN 3038-47-9, commercially available) in THF (100 mL) in argon slowly with stirring a 2 M solution of LDA in THF ( 48 ml, 96 mmol) was added, and the internal temperature was maintained between -70 and -60°C. The mixture was brought to 0°C and after 15 min re-cooled to -70°C. Then slowly while stirring

- 32 040220 at -70° C., a solution of tert-butyl-3-bromopropanoate (15 ml, 96 mmol) in THF (70 ml) was added dropwise. The mixture was further stirred overnight while the cooling bath (dry ice/acetone) was slowly brought to RT. The mixture was then slowly mixed with water (200 ml) and ethyl acetate (250 ml) at approximately 0° C. and shaken. After phase separation, the aqueous phase was extracted once with ethyl acetate (150 ml). The combined organic phases were washed once with saturated aqueous sodium chloride (250 ml), dried over sodium sulfate, filtered and concentrated, and the residue was adsorbed in dichloromethane and purified by flash column chromatography (400 g silica gel, cyclohexane/ethyl acetate 9:1). The combined desired fractions were concentrated and the residue was dried in vacuo. 18.7 g (100% pure, 75% th. y.) of the title compound were obtained.

LC-MS (method 1): Rt = 2.26 min; MS (ESIpos): m/z = 314 [M+H] ⁺ .

'H-NMR (400 MHz, DMSO-d6) δ [ppm]: 7.91-7.75 (m, 3H), 7.62 (t, 1H), 4.35 (dd, 1H), 2.44-2.33 (m, 2H), 2.31 -2.19 (m, 1H), 2.18-2.06 (m, 1H), 1.39 (s, 9H).

Example 15A.

(+/-)-tert-Butyl-4-cyano-4-[2-(trifluoromethoxy)phenyl]butanoate (racemate)

To a solution of [2-(trifluoromethoxy)phenyl]acetonitrile (5.00 g, 24.9 mmol) in THF (65 ml) in argon at -78°C was added slowly with stirring a 2 M solution of LDA in THF (15 ml, 30 mmol) . The mixture was brought to 0°C and after 15 min re-cooled to -78°C. A solution of tert-butyl-3-bromopropanoate (4.7 ml, 30 mmol) in THF (45 ml) was then slowly added dropwise with stirring at -78°C. The mixture was further stirred overnight while the cooling bath (dry ice/acetone) was slowly brought to RT. The mixture was then slowly mixed at approximately 0° C. with water and ethyl acetate (respectively 100 ml) and shaken. After phase separation, the aqueous phase was extracted once with ethyl acetate (100 ml). The combined organic phases were washed once with saturated aqueous sodium chloride (150 ml), dried over sodium sulfate, filtered and concentrated, and the residue was adsorbed in dichloromethane and purified by flash column chromatography (100 g Biotage Snap-Cartridge Ultra silica gel, cyclohexane/ethyl acetate -gradient 93:7 ^ 7:3, Isolera One). The combined desired fractions were concentrated and the residue was dried in vacuo. 3.13 g (80% pure, 31% th. y.) of the title compound was obtained.

LC-MS (method 1): R _t = 2.27 min; MS (ESIpos): m/z = 330 [M+H]+.

Example 16A.

(+/-)-tert-Butyl-4-(2-chloro-3-fluorophenyl)-4-cyanobutanoate (racemate)

A 2 M solution of LDA in THF (14 ml , 28 mmol). The mixture was brought to 0°C and after 15 min re-cooled to -78°C. A solution of tert-butyl-3-bromopropanoate (4.5 ml, 28 mmol) in THF (20 ml) was then slowly added dropwise with stirring at -78°C. The mixture was further stirred overnight while the cooling bath (dry ice/acetone) was slowly brought to RT. The mixture was then slowly mixed at approximately 0° C. with water and ethyl acetate (respectively 100 ml) and shaken. After phase separation, the aqueous phase was extracted once with ethyl acetate (100 ml). The combined organic phases were washed once with saturated aqueous sodium chloride (150 ml), dried over sodium sulfate, filtered and concentrated, and the residue was adsorbed in dichloromethane and purified by flash column chromatography (100 g Biotage Snap-Cartridge Ultra silica gel, cyclohexane/ethyl acetate gradient 93:7 ^ 7:3, Isolera One). The combined desired fractions were concentrated and the residue was dried in vacuo. 4.36 g (95% pure, 59% th. y.) of the title compound were obtained.

LC-MS (method 1): Rt = 2.24 min; MS (ESIpos): m/z = 298 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.007 (0.14), 1.174 (0.02), 1.222 (0.06), 1.342 (0.84), 1.346 (0.35), 1.382 (16.00), 1.429 (0.05) , 1.539 (0.06), 1.987 (0.03), 2.071 (0.04), 2.090 (0.09), 2.106 (0.20), 2.125 (0.45), 2.142 (0.53), 2.162 (0.44), 2.182 (0.23), 2.196 (0.08) . , 2.436 (0.04), 2.669 (0.03), 2.709 (0.02), 3.730 (0.02), 4.174 (0.10), 4.566 (0.34), 4.586 (0.43), 4.603 (0.33), 7.426 (0.24), 7.431

- 33 040220 (0.29), 7.444 (0.48), 7.449 (0.60), 7.460 (0.54), 7.466 (0.30), 7.476 (0.47), 7.482 (0.52), 7.491 (0.55), 7.508 (0.28), 7.529 (0.09) ).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 7.55-7.40 (m, 3H), 4.59 (dd, 1H), 2.45-2.29 (m, 2H), 2.23-2.06 (m, 2H ), 1.38 (s, 9H).

Example 17A.

(+/-)-tert-Butyl-4-(6-chloro-2,3-difluorophenyl)-4-cyanobutanoate (racemate)

A 2 M solution of LDA in THF (7.1 ml, 14 mmol). The mixture was brought to 0°C and after 15 min re-cooled to -78°C. Then, a solution of tert-butyl-3-bromopropanoate (4.5 ml, 28 mmol) in THF (10 ml) was slowly added dropwise with stirring at -78°C. The mixture was further stirred overnight while the cooling bath (dry ice/acetone) was slowly brought to RT. The mixture was then slowly mixed with water (50 ml) and ethyl acetate (100 ml) at approximately 0° C. and shaken. After phase separation, the aqueous phase was extracted once with ethyl acetate (50 ml). The combined organic phases were washed once with saturated aqueous sodium chloride (80 ml), dried over sodium sulfate, filtered and concentrated, and the residue was adsorbed in dichloromethane and purified by flash column chromatography (50 g of Biotage Snap-Cartridge Ultra silica gel, cyclohexane/ethyl acetate -gradient 93:7 ^ 7:3, Isolera One). The combined desired fractions were concentrated and the residue was dried in vacuo. 2.29 g (83% pure, 51% th. y.) of the title compound were obtained.

LC-MS (method 1): R _t = 2.17 min; MS (ESIpos): m/z = 316 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 7.73-7.53 (m, 1H), 7.52-7.41 (m, 1H), 4.68 (t, 1H), 2.43-2.32 (m, 2H) , 2.32-2.18 (m, 1H), 2.18-2.04 (m, 1H), 1.37 (s, 9H).

Example 18A.

(+/-)-tert-Butyl-4-cyano-4-(5-fluoro-2-methylphenyl)butanoate (racemate)

About sn ₃

A 2 M solution of LDA in THF (16 ml, 32 mmol ). The mixture was brought to 0°C and after 15 min re-cooled to -78°C. Then) a solution of tert-butyl-3-bromopropanoate (5.1 ml, 32 mmol) in THF (20 ml) was added slowly with stirring at -78° C. dropwise. The mixture was further stirred overnight, with a cooling bath (dry ice/acetone) slowly brought to RT The mixture was then slowly mixed with water and ethyl acetate (respectively 100 ml) at approximately 0°C and shaken After separation of the phases, the aqueous phase was extracted once with ethyl acetate (100 ml) The combined organic phases were washed once with saturated aqueous chloride solution sodium (150 ml), dried over sodium sulfate, filtered and concentrated, and the residue was adsorbed in dichloromethane and purified by flash column chromatography (100 g Biotage Snap-Cartridge Ultra silica gel, cyclohexane/ethyl acetate gradient 93:7^7:3, Isolera One) The combined desired fractions were concentrated and the residue was dried in vacuo to give 4.94 g (100% pure, 66% of theory) of the title compound.

LC-MS (method 1): R _t = 2.18 min; MS (ESIpos): m/z = 278 [M+H] ⁺ .

'H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 7.29 (dd, 1H), 7.23 (dd, 1H), 7.11 (td, 1H), 4.34 (dd, 1H), 2.422.34 ( m, 2H), 2.30 (s, 3H), 2.17–1.96 (m, 2H), 1.40 (s, 9H).

Example 19A.

(+/-)-tert-Butyl-4-(2-chloro-3,6-difluorophenyl)-4-cyanobutanoate (racemate)

A 2 M solution of LDA in THF ( 12 ml, 25 mmol). The mixture was brought to 0°C and after 15 min re-cooled to -78°C. Then slowly while changing

A solution of tert-butyl-3-bromopropanoate (2.6 ml, 16 mmol) in THF (10 ml) was added dropwise at -78°C. The mixture was further stirred overnight while the cooling bath (dry ice/acetone) was slowly brought to RT. The mixture was then slowly mixed at approximately 0° C. with water and ethyl acetate (respectively 100 ml) and shaken. After phase separation, the aqueous phase was extracted once with ethyl acetate (100 ml). The combined organic phases were washed once with saturated aqueous sodium chloride (150 ml), dried over sodium sulfate, filtered and concentrated, and the residue was adsorbed in dichloromethane and purified by flash column chromatography (100 g Biotage Snap-Cartridge Ultra silica gel, cyclohexane/ethyl acetate gradient 93:7 ^ 7:3, Isolera One). The combined desired fractions were concentrated and the residue was dried in vacuo. 4.14 g (95% pure, 61% th. y.) of the title compound were obtained.

LC-MS (method 1): R _t = 2.17 min; MS (ESIpos): m/z = 338 [M+Na]+.

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 7.58 (td, 1H), 7.45 (td, 1H), 4.68 (t, 1H), 2.39-2.32 (m, 2H), 2.29-2.17 (m, 1H), 2.17-2.05 (m, 1H), 1.37 (s, 9H).

Example 20A.

(+/-)-tert-Butyl-4-cyano-4-[2-fluoro-6-(trifluoromethyl)phenyl]butanoate (racemate)

The reaction was carried out in argon. To obtain an LDA solution, a solution of diisopropylamine (6.2 ml, 44 mmol) in THF (27 ml) at -15°C was slowly mixed with butyllithium (a solution of 1.6 M in hexane, 27 ml, 43 mmol), and the mixture was additionally stirred for 10 min at 0 °C. This solution was slowly added dropwise to a cooled -78°C solution of [2-fluoro-6-(trifluoromethyl)phenyl]acetonitrile (8.01 g, 98% pure, 38.7 mmol, CAS-RN 179946-34-0, commercially available) in 74 ml THF. After complete addition, the cold bath was removed, the mixture was brought to 0°C and after 15 min was further cooled to -78°C. Then a solution of tert-butyl-3-bromopropanoate (8.0 ml, 97% pure, 46 mmol) in 27 ml THF was slowly added dropwise, and the mixture was further stirred for 1 h at -78°C. The cooling bath was removed and the reaction mixture was further stirred overnight at RT. For work-up, ammonium chloride solution (10% in water, 300 ml) was added, the mixture was stirred vigorously for 5 minutes and then extracted twice with ethyl acetate. The combined organic phases were washed successively each twice with 1 M hydrochloric acid, saturated sodium hydrogen carbonate solution and saturated sodium chloride solution, then dried over sodium sulfate and concentrated in vacuo. The residue was taken up in a mixture of cyclohexane, a small amount of ethyl acetate and dichloromethane and purified by flash chromatography on silica gel (cyclohexane/ethyl acetate gradient 100:0-70:30). The combined target fractions were concentrated and the residue was dried in vacuo and then further purified by preparative HPLC (method 27). The fractions containing the product were concentrated and the residue was dried in vacuo. 4.52 g (100% pure, 35% th. y.) of the title compound was obtained.

LC-MS (method 1): Rt = 2.23 min; MS (ESIpos): m/z = 332 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.219 (0.06), 1.379 (16.00), 1.536 (0.07), 2.073 (0.16), 2.091 (0.22), 2.107 (0.28), 2.125 (0.26) , 2.144 (0.10) . , 7.698 (0.31), 7.711 (1.11), 7.722 (0.54), 7.748 (0.35), 7.766 (0.11).

Example 21A.

(+/-)-tert-Butyl-4-cyano-4-(2,3,6-trichlorophenyl)butanoate (racemate)

o sn ₃

The reaction was carried out in argon. To obtain an LDA solution, a solution of diisopropylamine (7.1 ml, 51 mmol) in THF (30 ml) at -15°C was slowly mixed with butyllithium (a solution of 1.6 M in hexane, 30 ml, 48 mmol), and the mixture was additionally stirred for 10 min at 0 °C. This solution was added slowly dropwise to a -78°C cooled solution of (2,3,6-trichlorophenyl)acetonitrile (10.0 g, 97% pure, 44.0 mmol, CAS-RN 3215-65-4, commercially available) in THF (84 ml). After complete addition, the cold bath was removed, the mixture was brought to 0°C and re-cooled to -78°C after 15 minutes. Then a solution of tert-butyl-3-bromopropanoate (9.1 ml, 97% pure, 53 mmol) in THF (30 ml) was added slowly dropwise and the mixture was further stirred for 1 h at -78°C. The cooling bath was removed and the reaction mixture was further stirred overnight at RT. Solution added for processing

- 35 040220 ammonium chloride (10% in water, 300 ml), the mixture was vigorously stirred for 5 minutes and then extracted twice with ethyl acetate. The combined organic phases were washed successively each twice with 1M hydrochloric acid, saturated aqueous sodium hydrogencarbonate and saturated aqueous sodium chloride and then dried over sodium sulfate and concentrated in vacuo. The residue was purified by preparative HPLC (method 24). The combined desired fractions were concentrated and the residue was dried in vacuo. 10.2 g (95% pure, 63% th. y.) of the title compound were obtained.

LC-MS (method 1): Rt = 2.41 min; MS (ESIpos): m/z = 348 [M+H]+.

1H-NMR (500 MHz, DMSO-d6) δ [ppm]: 1.382 (16.00), 1.997 (0.45), 2.316 (0.42), 2.367 (0.45), 2.381 (0.71), 2.403 (0.63), 3.322 (0.80) , 5.002 (0.48), 7.620 (0.69), 7.637 (0.90), 7.746 (0.92), 7.763 (0.70).

Example 22A.

(+/-)-tert-Butyl-4-cyano-4-[2-(difluoromethoxy)-6-fluorophenyl]butanoate (racemate)

To a solution of [2-(difluoromethoxy)-6-fluorophenyl]acetonitrile (7.24 g, 36.0 mmol, example 10A) in THF (30 ml) in argon at approximately (-70)-(-60)°C was added slowly with stirring 2 M solution from LDA in THF (22 ml, 43 mmol). The mixture was brought to 0°C and after 15 min re-cooled to -70°C. A solution of tert-butyl-3-bromopropanoate (6.8 ml, 43 mmol) in THF (15 ml) was then slowly added dropwise with stirring at approximately (-70)-(-60)°C. The mixture was further stirred overnight while the cooling bath (dry ice/isopropanol) was slowly brought to RT. The mixture was then slowly mixed at approximately 0° C. with water and ethyl acetate (respectively 100 ml) and shaken. After phase separation, the aqueous phase was extracted once with ethyl acetate (100 ml). The combined organic phases were washed once with saturated aqueous sodium chloride (150 ml), dried over sodium sulfate, filtered and concentrated, and the residue was adsorbed in dichloromethane and purified by flash column chromatography (400 g silica gel, cyclohexane/ethyl acetate gradient 10:1 ). The combined desired fractions were concentrated and the residue was dried in vacuo. 7.11 g (74% pure, 45% th. y.) of the title compound were obtained.

LC-MS (method 2): R _t = 1.10 min; MS (ESIpos): m/z = 330 [M+H]+.

Example 23A.

(+/-)-tert-Butyl-4-amino-3-(2-chloro-6-fluorophenyl)butanoate (racemate)

A solution of (+/-)-tert-butyl-3-(2-chloro-6-fluorophenyl)-3-cyanopropanoate (43.9 g, 79% pure, 122 mmol, example 11A) in tert-butanol (500 ml) was mixed with Raney nickel (7.15 g, 122 mmol) and hydrogenated for four days at normal pressure (1 atm). The mixture was then mixed again with Raney nickel (7.15 g, 122 mmol) and hydrogenated for an additional 24 h at normal pressure (1 atm). After that, the catalyst was filtered through silica gel and washed twice with tert-butanol (corresponding to 15 ml). The filtrate was concentrated and the residue in ethyl acetate (300 ml) was adsorbed and extracted twice with 1 M hydrochloric acid (corresponding to 250 ml). The pH of the aqueous phase was then adjusted to 8-9 with a saturated aqueous sodium hydrogen carbonate solution and extracted twice with ethyl acetate (corresponding to 200 ml). The combined organic phases were dried over sodium sulfate, filtered and concentrated and the residue dried in vacuo. 20.11 g (99% pure, 57% theoretical) of the title compound were obtained.

LC-MS (method 2): R _t = 0.55 min; MS (ESIpos): m/z = 288 [M+H]+.

Example 24A.

(+/-)-tert-Butyl-5-amino-4-(2-chloro-5-fluorophenyl)pentanoate (racemate)

A solution of (+/-)-tert-butyl-4-(2-chloro-5-fluorophenyl)-4-cyanobutanoate (14.0 g, 93% pure, 43.7 mmol, Example 12A) in tert-butanol (260 mL) was mixed with Raney nickel (2.57 g, 43.7 mmol) and hydrogenated

- 36 040220 during the night at normal pressure (1 atm). The mixture was then mixed again with Raney nickel (2.57 g, 43.7 mmol) and hydrogenated for an additional 24 h at normal pressure (1 atm). The mixture was then mixed once more with Raney nickel (2.57 g, 43.7 mmol) and hydrogenated for an additional 24 h at normal pressure (1 atm). Thereafter, the catalyst was filtered through silica gel and the mother liquor was concentrated. 14.4 g (60% pure, 65% th. y.) of the title compound were obtained.

LC-MS (method 1): R _t = 1.14 min; MS (ESIpos): m/z = 302 [M+H]+.

Example 25A.

(+/-)-tert-Butyl-5-amino-4-(2-chlorophenyl)pentanoate (racemate)

A solution of (+/-)-tert-butyl-4-(2-chlorophenyl)-4-cyanobutanoate (4.50 g, 16.1 mmol, example 13A) in tert-butanol (90 ml) was mixed with Raney nickel (944 mg, 16.1 mmol) and hydrogenated overnight at normal pressure (1 atm). The mixture was then mixed again with Raney nickel (944 mg, 16.1 mmol) and hydrogenated for an additional 24 hours at normal pressure (1 atm). Thereafter, the catalyst was filtered through silica gel and the mother liquor was concentrated. The residue was adsorbed into dichloromethane and purified by flash column chromatography (100 g Biotage Snap-Cartridge KPSil silica gel, 93:7^7:3 cyclohexane/ethyl acetate gradient, Isolera One). The combined desired fractions were concentrated and the residue was dried in vacuo. 1.62 g (91% pure, 32% th. y.) of the title compound was obtained.

LC-MS (method 3): R _t = 1.70 min; MS (ESIpos): m/z = 284 [M+H]+.

Example 26A.

(+/-)-tert-Butyl-5-amino-4-[2-(trifluoromethyl)phenyl]pentanoate (racemate)

A solution of (+/-)-tert-butyl-4-cyano-4-[2-(trifluoromethyl)phenyl]butanoate (18.6 g, 59.5 mmol, example 14A) in tert-butanol (200 ml) was mixed with Raney nickel ( 3.49 g, 59.5 mmol) and hydrogenated for 24 h at normal pressure (1 atm). After that, the catalyst was filtered through silica gel and washed twice with tert-butanol (respectively 50 ml). The filtrate was concentrated and the residue was dried in vacuo. 17.8 g (82% pure, 77% th. y.) of the title compound were obtained.

LC-MS (method 1): R _t = 1.23 min; MS (ESIpos): m/z = 318 [M+H]+.

Example 27A.

(+/-)-tert-Butyl-5-amino-4-[2-(trifluoromethoxy)phenyl]pentanoate (racemate)

A solution of (+/-)-tert-butyl-4-cyano-4-[2-(trifluoromethoxy)phenyl]butanoate (3.13 g, 80% pure, 7.59 mmol, Example 15A) in tert-butanol (45 ml) was mixed with Raney nickel (446 mg, 7.59 mmol) and hydrogenated overnight at normal pressure (1 atm). Raney nickel (446 mg, 7.59 mmol) was then added again and the mixture was hydrogenated for an additional 24 h at normal pressure (1 atm). Thereafter, the catalyst was filtered through silica gel and the filtrate was concentrated and dried in vacuo. 3.00 g (83% pure, 98% th. y.) of the title compound was obtained.

LC-MS (method 1): R _t = 1.29 min; MS (ESIpos): m/z = 334 [M+H]+.

Example 28A.

(+/-)-tert-Butyl-5-amino-4-(2-chloro-3-fluorophenyl)pentanoate (racemate)

A solution of (+/-)-tert-butyl-4-(2-chloro-3-fluorophenyl)-4-cyanobutanoate (4.32 g, 14.5 mmol, example 16A) in tert-butanol (85 ml) was mixed with Raney nickel ( 852 mg, 14.5 mmol) and hydrogenated overnight at normal pressure (1 atm). The catalyst was then filtered through kieselguhr, washed twice with t-butanol (15 ml) and the mother liquor was concentrated. Remainder adsor

- 37 040220 was taken up in ethyl acetate (80 ml) and extracted successively with 1 M hydrochloric acid and water (respectively 80 ml). The combined aqueous phases were adjusted to pH 8-9 with saturated aqueous sodium hydrogen carbonate and extracted twice with ethyl acetate (80 ml). The combined organic phases were dried over sodium sulfate, filtered and concentrated and the residue dried in vacuo. 2.43 g (85% pure, 47% th. y.) of the title compound were obtained.

LC-MS (method 1): R _t = 1.28 min; MS (ESIpos): m/z = 302 [M+H] ⁺ .

Example 29A.

(+/-)-tert-Butyl-5-amino-4-(6-chloro-2,3-difluorophenyl)pentanoate (racemate)

Solution of (+/-)-tert-butyl-4-(6-chloro-2,3-difluorophenyl)-4-cyanobutanoate (2.26 g, 83% pure, 5.95 mmol, Example 17A) in tert-butanol (35 ml ) was mixed with Raney nickel (349 mg, 5.95 mmol) and hydrogenated overnight at normal pressure (1 atm). The catalyst was then filtered through kieselguhr, washed twice with t-butanol (10 ml) and the filtrate was concentrated. The residue was adsorbed into ethyl acetate (50 ml) and extracted successively with 1 M hydrochloric acid and water (respectively 50 ml). The pH of the combined aqueous phases was adjusted to 8-9 with saturated aqueous sodium hydrogen carbonate and extracted twice with ethyl acetate (50 ml). The combined organic phases were dried over sodium sulfate, filtered and concentrated and the residue dried in vacuo. 1.05 g (97% pure, 53% th. y.) of the title compound was obtained.

LC-MS (method 4): R _t = 1.82 min; MS (ESIpos): m/z = 320 [M+H] ⁺ .

Example 30A.

(+/-)-tert-Butyl-5-amino-4-(5-fluoro-2-methylphenyl)pentanoate (racemate)

A solution of (+/-)-tert-butyl-4-cyano-4-(5-fluoro-2-methylphenyl)butanoate (4.92 g, 17.7 mmol, example 18A) in tert-butanol (100 ml) was mixed with Raney nickel (1.04 g, 17.7 mmol) and hydrogenated for 24 h at normal pressure (1 atm). The catalyst was then filtered through diatomaceous earth, washed additionally twice with t-butanol (15 ml) and the filtrate was concentrated. The residue was adsorbed into ethyl acetate (80 ml) and extracted successively with 1 M hydrochloric acid and water (respectively 80 ml). The pH of the combined aqueous phases was adjusted to 8-9 with saturated aqueous sodium hydrogen carbonate and extracted twice with ethyl acetate (80 ml). The combined organic phases were dried over sodium sulfate, filtered and concentrated and the residue dried in vacuo. 2.04 g (92% pure, 38% th. y.) of the title compound was obtained.

LC-MS (method 4): R _t = 1.94 min; MS (ESIpos): m/z = 282 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.109 (0.34), 1.197 (0.07), 1.293 (0.03), 1.357 (16.00), 1.394 (0.15), 1.513 (0.24), 1.609 (0.11) , 1.621 (0.11), 1.638 (0.25), 1.648 (0.17), 1.663 (0.22), 1.681 (0.14), 1.709 (0.06), 1.927 (0.05), 1.943 (0.10), 1.950 (0.13), 1.964 (0.28) . . , 6.866 (0.17), 6.873 (0.21), 6.887 (0.37), 6.894 (0.43), 6.909 (0.20), 6.916 (0.23), 6.968 (0.43), 6.974 (0.37), 6.994 (0.42), 7.001 (0.36) , 7.105 (0.03), 7.150 (0.35), 7.166 (0.40), 7.187 (0.30).

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 7.17 (dd, 1H), 6.99 (dd, 1H), 6.89 (td, 1H), 2.93-2.80 (m, 1H), 2.74-2.62 ( m, 2H), 2.23 (s, 3H), 2.06-1.87 (m, 3H), 1.74-1.60 (m, 1H), 1.50 (br. s, 2H), 1.36 (s, 9H).

Example 31A.

(+/-)-tert-Butyl-5-amino-4-(2-chloro-3,6-difluorophenyl)pentanoate (racemate)

A solution of (+/-)-tert-butyl-4-(2-chloro-3,6-difluorophenyl)-4-cyanobutanoate (4.10 g, 13.0 mmol, example 19A) in tert-butanol (75 ml) was mixed with nickel Raney (762 mg, 13.0 mmol) and hydrogenated for 24 h at normal pressure (1 atm). The catalyst was then filtered through kieselguhr, washed twice with t-butanol (15 ml) and the mother liquor was concentrated. The residue was adsorbed into ethyl acetate (80 ml) and the solution was extracted successively with 1 M hydrochloric acid and water (respectively 80 ml). The pH of the combined aqueous phases with a saturated aqueous sodium bicarbonate solution is set

- 38 040220 to 8-9 and extracted twice with ethyl acetate (corresponding to 100 ml). The combined organic phases were dried over sodium sulfate, filtered and concentrated and the residue dried in vacuo. 1.76 g (100% pure, 42% th. y.) of the title compound was obtained.

LC-MS (method 1): Rt = 1.21 min; MS (ESIpos): m/z = 320 [M+H] ⁺ .

Example 32A.

(+/-)-tert-Butyl-5-amino-4-[2-fluoro-6-(trifluoromethyl)phenyl]pentanoate (racemate)

Solution of (+/-)-tert-butyl-4-cyano-4-[2-fluoro-6-(trifluoromethyl)phenyl]butanoate (4.52 g, 13.6 mmol, example 20A) in tert-butanol (100 ml) and methanol (15 ml) was mixed with Raney nickel (801 mg, 13.6 mmol) and the mixture was hydrogenated overnight with stirring at normal pressure (1 atm). The reaction mixture was once more mixed with Raney nickel (2 g, 34.0 mmol) and vigorously stirred with hydrogen for 40 h at normal pressure (1 atm). The catalyst was then filtered through diatomaceous earth, washed additionally three times with methanol (30 ml each), and the filtrate was concentrated in vacuo. The residue was adsorbed in 200 ml of ethyl acetate. These organic phases were extracted twice with 200 ml of 1M hydrochloric acid. The combined aqueous phases were adjusted to pH 8-9 by slow addition of sodium hydrogen carbonate, then extracted twice with 200 ml of ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated on a rotary evaporator. The residue was dried in vacuo. 3.32 g (92% pure, 67% th. y.) of the title compound was obtained.

LC-MS (method 1): R _t = 1.21 min; MS (ESIpos): m/z = 336 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.109 (0.25), 1.156 (0.06), 1.167 (0.07), 1.174 (0.12), 1.191 (0.06), 1.327 (16.00), 1.390 (0.40) , 1.484 (0.07), 1.882 (0.09), 1.905 (0.14), 1.930 (0.25), 1.946 (0.23), 1.965 (0.29), 1.979 (0.15), 1.987 (0.45), 2.006 (0.19), 2.034 (0.10) , 2.055 (0.30), 2.074 (0.35), 2.093 (0.31), 2.118 (0.16), 2.129 (0.11), 2.150 (0.04), 2.310 (0.07), 2.365 (0.02), 2.669 (0.02) . , 4.019 (0.05), 4.037 (0.05), 7.476 (0.66), 7.485 (0.49), 7.489 (0.49) , 7.564 (0.37), 7.573 (0.26), 7.614 (0.04), 7.637 (0.04).

Example 33A.

(+/-)-tert-Butyl-5-amino-4-(2,3,6-trichlorophenyl)pentanoate (racemate)

nh ₂ o sn ₃

A solution of (+/-)-tert-butyl-4-cyano-4-(2,3,6-trichlorophenyl)butanoate (10.2 g, 95% pure, 27.9 mmol, Example 21A) in tert-butanol (210 ml) and methanol (9.1 ml) was mixed with Raney nickel (1.64 g, 27.9 mmol) and the mixture was hydrogenated overnight with stirring at normal pressure (1 atm). Additional Raney nickel (2.0 g, 34.0 mmol) was added and the mixture was hydrogenated for three days with stirring at normal pressure (1 atm). The catalyst was then filtered through kieselguhr, washed three times with methanol (respectively 30 ml) and the filtrate was concentrated. The residue was adsorbed in ethyl acetate (400 ml). These organic phases were extracted twice with 1 M hydrochloric acid (300 ml). The combined aqueous phases were adjusted to pH 8-9 by slow addition of sodium hydrogen carbonate and then extracted twice with ethyl acetate (respectively 300 ml). The combined organic phases were dried over sodium sulfate and concentrated on a rotary evaporator. Drying in vacuo yielded 2.54 g (89% pure, 23% th. y.) of the title compound.

LC-MS (method 1): Rt = 1.30 min; MS (ESIpos): m/z = 352 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.336 (16.00), 1.352 (1.85), 1.492 (0.42), 2.013 (0.65), 2.022 (0.61), 2.030 (0.63), 2.042 (0.89) , 2.055 (0.81), 2.070 (0.42), 2.082 (0.42), 2.097 (0.43), 3.049 (0.54), 3.069 (0.57), 7.426 (0.52), 7.506 (0.64), 7.532 (0.56) , 7.553 (0.41).

Example 34A.

(+/-)-tert-Butyl-5-amino-4-[2-(difluoromethoxy)-6-fluorophenyl]pentanoate (racemate)

Solution of (+/-)-tert-butyl-4-cyano-4-[2-(difluoromethoxy)-6-fluorophenyl]butanoate (7.07 g, 74% pure, 16.0 mmol, Example 22A) in tert-butanol (97 ml) was mixed with Raney nickel (937 mg, 16.0 mmol) and

- 39 040220 were hydrogenated for three days at normal pressure (1 atm). The catalyst was then filtered through kieselguhr and washed twice with tert-butanol (respectively 30 ml). The filtrate was concentrated and the residue was dried in vacuo. 6.21 g (65% pure, 76% theoretical) of the title compound was obtained.

LC-MS (method 1): R _t = 1.16 min; MS (ESIpos): m/z = 334 [M+H]+.

Example 35A.

(+/-)-tert-Butyl-4-{[(6-bromo-2-chloro-3-methylquinolin-4-yl)carbonyl]amino}-3-(2-chloro-6fluorophenyl)butanoate (racemate)

DIPEA ( 820 µl, 4.7 mmol). A suspension of 6-bromo-2-chloro-3-methylquinoline-4-carbonyl chloride (500 mg, 1.57 mmol, Example 3A) in dichloromethane (5 mL) was then added and the mixture was stirred for 16 h at RT. The mixture was then mixed with dichloromethane and water (respectively 30 ml) and shaken. After phase separation, 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 adsorbed in dichloromethane and purified by flash column chromatography (50 g Biotage Snap-Cartridge KP-Sil, cyclohexane/ethyl acetate gradient 93:7^7:3, Isolera one). The combined desired fractions were concentrated and the residue was dried in vacuo. 804 mg (96% pure, 86% thor.) of the title compound were obtained.

LC-MS (method 2): Rt = 1.30 min; MS (ESIpos): m/z = 569/571 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 1.241 (16.00), 1.397 (0.24), 2.250 (0.33), 2.755 (0.40), 2.770 (0.37), 3.730 (0.13), 4.051 (0.16 ), 7.206 (0.19), 7.219 (0.23), 7.246 (0.21), 7.340 (0.65), 7.882 (0.19), 7.905 (1.60), 7.934 (0.13), 8.968 (0.22), 8.983 (0.44), 8.998 (0.22 ).

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 8.98 (t, 1H), 7.97-7.86 (m, 2H), 7.86-7.43 (br., 1H), 7.38-7.31 (m, 2H) , 7.26-7.17 (m, 1H), 4.16-3.92 (m, 1H), 3.91-3.55 (m, 2H), 2.85-2.62 (m, 2H), 2.25 (br. s, 3H), 1.24 (s, 9H).

Example 36A.

(+/-)-tert-Butyl-5-{[(6-bromo-2-chloro-3-methylquinolin-4-yl)carbonyl]amino}-4-(2-chloro-5fluorophenyl)pentanoate (racemate)

DIPEA ( 3.9 ml, 23 mmol). A suspension of 6-bromo-2-chloro-3-methylquinoline-4-carbonyl chloride (2.45 g, 98% pure, 7.53 mmol, example 3A) in dichloromethane (35 mL) was then added and the mixture was stirred overnight at RT. The mixture was then stirred for an additional 20 hours at 50°C. After cooling to RT, the mixture was mixed with dichloromethane and water (respectively 50 ml) and shaken. After phase separation, the aqueous phase was extracted once with dichloromethane (50 ml). The combined organic phases were dried over sodium sulfate, filtered and concentrated, and the residue was adsorbed in dichloromethane and purified by flash column chromatography (100 g Biotage Snap-Cartridge Ultra silica gel, cyclohexane/ethyl acetate gradient 93:7^6:4, Isolera One) . The combined desired fractions were concentrated and the residue was dried in vacuo. 1.49 g (98% pure, 33% th. y.) of the title compound was obtained.

LC-MS (method 1): Rt = 2.58 min; MS (ESIpos): m/z = 583/585 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.87 (t, 1H), 7.93-7.86 (m, 2H), 7.65 (br. m, 1H, partially obscured), 7.51 (dd, 1H ), 7.43 (dd, 1H), 7.19-7.11 (m, 1H), 3.73 (br. s, 2H), 3.58 (br. s, 1H), 2.23 (br. s, 3H), 2.142.07 (m , 2H), 2.06-1.96 (m, 1H), 1.88-1.73 (m, 1H), 1.37 (s, 9H).

Example 37A.

(+/-)-tert-Butyl-5-{[(6-bromo-2-chloro-3-methylquinolin-4-yl)carbonyl]amino}-4-(2chlorophenyl)pentanoate (racemate)

- 40 040220

DIPEA ( 9.8 ml, 56 mmol). A suspension of 6-bromo-2-chloro-3-methylquinoline-4-carbonyl chloride (5.99 g, 18.8 mmol, Example 3A) in dichloromethane (30 mL) was then added and the mixture was stirred overnight at RT. The mixture was then mixed with dichloromethane and water (respectively 50 ml) and shaken. After phase separation, the aqueous phase was extracted once with dichloromethane (50 ml). The combined organic phases were dried over sodium sulfate, filtered and concentrated, and the residue was adsorbed into dichloromethane and purified by flash column chromatography (340 g Biotage Snap-Cartridge silica gel, 97:3^7:3 cyclohexane/ethyl acetate gradient, Isolera One). The combined desired fractions were concentrated to give two product fractions and the residue was dried in vacuo. 2.52 g (92% pure, 22% th. y., see Analysis section) of the first batch of the title compound was obtained.

The second batch of chromatography product was re-adsorbed in dichloromethane and further purified by flash column chromatography (100 g Biotage Snap-Cartridge KP-Sil, cyclohexane/ethyl acetate gradient 97:3^7:3, Isolera One). Received 1.35 g (88% pure, 11% theoretical. out.) of the second batch specified in the title compound.

LC-MS (method 1): R _t = 2.54 min; MS (ESIpos): m/z = 565/567 [M+H] ⁺ .

Example 38A.

(+/-)-tert-Butyl-5-{[(6-bromo-2-chloro-3-methylquinolin-4-yl)carbonyl]amino}-4-[2(trifluoromethyl)phenyl]pentanoate (racemate)

To a suspension of (+/-)-tert-butyl-5-amino-4-[2-(trifluoromethyl)phenyl]pentanoate (12.0 g, 82% pure, 30.9 mmol, Example 26A) in dichloromethane (250 mL) at RT DIPEA (13 ml, 77 mmol) was added. A suspension of 6-bromo-2-chloro-3-methylquinoline-4-carbonyl chloride (8.22 g, 25.8 mmol, example 3A) in dichloromethane (50 mL) was then added and the mixture was stirred for 18 h at RT. The mixture was then mixed with water (400 ml) and shaken. After phase separation, the aqueous phase was extracted once with dichloromethane (200 ml). The combined organic phases were washed with saturated aqueous sodium chloride, dried over sodium sulfate, filtered and concentrated, and the residue was purified by flash column chromatography (100 g Biotage Snap-Cartridge Ultra silica gel, cyclohexane/ethyl acetate gradient 97:3^75:25, Isolera One). The combined desired fractions were concentrated and the residue was dried in vacuo. 11.7 g (100% pure, 76% th. y.) of the title compound were obtained.

LC-MS (method 1): Rt = 2.60 min; MS (ESIpos): m/z = 599/601 [M+H] ⁺ .

1H-NMR(400 MHz, DMSO-d6) δ [ppm]: 1.188 (0.07), 1.318 (0.14), 1.349 (16.00), 1.398 (0.94), 1.505 (0.07), 1.871 (0.13), 1.894 (0.17) , 1.909 (0.20), 2.004 (0.25), 2.024 (0.50), 2.039 (0.49), 2.058 (0.33) , 3.752 (0.17), 5.754 (0.11), 7.487 (0.36), 7.505 (0.24), 7.692 (0.19), 7.712 (0.44), 7.728 (0.81), 7.747 (0.98), 7.765 (0.28), 7.904 (2.33) , 7.930 (0.08), 8.907 (0.34).

Separation of enantiomers.

The title target compound (7.0 g) was dissolved in isopropanol (140 ml) and separated into enantiomers by chiral phase preparative HPLC (see examples 39A and 40A) [column: Daicel Chiralcel OD-H, 5 μm, 250 mm x 50 mm; flow: 175 ml/min; sample injection: 1.2 ml; eluent: 17% isopropanol/83% carbon dioxide; duration of action 15 min, isocratic, UV detection 210 nm, temperature 38°C]. The combined target fractions were respectively concentrated and the corresponding residue was lyophilized.

Example 39A.

(-)-tert-Butyl-5-{[(6-bromo-2-chloro-3-methylquinolin-4-yl)carbonyl]amino}-4-[2(trifluoromethyl)phenyl]pentanoate (enantiomer 1).

The separation of enantiomers described in Example 38A gave 3.37 g (100% pure, >99% ee) of the title compound as the previously eluted enantiomer.

- 41 040220

[a] _D20 = -19.3°, 589 nm, c = 0.38 g ^/ 100 ml, methanol;

LC-MS (method 1): Rt = 2.60 min; MS (ESIpos): m/z = 599/601 [M+H]+.

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.009 (0.17), 0.007 (0.15), 1.029 (2.07), 1.044 (2.09), 1.187 (0.07), 1.310 (0.10), 1.317 (0.13 ), 1.348 (16.00), 1.503 (0.06), 1.871 (0.11), 1.894 (0.15), 1.908 (0.18), 1.918 (0.15), 1.941 (0.10), 1.963 (0.05), 1.984 (0.07), 2.003 (0.23 ), 2.023 (0.46), 2.038 (0.45), 2.057 (0.31), 2.080 (0.22), 2.087 (0.25), 2.100 (0.18), 2.117 (0.18), 2.130 (0.14), 2.151 (0.11), 2.239 (0.15 ), 2.365 (0.07), 2.669 (0.04), 3.669 (0.12), 3.751 (0.22), 3.762 (0.20), 3.766 (0.22), 3.777 (0.19), 3.782 (0.16), 3.792 (0.14), 4.323 (0.26 ), 4.334 (0.26), 7.467 (0.17), 7.485 (0.32), 7.503 (0.21), 7.691 (0.18), 7.710 (0.40), 7.727 (0.74), 7.745 (0.90), 7.764 (0.24), 7.881 (0.08 ), 7.902 (2.20), 7.929 (0.06), 8.907 (0.31).

Example 40A.

(+)-tert-Butyl-5-{[(6-bromo-2-chloro-3-methylquinolin-4-yl)carbonyl]amino}-4-[2(trifluoromethyl)phenyl]pentanoate (enantiomer 2).

The separation of enantiomers described in Example 38A gave 3.32 g (100% pure, ee 99%) of the title compound as the later eluted enantiomer.

[a] _D20 = +18.0°, 589 nm, c = 0.33 g/100 mL ^, methanol;

LC-MS (method 1): Rt = 2.60 min; MS (ESIpos): m/z = 599/601 [M+H]+.

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.029 (2.26), 1.044 (2.27), 1.187 (0.07), 1.317 (0.13), 1.347 (16.00), 1.503 (0.06), 1.870 (0.12) , 1.894 (0.16), 1.908 (0.19), 1.941 (0.10), 2.003 (0.24), 2.023 (0.48), 2.038 (0.47), 2.057 (0.32), 2.086 (0.26), 2.117 (0.18), 2.222 (0.16) , 2.365 (0.08) , 7.466 (0.17), 7.484 (0.34), 7.503 (0.23), 7.691 (0.18), 7.710 (0.42), 7.727 (0.77), 7.745 (0.94), 7.764 (0.25), 7.881 (0.08), 7.902 (2.28) , 7.929 (0.07), 8.906 (0.32).

Example 41A.

(+/-)-tert-Butyl-5-{[(6-bromo-2-chloro-3-methylquinolin-4-yl)carbonyl]amino}-4-[2(trifluoromethoxy)phenyl]pentanoate (racemate)

To a suspension of (+/-)-tert-butyl-5-amino-4-[2-(trifluoromethoxy)phenyl]pentanoate (10.0 g, 78% pure, 23.4 mmol, Example 27A) in dichloromethane (250 mL) at RT DIPEA (10 ml, 58 mmol) was added. A suspension of 6-bromo-2-chloro-3-methylquinoline-4-carbonyl chloride (6.21 g, 19.5 mmol, example 3A) in dichloromethane (50 mL) was then added and the mixture was stirred for 18 h at RT. The mixture was then mixed with water (400 ml) and shaken. After phase separation, the aqueous phase was extracted once with dichloromethane (200 ml). The combined organic phases were washed with saturated aqueous sodium chloride, dried over sodium sulfate, filtered and concentrated, and the residue was purified by flash column chromatography (100 g Biotage Snap-Cartridge Ultra silica gel, cyclohexane/ethyl acetate gradient 97:3 β 75:25, Isolera One). The combined desired fractions were concentrated and the residue was dried in vacuo. 9.91 g (92% pure, 76% th. y.) of the title compound was obtained.

LC-MS (method 1): Rt = 2.63 min; MS (ESIpos): m/z = 615/617 [M+H]+.

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.202 (0.07), 1.300 (0.34), 1.361 (16.00), 1.787 (0.09), 1.807 (0.20), 1.830 (0.19), 2.038 (0.28) , 2.062 (0.92) . , 7.901 (1.98), 8.882 (0.34).

Separation of enantiomers.

The title target compound (5.26 g) was adsorbed in isopropanol (120 ml). Then it was filtered, the filter residue was washed with an additional 12 ml of isopropanol, and the solution was separated into enantiomers by preparative SLC (supercritical liquid chromatography) on a chiral phase (see examples 42A and 43A) [column: Daicel Chiralcel OD-H, 5 μm, 250 mmx50 mm; flow: 175 ml/min; sample injection: 0.8 ml; eluent: 15% isopropanol/85% carbon dioxide; duration of action 14.5 min, isocratic, UV detection 210 nm, temperature 40°C]. The combined target fractions were concentrated and the corresponding residue was lyophilized.

Example 42A.

(+)-tert-Butyl-5-{[(6-bromo-2-chloro-3-methylquinolin-4-yl)carbonyl]amino}-4-[2(trifluoromethoxy)phenyl]pentanoate (enantiomer 1).

The separation of enantiomers described in Example 41A gave 2.37 g (100% pure, ee 100%) of the title compound as the previously eluted enantiomer.

- 42 040220

[a] _D20 = +16.3°, 589 nm, c = 0.45 g/100 ml ^, methanol;

LC-MS (method 1): Rt = 2.64 min; MS (ESIpos): m/z = 615/617 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 1.029 (0.18), 1.044 (0.18), 1.201 (0.07), 1.300 (0.06), 1.317 (0.07), 1.325 (0.09), 1.361 (16.00) ), 1.517 (0.07), 1.788 (0.10), 1.807 (0.21), 1.830 (0.21), 1.877 (0.06), 2.038 (0.31), 2.063 (1.04), 2.069 (1.28), 2.096 (0.25), 2.223 (0.20 ), 2.365 (0.06), 2.669 (0.05), 3.384 (0.22), 3.617 (0.08), 3.632 (0.14), 3.650 (0.27), 3.665 (0.35), 3.683 (0.32), 3.702 (0.31), 3.720 (0.26 ), 3.735 (0.13), 3.754 (0.08), 7.370 (0.43), 7.405 (0.68), 7.422 (0.54), 7.428 (0.52), 7.554 (0.44), 7.567 (0.41), 7.577 (0.32), 7.879 (0.11 ), 7.901 (2.03), 7.928 (0.08), 8.882 (0.39).

Example 43A.

(-)-tert-Butyl-5-{[(6-bromo-2-chloro-3-methylquinolin-4-yl)carbonyl]amino}-4-[2(trifluoromethoxy)phenyl]pentanoate (enantiomer 2).

The separation of enantiomers described in Example 41A gave 2.40 g (100% pure, ee 99%) of the title compound as the later eluted enantiomer.

[a] _D20 = -15.9°, 589 nm, c = 0.44 g ^/ 100 ml, methanol;

LC-MS (method 1): Rt = 2.63 min; MS (ESIpos): m/z = 615/617 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.029 (0.50), 1.044 (0.50), 1.201 (0.07), 1.316 (0.07), 1.325 (0.09), 1.361 (16.00), 1.517 (0.06) , 1.788 (0.09), 1.807 (0.20), 1.830 (0.20), 2.038 (0.28), 2.063 (0.96), 2.069 (1.20), 2.096 (0.22), 2.222 (0.17), 2.308 (0.19), 2.365 (0.06) . . , 7.879 (0.11), 7.901 (1.97), 8.882 (0.36).

Example 44A.

(+/-)-tert-Butyl-5 - {[(6-bromo-2-chloro-3-methylquinolin-4-yl)carbonyl] amino } -4-(2-chloro-3 fluorophenyl)pentanoate (racemate)

To a solution of (+/-)-tert-butyl-5-amino-4-(2-chloro-3-fluorophenyl)pentanoate (1.40 g, 85% pure, 3.94 mmol, Example 28A) in dichloromethane (45 ml) at RT added DIPEA (1.7 ml, 9.9 mmol). Then 6-bromo-2-chloro-3-methylquinoline-4-carbonyl chloride (1.07 g, 98% pure, 3.29 mmol, example 3A) was added and the mixture was stirred for 20 h at RT. The mixture was then mixed with water and dichloromethane (respectively 150 ml) and shaken. After phase separation, the aqueous phase was extracted once with dichloromethane (150 ml). The combined organic phases were dried over sodium sulfate, filtered and concentrated, and the residue was adsorbed in dichloromethane and purified by flash column chromatography (100 g Biotage Snap-Cartridge Ultra silica gel, cyclohexane/ethyl acetate gradient 97:3^7:3, Isolera One) . The combined desired fractions were concentrated and the residue was dried in vacuo. 206 mg (100% pure, 11% thor.) of the title compound were obtained.

LC-MS (method 2): R _t = 1.32 min; MS (ESIpos): m/z = 583/585 [M-H] ^- .

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 1.210 (0.08), 1.370 (16.00), 1.397 (2.57), 1.828 (0.24), 2.035 (0.25), 2.052 (0.26), 2.071 (0.32 ), 2.090 (1.00), 2.106 (1.01), 2.126 (0.40), 2.218 (0.37), 3.603 (0.25), 3.733 (0.32), 7.313 (0.33), 7.335 (0.25), 7.355 (0.33), 7.374 (0.52 ), 7.419 (0.29), 7.896 (2.22), 7.923 (0.14), 8.855 (0.29), 8.870 (0.52).

Example 45A.

(+/-)-tert-Butyl-5 - {[(6-bromo-2-chloro-3-methylquinolin-4-yl)carbonyl] amino } -4-(6-chloro-2,3difluorophenyl)pentanoate (racemate )

To a solution of (+/-)-tert-butyl-5-amino-4-(6-chloro-2,3-difluorophenyl)pentanoate (400 mg, 96% pure, 1.20 mmol, Example 29A) in dichloromethane (12 ml ) DIPEA (520 µl, 3.0 mmol) was added at RT. Then 6-bromo-2-chloro-3-methylquinoline-4-carbonyl chloride (326 mg, 98% pure, 1.00 mmol, example 3A) was added and the mixture was stirred for 20 hours at RT. The mixture was then mixed with water and dichloromethane (respectively 10 ml) and shaken. After phase separation, the aqueous phase was extracted once with dichloromethane (100

- 43 040220 ml). The combined organic phases were dried over sodium sulfate, filtered and concentrated, and the residue was adsorbed into dichloromethane and purified by flash column chromatography (25 g Biotage Snap-Cartridge Ultra silica gel, cyclohexane/ethyl acetate gradient 97:3^7:3, Isolera One). The combined desired fractions were concentrated and the residue was dried in vacuo. 156 mg (87% pure, 23% th. y.) of the title compound were obtained.

LC-MS (method 2): Rt = 1.34 min; MS (ESIpos): m/z = 601/603 [M+H]+.

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 0.007 (0.31), 1.203 (0.08), 1.260 (0.09), 1.309 (0.11), 1.363 (16.00), 1.397 (2.44), 1.970 (0.12 ), 2.056 (0.23), 2.075 (0.22), 2.159 (0.48), 2.176 (0.70), 2.242 (1.02), 2.351 (0.88), 2.365 (0.11), 2.669 (0.08), 2.709 (0.08), 3.097 (0.10 ), 3.702 (0.26), 3.804 (0.30), 7.402 (0.45), 7.737 (0.19), 7.878 (0.19), 7.901 (1.91), 7.908 (1.10), 7.929 (0.48), 8.965 (0.37).

Example 46A.

(+/-)-tert-Butyl-5-{[(6-bromo-2-chloro-3-methylquinolin-4-yl)carbonyl]amino}-4-(5-fluoro-2methylphenyl)pentanoate (racemate)

To a solution of (+/-)-tert-butyl-5-amino-4-(5-fluoro-2-methylphenyl)pentanoate (1.40 g, 92% pure, 4.58 mmol, Example 30A) in dichloromethane (45 ml) at RT added DIPEA (2.0 ml, 11 mmol). Then 6-bromo-2-chloro-3-methylquinoline-4-carbonyl chloride (1.25 g, 97% pure, 3.81 mmol, Example 3A) was added and the mixture was stirred for 20 hours at RT. The mixture was then mixed with water and dichloromethane (respectively 150 ml) and shaken. After phase separation, the aqueous phase was extracted once with dichloromethane (100 ml). The combined organic phases were dried over sodium sulfate, filtered and concentrated, and the residue was adsorbed in dichloromethane and purified by flash column chromatography (100 g Biotage Snap-Cartridge Ultra silica gel, cyclohexane/ethyl acetate gradient 97:3^7:3, Isolera One) . The combined desired fractions were concentrated and the residue was dried in vacuo. Received 538 mg (100% pure, 25% theoretical. yield) specified in the title compound.

LC-MS (method 2): Rt = 1.34 min; MS (ESIpos): m/z = 563/565 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.007 (0.21), 1.211 (0.07), 1.300 (0.11), 1.332 (0.11), 1.372 (16.00), 1.397 (2.79), 1.755 (0.12) , 1.789 (0.19), 1.812 (0.17), 1.969 (0.16), 1.982 (0.20), 1.999 (0.20) . . , 8.851 (0.31).

Example 47A.

(+/-)-tert-Butyl-5-{[(6-bromo-2-chloro-3-methylquinolin-4-yl)carbonyl]amino}-4-(2-chloro-3,6difluorophenyl)pentanoate (racemate )

To a solution of (+/-)-tert-butyl-5-amino-4-(2-chloro-3,6-difluorophenyl)pentanoate (9.53 g, 81% pure, 24.0 mmol, Example 31A) in dichloromethane (200 ml ) DIPEA (10 ml, 60 mmol) was added at RT. Then 6-bromo-2-chloro-3-methylquinoline-4-carbonyl chloride (6.38 g, 20.0 mmol, example 3A) was added and the mixture was stirred for 20 h at RT. The mixture was then mixed with water and dichloromethane (respectively 150 ml) and shaken. After phase separation, the aqueous phase was extracted once with dichloromethane (150 ml). The combined organic phases were dried over sodium sulfate, filtered and concentrated, and the residue was adsorbed in dichloromethane and purified by flash column chromatography (100 g Biotage Snap-Cartridge Ultra silica gel, cyclohexane/ethyl acetate gradient 97:3^7:3, Isolera One) . The combined desired fractions were concentrated and the residue was dried in vacuo. 8.40 g (90% pure, 63% th. y.) of the title compound was obtained.

LC-MS (method 1): R _t = 2.54 min; MS (ESIpos): m/z = 601/603 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.157 (0.23), 1.175 (0.45), 1.193 (0.24), 1.202 (0.08), 1.268 (0.07), 1.311 (0.35), 1.321 (0.40) , 1.363 (16.00), 1.380 (0.76), 1.407 (0.25), 1.519 (0.07), 1.989 (0.95), 2.046

- 44 040220 (0.21), 2.060 (0.26), 2.077 (0.24), 2.097 (0.18), 2.143 (0.58), 2.161 (0.76), 2.237 (0.60), 2.351 (0.07), 2.366 (0.05), 2.670 (0.04 ), 2.711 (0.03), 3.697 (0.24), 3.800 (0.28), 4.003 (0.08), 4.021 (0.21), 4.039 (0.21), 4.057 (0.08), 7.312 (0.25), 7.327 (0.19), 7.417 (0.21 ), 7.750 (0.05), 7.882 (0.18), 7.905 (2.10), 7.934 (0.14), 8.950 (0.24), 8.964 (0.43).

Separation of enantiomers.

The title title compound (4.8 g) was dissolved in acetonitrile and separated into enantiomers by preparative HPLC in chiral phase (see Examples 48A and 49A) [column: Daicel Chiralcel OX-H, 5 μm, 250 mm x 20 mm; flow: 20 ml/min; detection: 220 nm; temperature: 30°C; sample injection: 30 ml; eluent: 20% isopropanol/80% heptane; duration of action 18 min, isocratic]. The combined target fractions were respectively concentrated and the corresponding residue was dried in vacuo.

Example 48A.

(+)-tert-Butyl-5 - {[(6-bromo-2-chloro-3 -methylquinolin-4-yl)carbonyl]amino} -4-(2-chloro-3,6difluorophenyl)pentanoate (enantiomer 1) .

The separation of enantiomers described in Example 47A gave 1.52 g (81% pure, ee 100%) of the title compound as the previously eluted enantiomer.

[a] _D20 = +31.9°, 589 nm, c = 0.31 g/100 mL ^, methanol;

LC-MS (method 1): Rt = 2.56 min; MS (ESIpos): m/z = 601/603 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.151 (0.03), 1.009 (0.23), 1.029 (3.00), 1.044 (3.00), 1.105 (0.49), 1.108 (0.83), 1.120 (0.35 ), 1.139 (0.06), 1.201 (0.08), 1.267 (0.07), 1.309 (0.32), 1.362 (16.00), 1.406 (0.23), 1.518 (0.07), 1.595 (0.04), 1.681 (0.12), 1.979 (0.14 ), 2.045 (0.23), 2.059 (0.28), 2.075 (0.27), 2.096 (0.21), 2.142 (0.65), 2.160 (0.82), 2.236 (0.67), 2.350 (0.12), 2.417 (0.04), 2.669 (0.04 ), 3.533 (0.53), 3.696 (0.29), 3.741 (0.21), 3.756 (0.35), 3.772 (0.47), 3.787 (0.49), 3.802 (0.40), 7.311 (0.29), 7.326 (0.21), 7.417 (0.25 ), 7.748 (0.07), 7.881 (0.20), 7.904 (2.30), 7.928 (0.16), 8.963 (0.48).

Example 49A.

(-)-tert-Butyl-5-{[(6-bromo-2-chloro-3-methylquinolin-4-yl)carbonyl]amino}-4-(2-chloro-3,6difluorophenyl)pentanoate (enantiomer 2) .

The separation of enantiomers described in Example 47A gave 1.46 g (82% pure, ee 97%) of the title compound as the later eluted enantiomer.

[a] _D20 = -32.3°, 589 nm, c = 0.36 ^g /100 ml, methanol;

LC-MS (method 1): Rt = 2.56 min; MS (ESIpos): m/z = 601/603 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.850 (0.05), 1.009 (0.34), 1.029 (2.07), 1.044 (2.03), 1.104 (0.77), 1.108 (1.13), 1.120 (0.64) , 1.139 (0.11), 1.155 (0.06), 1.201 (0.08), 1.267 (0.10), 1.309 (0.37) , 1.681 (0.09), 1.974 (0.16), 2.044 (0.25), 2.061 (0.32), 2.075 (0.30), 2.095 (0.24), 2.142 (0.72), 2.159 (0.86), 2.236 (0.75), 2.669 (0.05) . , 7.417 (0.28), 7.763 (0.07), 7.881 (0.28), 7.904 (2.52), 7.932 (0.15), 8.963 (0.51).

Example 50A.

(+/-)-tert-Butyl-5-{[(6-bromo-2-chloro-3-methylquinolin-4-yl)carbonyl]amino}-4-[2-fluoro-6(trifluoromethyl)phenyl]pentanoate (racemate)

To a solution of (+/-)-tert-butyl-5-amino-4-[2-fluoro-6-(trifluoromethyl)phenyl]pentanoate (2.15 g, 92% pure, 5.91 mmol, Example 32A) and DIPEA (2.6 ml , 15 mmol) in dichloromethane (57 ml) at RT was added a solution of 6-bromo-2-chloro-3-methylquinoline-4-carbonyl chloride (1.57 g, 4.92 mmol, example 3A) in a small amount of dichloromethane. The mixture was stirred overnight at RT. Water and dichloromethane (corresponding to 200 ml) were added for working up. The phases are separated. The aqueous phase was back extracted with dichloromethane (200 ml). The combined organic phases were washed with saturated aqueous sodium chloride (200 ml), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was taken up in a small amount of cyclohexane and ethyl acetate and purified by column chromatography (Biotage, 100 g silica gel, Snap-Cartridge Ultra, 8:2 cyclohexane/ethyl acetate eluent). The resulting product fraction was concentrated in vacuo and the residue was dried in vacuo. 2.20 g (97% pure, 70% th. y.) of the title compound was obtained.

LC-MS (method 1): Rt = 2.57 min; MS (ESIpos): m/z = 617 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 8.96 (t, 1H), 7.94-7.86 (m, 2H) 7.87-7.25 (m, 4H), 3.93 (br. s, 1H), 3.73 (br. s, 1H), 3.34-3.24 (1H, hidden), 2.45-1.99 (m, 7H), 1.34 (s, 9H).

- 45 040220

Example 51A.

(+/-)-tert-Butyl-5-{[(6-bromo-2-chloro-3-methylquinolin-4-yl)carbonyl]amino}-4-(2,3,6trichlorophenyl)pentanoate (racemate)

To a solution of (+/-)-tert-butyl-5-amino-4-(2,3,6-trichlorophenyl)pentanoate (1.84 g, 89% pure, 4.64 mmol, Example 33A) and DIPEA (2.0 ml, 12 mmol ) in dichloromethane (45 ml) at RT was added a solution of 6bromo-2-chloro-3-methylquinoline-4-carbonyl chloride (1.23 g, 3.87 mmol, example 3A) in a small amount of dichloromethane. The mixture was stirred for 2 h at RT. Water and dichloromethane (corresponding to 200 ml) were added for working up. The phases are separated. The aqueous phase was back extracted with dichloromethane (200 ml). The combined organic phases were washed with saturated aqueous sodium chloride (200 ml), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was dissolved in a small amount of DMSO and purified by preparative HPLC (method 13). The resulting product fraction was concentrated in vacuo and the residue was dried in vacuo. 2.03 g (93% pure, 77% th. y.) of the title compound was obtained.

LC-MS (method 4): R _t = 1.75 min; Ionization without target mass detection.

'H-NMR (500 MHz, DMSO-d6): δ [ppm] = 8.98-8.88 (m, 1H), 7.97-7.34 (m, 5H), 4.22-3.95 (m, 2H), 3.953.79 (m , 1H), 2.35-1.99 (m, 7H), 1.37-1.34 (m, 9H).

Example 52A.

(+/-)-tert-Butyl-5-{[(6-bromo-2-chloro-3-methylquinolin-4-yl)carbonyl]amino}-4-[2-(difluoromethoxy)6-fluorophenyl]pentanoate ( racemate)

To a solution of (+/-)-tert-butyl-5-amino-4-[2-(difluoromethoxy)-6-fluorophenyl]pentanoate (5.51 g, 65% pure, 10.7 mmol, Example 34A) in dichloromethane (100 ml ) DIPEA (4.7 mL, 27 mmol) was added at RT. Then 6-bromo-2-chloro-3-methylquinoline-4-carbonyl chloride (2.85 g, 8.94 mmol, example 3A) was added and the mixture was stirred for 20 h at RT. The mixture was then mixed with water and dichloromethane (respectively 150 ml) and shaken. After phase separation, the aqueous phase was extracted once with dichloromethane (150 ml). The combined organic phases were dried over sodium sulfate, filtered and concentrated, and the residue was adsorbed in dichloromethane and purified by flash column chromatography (100 g Biotage Snap-Cartridge Ultra silica gel, cyclohexane/ethyl acetate gradient 97:3^7:3, Isolera One) . The combined desired fractions were concentrated and the residue was dried in vacuo. 4.78 g (91% pure, 79% th. y.) of the title compound were obtained.

LC-MS (method 1): R _t = 2.49 min; MS (ESIpos): m/z = 615/617 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.158 (0.05), 1.175 (0.11), 1.199 (0.07), 1.292 (0.08), 1.308 (0.28), 1.320 (0.37), 1.337 (1.76) , 1.360 (16.00), 1.372 (0.72), 1.394 (0.28), 1.516 (0.07), 1.957 (0.22), 1.989 (0.32), 1.998 (0.30) . . , 7.385 (0.25), 7.402 (0.24), 7.436 (0.37), 7.751 (0.15), 8.918 (0.25), 8.933 (0.50), 8.948 (0.26).

(0.04), (0.46), (0.70), (0.07),

3.522

7.048

7.288

7.878 (0.22), 3.741 (0.20), 3.797 (0.53), 7.069 (0.41), 7.097 (0.09), 7.305 (0.11), 7.323 (0.17), 7.901 (1.98), 7.930

Example 53A.

(+/-)-tert-Butyl-4-({[6-bromo-3-methyl-2-(piperidin-1-yl)quinolin-4-yl]carbonyl}amino)-3 -(2-chloro6- fluorophenyl)butanoate (racemate)

- 46 040220

To a suspension of (+/-)-tert-butyl-4-{[(6-bromo-2-chloro-3-methylquinolin-4-yl)carbonyl]amino}-3-(2chloro-6-fluorophenyl)butanoate ( 300 mg, 526 µmol, example 35A) in 1-butanol (3.8 ml) was added piperidine (160 µl, 1.6 mmol) and the mixture was stirred for 16 h at 100°C. After cooling to RT, the mixture was mixed with water and ethyl acetate (respectively 50 ml) 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, and the residue was adsorbed in dichloromethane and previously purified by flash column chromatography (25 g Biotage Snap-Cartridge KP-Sil, cyclohexane/ethyl acetate gradient 93:7^6:4, Isolera One). Then further purified by preparative HPLC (method 9). The combined desired fractions were concentrated and the residue was dried in vacuo. 184 mg (98% pure, 55% thor.) of the title compound were obtained.

LC-MS (method 1): R _t = 2.74 min; MS (ESIpos): m/z = 618/620 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.236 (16.00), 1.613 (0.55), 1.678 (1.07), 2.169 (1.96), 2.758 (0.44), 2.772 (0.40), 3.161 (1.37) . , 7.683 (0.88), 7.705 (0.21), 8.825 (0.26), 8.840 (0.53), 8.855 (0.26).

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.84 (t, 1H), 7.72-7.63 (m, 2H), 7.50 (br. s, 1H), 7.39-7.30 (m, 2H) , 7.25-7.17 (m, 1H), 4.13-3.96 (m, 1H), 3.87-3.57 (m, 2H), 3.16 (br. s, 4H), 2.86-2.60 (m, 2H), 2.17 (s, 3H), 1.79-1.55 (m, 6H), 1.24 (s, 9H).

Example 54A.

(+/-)-tert-Butyl-4-[({6-bromo-3-methyl-2-[(2-phenylethyl)amino]quinolin-4-yl}carbonyl)amino]-3-(2chloro-6 -fluorophenyl)butanoate (racemate)

XjL ⁰

CH ₃

O^NH O—|—CH ₃ ]CH ₃ η 3 ³

LIX

Ϊ1

To a suspension of (+/-)-tert-butyl-4-{[(6-bromo-2-chloro-3-methylquinolin-4-yl)carbonyl]amino}-3-(2chloro-6-fluorophenyl)butanoate ( 300 mg, 526 µmol, example 35A) in 1-butanol (3.8 ml) was added 2phenylethanamine (200 µl, 1.6 mmol) and the mixture was stirred overnight at 100°C. The mixture was then further stirred for 24 hours at 130°C. After cooling to RT, the mixture was mixed with water and ethyl acetate (respectively 50 ml) 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, and the residue was adsorbed in dichloromethane and previously purified by flash column chromatography (25 g Biotage Snap-Cartridge KP-Sil, cyclohexane/ethyl acetate gradient 93:7^6:4, Isolera One). Then further purified by preparative HPLC (method 9). The combined desired fractions were concentrated and the residue was dried in vacuo. 162 mg (98% pure, 46% thor.) of the title compound were obtained.

LC-MS (method 1): R _t = 2.41 min; MS (ESIpos): m/z = 654/656 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.88 (br. s, 1H), 7.68 (br. s, 1H), 7.41-7.15 (m, 11H), 4.04 (br. s, 1H), 3.90-3.62 (m, 4H), 2.97 (br. t, 2H), 2.82-2.66 (m, 2H), 2.10-1.88 (m, 3H), 1.24 (s, 9H).

Example 55A.

(+/-)-tert-Butyl-5-({[6-bromo-3-methyl-2-(piperidin-1-yl)quinolin-4-yl]carbonyl}amino)-4-(2-chloro5- fluorophenyl)pentanoate (racemate)

- 47 040220

To a suspension of (+/-)-tert-butyl-5-{[(6-bromo-2-chloro-3-methylquinolin-4-yl)carbonyl]amino}-4-(2chloro-5-fluorophenyl)pentanoate ( 1.10 g, 1.88 mmol, example 36A) in 1-butanol (14 ml) was added piperidine (560 μl, 5.6 mmol) and the mixture was stirred for three days at 100°C. After cooling to RT, the mixture was mixed with water and ethyl acetate (respectively 50 ml) 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, and the residue was adsorbed in dichloromethane and purified by flash column chromatography (100 g Biotage Snap-Cartridge KP-Sil, cyclohexane/ethyl acetate gradient 93:7^6:4, Isolera one). The combined desired fractions were concentrated and the residue was dried in vacuo. 676 mg (98% pure, 56% thor.) of the title compound were obtained.

LC-MS (method 1): R _t = 2.83 min; MS (ESIpos): m/z = 632/634 [M+H] ⁺ .

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: 8.72 (t, 1H), 7.69-7.61 (m, 2H), 7.50 (dd, 1H), 7.47 (br. s, 1H, partially hidden ), 7.41 (dd, 1H), 7.14 (td, 1H), 3.74-3.64 (m, 2H), 3.63-3.53 (m, 1H), 3.17-3.10 (m, 4H), 2.171.94 (m, 6H ), 1.86-1.74 (m, 1H), 1.72-1.55 (m, 6H), 1.37 (s, 9H).

Separation of enantiomers.

The title title compound (675 mg) was dissolved in ethanol (7 ml) and separated into enantiomers by preparative HPLC in chiral phase (see Examples 56A and 57A) [column: Daicel Chiralcel OX-H, 5 µm, 250 mm x 20 mm ; flow: 40 ml/min; sample injection: 0.1 ml; eluent: 20% ethanol/80% heptane; duration of action 10 min, isocratic]. The combined target fractions were concentrated and the residue was lyophilized.

Example 56A.

(-)-tert-Butyl-5 -({[6-bromo-3-methyl-2-(piperidin-1 -yl)quinolin-4-yl]carbonyl}amino)-4-(2-chloro-5fluorophenyl) pentanoate (enantiomer 1).

The separation of enantiomers described in Example 55A gave 237 mg (98% pure, ee 99%) of the title compound as the previously eluted enantiomer.

[a] _D20 = -12.8°, 589 nm, c = 0.34 g ^/ 100 ml, methanol;

LC-MS (method 1): R _t = 2.83 min; MS (ESIpos): m/z = 632/634 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.72 (t, 1H), 7.69-7.61 (m, 2H), 7.50 (dd, 1H), 7.47 (br. s, 1H, partially obscured ), 7.41 (dd, 1H), 7.14 (td, 1H), 3.74-3.64 (m, 2H), 3.63-3.53 (m, 1H), 3.17-3.09 (m, 4H), 2.161.97 (m, 6H ), 1.87-1.74 (m, 1H), 1.72-1.55 (m, 6H), 1.37 (s, 9H).

Example 57A.

(+)-tert-Butyl-5-({[6-bromo-3-methyl-2-(piperidin-1-yl)quinolin-4-yl]carbonyl}amino)-4-(2-chloro5-fluorophenyl) pentanoate (enantiomer 2).

The separation of enantiomers described in Example 55A gave 207 mg (98% pure, ee 99%) of the title compound as the later eluted enantiomer.

[a] _D20 = +13.1°, 589 nm, c = 0.38 g/100 ml ^, methanol;

LC-MS (method 1): R _t = 2.83 min; MS (ESIpos): m/z = 632/634 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 8.72 (t, 1H), 7.70-7.60 (m, 2H), 7.50 (dd, 1H), 7.47 (br. s, 1H, partially obscured) , 7.41 (dd, 1H), 7.14 (td, 1H), 3.74-3.64 (m, 2H), 3.63-3.53 (m, 1H), 3.17-3.10 (m, 4H), 2.161.96 (m, 6H) , 1.87-1.74 (m, 1H), 1.73-1.54 (m, 6H), 1.37 (s, 9H).

Example 58A.

(+/-)-tert-Butyl-5 -({[6-bromo-2-(4,4-difluoropiperidin-1 -yl)-3-methylquinolin-4yl]carbonyl}amino)-4-(2-chloro -5-fluorophenyl)pentanoate (racemate)

To a suspension of (+/-)-tert-butyl-5-{[(6-bromo-2-chloro-3-methylquinolin-4-yl)carbonyl]amino}-4-(2chloro-5-fluorophenyl)pentanoate ( 135 mg, 231 µmol, example 36A) in 1-butanol (1.7 ml) was added 4,4 difluoropiperidine (84 mg, 693 µmol) and the mixture was stirred for four days at 100°C. After cooling

- 48 040220 to RT the mixture was mixed with water and ethyl acetate (respectively 20 ml) and shaken. After phase separation, the aqueous phase was extracted once with ethyl acetate (20 ml). The combined organic phases were dried over sodium sulfate, filtered and concentrated, and the residue was adsorbed in dichloromethane and prepurified by flash column chromatography (25 g Biotage Snap-Cartridge KP-Sil, cyclohexane/ethyl acetate gradient 93:7^5:5, Isolera One). Then further purified by preparative HPLC (method 9). The combined desired fractions were concentrated and the residue was dried in vacuo. 19 mg (72% pure, 9% theoretical) of the title compound were obtained.

LC-MS (method 1): R _t = 2.72 min; MS (ESIpos): m/z = 668/670 [M+H]+.

Example 59A.

(+/-)-tert-Butyl-5-({[6-bromo-3-methyl-2-(morpholin-4-yl)quinolin-4-yl]carbonyl}amino)-4-(2-chloro5- fluorophenyl)pentanoate (racemate)

To a suspension of (+/-)-tert-butyl-5-{[(6-bromo-2-chloro-3-methylquinolin-4-yl)carbonyl]amino}-4-(2chloro-5-fluorophenyl)pentanoate ( 135 mg, 231 µmol, example 36A) in 1-butanol (1.7 ml) was added morpholine (60 µl, 690 µmol) and the mixture was stirred for four days at 100°C. After cooling to RT, the mixture was mixed with water and ethyl acetate (respectively 20 ml) and shaken. After phase separation, the aqueous phase was extracted once with ethyl acetate (20 ml). The combined organic phases were dried over sodium sulfate, filtered and concentrated, and the residue was adsorbed in dichloromethane and prepurified by flash column chromatography (25 g Biotage SnapCartridge KP-Sil, 93:7 ^ 6:4 cyclohexane/ethyl acetate gradient, Isolera One ). Then further purified by preparative HPLC (method 9). The combined desired fractions were concentrated and the residue was dried in vacuo. 61 mg (98% pure, 41% theoretical) of the title compound were obtained.

LC-MS (method 1): R _t = 2.55 min; MS (ESIpos): m/z = 634/636 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: -0.009 (0.21), 0.007 (0.19), 1.211 (0.06), 1.296 (0.07), 1.328 (0.09), 1.371 (16.00), 1.527 ( 0.06), 1.773 (0.12), 1.790 (0.14), 1.808 (0.16), 1.829 (0.13), 1.999 (0.14), 2.011 (0.18), 2.029 (0.18), 2.050 (0.15), (0.04) ), 2.669 (0.04), (0.46), 3.753 (1.33), 3.764 (1.83), (0.26), 7.157 (0.15), 7.165 (0.15), (0.50), 7.505 (0.47), 7.518 (0.43),

2.063 (0.12), 2.085 (0.65), 2.102 (0.88), 2.122 (0.35), 2.147 (1.79), 2.327

2.709 (0.04), 3.172 (1.20), 3.177 (1.21), 3.185 (0.93), 3.587 (0.21), 3.692

3.775 (1.35), 3.838 (0.55), 7.115 (0.13), 7.123 (0.15), 7.137 (0.24), 7.143

7.395 (0.34), 7.402 (0.35), 7.420 (0.36), 7.428 (0.34), 7.483 (0.48), 7.496

7.661 (0.18), 7.683 (1.46), 7.691 (0.90), 7.708 (0.11), 7.713 (0.13), 8.731 (0.20), 8.746 (0.40), 8.760 (0.19).

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.75 (t, 1H), 7.73-7.65 (m, 2H), 7.50 (dd, 1H), 7.46 (br. s, 1H, hidden) , 7.41 (dd, 1H), 7.14 (td, 1H), 3.80-3.65 (m, 6H, partially hidden), 3.59 (br. s, 1H), 3.25-3.12 (m, 4H), 2.20-1.95 (m , 6H), 1.87–1.73 (m, 1H), 1.37 (s, 9H).

Example 60A.

(+/-)-tert-Butyl-5 -({[6-bromo-2-(3,6-dihydropyridin-1 (2H)-yl)-3-methylquinolin-4yl]carbonyl}amino)-4-( 2-chloro-5-fluorophenyl)pentanoate (racemate)

To a suspension of (+/-)-tert-butyl-5-{[(6-bromo-2-chloro-3-methylquinolin-4-yl)carbonyl]amino}-4-(2chloro-5-fluorophenyl)pentanoate ( 100 mg, 171 µmol, example 36A) in 1-butanol (1.2 ml) was added 1,2,3,6 tetrahydropyridine (43 mg, 513 µmol) and the mixture was stirred for three days at 100°C. After cooling to RT, the mixture was directly (without further workup) purified by preparative HPLC (method 18). The combined target fractions were concentrated and the residue was lyophilized. 50 mg (98% pure, 45% thor.) of the title compound were obtained.

LC-MS (method 1): R _t = 2.73 min; MS (ESIpos): m/z = 630/632 [M+H] ⁺ .

- 49 040220

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.150 (0.07), -0.009 (0.56), 0.007 (0.62), 0.146 (0.07), 1.213 (0.06), 1.297 (0.06), 1.331 ( 0.09), 1.373 (16.00), 1.529 (0.07), 1.780 (0.12), 1.814 (0.18), 1.836 (0.14), 2.007 (0.15), 2.019 (0.18), 2.037 (0.18), 2.057 (0.17), 0.16), 2.086 (0.71), 2.103 (0.93), 2.124 (0.46), 2.140 (2.18), 2.302 (0.44), 2.365 (0.07), 2.669 (0.07), 2.709 (0.06), 3.274 (0.31), 0.19), 3.689 (0.35),3.795 (0.79), 5.817 (0.15), 5.843 (0.49), 5.863 (0.45), 5.888 (0.14), 7.123 (0.16), 7.144 (0.28), 7.158 (0.16), 0.16), 7.397 (0.35), 7.404 (0.37), 7.422 (0.38), 7.429 (0.37), 7.482 (0.48), 7.496 (0.48), 7.504 (0.45), 7.517 (0.41), 7.619 (0.38), 1.32), 7.654 (0.81), 7.659 (0.75), 7.677 (0.22), 7.682 (0.24), 8.720 (0.21), 8.734 (0.41), 8.748 (0.20).

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 8.73 (t, 1H), 7.69-7.61 (m, 2H), 7.50 (dd, 1H), 7.47 (br. s, 1H), 7.41 ( dd, 1H), 7.14 (td, 1H), 5.91-5.79 (m, 2H), 3.80 (br. s, 2H), 3.69 (br. s, 2H), 3.59 (br. s, 1H), 3.27 ( br. s, 2H, partially hidden), 2.30 (br. s, 2H), 2.18-1.97 (m, 6H), 1.88-1.74 (m, 1H), 1.37 (s, 9H).

Example 61A.

(+/-)-tert-Butyl-5-({[6-bromo-3-methyl-2-(thiomorpholin-4-yl)quinolin-4-yl]carbonyl}amino)-4-(2chloro-5 - fluorophenyl)pentanoate (racemate)

To a suspension of (+/-)-tert-butyl-5-{[(6-bromo-2-chloro-3-methylquinolin-4-yl)carbonyl]amino}-4-(2chloro-5-fluorophenyl)pentanoate ( 100 mg, 171 µmol, example 36A) in 1-butanol (1.2 ml) was added thiomorpholine (53 mg, 513 µmol) and the mixture was stirred for 18 h at 100°C. Thiomorpholine (53 mg, 513 μmol) was then added again and the mixture was stirred for an additional four days at 100°C. After cooling to RT, the mixture was directly (without further workup) purified by preparative HPLC (method 18). The combined target fractions were concentrated and the residue was lyophilized. 55 mg (98% pure, 48% thor.) of the title compound were obtained.

LC-MS (method 1): R _t = 2.69 min; MS (ESIpos): m/z = 650/652 [M+H]+.

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.150 (0.07), -0.009 (0.65), 0.007 (0.57), 0.145 (0.08), 1.212 (0.06), 1.298 (0.07), 1.329 ( 0.09), 1.372 (16.00), 1.528 (0.07), 1.775 (0.12), 1.809 (0.18), 1.830 (0.15), 2.000 (0.15), 2.013 (0.19), 2.030 (0.19), 2.051 (0.16), 0.14), 2.084 (0.71), 2.101 (0.99), 2.128 (2.24), 2.327 (0.06), 2.365 (0.05), 2.669 (0.07), 2.709 (0.06), 2.785 (1.20), 2.797 (1.13), 3.424 ( 1.18), 3.583 (0.20),3.687 (0.35), 7.124 (0.16), 7.144 (0.28), 7.165 (0.17), 7.395 (0.35), 7.402 (0.36), 7.420 (0.37), 7.427 (0.36), 0.49), 7.495 (0.51), 7.504 (0.48), 7.517 (0.44), 7.656 (0.22), 7.678 (1.47), 7.683 (1.07), 7.688 (0.88), 7.706 (0.15), 7.710 (0.17), 0.22), 8.728 (0.43), 8.742 (0.21).

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 8.73 (t, 1H), 7.72-7.65 (m, 2H), 7.50 (dd, 1H), 7.46 (br. s, 1H, partially obscured) , 7.41 (dd, 1H), 7.14 (td, 1H), 3.69 (br. s, 2H), 3.58 (br. s, 1H), 3.46-3.39 (m, 4H), 2.82-2.75 (m, 4H) , 2.17-1.97 (m, 6H), 1.88-1.74 (m, 1H), 1.37 (s, 9H).

Example 62A.

(+/-)-tert-Butyl-5-[({6-bromo-2-[cis-2,6-dimethylmorpholin-4-yl]-3-methylquinolin-4yl}carbonyl)amino]-4-(2 -chloro-5-fluorophenyl)pentanoate (racemate)

To a suspension of (+/-)-tert-butyl-5-{[(6-bromo-2-chloro-3-methylquinolin-4-yl)carbonyl]amino}-4-(2chloro-5-fluorophenyl)pentanoate ( 100 mg, 171 µmol, example 36A) in 1-butanol (1.2 ml) was added cis-2,6dimethylmorpholine (59 mg, 513 µmol) and the mixture was stirred for three days at 100°C. After cooling to RT, the mixture was directly (without further workup) purified by preparative HPLC (method 18). The combined target fractions were concentrated and the residue was lyophilized. 70 mg (98% pure, 60% thor.) of the title compound were obtained.

LC-MS (method 1): R _t = 2.71 min; MS (ESIpos): m/z = 662/664 [M+H] ⁺ .

- 50 040220

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.149 (0.06), 0.007 (0.42), 0.146 (0.06), 1.133 (3.52), 1.148 (3.54), 1.212 (0.07), 1.299 (0.08 ), 1.330 (0.09), 1.372 (16.00), 1.528 (0.07), 1.813 (0.18), 2.017 (0.18), 2.035 (0.17), 2.055 (0.15), 2.067 (0.15), 2.085 (0.69), 2.101 (0.90 ), 2.121 (0.34), 2.156 (2.32), 2.327 (0.08), 2.366 (0.07), 2.669 (0.09), 2.709 (0.08), 3.431 (0.58), 3.461 (0.54), 3.581 (0.19), 3.685 (0.31 ), 3.777 (0.41), 7.124 (0.16), 7.145 (0.28), 7.159 (0.16), 7.393 (0.35), 7.400 (0.35), 7.418 (0.36), 7.425 (0.35), 7.483 (0.49), 7.496 (0.50 ), 7.505 (0.46), 7.518 (0.42), 7.655 (0.08), 7.676 (2.30), 8.707 (0.22), 8.721 (0.42).

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.72 (t, 1H), 7.71-7.64 (m, 2H), 7.50 (dd, 1H), 7.46 (br. s, 1H, partially obscured ), 7.41 (dd, 1H), 7.14 (td, 1H), 3.84-3.73 (m, 2H), 3.69 (br. s, 2H), 3.58 (br. s, 1H), 3.45 (br. d, 2H ), 2.54-2.48 (hidden, 2H), 2.16 (s, 3H), 2.13-1.96 (m, 3H), 1.87-1.75 (m, 1H), 1.37 (s, 9H), 1.15 (s, 3H), 1.13(s, 3H).

Example 63A.

(+/-)-tert-Butyl-5-({[6-bromo-3-methyl-2-(pyrrolidin-1-yl)quinolin-4-yl]carbonyl}amino)-4-(2chloro-5 - fluorophenyl)pentanoate (racemate)

To a suspension of (+/-)-tert-butyl-5-{[(6-bromo-2-chloro-3-methylquinolin-4-yl)carbonyl]amino}-4-(2chloro-5-fluorophenyl)pentanoate ( 100 mg, 171 µmol, example 36A) in 1-butanol (1.2 ml) was added pyrrolidine (43 µl, 510 µmol) and the mixture was stirred for three days at 100°C. After cooling to RT, the mixture was directly (without further workup) purified by preparative HPLC (method 20). The combined target fractions were concentrated and the residue was lyophilized. 63 mg (98% pure, 58% thor.) of the title compound were obtained.

LC-MS (method 1): Rt = 2.28 min; MS (ESIpos): m/z = 618/620 [M+H]+.

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: -0.150 (0.06), -0.008 (0.54), 0.007 (0.50), 0.146 (0.06), 1.211 (0.06), 1.299 (0.08), 1.332 (0.11), 1.343 (0.12), 1.371 (16.00), 1.527 (0.07), 1.775 (0.13), 1.791 (0.16), 1.809 (0.20) (0.20) (0.06) (0.74), 7.474 (0.45), 7.488 (1.61), 7.496 (0.45), 7.510 (0.39), 7.544 (0.66), 7.549 (0.62), 7.566 (0.39), 7.572 (0.38), 8.674 (0.39).

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.67 (t, 1H), 7.56 (dd, 1H), 7.52-7.46 (m, 2H), 7.40 (dd, 1H), 7.37 (br . s, 1H, hidden), 7.14 (td, 1H), 3.67 (br. s, 2H), 3.57 (br. s, 5H), 2.20-1.96 (m, 6H), 1.91-1.74 (m, 5H) .

Example 64A.

(+/-)-tert-Butyl-5-({[6-bromo-3-methyl-2-(1,2-oxazolidin-2-yl)quinolin-4-yl]carbonyl}amino)-4-( 2chloro-5-fluorophenyl)pentanoate (racemate)

To a suspension of (+/-)-tert-butyl-5-{[(6-bromo-2-chloro-3-methylquinolin-4-yl)carbonyl]amino}-4-(2chloro-5-fluorophenyl)pentanoate ( 100 mg, 171 µmol, example 36A) in 1-butanol (1.2 ml) was added 1,2oxazolidine (37.5 mg, 513 µmol) and the mixture was stirred for three days at 100°C. After cooling to RT, the mixture was directly (without further workup) purified by preparative HPLC (method 23). The combined target fractions were concentrated and the residue was lyophilized. 35 mg (98% pure, 32% thor.) of the title compound were obtained.

LC-MS (method 1): Rt = 2.57 min; MS (ESIpos): m/z = 620/622 [M+H]+.

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: -0.150 (0.04), -0.009 (0.31), 0.145 (0.04), 1.212 (0.06), 1.288 (0.06), 1.324 (0.09), 1.373 (16.00), 1.529 (0.07), 1.757 (0.05), 1.775 (0.13), 1.792 (0.16), 1.810 (0.19), 1.831 (0.15) 2.062 (0.13), 2.087 (0.71), 2.104 (0.92), 2.122 (0.32), 2.210 (1.47), 2.239 (0.64), 2.257 (0.85), 2.275 (0.62), 2.293 (0.19), 2.331 (0.05) (0.58), 7.124 (0.15), 7.145 (0.27), 7.159 (0.16), 7.394 (0.36), 7.401 (0.36), 7.419 (0.36), 7.426 (0.35), 7.486

- 51 040220 (0.43), 7.499 (0.46), 7.508 (0.45), 7.521 (0.43), 7.709 (0.11), 7.731 (2.33), 7.757 (0.09), 8.772 (0.22), 8.787 (0.42), 8.800 (0.21 ).

1H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 8.79 (t, 1H), 7.77-7.69 (m, 2H), 7.53 (br. s, 1H, hidden), 7.50 (dd, 1H ), 7.41 (dd, 1H), 7.14 (td, 1H), 3.84 (t, 2H), 3.77 (br. s, 2H), 3.74-3.65 (m, 2H), 3.65-3.54 (m, 1H), 2.31-2.17 (m, 5H), 2.15-2.07 (m, 2H), 2.07-1.97 (m, 1H), 1.88-1.73 (m, 1H), 1.37 (s, 9H).

Example 65A.

(+/-)-tert-Butyl-5 -({[6-bromo-2-(2,5-dihydro-1 H-pyrrol-1 -yl)-3-methylquinolin-4yl]carbonyl}amino)-4 -(2-chloro-5-fluorophenyl)pentanoate (racemate)

To a suspension of (+/-)-tert-butyl-5-{[(6-bromo-2-chloro-3-methylquinolin-4-yl)carbonyl]amino}-4-(2chloro-5-fluorophenyl)pentanoate ( 100 mg, 171 µmol, example 36A) in 1-butanol (1.2 ml) was added 2,5dihydro-1H-pyrrole (36 mg, 513 µmol) and the mixture was stirred for three days at 100°C. After cooling to RT, the mixture was directly (without further workup) purified by preparative HPLC (method 23). The combined target fractions were concentrated and the residue was lyophilized. 32 mg (81% pure, 25% thor.) of the title compound were obtained.

LC-MS (method 1): Rt = 2.55 min; MS (ESIpos): m/z = 616/618 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6): δ [ppm] = 8.69 (t, 1H), 7.57 (dd, 1H), 7.52-7.46 (m, 2H), 7.40 (dd, 1H), 7.36 (wide , hidden, 1H), 7.17-7.10 (m, 1H), 5.96 (s, 2H), 4.53 (br. s, 4H), 3.77-3.52 (m, 3H), 2.25 (br. s, 3H), 2.14 -1.95 (m, 3H), 1.87-1.74 (m, 1H), 1.37 (s, 9H).

Example 66A.

tert-Butyl 5-[({6-bromo-2-[3-hydroxypyrrolidin-1-yl]-3-methylquinolin-4-yl}carbonyl)amino]-4(2-chloro-5-fluorophenyl)pentanoate ( mixture of diastereoisomers)

To a suspension of (+/-)-tert-butyl-5-{[(6-bromo-2-chloro-3-methylquinolin-4-yl)carbonyl]amino}-4-(2chloro-5-fluorophenyl)pentanoate ( 100 mg, 171 µmol, example 36A) in 1-butanol (1.2 ml) was added (+/-)pyrrolidin-3-ol (45 mg, 513 µmol) and the mixture was stirred for three days at 100°C. After cooling to RT, the mixture was directly (without further workup) purified by preparative HPLC (method 20). The combined target fractions were concentrated and the residue was lyophilized. 60 mg (98% pure, 54% th. y.) of the title compound were obtained.

LC-MS (method 1): R _t = 2.02 min; MS (ESIpos): m/z = 634/636 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (0.82), 0.008 (0.78), 1.371 (16.00), 1.832 (0.42), 2.084 (0.90), 2.101 (1.17), 2.122 (0.54 ), 2.146 (1.73), 3.669 (0.41), 4.331 (0.42), 4.897 (0.43), 4.905 (0.74), 4.912 (0.46), 7.390 (0.51), 7.416 (0.50), 7.466 (0.85), 7.478 (0.44 ), 7.488 (1.75), 7.497 (0.43), 7.500 (0.41), 7.545 (0.70), 7.548 (0.65), 7.567 (0.41), 8.696 (0.44).

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.70 (br. t, 1H), 7.59-7.53 (m, 1H), 7.52-7.46 (m, 2H), 7.43-7.38 (m, 1H), 7.36 (br. s, partially hidden, 1H), 7.18-7.09 (m, 1H), 4.90 (t, 1H), 4.33 (br. s, 1H), 3.90-3.46 (m, 7H), 2.19 -1.72 (m, 9H), 1.37 (s, 9H).

Example 67A.

tert-Butyl 5-[({6-bromo-3-methyl-2-[3-methylpiperidin-1-yl]quinolin-4-yl}carbonyl)amino]-4-(2chloro-5-fluorophenyl)pentanoate ( mixture of diastereoisomers)

- 52 040220

To a suspension of (+/-)-tert-butyl-5-{[(6-bromo-2-chloro-3-methylquinolin-4-yl)carbonyl]amino}-4-(2chloro-5-fluorophenyl)pentanoate ( 100 mg, 171 µmol, example 36A) in 1-butanol (1.2 ml) was added (+/-)-3 methylpiperidine (51 mg, 513 µmol) and the mixture was stirred for two days at 100°C. After cooling to RT, the mixture was directly (without further workup) purified by preparative HPLC (method 18). The combined target fractions were concentrated and the residue was lyophilized. 78 mg (98% pure, 69% thor.) of the title compound were obtained.

LC-MS (method 1): R _t = 2.89 min; MS (ESIpos): m/z = 646/648 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.008 (0.63), 0.919 (1.45), 0.936 (1.34), 1.373 (16.00), 1.794 (0.50), 2.084 (0.80), 2.101 (1.03) , 2.132 (2.37), 3.459 (0.49), 3.678 (0.42), 7.483 (0.57), 7.496 (0.55), 7.505 (0.51), 7.518 (0.42), 7.648 (1.52), 7.656 (0.95) .

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.72 (t, 1H), 7.68-7.62 (m, 2H), 7.50 (dd, 1H), 7.46 (br. s, partially obscured, 1H ), 7.41 (dd, 1H), 7.19-7.10 (m, 1H), 3.78-3.39 (m, 5H), 2.69 (br. d, 1H), 2.45-2.41 (hidden, 1H), 2.18-1.94 (m , 6H), 1.86–1.58 (m, 5H), 1.37 (s, 9H), 1.17–1.01 (m, 1H), 0.93 (d, 3H).

Example 68A.

(+/-)-tert-Butyl-5-({[6-bromo-3-methyl-2-(4-methylpiperidin-1-yl)quinolin-4-yl]carbonyl}amino)-4(2-chloro -5-fluorophenyl)pentanoate (racemate)

To a suspension of (+/-)-tert-butyl-5-{[(6-bromo-2-chloro-3-methylquinolin-4-yl)carbonyl]amino}-4-(2chloro-5-fluorophenyl)pentanoate ( 100 mg, 171 µmol, example 36A) in 1-butanol (1.2 ml) was added 4-methylpiperidine (51 mg, 513 µmol) and the mixture was stirred for two days at 100°C. After cooling to RT, the mixture was directly (without further workup) purified by preparative HPLC (method 18). The combined target fractions were concentrated and the residue was lyophilized. 72 mg (98% pure, 64% th. y.) of the title compound were obtained.

LC-MS (method 1): Rt = 2.88 min; MS (ESIpos): m/z = 646/648 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.009 (0.32), 0.007 (0.30), 0.865 (0.06), 0.964 (1.71), 0.980 (1.80), 1.212 (0.06), 1.285 (0.31 ), 1.314 (0.35), 1.372 (16.00), 1.562 (0.16), 1.717 (0.43), 1.747 (0.39), 1.774 (0.14), 1.809 (0.17), 1.829 (0.14), 2.001 (0.14), 2.014 (0.18 ), 2.031 (0.18), 2.051 (0.17), 2.065 (0.15), 2.084 (0.69), 2.100 (0.98), 2.119 (2.48), 2.327 (0.06), 2.365 (0.07), 2.669 (0.07), 2.709 (0.10 ), 2.756 (0.29), 2.777 (0.32), 2.805 (0.16), 3.508 (0.47), 3.540 (0.46), 3.580 (0.20), 3.683 (0.41), 7.123 (0.16), 7.144 (0.28), 7.157 (0.17 ), 7.165 (0.17), 7.391 (0.36), 7.398 (0.37), 7.416 (0.38), 7.424 (0.36), 7.481 (0.49), 7.495 (0.48), 7.503 (0.44), 7.517 (0.40), 7.618 (0.33 ), 7.640 (1.38), 7.650 (0.88), 7.655 (0.78), 7.673 (0.19), 7.678 (0.21), 8.704 (0.21), 8.719 (0.42), 8.733 (0.21).

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 8.72 (t, 1H), 7.69-7.61 (m, 2H), 7.50 (dd, 1H), 7.47 (br. s, partially obscured, 1H) , 7.41 (dd, 1H), 7.14 (td, 1H), 3.74-3.64 (m, 2H), 3.63-3.56 (m, 1H), 3.52 (br. d, 2H), 2.832.70 (m, 2H) , 2.15-1.97 (m, 6H), 1.86-1.76 (m, 1H), 1.73 (br. d, 2H), 1.62-1.50 (m, 1H), 1.37 (s, 9H), 1.36-1.22 (m, 2H), 0.97 (d, 3H).

Example 69A.

tert-Butyl 5-[({6-bromo-2-[3-methoxypiperidin-1-yl]-3-methylquinolin-4-yl}carbonyl)amino]-4-(2chloro-5-fluorophenyl)pentanoate (mixture diastereoisomers)

- 53 040220

To a suspension of (+/-)-tert-butyl-5-{[(6-bromo-2-chloro-3-methylquinolin-4-yl)carbonyl]amino}-4-(2chloro-5-fluorophenyl)pentanoate ( 100 mg, 171 µmol, example 36A) in 1-butanol (1.2 ml) was added (+/-)-3 methoxypiperidine (59.1 mg, 513 µmol) and the mixture was stirred for two days at 100°C. After cooling to RT, the mixture was directly (without further workup) purified by preparative HPLC (method 18). The combined target fractions were concentrated and the residue was lyophilized. 68 mg (98% pure, 58% thor.) of the title compound were obtained.

LC-MS (method 1): R _t = 2.66 min; MS (ESIpos): m/z = 662/664 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 0.007 (0.53), 1.233 (0.14), 1.373 (16.00), 1.573 (0.15), 1.794 (0.35), 2.035 (0.36), 2.085 (0.75 ), 2.102 (0.96), 2.133 (2.46), 2.731 (0.18), 2.840 (0.18), 3.301 (6.14), 3.425 (0.25), 3.585 (0.45), 3.614 (0.33), 3.687 (0.47), 7.122 (0.18 ), 7.143 (0.30), 7.156 (0.18), 7.395 (0.37), 7.402 (0.37), 7.420 (0.38), 7.428 (0.36), 7.479 (0.54), 7.493 (0.55), 7.502 (0.49), 7.515 (0.43 ), 7.635 (0.30), 7.657 (1.46), 7.664 (1.01), 7.669 (0.84), 7.691 (0.18), 8.721 (0.43).

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.72 (t, 1H), 7.70-7.62 (m, 2H), 7.50 (dd, 1H), 7.46 (br. s, partially obscured, 1H ), 7.41 (dd, 1H), 7.14 (td, 1H), 3.76-3.64 (m, 2H), 3.64-3.54 (m, 2H), 3.47-3.38 (m, 1H), 3.30 (s, partially hidden, 3Н), 2.92-2.79 (m, 1H), 2.78-2.67 (m, 1H), 2.18-1.95 (m, 7H), 1.87-1.74 (m, 2H), 1.65-1.52 (m, 1H), 1.46- 1.32 (m, partially hidden, 1H), 1.37 (s, 9H).

Example 70A.

tert-Butyl-5-[({6-bromo-2-[2-(hydroxymethyl)morpholin-4-yl]-3-methylquinolin-4yl}carbonyl)amino]-4-(2-chloro-5-fluorophenyl) pentanoate (mixture of diastereoisomers)

To a suspension of (+/-)-tert-butyl-5-{[(6-bromo-2-chloro-3-methylquinolin-4-yl)carbonyl]amino}-4-(2chloro-5-fluorophenyl)pentanoate ( 100 mg, 171 µmol, example 36A) in 1-butanol (1.2 ml) was added (+/-) morpholin-2-ylmethanol (60 mg, 513 µmol) and the mixture was stirred for two days at 100°C. After cooling to RT, the mixture was directly (without further processing) purified by preparative HPLC (method 23). The combined target fractions were concentrated and the residue was lyophilized. 35 mg (98% pure, 30% thor.) of the title compound were obtained.

LC-MS (method 1): R _t = 2.28 min; MS (ESIpos): m/z = 664/666 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.009 (0.40), 0.007 (0.40), 1.213 (0.06), 1.329 (0.08), 1.372 (16.00), 1.529 (0.06), 1.776 (0.12 ), 1.810 (0.17), 1.832 (0.14), 2.000 (0.14), 2.013 (0.18), 2.031 (0.17), 2.051 (0.15), 2.086 (0.66), 2.103 (0.89), 2.123 (0.35), 2.153 (1.90 ), 2.327 (0.08), 2.366 (0.07), 2.669 (0.23), 2.692 (0.17), 2.710 (0.12), 2.898 (0.16), 3.380 (0.32), 3.417 (0.42), 3.481 (0.21), 3.494 (0.42 ), 3.508 (0.51), 3.522 (0.45), 3.535 (0.25), 3.549 (0.29), 3.618 (0.29), 3.680 (0.41), 3.708 (0.52), 3.737 (0.22), 3.908 (0.32), 3.935 (0.26 ), 4.748 (0.34), 4.762 (0.68), 4.776 (0.32), 7.123 (0.15), 7.144 (0.27), 7.158 (0.15), 7.396 (0.30), 7.403 (0.31), 7.421 (0.32), 7.428 (0.30 ), 7.482 (0.48), 7.496 (0.50), 7.504 (0.47), 7.517 (0.43), 7.661 (0.14), 7.683 (1.97), 7.689 (0.99), 7.711 (0.12), 8.749 (0.37).

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.75 (t, 1H), 7.72-7.65 (m, 2H), 7.50 (dd, 1H), 7.47 (br s, 1H),

7.41 (dd, 1H), 7.14 (td, 1H), 4.76 (t, 1H), 3.92 (br d, 1H), 3.77-3.47 (m, 7H), 3.46-3.35 (m, 2H), 2.96-2.82 (m,

1H), 2.74-2.60 (m, 1H), 2.15 (s, 3H), 2.13-2.07 (m, 2H), 2.07-1.96 (m, 1H), 1.88-1.73 (m, 1H), 1.37 (s, 9H).

Example 71A.

tert-Butyl-5-[({6-bromo-2-[3-(hydroxymethyl)piperidin-1-yl]-3-methylquinolin-4yl}carbonyl)amino]-4-(2-chloro-5-fluorophenyl) pentanoate (mixture of diastereoisomers)

- 54 040220

To a suspension of (+/-)-tert-butyl-5-{[(6-bromo-2-chloro-3-methylquinolin-4-yl)carbonyl]amino}-4-(2chloro-5-fluorophenyl)pentanoate ( 100 mg, 171 µmol, example 36A) in 1-butanol (1.2 ml) was added (+/-) piperidin-3-ylmethanol (59 mg, 513 µmol) and the mixture was stirred for three days at 100°C. After cooling to RT, the mixture was directly (without further workup) purified by preparative HPLC (method 23). The combined target fractions were concentrated and the residue was lyophilized.

63 mg (98% pure, 54% th. y.) of the title compound were obtained.

LC-MS (method 1): Rt = 2.43 min; MS (ESIpos): m/z = 662/664 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.154 (0.04), 0.142 (0.04), 1.118 (0.19), 1.141 (0.21), 1.209 (0.07), 1.295 (0.07), 1.326 (0.10 ), 1.369 (16.00), 1.525 (0.07), 1.640 (0.17), 1.747 (0.56), 1.773 (0.71), 1.807 (0.34), 1.999 (0.16), 2.011 (0.20), 2.029 (0.20), 2.049 (0.18 ), 2.062 (0.16), 2.081 (2.35), 2.323 (0.05), 2.362 (0.04), 2.665 (0.06), 2.721 (0.17), 2.741 (0.19), 3.356 (0.33), 3.394 (0.23), 3.407 (0.13 ), 3.438 (0.24), 3.468 (0.21), 3.585 (0.48), 3.613 (0.34), 4.517 (0.69), 4.530 (0.33), 7.118 (0.17), 7.139 (0.31), 7.153 (0.18), 7.160 (0.37 ), 7.413 (0.38), 7.421 (0.37), 7.477 (0.50), 7.490 (0.50), 7.499 (0.45), 7.513 (0.76), 2.098 (1.02), 2.128 (0.20), 3.368 (0.37), 3.381 (0.36 ), 3.680 (0.34), 4.505 (0.18), 7.388 (0.36), 7.395 (0.41), 7.623 (0.21), 7.645 (1.52), 7.654 (0.92), 7.676 (0.15), 8.728 (0.41).

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.73 (t, 1H), 7.69-7.62 (m, 2H), 7.50 (dd, 1H), 7.47 (br. s, partially obscured, 1H), 7.41 (dd, 1H), 7.14 (td, 1H), 4.52 (t, 1H), 3.75-3.53 (m, 4H), 3.46 (br. d, 1H), 3.42-3.35 (m,

1H), 3.33-3.26 (m, hidden, 2H), 2.81-2.64 (m, 1H), 2.18-1.96 (m, 6H), 1.87-1.71 (m, 4H), 1.69-1.57 (m, 1H),

1.37 (s, 9H), 1.21-1.05 (m, 1H).

Example 72A.

(+/-)-tert-Butyl-5-({[6-bromo-3-methyl-2-(piperidin-1-yl)quinolin-4-yl]carbonyl}amino)-4-(2chlorophenyl)pentanoate ( racemate)

To a suspension of (+/-)-tert-butyl-5-{[(6-bromo-2-chloro-3-methylquinolin-4-yl)carbonyl]amino}-4-(2chlorophenyl)pentanoate (1.10 g, 1.94 mmol, example 37A) in 1-butanol (14 ml) was added piperidine (580 μl, 5.8 mmol) and the mixture was stirred for three days at 100°C. After cooling to RT, the mixture was mixed with water and ethyl acetate (respectively 50 ml) 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, and the residue was adsorbed in dichloromethane and purified by flash column chromatography (100 g Biotage Snap-Cartridge KP-Sil, cyclohexane/ethyl acetate gradient 93:7^6:4, Isolera one). The combined desired fractions were concentrated and the residue was dried in vacuo. 557 mg (84% pure, 39% thor.) of the title compound were obtained.

LC-MS (method 1): R _t = 2.82 min; MS (ESIpos): m/z = 614/616 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 8.72 (t, 1H), 7.69-7.61 (m, 2H), 7.51-7.43 (m, 2H), 7.49 (br., 1H), 7.40 -7.34 (m, 1H), 7.30-7.24 (m, 1H), 3.73-3.53 (m, 3H), 3.13 (br s, 4H), 2.17-2.00 (m, 6H), 1.87-1.75 (m, 1H ), 1.71-1.55 (m, 6H), 1.37 (s, 9H).

Separation of enantiomers.

The title target compound (550 mg) was dissolved in methanol (20 ml) and separated into enantiomers by chiral phase preparative HPLC (see Examples 73A and 74A) [column: Daicel Chiralpak OX-H, 5 μm, 250 mm x 20 mm; flow: 80 ml/min; detection: 210 nm; temperature: 40°C; sample injection: 0.3 ml; eluent: 15% isopropanol/85% heptane; duration of action 16 min, isocratic]. The combined desired fractions were concentrated and the residue was dried in vacuo.

Example 73A.

(-)-tert-Butyl-5-({[6-bromo-3-methyl-2-(piperidin-1-yl)quinolin-4-yl]carbonyl}amino)-4-(2

- 55 040220 chlorophenyl) pentanoate (enantiomer 1).

The separation of enantiomers described in Example 72A gave the prepurified title compound as the previously eluted enantiomer (ee value 99%). Then further purified by preparative HPLC (method 6). The combined desired fractions were concentrated and the residue was dried in vacuo. 150 mg (95% pure) of further purified title compound was obtained.

[a] _D20 = -8.4°, 589 nm, c = 0.31 g/100 ml ^, methanol;

LC-MS (method 2): Rt = 1.51 min; MS (ESIpos): m/z = 614/616 [M+H]+.

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 1.208 (0.07), 1.312 (0.09), 1.333 (0.12), 1.368 (16.00), 1.525 (0.08), 1.604 (0.60), 1.668 (1.18) ), 1.814 (0.26), 2.045 (0.27), 2.074 (1.54), 2.085 (0.84), 2.108 (0.38), 2.131 (1.97), 3.132 (1.52), 3.584 (0.27), 3.671 (0.49), 7.251 (0.23 ), 7.270 (0.53), 7.289 (0.37), 7.351 (0.32), 7.370 (0.57), 7.388 (0.30), 7.438 (0.79), 7.458 (0.67), 7.479 (0.73), 7.497 (0.64), 7.623 (0.30 ), 7.645 (1.58), 7.652 (1.07), 7.675 (0.20), 8.705 (0.28), 8.720 (0.54), 8.733 (0.26).

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.72 (t, 1H), 7.69-7.61 (m, 2H), 7.47 (dd, 2H), 7.49 (br., hidden, 1H), 7.37 (t, 1H), 7.27 (t, 1H), 3.74-3.50 (m, 3H), 3.13 (br. s, 4H), 2.17-1.98 (m, 6H), 1.89-1.74 (m, 1H), 1.72-1.55 (m, 6H), 1.37 (s, 9H).

Example 74A.

(+)-tert-Butyl-5-({[6-bromo-3-methyl-2-(piperidin-1-yl)quinolin-4-yl]carbonyl}amino)-4-(2chlorophenyl)pentanoate (enantiomer 2 ).

The separation of enantiomers described in Example 72A gave the prepurified title compound as the later eluted enantiomer (ee value 98%). Then further purified by preparative HPLC (method 6). The combined desired fractions were concentrated and the residue was dried in vacuo. 141 mg (98% pure) of further purified title compound was obtained.

[a] _D20 = +8.0°, 589 nm, c = ^0.26 g/100 mL, methanol;

LC-MS (method 2): Rt = 1.51 min; MS (ESIpos): m/z = 614/616 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.368 (16.00), 1.604 (0.61), 1.669 (1.21), 1.814 (0.27), 2.073 (1.61), 2.085 (0.85), 2.107 (0.39) , 2.131 (2.06), 3.132 (1.57), 3.584 (0.28), 3.672 (0.51), 7.251 (0.24), 7.270 (0.55), 7.289 (0.39), 7.351 (0.33), 7.370 (0.60) , 7.438 (0.83), 7.458 (0.71), 7.479 (0.78), 7.498 (0.66), 7.622 (0.31), 7.645 (1.57), 7.653 (1.05), 7.675 (0.20), 8.720 (0.56).

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 8.72 (t, 1H), 7.70-7.61 (m, 2H), 7.47 (dd, 2H), 7.49 (br., 1H), 7.37 (t , 1H), 7.27 (t, 1H), 3.74-3.52 (m, 3H), 3.13 (br. s, 4H), 2.18-1.99 (m, 6H), 1.88-1.74 (m, 1H), 1.72-1.54 (m, 6H), 1.37 (s, 9H).

Example 75A.

(+/-)-tert-Butyl-5-({[6-bromo-3-methyl-2-(thiomorpholin-4-yl)quinolin-4-yl]carbonyl}amino)-4-(2chlorophenyl)pentanoate ( racemate)

To a suspension of (+/-)-tert-butyl-5-{[(6-bromo-2-chloro-3-methylquinolin-4-yl)carbonyl]amino}-4-(2chlorophenyl)pentanoate (250 mg, 91 % purity, 402 µmol, example 37A) in 1-butanol (2.9 ml) was added thiomorpholine (124 mg, 1.21 mmol) and the mixture was stirred for two days at 100°C. After cooling to RT, the mixture was directly (without further workup) purified by preparative HPLC (method 6). The combined desired fractions were concentrated and the residue was dried in vacuo. 77 mg (98% pure, 30% thor.) of the title compound were obtained.

LC-MS (method 2): Rt = 1.42 min; MS (ESIpos): m/z = 632/634 [M+H]+.

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (0.51), 0.008 (0.46), 1.369 (16.00), 2.073 (1.08), 2.086 (0.66), 2.132 (1.34), 2.774 (0.88 ), 2.786 (1.01), 2.798 (0.95), 3.413 (0.94), 3.419 (0.94), 3.426 (0.99), 3.437 (0.86), 7.372 (0.41), 7.438 (0.61), 7.441 (0.57), 7.458 (0.51 ), 7.461 (0.48), 7.479 (0.49), 7.482 (0.49), 7.499 (0.41), 7.678 (1.34), 7.684 (0.99), 7.688 (0.81).

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.72 (t, 1H), 7.74-7.62 (m, 2H), 7.60-7.42 (m, 3H), 7.37 (t, 1H), 7.31 -7.23 (m, 1H), 3.67 (br. s, 2H), 3.62-3.53 (m, 1H), 3.46-3.38 (m, 4H), 2.83-2.74 (m, 4H), 2.19-1.97 (m, 6H), 1.88-1.73 (m, 1H), 1.37 (s, 9H).

Example 76A.

(+/-)-tert-Butyl-5-({[6-bromo-2-(4,4-difluoropiperidin-1-yl)-3-methylquinolin-4yl]carbonyl}amino)-4-(2-chlorophenyl )pentanoate (racemate)

- 56 040220

To a suspension of (+/-)-tert-butyl-5-{[(6-bromo-2-chloro-3-methylquinolin-4-yl)carbonyl]amino}-4-(2chlorophenyl)pentanoate (100 mg, 88 % purity, 155 µmol, example 37A) in 1-butanol (1.1 ml) was added 4,4-difluoropiperidine (94 mg, 777 µmol) and the mixture was stirred for two days at 100°C. After cooling to RT, the mixture was purified by preparative HPLC (method 18). The combined desired fractions were concentrated and the residue was dried in vacuo. 28 mg (98% pure, 27% theoretical) of the title compound were obtained.

LC-MS (method 1): Rt = 2.71 min; MS (ESIpos): m/z = 650/652 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: -0.008 (0.67), 1.369 (16.00), 2.075 (1.36), 2.088 (0.85), 2.111 (0.57), 2.167 (1.98), 2.523 ( 0.67), 7.272 (0.44), 7.373 (0.48), 7.439 (0.66), 7.459 (0.57), 7.486 (0.59), 7.503 (0.48), 7.682 (1.32), 7.691 (0.87), 7.695 (0.76), 0.45).

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 8.74 (t, 1H), 7.74-7.64 (m, 2H), 7.59-7.42 (m, 3H), 7.37 (t, 1H), 7.30- 7.23 (m, 1H), 3.68 (br. s, 2H), 3.62-3.53 (m, 1H), 2.23-1.94 (m, 11H), 1.89-1.70 (m, 1H), 1.37 (s, 9H).

Example 77A.

(+/-)-tert-Butyl-5 -({[6-bromo-2-(3,6-dihydropyridin-1 (2H)-yl)-3-methylquinolin-4yl]carbonyl}amino)-4-( 2-chlorophenyl)pentanoate (racemate)

To a suspension of (+/-)-tert-butyl-5-{[(6-bromo-2-chloro-3-methylquinolin-4-yl)carbonyl]amino}-4-(2chlorophenyl)pentanoate (250 mg, 91 % purity, 402 µmol, example 37A) in 1-butanol (2.9 ml) was added 1,2,3,6-tetrahydropyridine (100 mg, 1.21 mmol) and the mixture was stirred for two days at 100°C. After cooling to RT, the mixture was directly (without further workup) purified by preparative HPLC (method 6). The combined desired fractions were concentrated and the residue was dried in vacuo. 158 mg (98% pure, 63% thor.) of the title compound were obtained.

LC-MS (method 1): R _t = 2.75 min; MS (ESIpos): m/z = 612/614 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.370 (16.00), 2.077 (1.26), 2.089 (0.70), 2.144 (1.50), 2.303 (0.46), 3.797 (0.80), 5.844 (0.51) , 5.864 (0.46), 7.273 (0.41), 7.374 (0.45), 7.439 (0.61), 7.441 (0.64), 7.458 (0.53), 7.461 (0.54), 7.485 (0.60), 7.502 (0.47), 7.642 (1.32) , 7.655 (0.81), 7.660 (0.74), 8.732 (0.44).

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 8.73 (t, 1H), 7.70-7.60 (m, 2H), 7.58-7.41 (m, 3H), 7.37 (t, 1H), 7.31- 7.23 (m, 1H), 5.95-5.77 (m, 2H), 3.80 (br. s, 2H), 3.68 (br. s, 2H), 3.63-3.53 (m, 1H), 3.28 (br. s, 2H ), 2.30 (br. s, 2H), 2.18-1.98 (m, 6H), 1.87-1.74 (m, 1H), 1.37 (s, 9H).

Example 78A.

(+/-)-tert-Butyl-5-({[6-bromo-3-methyl-2-(1,2-oxazinan-2-yl)quinolin-4-yl]carbonyl}amino)-4-( 2chlorophenyl)pentanoate (racemate)

To a suspension of (+/-)-tert-butyl-5-{[(6-bromo-2-chloro-3-methylquinolin-4-yl)carbonyl]amino}-4-(2chlorophenyl)pentanoate (100 mg, 88 % purity, 155 µmol, example 37A) in 1-butanol (1.1 ml) was added 1,2-oxazinan (67.7 mg, 777 µmol) and DIPEA (140 µl, 780 µmol) and the mixture was stirred for two days at 100°C. After cooling to RT, the mixture was purified by preparative HPLC (method 18). The combined desired fractions were concentrated and the residue was dried in vacuo. Received 24 mg (98% pure

- 57 040220 you, 25% of theor. out) specified in the connection header.

LC-MS (method 1): Rt = 2.75 min; MS (ESIpos): m/z = 616/618 [M+H]+.

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 1.369 (16.00), 1.697 (0.63), 1.870 (0.56), 1.884 (0.67), 1.898 (0.45), 2.075 (1.56), 2.086 (0.82 ), 2.145 (1.44), 3.573 (0.69), 3.680 (0.54), 4.041 (0.59), 4.053 (0.94), 4.065 (0.59), 7.274 (0.52), 7.371 (0.56), 7.444 (0.75), 7.464 (0.65 ), 7.479 (0.65), 7.498 (0.50), 7.731 (2.67), 8.805 (0.54).

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 8.81 (t, 1H), 7.73 (s, 2H), 7.55 (br. s, 1H), 7.47 (dd, 2H), 7.37 (t, 1H), 7.31-7.24 (m, 1H), 4.05 (t, 2H), 3.77-3.48 (m, 5H), 2.20-1.98 (m, 6H), 1.93-1.75 (m, 3H), 1.74-1.64 ( m, 2H), 1.37 (s, 9H).

Example 79A.

(+/-)-tert-Butyl-5-({[6-bromo-3-methyl-2-(pyrrolidin-1-yl)quinolin-4-yl]carbonyl}amino)-4-(2chlorophenyl)pentanoate ( racemate)

To a suspension of (+/-)-tert-butyl-5-{[(6-bromo-2-chloro-3-methylquinolin-4-yl)carbonyl]amino}-4-(2chlorophenyl)pentanoate (500 mg, 91 % purity, 803 µmol, example 37A) in 1-butanol (5.8 ml) was added pyrrolidine (200 µl, 2.4 mmol) and the mixture was stirred for two days at 100°C. After cooling to RT, the mixture was purified by preparative HPLC (method 6). The combined desired fractions were concentrated and the residue was dried in vacuo. 450 mg (96% pure, 89% th. y.) of the title compound were obtained.

LC-MS (method 2): Rt = 1.08 min; MS (ESIpos): m/z = 600/602 [M+H]+.

'H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.67 (t, 1H), 7.56 (dd, 1H), 7.52-7.40 (m, 4H), 7.37 (t, 1H), 7.307. 23 (m, 1H), 3.76-3.47 (m, 7H), 2.23-1.98 (m, 6H), 1.92-1.73 (m, 5H), 1.37 (s, 9H).

Example 80A.

tert-Butyl 5-[({6-bromo-3-methyl-2-[3-methylpyrrolidin-1-yl]quinolin-4-yl}carbonyl)amino]-4-(2chlorophenyl)pentanoate (mixture of diastereoisomers)

To a suspension of (+/-)-tert-butyl-5-{[(6-bromo-2-chloro-3-methylquinolin-4-yl)carbonyl]amino}-4-(2chlorophenyl)pentanoate (100 mg, 88 % purity, 155 µmol, example 37A) in 1-butanol (1.1 ml) was added (+/-)-3-methylpyrrolidine hydrochloride (95 mg, 777 µmol) and DIPEA (140 µl, 780 µmol) and the mixture was stirred for two days at 100°C. After cooling to RT, the mixture was purified by preparative HPLC (method 19). The combined desired fractions were concentrated and the residue was dried in vacuo. 27 mg (98% pure by LC-MS, 28% thor. y.) of the title compound was obtained in admixture with the appropriate n-butyl ether.

LC-MS (method 1): Rt = 2.41 min; MS (ESIpos): m/z = 614/616 [M+H]+.

Example 81A.

(+/-)-tert-Butyl-5 -({[6-bromo-2-(3,3-difluoropyrrolidin-1 -yl)-3-methylquinolin-4yl]carbonyl}amino)-4-(2-chlorophenyl )pentanoate (racemate)

To a suspension of (+/-)-tert-butyl-5-{[(6-bromo-2-chloro-3-methylquinolin-4-yl)carbonyl]amino}-4-(2chlorophenyl)pentanoate (100 mg, 88 % purity, 155 µmol, example 37A) in 1-butanol (1.1 ml) was added

- 58 040220 difluoropyrrolidine hydrochloride (112 mg, 777 μmol) and DIPEA (140 μl, 780 μmol) and the mixture was stirred for two days at 100°C. After cooling to RT, the mixture was purified by preparative HPLC (method 18). The combined desired fractions were concentrated and the residue was dried in vacuo. 32 mg (98% pure by LC-MS, 32% thor. y.) of the title compound was obtained in admixture with the appropriate n-butyl ether.

LC-MS (method 1): R _t = 2.66 min; MS (ESIpos): m/z = 636/638 [M+H] ⁺ .

Example 82A.

(+/-)-tert-Butyl-5-({[6-bromo-3-methyl-2-(1,2-oxazolidin-2-yl)quinolin-4-yl]carbonyl}amino)-4-( 2chlorophenyl)pentanoate (racemate)

To a suspension of (+/-)-tert-butyl-5-{[(6-bromo-2-chloro-3-methylquinolin-4-yl)carbonyl]amino}-4-(2chlorophenyl)pentanoate (250 mg, 91 % purity, 402 µmol, example 37A) in 1-butanol (2.9 ml) was added 1,2-oxazolidine (88 mg, 1.21 mmol) and the mixture was stirred for two days at 100°C. After cooling to RT, the mixture was purified by preparative HPLC (method 6). The combined desired fractions were concentrated and the residue was dried in vacuo. 137 mg (98% pure, 55% thor.) of the title compound were obtained.

LC-MS (method 2): R _t = 1.31 min; MS (ESIpos): m/z = 602/604 [M+H]+.

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.326 (0.11), 1.345 (0.22), 1.368 (16.00), 1.812 (0.20), 2.051 (0.20), 2.073 (1.19), 2.085 (0.63) , 2.102 (0.25), 2.212 (0.90), 2.239 (0.67), 2.257 (0.83), 2.275 (0.61) , 3.838 (1.03), 3.856 (0.56), 7.253 (0.18),7.272 (0.41), 7.291 (0.29), 7.352 (0.24), 7.371 (0.44), 7.390 (0.23), 7.443 (0.65), 7.461 (0.53) , 7.483 (0.54), 7.501 (0.42), 7.708 (0.11), 7.730 (2.34), 8.783 (0.42), 8.797 (0.22).

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 8.78 (t, 1H), 7.79-7.69 (m, 2H), 7.55 (br. s, 1H), 7.51-7.43 (m, 2H), 7.37 (t, 1H), 7.31-7.23 (m, 1H), 3.84 (t, 2H), 3.80-3.52 (m, 5H), 2.31-2.15 (m, 5H), 2.12-1.98 (m, 3H), 1.89-1.74 (m, 1H), 1.37 (s, 9H).

Example 83A.

Butyl 5-({[6-bromo-2-(3-methoxypyrrolidin-1-yl)-3-methylquinolin-4-yl]carbonyl}amino)-4-(2chlorophenyl)pentanoate (mixture of diastereoisomers)

To a suspension of (+/-)-tert-butyl-5-{[(6-bromo-2-chloro-3-methylquinolin-4-yl)carbonyl]amino}-4-(2chlorophenyl)pentanoate (100 mg, 88 % purity, 155 µmol, example 37A) in 1-butanol (1.1 ml) was added (+/-)-3-methoxypyrrolidine hydrochloride (107 mg, 777 µmol) and DIPEA (140 µl, 780 µmol) and the mixture was stirred for two days at 100°C. After cooling to RT, the mixture was purified by preparative HPLC (method 19). The combined desired fractions were concentrated and the residue was dried in vacuo. 36 mg (98% pure, 36% thor.) of the title compound were obtained.

LC-MS (method 1): R _t = 2.38 min; MS (ESIpos): m/z = 630/632 [M+H]+. 1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 0.841 (6.92), 0.859 (16.00), (2.27), 1.279 (3.99), 1.297 (4.01), 1.316 (2.45), 1.335 (0.68) , 1.472 (1.34), (3.19), 1.542 (0.92), 1.836 (0.66), 1.849 (0.86), 1.870 (1.04), 1.884 (0.78) (1.34), 2.132 (1.26), 2.170 (7.46), (0.50), 2.327 (0.46), 2.422 (0.74), 2.440 (1.52), 2.458 (2.17), 2.476 (3.21), (1.62), 3.783 (2.51 ), 3.910 (0.72), 3.926 (1.48), 3.937 (3.09), 3.944 (3.49), (3.85), 3.978 (3.23), 3.988 (1.62), 4.004 (1.04), 7.252 (0.96), 7.271 (2.27) , (2.51), 7.388 (1.38), 7.436 (4.09), 7.455 (3.47), 7.480 (3.31), 7.500 (2.49),

0.878 (8.20), 1.242 (0.62), 1.260

1.488

1.904

2.190

2.669

3.953

7.289

7.570 (3.43), 1.508 (4.15), 1.525 (0.42), 2.050 (0.40), 2.070 (4.09), 2.209 (1.68), 2.229 (0.40), 3.585 (1.18), 3.675 (5.65), 3.961 (5.89), 3.970 (1.70), 7.351 (1.40), 7.369 (3.37), 7.592 (6.68), 7.630 (3.79), 7.636 (3.45), 7.653 (1.86), 7.658 (1.76), 8.693 (1.22), 8.706 (2.39), 8.720 (1.20).

- 59 040220

Example 84A.

(+/-)-tert-Butyl-5 -({[6-bromo-2-(3,3-dimethylpiperidin-1 -yl)-3-methylquinolin-4yl]carbonyl}amino)-4-(2-chlorophenyl )pentanoate (racemate)

To suspension from (+/-)-tert-butyl-5-{[(6-bromo-2-chloro-3-methylquinolin-4-yl)carbonyl]amino}-4-(2chlorophenyl)pentanoate (500 mg, 883 µmol, example 37A) in 1-butanol (6.4 ml) was added 3,3dimethylpiperidine (370 µl, 2.6 mmol) and the mixture was stirred for two days at 100°C. Then 3,3-dimethylpiperidine (370 µl, 2.6 mmol) was added again and the mixture was stirred for an additional three days at 100°C. After cooling to RT, the mixture was concentrated and the residue was adsorbed into dichloromethane and purified by flash column chromatography (50 g silica gel, Biotage Snap-Cartridge Ultra, cyclohexane/ethyl acetate gradient 93:7^7:3, Isolera One). The combined desired fractions were concentrated and the residue was dried in vacuo. 420 mg (94% pure, 69% thor.) of the title compound were obtained.

LC-MS (method 2): R _t = 1.58 min; MS (ESIpos): m/z = 642/644 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 8.72 (t, 1H), 7.70-7.61 (m, 2H), 7.59-7.42 (m, 3H), 7.37 (t, 1H), 7.30- 7.24 (m, 1H), 3.75-3.62 (m, 2H), 3.62-3.53 (m, 1H), 3.05 (br. s, 2H), 2.86 (s, 2H), 2.17 (s, 3H), 2.13- 1.99 (m, 3H), 1.92-1.75 (m, 1H), 1.75-1.65 (m, 2H), 1.44-1.35 (m, 2H, partially hidden), 1.37 (s, 9H), 1.00 (s, 6H).

Example 85A.

tert-Butyl 5-[({6-bromo-3-methyl-2-[3-methylpiperidin-1-yl]quinolin-4-yl}carbonyl)amino]-4-(2chlorophenyl)pentanoate (mixture of diastereoisomers)

To a suspension of (+/-)-tert-butyl-5-{[(6-bromo-2-chloro-3-methylquinolin-4-yl)carbonyl]amino}-4-(2chlorophenyl)pentanoate (1.10 g, 1.94 mmol, example 37A) in 1-butanol (14 ml) was added (+/-)-3methylpiperidine (680 μl, 5.8 mmol) and the mixture was stirred for two days at 100°C. After cooling to RT, the mixture was concentrated and the residue was adsorbed into dichloromethane and purified by flash column chromatography (50 g silica gel, Biotage Snap-Cartridge Ultra, cyclohexane/ethyl acetate gradient 93:7^7:3, Isolera One). The combined desired fractions were concentrated and the residue was dried in vacuo. 982 mg (96% pure, 77% thor.) of the title compound were obtained.

LC-MS (method 2): R _t = 1.54 min; MS (ESIpos): m/z = 628/630 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.72 (t, 1H), 7.71-7.60 (m, 2H), 7.59-7.41 (m, 3H), 7.37 (t, 1H), 7.31 -7.23 (m, 1H), 3.67 (br. s, 2H), 3.62-3.54 (m, 1H), 3.46 (br. t, 2H), 2.78-2.64 (m, 1H), 2.48-2.39 (m, 1H), 2.19-2.00 (m, 6H), 1.89-1.57 (m, 5H), 1.37 (s, 9H), 1.15-1.02 (m, 1H), 0.93 (d, 3H).

Separation of diastereoisomers/enantiomers.

The title target compound (850 mg) was dissolved in a mixture of isopropanol (5 ml) and heptane (6 ml) and first pre-separated by chiral phase preparative HPLC [column: Daicel Chiralcel OX-H, 5 μm, 250 mm x 20 mm; flow: 15 ml/min; sample injection: 0.13 ml; eluent: 20% isopropanol/80% heptane; duration of action 16 min, isocratic]. A fairly pure fraction (peak 1, see Example 86A) and two mixed fractions were obtained. The first mixed fraction (peak 2 and peak 3) was purified by preparative HPLC on a chiral phase [column: Daicel Chiralcel OZ-H, 5 μm, 250 mm x 20 mm; flow: 15 ml/min; eluent: 15% isopropanol/85% heptane] (see examples 87A and 88A). A second mixed fraction (predominantly peak 4) was also purified by preparative HPLC on a chiral phase [column: Daicel Chiralcel OZ-H, 5 μm, 250 mm x 20 mm; flow: 15 ml/min; eluent: 10% isopropanol/90% heptane] (see example 89A). The combined target fractions were suitably concentrated and the residue was suitably lyophilized.

- 60 040220

Example 86A.

(-)-tert-Butyl-5-[({6-bromo-3-methyl-2-[3-methylpiperidin-1-yl]quinolin-4-yl}carbonyl)amino]-4-(2chlorophenyl)pentanoate ( diastereoisomer 1).

The separation of diastereoisomers described in Example 85A gave 194 mg (96% pure, ee 99%) of the title compound as the first eluting diastereoisomer (peak 1).

[a] _D20 = -16.2°, 589 nm, c = ^0.38 g/100 ml, methanol;

LC-MS (method 1): Rt = 2.90 min; MS (ESIpos): m/z = 628/630 [M+H]+.

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.945 (1.66), 0.961 (1.68), 1.103 (0.18), 1.131 (0.20), 1.159 (0.16), 1.177 (0.21), 1.195 (0.10) , 1.235 (0.07), 1.340 (0.34), 1.359 (0.12), 1.395 (16.00), 1.420 (0.31), 1.551 (0.07), 1.645 (0.16), 1.676 (0.19), 1.755 (0.33), 1.790 (0.25) , 2.082 (0.22) . . . , 7.704 (0.14), 8.727 (0.22), 8.741 (0.43), 8.755 (0.20).

Example 87A.

(+)-tert-Butyl-5-[({6-bromo-3-methyl-2-[3-methylpiperidin-1-yl]quinolin-4-yl}carbonyl)amino]-4(2-chlorophenyl)pentanoate (diastereoisomer 2).

The separation of diastereoisomers described in Example 85A gave 157 mg (100% pure, ee 99%) of the title compound as the second eluting diastereoisomer (peak 2).

[a] _D20 = +15.5°, 589 nm, c = 0.37 ^g /100 mL, methanol;

LC-MS (method 1): Rt = 2.90 min; MS (ESIpos): m/z = 628/630 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.919 (1.60), 0.935 (1.63), 1.077 (0.18), 1.101 (0.19), 1.139 (0.11), 1.157 (0.10), 1.176 (0.05) , 1.208 (0.07), 1.311 (0.08), 1.333 (0.11), 1.368 (16.00), 1.525 (0.07), 1.619 (0.15), 1.649 (0.18), 1.729 (0.31), 1.764 (0.36), 1.791 (0.51) , 1.820 (0.43), 2.046 (0.24), 2.056 (0.21), 2.074 (1.34), 2.085 (0.75), 2.101 (0.29), 2.107 (0.27), 2.136 (1.68), 2.327 (0.04), 2.365 (0.04) . , 3.672 (0.40), 7.253 (0.19), 7.271 (0.44), 7.288 (0.31), 7.353 (0.27), 7.371 (0.48), 7.389 (0.25) , 7.497 (0.52), 7.625 (0.20), 7.648 (1.58), 7.655 (0.94), 7.673 (0.12), 7.678 (0.14), 8.701 (0.23), 8.715 (0.44), 8.729 (0.21).

Example 88A.

(+)-tert-Butyl-5-[({6-bromo-3-methyl-2-[3-methylpiperidin-1-yl]quinolin-4-yl}carbonyl)amino]-4 (2-chlorophenyl)pentanoate (diastereoisomer 3).

The separation of diastereoisomers described in Example 85A gave 169 mg (100% pure, 99% ee) of the title compound as the third eluting diastereoisomer (peak 3).

[a] _D20 = +9.6°, 436 nm ^, c = 0.42 g/100 mL, methanol;

LC-MS (method 1): Rt = 2.91 min; MS (ESIpos): m/z = 628/630 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.920 (1.65), 0.936 (1.68), 1.078 (0.18), 1.101 (0.19), 1.139 (0.15), 1.157 (0.18), 1.176 (0.09) , 1.208 (0.07), 1.314 (0.08), 1.331 (0.10), 1.369 (16.00), 1.525 (0.07), 1.626 (0.16), 1.656 (0.19), 1.728 (0.33), 1.760 (0.36), 1.794 (0.49) , 1.820 (0.43), 2.047 (0.23), 2.056 (0.21), 2.074 (1.37), 2.085 (0.79), 2.102 (0.29), 2.137 (1.81), 2.327 (0.04), 2.365 (0.04) . , 7.253 (0.19), 7.272 (0.44), 7.292 (0.31), 7.353 (0.27), 7.372 (0.49), 7.390 (0.26), 7.440 (0.66) , 7.626 (0.18), 7.649 (1.66), 7.655 (0.96), 7.677 (0.14), 8.702 (0.25), 8.716 (0.49), 8.730 (0.24).

Example 89A.

(-)-tert-Butyl-5-[({6-bromo-3-methyl-2-[3-methylpiperidin-1-yl]quinolin-4-yl}carbonyl)amino]-4-(2chlorophenyl)pentanoate ( enantiomer 4).

The separation of diastereoisomers described in Example 85A gave 158 mg (96% pure, ee 99%) of the title compound as the last eluting diastereoisomer (peak 4).

[a] _D20 = -10.4°, 436 nm, c = 0.44 g ^/ 100 ml, methanol;

LC-MS (method 1): Rt = 2.90 min; MS (ESIpos): m/z = 628/630 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.920 (1.61), 0.936 (1.63), 1.077 (0.17), 1.100 (0.18), 1.139 (0.09), 1.157 (0.06), 1.208 (0.06) , 1.314 (0.10), 1.331 (0.09), 1.369 (16.00), 1.525 (0.06), 1.626 (0.15), 1.657 (0.18), 1.728 (0.32), 1.761 (0.34), 1.794 (0.46), 1.820 (0.40) . , 2.669 (0.16), 2.699

- 61 040220 (0.22), 2.728 (0.12), 3.433 (0.26), 3.462 (0.46), 3.493 (0.21), 3.583 (0.21), 3.667 (0.34), 7.254 (0.18), 7.272 (0.43), 7.288 (0.33 ), 7.325 (0.05), 7.353 (0.26), 7.372 (0.46), 7.390 (0.24), 7.437 (0.63), 7.440 (0.64), 7.457 (0.54), 7.460 (0.54), 7.481 (0.60), 7.498 (0.48 ), 7.626 (0.18), 7.649 (1.60), 7.655 (0.94), 7.678 (0.14), 8.702 (0.23), 8.716 (0.45), 8.730 (0.22).

Example 90A.

(+/-)-tert-Butyl-5-({[6-bromo-2-(3,3-difluoropiperidin-1-yl)-3-methylquinolin-4yl]carbonyl}amino)-4-(2-chlorophenyl )pentanoate (racemate)

To a suspension of (+/-)-tert-butyl-5-{[(6-bromo-2-chloro-3-methylquinolin-4-yl)carbonyl]amino}-4-(2chlorophenyl)pentanoate (1.50 g, 98 % purity, 2.60 mmol, example 37A) in NMP (24 ml) was added 3,3difluoropiperidine hydrochloride (3.27 g, 20.8 mmol) and DIPEA (5.42 ml, 31.15 mmol), and the mixture was stirred for 18 h at 120°C. After cooling to RT, the mixture was mixed with water (200 ml) and ethyl acetate (100 ml) and shaken. After phase separation, the aqueous phase was extracted several times with ethyl acetate (corresponding to 100 ml). The combined organic phases were dried over sodium sulfate, filtered and concentrated, and the residue was purified by flash column chromatography (100 g silica gel, Biotage Snap-Cartridge Ultra, 97:3^9:1 cyclohexane/ethyl acetate gradient, Isolera One). The combined desired fractions were concentrated and the residue was dried in vacuo. 933 mg (96% pure, 53% thor.) of the title compound were obtained.

LC-MS (method 1): Rt = 2.70 min; MS (ESIpos): m/z = 650/652 [M+H]+.

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.149 (0.04), 0.146 (0.04), 1.210 (0.08), 1.234 (0.04), 1.311 (0.07), 1.333 (0.09), 1.370 (16.00 ), 1.398 (3.71), 1.526 (0.08), 1.764 (0.07), 1.797 (0.17), 1.817 (0.23), 1.880 (0.52), 2.046 (0.34), 2.056 (0.38), 2.076 (1.68), 2.088 (1.06 ), 2.110 (0.55), 2.152 (1.68), 2.327 (0.05), 2.366 (0.05), 2.670 (0.04), 2.710 (0.04), 3.167 (0.60), 3.447 (0.40), 3.476 (0.76), 3.505 (0.38 ), 3.587 (0.24), 3.683 (0.40), 7.254 (0.20), 7.273 (0.48), 7.291 (0.35), 7.355 (0.28), 7.374 (0.51), 7.392 (0.26), 7.441 (0.69), 7.461 (0.57 ), 7.485 (0.60), 7.504 (0.47), 7.674 (0.26), 7.696 (1.50), 7.703 (0.97), 7.707 (0.83), 7.729 (0.17), 8.718 (0.24), 8.732 (0.49), 8.746 (0.24 ).

Separation of enantiomers.

The title target compound (1.51 g) was dissolved in methanol (40 ml) and separated into enantiomers by chiral phase preparative HPLC (see examples 91A and 92A) [column: Daicel Chiralcel OZ-H, 5 μm, 250 mm x 30 mm; flow: 114 ml/min; sample injection: 0.40 ml; eluent: 22% methanol/78% carbon dioxide; duration of action 9 min, isocratic]. The combined desired fractions were concentrated and the corresponding residue was dried in vacuo.

Example 91A.

tert-Butyl 5-({[6-bromo-2-(3,3-difluoropiperidin-1-yl)-3-methylquinolin-4-yl]carbonyl}amino)-4-(2chlorophenyl)pentanoate (enantiomer 1) .

The separation of enantiomers described in Example 90A gave 672 mg (97% pure, ee 98%) of the title compound as the previously eluted enantiomer.

R _t = 2.35 min (chiral analytical SLC; Agilent Saule Phenyl Cellulose-2, 3 µm, 50 mm x 4.6 mm, eluent carbon dioxide/methanol 95:5^4:6; flow 3 ml/min; temperature 40°C; detection at 220 nm).

LC-MS (method 1): Rt = 2.70 min; MS (ESIpos): m/z = 650/652 [M+H]+.

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.009 (0.28), 0.007 (0.29), 1.038 (0.05), 1.055 (0.10), 1.073 (0.05), 1.209 (0.06), 1.310 (0.07 ), 1.332 (0.10), 1.369 (16.00), 1.525 (0.06), 1.795 (0.14), 1.816 (0.18), 1.879 (0.44), 2.045 (0.28), 2.075 (1.41), 2.087 (0.90), 2.109 (0.46 ), 2.151 (1.41), 2.327 (0.05), 2.669 (0.06), 2.709 (0.04), 3.162 (0.52), 3.446 (0.34), 3.475 (0.65), 3.504 (0.32), 3.586 (0.20), 3.681 (0.34 ), 7.255 (0.17), 7.273 (0.40), 7.290 (0.30), 7.355 (0.24), 7.373 (0.43), 7.391 (0.22), 7.439 (0.60), 7.442 (0.58), 7.459 (0.50), 7.462 (0.48 ), 7.486 (0.50), 7.502 (0.40), 7.674 (0.24), 7.696 (1.37), 7.702 (0.97), 7.707 (0.83), 7.724 (0.15), 7.729 (0.17), 8.716 (0.21), 8.731 (0.43 ), 8.745 (0.21).

Example 92A.

tert-Butyl 5-({[6-bromo-2-(3,3-difluoropiperidin-1-yl)-3-methylquinolin-4-yl]carbonyl}amino)-4-(2chlorophenyl)pentanoate (enantiomer 2) .

The separation of enantiomers described in Example 90A gave 634 mg (98% pure, ee 98%) of the title compound as the later eluted enantiomer.

R _t = 2.67 min (chiral analytical SLC; Agilent Saule Phenyl Cellulose-2, 3 µm, 50 mm x 4.6 mm,

- 62 040220 eluent carbon dioxide/methanol 95:5 ^ 4:6; flow 3 ml/min; temperature 40°C; detection at 220 nm).

LC-MS (method 1): Rt = 2.70 min; MS (ESIpos): m/z = 650/652 [M+H]+.

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 1.038 (0.09), 1.055 (0.18), 1.073 (0.09), 1.208 (0.06), 1.310 (0.06), 1.332 (0.09), 1.369 (16.00 ), 1.525 (0.07), 1.796 (0.15), 1.816 (0.20), 1.878 (0.45), 2.045 (0.28), 2.075 (1.47), 2.087 (0.94), 2.110 (0.47), 2.151 (1.50), 2.327 (0.05 ), 2.669 (0.06), 3.162 (0.54), 3.446 (0.36), 3.475 (0.67), 3.504 (0.33), 3.587 (0.21), 3.681 (0.36), 4.335 (0.06), 7.254 (0.17), 7.273 (0.41 ), 7.290 (0.29), 7.355 (0.24), 7.373 (0.45), 7.391 (0.23), 7.439 (0.64), 7.459 (0.53), 7.483 (0.52), 7.502 (0.42), 7.674 (0.24), 7.696 (1.40 ), 7.702 (0.97), 7.707 (0.82), 7.724 (0.15), 7.729 (0.17), 8.717 (0.22), 8.731 (0.45), 8.745 (0.22).

Example 93A.

tert-Butyl 5-[({6-bromo-3-methyl-2-[3-(trifluoromethyl)piperidin-1-yl]quinolin-4yl}carbonyl)amino]-4-(2-chlorophenyl)pentanoate (mixture diastereoisomers)

To a suspension of (+/-)-tert-butyl-5-{[(6-bromo-2-chloro-3-methylquinolin-4-yl)carbonyl]amino}-4-(2chlorophenyl)pentanoate (250 mg, 98 % purity, 433 µmol, example 37A) in NMP (4 ml) was added (+/-)-3(trifluoromethyl)piperidine (530 mg, 3.46 mmol) and DIPEA (602 µl, 3.46 mmol) and the mixture was stirred for two days at 120°C. After cooling to RT, the mixture was concentrated and the residue was taken up in acetonitrile and purified by preparative HPLC (method 6). The combined desired fractions were concentrated and the residue was dried in vacuo. 156 mg (98% pure, 52% theoretical) of the title compound were obtained.

LC-MS (method 1): R _t = 2.85 min; MS (ESIpos): m/z = 682/684 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.153 (3.05), 1.181 (2.46), 1.268 (0.43), 1.284 (0.44), 1.308 (0.41), 1.370 (16.00), 1.504 (0.40) , 1.521 (0.50), 2.076 (1.13), 2.089 (0.66), 2.144 (1.11), 7.271 (0.44), 7.373 (0.43), 7.436 (0.60), 7.456 (0.49), 7.484 (0.58) , 7.503 (0.47), 7.689 (2.18).

Example 94A.

(+/-)-tert-Butyl-5-({[6-bromo-3-methyl-2-(4-methylpiperazin-1-yl)quinolin-4-yl]carbonyl}amino)-4(2-chlorophenyl )pentanoate (racemate)

To a suspension of (+/-)-tert-butyl-5-{[(6-bromo-2-chloro-3-methylquinolin-4-yl)carbonyl]amino}-4-(2chlorophenyl)pentanoate (200 mg, 98 % purity, 346 μmol, example 37A) in NMP (4 ml) was added 1-methylpiperazine (277 mg, 2.77 mmol) and DIPEA (482 μl, 2.77 mmol) and the mixture was stirred for two days at

120°C. After cooling to RT, the mixture was concentrated and the residue was taken up in acetonitrile and purified by preparative HPLC (method 6). The combined desired fractions were concentrated and the residue was dried in vacuo. 135 mg (98% pure, 61% th. y.) of the title compound were obtained.

LC-MS (method 1): R _t = 1.72 min; MS (ESIpos): m/z = 629/631 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: -0.023 (0.08), -0.008 (0.22), 0.008 (0.24), 1.027 (0.04), 1.208 (0.06), 1.234 (0.21), 1.312 (0.07), 1.333 (0.09), 1.368 (16.00), 1.525 (0.06), 1.793 (0.13) (0.28) 2.132 (1.31) (0.17) (0.52), 7.497 (0.44), 7.640 (0.20), 7.662 (1.35), 7.666 (1.05), 7.671 (0.81), 7.688 (0.12), 7.693 (0.14) (0.19).

Example 95A.

tert-Butyl 5-[({6-bromo-2-[3-hydroxypiperidin-1-yl]-3-methylquinolin-4-yl}carbonyl)amino]-4(2-chlorophenyl)pentanoate (mixture of diastereoisomers)

- 63 040220

To a suspension of (+/-)-tert-butyl-5-{[(6-bromo-2-chloro-3-methylquinolin-4-yl)carbonyl]amino}-4-(2chlorophenyl)pentanoate (200 mg, 98 % purity, 346 µmol, example 37A) in NMP (3 ml) was added (+/-)piperidin-3-ol (280 mg, 2.77 mmol) and DIPEA (482 µl, 2.77 mmol) and the mixture was stirred for two days at 120 °C. After cooling to RT, the mixture was concentrated and the residue was taken up in acetonitrile and purified by preparative HPLC (method 6). The combined desired fractions were concentrated and the residue was dried in vacuo. 154 mg (98% pure, 69% thor.) of the title compound were obtained.

LC-MS (method 1): Rt = 2.39 min; MS (ESIpos): m/z = 630/632 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: -0.008 (0.24), 0.008 (0.23), 1.209 (0.06), 1.313 (0.17), 1.369 (16.00), 1.526 (0.07), 1.603 ( 0.13), 1.783 (0.25), 1.813 (0.28), 1.922 (0.18), 1.943 (0.17), 2.052 (0.18), 2.074 (1.10), 2.087 (0.64), 2.110 (0.30), 2.132 (1.38), 0.05), 2.366 (0.06), 2.635 (0.16), 2.665 (0.13),2.710 (0.07), 2.778 (0.17), 3.356 (0.21), 3.387 (0.19), 3.512 (0.22), 3.543 (0.22), 3.589 ( 0.19), 3.677 (0.47),4.852 (0.66), 4.864 (0.65), 7.254 (0.16), 7.272 (0.37), 7.291 (0.27), 7.353 (0.22), 7.372 (0.41), 7.391 (0.21), 0.62), 7.442 (0.63), 7.458 (0.53), 7.462 (0.52), 7.482 (0.55), 7.501 (0.44), 7.621 (0.36), 7.643 (1.27), 7.656 (0.83), 7.661 (0.76), 0.23), 7.684 (0.24), 8.713 (0.19), 8.727 (0.39), 8.741 (0.19).

Example 96A.

tert-Butyl-5-{[(6-bromo-2-{3-[(tert-butoxycarbonyl)amino]piperidin-1-yl}-3-methylquinolin-4yl)carbonyl]amino}-4-(2-chlorophenyl )pentanoate (mixture of deastereoisomers)

To a suspension of (+/-)-tert-butyl-5-{[(6-bromo-2-chloro-3-methylquinolin-4-yl)carbonyl]amino}-4-(2chlorophenyl)pentanoate (200 mg, 98 % purity, 346 µmol, example 37A) in NMP (3 ml) was added (+/-) tert-butyl-piperidin-3-ylcarbamate (555 mg, 2.77 mmol) and DIPEA (482 µl, 2.77 mmol), and the mixture stirred for two days at 120°C. After cooling to RT, the mixture was concentrated and the residue was taken up in acetonitrile and purified by preparative HPLC (method 6). The combined desired fractions were concentrated and the residue was dried in vacuo. 162 mg (98% pure, 63% theoretical) of the title compound were obtained.

LC-MS (method 1): Rt = 2.78 min; MS (ESIpos): m/z = 729/731 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 1.209 (0.07), 1.235 (0.09), 1.369 (16.00), 1.395 (10.53), 1.525 (0.08), 1.551 (0.07), 1.643 (0.13 ), 1.797 (0.32), 1.831 (0.36), 2.073 (1.14), 2.086 (0.69), 2.103 (0.26), 2.155 (0.93), 2.328 (0.06), 2.615 (0.10), 2.670 (0.10), 2.752 (0.19 ), 3.369 (0.20), 3.401 (0.18), 3.473 (0.18), 3.501 (0.18), 3.581 (0.33), 3.679 (0.35), 6.961 (0.19), 7.251 (0.16), 7.269 (0.39), 7.289 (0.27 ), 7.352 (0.22), 7.371 (0.41), 7.389 (0.22), 7.436 (0.57), 7.455 (0.49), 7.482 (0.55), 7.499 (0.46), 7.631 (0.31), 7.653 (1.19), 7.665 (0.76 ), 7.670 (0.69), 7.687 (0.20), 7.692 (0.21), 8.730 (0.34).

Example 97A.

tert-Butyl 5-[({6-bromo-2-[3-ethylpiperidin-1-yl]-3-methylquinolin-4-yl}carbonyl)amino]-4-(2chlorophenyl)pentanoate (mixture of diastereoisomers)

To a suspension of (+/-)-tert-butyl-5-{[(6-bromo-2-chloro-3-methylquinolin-4-yl)carbonyl]amino}-4-(2-64 040220 chlorophenyl)pentanoate ( 2.50 g, 98% pure, 4.33 mmol, example 37A) in NMP (37 ml) was added (+/-)-3ethylpiperidine (3.92 g, 34.6 mmol) and DIPEA (6.0 ml, 34.6 mmol) and the mixture was stirred for 4 h at 120°C. After cooling to RT, the mixture was concentrated and the residue was adsorbed in dichloromethane and washed with water and saturated aqueous sodium chloride. The combined aqueous phases were then extracted twice with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated and the residue dried in vacuo. 2.40 g (98% pure, 85% th. y.) of the title compound were obtained.

LC-MS (method 1): Rt = 3.04 min; MS (ESIpos): m/z = 642/644 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.078 (0.08), 0.218 (0.08), 0.962 (0.85), 0.980 (2.01), 0.999 (1.05), 1.135 (0.19), 1.158 (0.20 ), 1.187 (0.09), 1.228 (0.15), 1.246 (0.30), 1.264 (0.15), 1.281 (0.08), 1.329 (0.39), 1.347 (0.51), 1.364 (0.36), 1.403 (0.11), 1.440 (16.00 ), 1.636 (0.22), 1.817 (0.28), 1.849 (0.27), 1.889 (0.24), 1.917 (0.27), 1.948 (0.22), 2.059 (0.56), 2.118 (0.24), 2.146 (1.40), 2.157 (0.81 ), 2.201 (1.34), 2.816 (0.18), 3.566 (0.40), 3.591 (0.36), 3.658 (0.24), 3.744 (0.46), 4.092 (0.14), 4.110 (0.13), 5.825 (0.10), 7.322 (0.20 ), 7.341 (0.49), 7.359 (0.36), 7.423 (0.27), 7.442 (0.51), 7.460 (0.26), 7.506 (0.65), 7.526 (0.55), 7.554 (0.67), 7.571 (0.54), 7.697 (0.19 ), 7.720 (1.78), 7.749 (0.15), 8.772 (0.24), 8.787 (0.50), 8.801 (0.24).

Separation of diastereoisomers/enantiomers.

The title target compound (2.4 g) was dissolved in methanol (60 ml) and separated into diastereoisomers by preparative SLC on chiral phase [column: Daicel Chiralcel OX-H, 5 μm, 250 mm x 30 mm, flow: 80 ml/min, detection : 210 nm; temperature: 40°C, sample injection: 0.40 ml; eluent: 22% methanol/78% carbon dioxide, isocratic]. A mixed fraction was obtained (peak 1 and peak 2) and two corresponding sufficiently pure fractions (peak 3, see example 100A, respectively peak 4, see example 101A). The mixed fraction was further separated into diastereoisomers by preparative SLC on the chiral phase [column: Daicel Chiralcel OX-H, 5 μm, 250 mm x 20 mm, flow: 80 ml/min, detection: 210 nm; temperature: 40°C, sample injection: 2.20 ml; eluent: 15% isopropanol/85% carbon dioxide, isocratic]. Two sufficiently pure fractions were obtained (peak 1, see example 98A, respectively peak 2, see example 99A). The combined target fractions were respectively concentrated and the corresponding residue was lyophilized.

Example 98A.

(+)-tert-Butyl-5-[({6-bromo-2-[3-ethylpiperidin-1-yl]-3-methylquinolin-4-yl}carbonyl)amino]-4-(2chlorophenyl)pentanoate (diastereoisomer 1).

The separation of diastereoisomers described in Example 97A gave 200 mg (100% pure, >99% ee) of the title compound as the first eluting diastereoisomer (peak 1).

[a] _D20 = +7.7°, 589 nm ^, c = 0.39 g/100 mL, methanol;

LC-MS (method 1): Rt = 3.03 min; MS (ESIpos): m/z = 642/644 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.976 (0.88), 0.995 (2.21), 1.014 (1.10), 1.121 (0.06), 1.149 (0.17), 1.179 (0.17), 1.200 (0.08) , 1.294 (0.07), 1.325 (0.13), 1.342 (0.35), 1.360 (0.47), 1.377 (0.32),1.397 (0.17), 1.415 (0.11), 1.454 (16.00), 1.611 (0.12), 1.649 (0.22) , 1.682 (0.20), 1.713 (0.17), 1.831 (0.24),1.872 (1.28), 2.169 (0.75), 2.203 (0.38), 3.607 (0.28), 3.671 (0.46), 7.473 (0.23), 7.519 (0.89) , 7.759 (0.12), 7.764

(0.23), 1.902 (0.21), 1.930 (0.23), 1.961 (0.19), 2.131 (0.24), 2.140 (0.20), 2.158 (1.17), 2.413 (0.04), 2.755 (0.04), 2.804 (0.13), 2.832 (0.23), 2.861 (0.13), 3.584 (0.21), 3.757 (0.39), 7.336 (0.18), 7.354 (0.42), 7.371 (0.30), 7.436 (0.25), 7.455 (0.57), 7.537 (0.47), 7.568 (0.57), 7.584 (0.48), 7.711 (0.19), 7.733 (1.47), 7.741

(0.14), 8.786 (0.21), 8.801 (0.43), 8.815 (0.21).

Example 99A.

(-)-tert-Butyl-5-[({6-bromo-2-[3-ethylpiperidin-1 -yl] -3-methylquinolin-4-yl}carbonyl)amino]-4-(2chlorophenyl)pentanoate (diastereoisomer 2).

The separation of diastereoisomers described in Example 97A gave 219 mg (100% pure, ee 95%) of the title compound as the second eluting diastereoisomer (peak 2).

[a] _D20 = -23.1°, 589 nm, c = 0.42 g ^/ 100 ml, methanol;

LC-MS (method 1): Rt = 3.02 min; MS (ESIpos): m/z = 642/644 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.961 (0.87), 0.979 (2.07), 0.998 (1.02), 1.107 (0.07), 1.135 (0.17), 1.157 (0.17), 1.187 (0.08) , 1.280 (0.08), 1.311 (0.15), 1.329 (0.34), 1.346 (0.45), 1.364 (0.31), 1.385 (0.18), 1.440 (16.00), 1.597 (0.15), 1.629 (0.19), 1.675 (0.18) , 1.706 (0.16), 1.816 (0.25), 1.849 (0.24), 1.888 (0.21), 1.917 (0.23), (1.75), 2.239 (0.09), (0.35), 3.658 (0.21), (0.30), 7.425 ( 0.25), (0.60), 7.570 (0.47),

1.948 (0.19), 2.118 (0.22), 2.128 (0.23), 2.147 (1.23), 2.158 2.399 (0.04), 2.473 (0.12), 2.776 (0.11), 2.803 (0.20), 2.831 3.744 (0.41), 3.791 (0.10), 3.896 (0.07), 4.109 (0.04), 7.324 7.443 (0.44), 7.461 (0.23), 7.507 (0.62), 7.509 (0.57), 7.526 7.697 (0.19), 7.720 (1.51), 7.727 (0.87), 7.744 (0.12), 7.749

(0.74), 2.180 (0.37), 2.201 (0.11), 3.559 (0.38), 3.588 (0.19), 7.342 (0.41), 7.362 (0.53) (0.23), 8.787 (0.45), 8.801 (0.21).

Example 100A.

(-)-tert-Butyl-5-[({6-bromo-2-[3-ethylpiperidin-1 -yl] -3-methylquinolin-4-yl}carbonyl)amino]-4-(2

- 65 040220 chlorophenyl) pentanoate (diastereoisomer 3).

Separation of diastereomers as described in Example 97A gave 462 mg (100% pure, >99% ee) of the title compound as the third eluting diastereoisomer (peak 3).

[a] ^D20 = -6.9°, 589 nm, c = 0.36 g/100 ml, methanol;

LC-MS (method 1): Rt = 3.03 min; MS (ESIpos): m/z = 642/644 [M+H]+.

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 0.077 (0.11), 0.093 (0.12), 0.976 (0.84), 0.995 (2.12), 1.014 (1.04), 1.121 (0.06), 1.150 (0.16 ), 1.179 (0.16), 1.201 (0.08), 1.294 (0.07), 1.325 (0.13), 1.342 (0.33), 1.359 (0.45), 1.377 (0.31), 1.397 (0.16), 1.416 (0.11), 1.454 (16.00 ), 1.611 (0.12), 1.649 (0.20), 1.682 (0.19), 1.713 (0.15), 1.831 (0.23), 1.863 (0.22), 1.901 (0.20), 1.930 (0.22), 1.961 (0.18), 2.131 (0.22 ), 2.140 (0.19), 2.158 (1.19), 2.169 (0.70), 2.203 (1.05), 2.413 (0.04), 2.755 (0.04), 2.805 (0.12), 2.832 (0.21), 2.861 (0.11), 3.584 (0.35 ), 3.605 (0.26), 3.671 (0.19), 3.757 (0.36), 7.336 (0.17), 7.354 (0.39), 7.371 (0.29), 7.437 (0.24), 7.455 (0.43), 7.474 (0.22), 7.517 (0.53 ), 7.520 (0.55), 7.537 (0.44), 7.539 (0.45), 7.565 (0.52), 7.568 (0.53), 7.584 (0.45), 7.711 (0.18), 7.734 (1.41), 7.736 (1.18), 7.741 (0.85 ), 7.759 (0.12), 7.764 (0.14), 8.786 (0.20), 8.801 (0.40), 8.815 (0.20).

Example 101A.

(+)-tert-Butyl-5-[({6-bromo-2-[3-ethylpiperidin-1-yl]-3-methylquinolin-4-yl}carbonyl)amino]-4-(2chlorophenyl)pentanoate (diastereoisomer 4).

The separation of diastereoisomers described in Example 97A gave 483 mg (100% pure, ee 93%) of the title compound as the last eluting diastereoisomer (peak 4).

[a] _D20 = +23.3°, 589 nm, c = 0.39 ^g /100 mL, methanol;

LC-MS (method 1): Rt = 3.02 min; MS (ESIpos): m/z = 642/644 [M+H]+.

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.931 (0.89), 0.950 (2.16), 0.968 (1.10), 1.077 (0.07), 1.106 (0.18), 1.136 (0.19), 1.156 (0.08) , 1.251 (0.08), 1.282 (0.15), 1.299 (0.35), 1.317 (0.48), 1.334 (0.34) . . , 3.628 (0.24), 3.715 (0.46), 7.294 (0.20), 7.312 (0.47), 7.330 (0.33), 7.395 (0.28), 7.414 (0.51),7.432 (0.27), 7.478 (0.68), 7.498 (0.58) , 7.524 (0.68), 7.541 (0.54), 7.668 (0.17), 7.691 (1.78), 7.697 (0.99), 7.719 (0.14), 8.743 (0.25), 8.758 (0.50), 8.772 (0.24).

Example 102A.

tert-Butyl 5-[({6-bromo-2-[3-hydroxy-3-methylpiperidin-1-yl]-3-methylquinolin-4yl}carbonyl)amino]-4-(2-chlorophenyl)pentanoate (mixture diastereoisomers)

To a suspension of (+/-)-tert-butyl-5-{[(6-bromo-2-chloro-3-methylquinolin-4-yl)carbonyl]amino}-4-(2chlorophenyl)pentanoate (200 mg, 98 % purity, 346 µmol, example 37A) in NMP (3.0 ml) was added (+/-)-3methylpiperidin-3-ol-hydrochloride (420 mg, 2.77 mmol) and DIPEA (482 µl, 2.77 mmol) and the mixture was stirred for two days at 120°C. After cooling to RT, the mixture was concentrated and the residue was purified by preparative HPLC (method 6). The combined desired fractions were concentrated and the residue was dried in vacuo. 148 mg (98% pure, 65% thor.) of the title compound were obtained.

LC-MS (method 1): R _t = 2.52 min; MS (ESIpos): m/z = 644/646 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.024 (0.28), 1.190 (2.69), 1.333 (0.13), 1.356 (0.61), 1.370 (16.00), 1.558 (0.67), 1.571 (0.73) , 1.612 (0.18), 1.819 (0.32), 2.047 (0.21), 2.075 (1.34), 2.087 (0.74),2.103 (0.26), 2.167 (1.65), 2.327 (0.05), 2.393 (0.05), 2.411 (0.05) . . , 7.656 (0.75), 7.674 (0.23), 7.678 (0.23), 8.709 (0.24), 8.723 (0.48), 8.737 (0.23).

Example 103A.

tert-Butyl 5-[({6-bromo-2-[3,5-dimethylpiperidin-1-yl]-3-methylquinolin-4-yl}carbonyl)amino]-4(2-chlorophenyl)pentanoate (mixture of diastereoisomers )

- 66 040220

To a mixture of (+/-)-tert-butyl-5-{[(6-bromo-2-chloro-3-methylquinolin-4-yl)carbonyl]amino}-4-(2chlorophenyl)pentanoate (200 mg, 353 µmol, example 37A) in NMP (2.5 ml) was added (+/-)-(cis-trans)-3,5dimethylpiperidine (80 mg, 706 µmol, mixture of diastereoisomers, CAS-RN 35794-11-7) and DIPEA (140 µl, 780 µmol) and the mixture was stirred for 18 h at 100°C. Then (+/-)-(cis-trans)-3,5dimethylpiperidine (40 mg, 353 µmol, mixture of diastereoisomers, CAS-RN 35794-11-7) and DIPEA (76 µl, 425 µmol) were added again and the mixture was stirred further at 100°C. After a total of 42 hours, the mixture was cooled to RT and filtered. The filtrate was purified by preparative HPLC (method 6). The combined desired fractions were concentrated and the residue was dried in vacuo. 91 mg (100% pure, 40% thor.) of the title compound were obtained.

LC-MS (method 2): Rt = 1.59 min; MS (ESIpos): m/z = 642/644 [M+H]+.

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.008 (0.63), 0.719 (0.19), 0.749 (0.22), 0.897 (2.28), 0.913 (2.32), 1.007 (0.49), 1.020 (0.49) , 1.234 (0.32), 1.369 (16.00), 1.438 (0.18), 1.807 (0.53), 1.988 (0.18) . , 7.391 (0.25), 7.440 (0.61), 7.458 (0.53), 7.481 (0.59), 7.498 (0.47), 7.649 (2.04), 8.708 (0.37).

Example 104A.

tert-Butyl 5-[({6-bromo-2-[3-(difluoromethyl)piperidin-1-yl]-3-methylquinolin-4yl}carbonyl)amino]-4-(2-chlorophenyl)pentanoate (mixture of diastereoisomers )

To a mixture of (+/-)-tert-butyl-5-{[(6-bromo-2-chloro-3-methylquinolin-4-yl)carbonyl]amino}-4-(2chlorophenyl)pentanoate (200 mg, 353 µmol, example 37A) in NMP (2.5 ml) was added (+/-)-3(difluoromethyl)piperidine hydrochloride (121 mg, 706 µmol) and DIPEA (140 µl, 780 µmol), and the mixture was stirred for 18 h at 100° WITH. Then (+/-)-3-(difluoromethyl)piperidine hydrochloride (60 mg, 353 µmol) and DIPEA (70 µl, 390 µmol) were added again and the mixture was stirred for an additional 24 h at 100°C. After that, the mixture was stirred for 15 min in a closed glass vessel in a microwave oven (Biotage) at 100°C. After cooling to RT, the mixture was mixed with saturated aqueous sodium hydrogen carbonate and extracted several times with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated, and the residue was adsorbed in dichloromethane and purified by flash column chromatography (100 g silica gel, Biotage Snap-Cartridge Ultra, cyclohexane/ethyl acetate gradient 95:5^20:80, Isolera One ). The two combined target fractions were concentrated and the corresponding residue was dried in vacuo. 98 mg (41% pure, 17% th. y.) of the first batch of the title compound and 18 g (54% pure, 4% th. y.) of the second batch of the title compound were obtained, which were then united.

LC-MS (method 1): Rt = 2.75 min; MS (ESIpos): m/z = 664/666 [M+H]+.

Example 105A.

tert-Butyl 5-[({6-bromo-2-[(3S)-3-fluoropyrrolidin-1-yl]-3-methylquinolin-4-yl}carbonyl)amino]-4(2-chlorophenyl)pentanoate ( mixture of epimers)

- 67 040220

To a mixture of (+/-)-tert-butyl-5-{[(6-bromo-2-chloro-3-methylquinolin-4-yl)carbonyl]amino}-4-(2chlorophenyl)pentanoate (200 mg, 353 µmol, example 37A) in NMP (2.5 ml) was added (3S)-3fluoropyrrolidine hydrochloride (89 mg, 706 µmol) and DIPEA (140 µl, 780 µmol) and the mixture was stirred for 18 h at 100°C. Then (3S)-3-fluoropyrrolidine-hydrochloride (45 mg, 353 µmol) and DIPEA (76 µl, 425 µmol) were added again and the mixture was stirred for an additional 24 h at 100°C. After cooling to RT, the mixture was filtered. The filtrate was purified by preparative HPLC (method 6). The combined desired fractions were concentrated and the residue was dried in vacuo. 141 mg (89% pure, 57% thor.) of the title compound were obtained.

LC-MS (method 2): Rt = 1.26 min; MS (ESIpos): m/z = 618/620 [M+H]+.

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.150 (0.32), -0.008 (3.09), 0.007 (3.00), 0.146 (0.31), 1.156 (0.38), 1.175 (0.78), 1.192 ( 0.41), 1.366 (15.46), 1.370 (16.00), 1.818 (0.30), 1.988 (1.44), 2.074 (1.85), 2.175 (1.40), 2.327 (0.23), 2.366 (0.27), 2.523 (0.66), 0.21), 2.709 (0.24), 3.598 (0.58), 3.867 (0.24), 4.020 (0.45), 4.038 (0.40), 5.330 (0.35), 5.464 (0.34), 7.260 (0.44), 7.277 (0.49), 0.56), 7.380 (0.52),7.435 (0.94), 7.454 (0.79), 7.476 (0.57), 7.504 (0.83), 7.526 (1.00), 7.531 (1.04), 7.575 (0.54), 7.581 (0.97), 0.53), 7.603 (0.55), 7.895 (0.27), 8.688 (0.52).

Example 106A.

tert-Butyl 5-[({6-bromo-2-[(3R)-3-fluoropyrrolidin-1-yl]-3-methylquinolin-4-yl}carbonyl)amino]-4(2-chlorophenyl)pentanoate ( mixture of epimers)

To a mixture of (+/-)-tert-butyl-5-{[(6-bromo-2-chloro-3-methylquinolin-4-yl)carbonyl]amino}-4-(2chlorophenyl)pentanoate (200 mg, 353 µmol, example 37A) in NMP (2.6 ml) was added (1R)-3fluoropyrrolidine hydrochloride (89 mg, 706 µmol) and DIPEA (140 µl, 780 µmol) and the mixture was stirred for 18 h at 100°C. Then (3R)-3-fluoropyrrolidine hydrochloride (45 mg, 353 µmol) and DIPEA (76 µl, 425 µmol) were added again and the mixture was stirred for an additional 24 h at 100°C. After cooling to RT, the mixture was mixed with saturated aqueous sodium hydrogen carbonate and extracted several times with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated, and the residue was adsorbed in dichloromethane and purified by flash column chromatography (100 g silica gel, Biotage Snap-Cartridge Ultra, cyclohexane/ethyl acetate gradient 97:3^4:6, Isolera One). The combined desired fractions were concentrated and the residue was dried in vacuo. 98 mg (41% pure, 17% thor.) of the title compound were obtained.

LC-MS (method 1): Rt = 2.50 min; MS (ESIpos): m/z = 618/620 [M+H]+.

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: -0.008 (1.50), 0.008 (0.91), 1.157 (0.46), 1.175 (0.91), 1.192 (0.46), 1.366 (16.00), 1.370 ( 14.31), 1.817 (0.28), 1.988 (1.65), 2.074 (1.82), 2.085 (1.02), 2.174 (1.43), 2.327 (0.20), 2.366 (0.24), 2.669 (0.21), 2.709 (0.24), 0.63), 3.867 (0.27), 4.020 (0.51), 4.038 (0.47), 5.330 (0.36), 5.465 (0.36), 7.261 (0.44), 7.278 (0.48), 7.344 (0.31), 7.363 (0.56), 0.49), 7.435 (0.95),7.455 (0.80), 7.476 (0.59), 7.504 (0.86), 7.508 (0.77), 7.526 (1.06), 7.530 (1.06), 7.575 (0.58), 7.581 (1.00),7.587 0.55), 7.598 (0.33), 7.603 (0.57), 7.609 (0.32), 8.689 (0.55).

Example 107A.

tert-Butyl 5-[({6-bromo-2-[trans-3,4-difluoropyrrolidin-1-yl]-3-methylquinolin-4yl}carbonyl)amino]-4-(2-chlorophenyl)pentanoate (mixture diastereoisomers)

- 68 040220

To a mixture of (+/-)-tert-butyl-5-{[(6-bromo-2-chloro-3-methylquinolin-4-yl)carbonyl]amino}-4-(2chlorophenyl)pentanoate (200 mg, 353 µmol, example 37A), (+/-)-trans-3,4difluoropyrrolidine hydrochloride (101 mg, 706 µmol) and DIPEA (140 µl, 780 µmol) were added to NMP (2.5 ml), and the mixture was stirred for 18 h at 100° WITH. Then (+/-)-trans-3,4-difluoropyrrolidine hydrochloride (50 mg, 353 µmol) and DIPEA (70 µl, 390 µmol) were added again and the mixture was stirred for an additional 24 h at 100°C. After that, the mixture was stirred for 15 min in a closed glass vessel in a microwave oven (Biotage) at 100°C. After cooling to RT, the mixture was filtered and purified by preparative HPLC (method 6). The combined desired fractions were concentrated and the residue was dried in vacuo. 169 mg (77% pure, 58% thor.) of the title compound were obtained.

LC-MS (method 2): Rt = 1.33 min; MS (ESIpos): m/z = 636/638 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.008 (0.49), 1.157 (2.03), 1.175 (4.09), 1.193 (2.07), 1.333 (0.19), 1.367 (13.18), 1.371 (16.00) , 1.820 (0.30), 1.988 (7.63), 2.076 (1.81), 2.089 (1.06), 2.106 (0.39), 2.192 (1.13), 2.327 (0.11), 2.366 (0.09), 3.596 (0.32), 3.714 (0.37) 4.003 (0.63), 4.021 (1.85), 4.039 (1.84), 4.056 (0.69), 4.185 (0.19), 5.360 (0.41), 5.494 (0.41), 7.261 (0.39), 7.280 (0.47), 7.345 (0.22) . , 7.617 (0.73), 7.639 (0.40), 7.895 (0.86), 8.696 (0.43), 8.859 (0.16).

Example 108A.

(+/-)-tert-Butyl-5-[({6-bromo-2-[cis-3,4-difluoropyrrolidin-1-yl]-3-methylquinolin-4yl}carbonyl)amino]-4-(2 -chlorophenyl)pentanoate (racemate)

To a mixture of (+/-)-tert-butyl-5-{[(6-bromo-2-chloro-3-methylquinolin-4-yl)carbonyl]amino}-4-(2chlorophenyl)pentanoate (200 mg, 353 µmol, example 37A) in NMP (2.5 ml) was added cis-3,4difluoropyrrolidine hydrochloride (101 mg, 706 µmol) and DIPEA (140 µl, 780 µmol) and the mixture was stirred for 18 h at 100°C. Then cis-3,4-difluoropyrrolidine hydrochloride (50 mg, 353 µmol) and DIPEA (70 µl, 390 µmol) were added again and the mixture was stirred for an additional 24 h at 100°C. After cooling to RT, the mixture was filtered and purified by preparative HPLC (method 6). The combined target fractions were respectively concentrated and the corresponding residue was dried in vacuo. 60 mg (97% pure, 26% theoretical) of the first batch of the title compound and 100 mg (88% pure, 39% of theor.) of the second batch of the title compound were obtained, which were combined for the subsequent reaction.

Analysis of the first batch:

LC-MS (method 2): R _t = 1.31 min; MS (ESIpos): m/z = 636/638 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.157 (1.14), 1.175 (2.31), 1.192 (1.17), 1.308 (0.09), 1.335 (0.15), 1.368 (16.00), 1.818 (0.20) , 1.988 (4.34), 2.074 (1.23), 2.086 (0.67), 2.103 (0.28), 2.159 (0.85), 3.581 (0.22), 3.670 (0.24), 3.782 (0.23), 4.002 (0.52), 4.020 (1.17) . . , 7.633 (0.36), 7.638 (0.35), 8.690 (0.40).

Analysis of the second batch:

LC-MS (method 2): R _t = 1.31 min; MS (ESIpos): m/z = 636/638 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.009 (0.47), 0.007 (0.35), 1.156 (1.58), 1.174 (3.21), 1.192 (1.61), 1.208 (0.07), 1.308 (0.10 ), 1.335 (0.15), 1.368 (16.00), 1.524 (0.06), 1.817 (0.19), 1.988 (5.93), 2.046 (0.19), 2.074 (1.20), 2.086 (0.64), 2.103 (0.26), 2.158 (0.75 ), 2.327 (0.06), 2.365 (0.06), 3.582 (0.21), 3.670

- 69 040220 (0.22), 3.779 (0.20), 4.002 (0.61), 4.020 (1.51), 4.038 (1.48), 4.056 (0.49), 5.298 (0.20), 5.324 (0.16), 5.426 (0.17), 5.435 (0.18 ), 5.460 (0.20), 7.251 (0.15), 7.269 (0.34), 7.288 (0.25), 7.353 (0.22), 7.371 (0.40), 7.390 (0.23), 7.434 (0.64), 7.437 (0.62), 7.454 (0.55 ), 7.481 (0.51), 7.497 (0.39), 7.542 (0.63), 7.564 (1.13), 7.610 (0.63), 7.616 (0.57), 7.632 (0.34), 7.638 (0.33), 7.894 (0.26), 8.690 (0.36 ).

Example 109A.

tert-Butyl 5-[({6-bromo-2-[3-fluoro-3-methylpyrrolidin-1-yl]-3-methylquinolin-4yl}carbonyl)amino]-4-(2-chlorophenyl)pentanoate (mixture diastereoisomers)

To a mixture of (+/-)-tert-butyl-5-{[(6-bromo-2-chloro-3-methylquinolin-4-yl)carbonyl]amino}-4-(2chlorophenyl)pentanoate (200 mg, 353 µmol, example 37A) in NMP (2.5 ml) was added (+/-)-3-fluoro-3methylpyrrolidine hydrochloride (99 mg, 706 µmol) and DIPEA (140 µl, 780 µmol), and the mixture was stirred for 18 h at 100° WITH. Then (+/-)-3-fluoro-3-methylpyrrolidine hydrochloride (50 mg, 353 µmol) and DIPEA (76 µl, 425 µmol) were added again and the mixture was stirred for an additional 24 h at 100°C. After cooling to RT, the mixture was mixed with saturated aqueous sodium hydrogen carbonate and extracted several times with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated, and the residue was adsorbed in dichloromethane and purified by flash column chromatography (100 g silica gel, Biotage Snap-Cartridge Ultra, cyclohexane/ethyl acetate gradient 97:3^4:6, Isolera One ). The combined desired fractions were concentrated and the residue was dried in vacuo. 98 mg (41% pure, 17% thor.) of the title compound were obtained.

LC-MS (method 1): R _t = 2.58 min; MS (ESIpos): m/z = 632/634 [M+H]+.

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: -0.009 (0.89), 0.007 (0.80), 1.366 (11.66), 1.370 (10.65), (16.00), 1.539 (2.15), 1.591 (2.13 ), 1.815 (0.21), 2.073 (1.38), 2.084 (0.84), 2.100 (0.38), 2.169 (1.12), (0.17), 2.365 (0.21), 2.669 (0.18), 2.709 (0.21), 3.608 (0.44) , 3.798 (0.16), 3.920 (0.28), 7.259 (0.33), (0.37), 7.343 (0.23), 7.362 (0.42), 7.378 (0.36), 7.434 (0.71), 7.454 (0.59), 7.473 (0.40), 7.494 (0.66), (0.63), 7.517 (0.80), 7.521 (0.79), 7.567 (0.41), 7.573 (0.72), 7.579 (0.39), 7.595 (0.43), 8.688 (0.37).

Example 110A.

(+/-)-tert-Butyl-5-({[6-bromo-3-methyl-2-(3,3,4,4-tetrafluoropyrrolidin-1-yl)quinolin-4yl]carbonyl}amino)-4 -(2-chlorophenyl)pentanoate (racemate)

1.398

2.327

7.278

7.499

To a mixture of (+/-)-tert-butyl-5-{[(6-bromo-2-chloro-3-methylquinolin-4-yl)carbonyl]amino}-4-(2chlorophenyl)pentanoate (200 mg, 353 µmol, example 37A) in NMP (2.5 ml) was added (+/-)-3,3,4,4tetrafluoropyrrolidine hydrochloride (127 mg, 706 µmol) and DIPEA (140 µl, 780 µmol) and the mixture was stirred for 18 h at 100°C. Then (+/-)-3,3,4,4-tetrafluoropyrrolidine hydrochloride (64 mg, 353 µmol) and DIPEA (76 µl, 425 µmol) were added again and the mixture was stirred for an additional 24 h at 100°C. After that, the mixture was stirred for 15 min in a closed glass vessel in a microwave oven (Biotage) at 100°C. The mixture was then stirred for 1 h in a closed glass vessel in a microwave oven (Biotage) at 120°C. After cooling to RT, the mixture was mixed with saturated aqueous sodium hydrogen carbonate and extracted several times with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated, and the residue was adsorbed in dichloromethane and purified by flash column chromatography (100 g silica gel, Biotage Snap-Cartridge Ultra, cyclohexane/ethyl acetate gradient 97:3^7:3, Isolera One ). The combined desired fractions were concentrated and the residue was dried in vacuo. 71 mg (9% pure, 3% th. y.) of the title compound were obtained.

LC-MS (method 2): R _t = 1.43 min; MS (ESIpos): m/z = 672/674 [M+H]+.

- 70 040220

Example 111A.

(+/-)-tert-Butyl-5 -[({2-[3-azabicyclo[3.1.1] hept-3-yl]-6-bromo-3-methylquinolin-4yl}carbonyl)amino]-4- (2-chlorophenyl)pentanoate (racemate)

To a mixture of (+/-)-tert-butyl-5-{[(6-bromo-2-chloro-3-methylquinolin-4-yl)carbonyl]amino}-4-(2chlorophenyl)pentanoate (200 mg, 353 µmol, example 37A) in NMP (1.9 ml) was added 3azabicyclo[3.1.1]heptane hydrochloride (92 mg, 689 µmol) and DIPEA (150 µl, 860 µmol) and the mixture was stirred for four days at 100°C. After cooling to RT, the mixture was filtered and purified by preparative HPLC (method 8). The combined desired fractions were concentrated and the residue was dried in vacuo. 66 mg (100% pure, 31% thor.) of the title compound were obtained.

LC-MS (method 1): Rt = 2.81 min; MS (ESIpos): m/z = 626/628 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 1.234 (0.16), 1.330 (0.12), 1.367 (16.00), 1.438 (0.73), 1.444 (0.67), 1.454 (0.69), 1.460 (0.77 ), 1.816 (0.21), 2.045 (0.25), 2.074 (1.55), 2.086 (1.09), 2.102 (0.76), 2.192 (1.21), 3.584 (0.24), 3.663 (0.33), 3.868 (0.34), 7.249 (0.19 ), 7.269 (0.44), 7.287 (0.32), 7.351 (0.28), 7.370 (0.51), 7.388 (0.29), 7.436 (0.77), 7.456 (0.61), 7.480 (0.59), 7.497 (0.43), 7.524 (0.63 ), 7.546 (1.26), 7.583 (0.68), 7.588 (0.63), 7.605 (0.33), 7.610 (0.32), 8.713 (0.45).

Example 112A.

(+/-)-tert-Butyl-5 -[({2-[3-azabicyclo[3.2.1] oct-3-yl]-6-bromo-3-methylquinolin-4yl}carbonyl)amino]-4- (2-chlorophenyl)pentanoate (racemate)

To a mixture of (+/-)-tert-butyl-5-{[(6-bromo-2-chloro-3-methylquinolin-4-yl)carbonyl]amino}-4-(2chlorophenyl)pentanoate (108 mg, 98 % purity, 185 µmol, Example 37A), 3azabicyclo[3.2.1]octane hydrochloride (219 mg, 1.48 mmol) and DIPEA (390 µL, 2.2 mmol) were added to NMP (1.0 mL), and the mixture was stirred for 48 h at 100 °C. After cooling to RT, the mixture was mixed with water and ethyl acetate (respectively 50 ml) and shaken. After phase separation, the aqueous phase was extracted twice with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and concentrated and the residue was purified by preparative HPLC (method 8). The combined target fractions were concentrated and the residue was lyophilized. 80 mg (100% pure, 67% theoretical) of the title compound were obtained.

LC-MS (method 1): Rt = 3.01 min; MS (ESIpos): m/z = 640/642 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.028 (0.90), -0.013 (0.70), 0.848 (0.17), 1.229 (2.08), 1.254 (0.24), 1.364 (16.00), 1.547 ( 0.92), 1.659 (0.41), 1.742 (0.48), 1.761 (0.50), 1.810 (0.21), 2.040 (0.21), 2.068 (1.18), 2.079 (0.59), 2.095 (0.22), 2.178 (1.29), 2.292 ( 0.63), 2.361 (0.15), 2.664 (0.12), 2.705 (0.16), 2.906 (0.35), 2.932 (0.29), 3.577 (0.20), 3.662 (0.35), 7.251 (0.17), 7.270 (0.38), 0.28), 7.349 (0.24), 7.368 (0.43), 7.386 (0.22), 7.440 (0.60), 7.460 (0.54), 7.475 (0.59), 7.491 (0.44), 7.602 (0.41), 7.624 (1.25), 0.77), 7.647 (0.69), 7.664 (0.25), 7.669 (0.25), 8.728 (0.42).

Example 113A.

(+/-)-tert-Butyl-5-({[6-bromo-2-(3,3-difluoroazetidin-1-yl)-3-methylquinolin-4-yl]carbonyl}amino)4-(2- chlorophenyl)pentanoate (racemate)

- 71 040220

To a mixture of (+/-)-tert-butyl-5-{[(6-bromo-2-chloro-3-methylquinolin-4-yl)carbonyl]amino}-4-(2chlorophenyl)pentanoate (200 mg, 353 µmol, example 37A) in NMP (2.5 ml) was added 3,3-difluoroazetidine hydrochloride (92 mg, 706 µmol) and DIPEA (140 µl, 780 µmol) and the mixture was stirred for 18 h at 100°C. Then 3,3-difluoroazetidine hydrochloride (46 mg, 353 µmol) and DIPEA (76 µl, 425 µmol) were added again and the mixture was stirred for 24 h at 100°C. After that, the mixture was stirred for 15 min in a closed glass vessel in a microwave oven (Biotage) at 100°C. After cooling to RT, the mixture was mixed with saturated aqueous sodium hydrogen carbonate and extracted several times with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated, and the residue was adsorbed in dichloromethane and purified by flash column chromatography (100 g silica gel, Biotage Snap-Cartridge Ultra, cyclohexane/ethyl acetate gradient 95:5^5:5, Isolera One ). The combined target fractions were concentrated and the residue was lyophilized. 32 mg (96% pure, 14% thor.) of the title compound were obtained.

LC-MS (method 2): Rt = 1.35 min; MS (ESIpos): m/z = 622/624 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.149 (0.48), -0.008 (4.16), 0.008 (4.20), 0.146 (0.48), 1.367 (16.00), 1.398 (1.97), 2.070 ( 1.48), 2.084 (0.81), 2.327 (0.52), 2.366 (0.69), 2.523 (1.89), 2.670 (0.58), 2.710 (0.67), 4.581 (0.48), 4.613 (0.89), 4.645 (0.44), 7.435 ( 0.60), 7.455 (0.50), 7.475 (0.50), 7.492 (0.40), 7.589 (0.60), 7.611 (1.20), 7.648 (0.64), 7.654 (0.60).

Example 114A.

tert-Butyl 5-[({6-bromo-2-[3-cyanopiperidin-1-yl]-3-methylquinolin-4-yl}carbonyl)amino]-4-(2chlorophenyl)pentanoate (mixture of diastereoisomers)

To a mixture of (+/-)-tert-butyl-5-{[(6-bromo-2-chloro-3-methylquinolin-4-yl)carbonyl]amino}-4-(2chlorophenyl)pentanoate (250 mg, 441 µmol, example 37A) in NMP (2.0 ml) was added (+/-)-piperidine-3carbonitrile (389 mg, 3.53 mmol) and DIPEA (620 µl, 3.5 mmol) and the mixture was stirred for 42 h at 110°C. After cooling to RT, the mixture was filtered and purified by preparative HPLC (method 8). The combined target fractions were concentrated and the residue was lyophilized. 197 mg (91% pure, 63% th. y.) of the title compound were obtained.

LC-MS (method 1): Rt = 2.58 min; MS (ESIpos): m/z = 639/641 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.209 (0.07), 1.309 (0.05), 1.333 (0.10), 1.369 (16.00), 1.526 (0.08), 1.714 (0.17), 1.819 (0.35) , 1.876 (0.37), 1.889 (0.55), 1.902 (0.46), 2.046 (0.19), 2.075 (1.26), 2.088 (0.72), 2.104 (0.25), 2.183 (1.43), 2.327 (0.05), 2.365 (0.05) , 2.669 (0.05), 2.709 (0.05), 3.020 (0.16),3.268 (0.30), 3.293 (0.34), 3.444 (0.22), 3.458 (0.22), 3.475 (0.18), 3.490 (0.14), 3.588 (0.21) . , 7.505 (0.42), 7.671 (0.21), 7.693 (1.42), 7.697 (1.08), 7.702 (0.83), 7.724 (0.14), 7.894 (0.21) .

Example 115A.

(+/-)-tert-Butyl-5-({[6-bromo-2-(3,6-dihydro-2H-1,2-oxazin-2-yl)-3-methylquinolin-4yl]carbonyl}amino )-4-(2-chlorophenyl)pentanoate (racemate)

To a mixture of (+/-)-tert-butyl-5-{[(6-bromo-2-chloro-3-methylquinolin-4-yl)carbonyl]amino}-4-(2chlorophenyl)pentanoate (300 mg, 530 µmol, example 37A), 3,6-dihydro-2H-1,2oxazine hydrochloride (515 mg, 4.24 mmol) and DIPEA (920 µl, 5.3 mmol) were added to NMP (3.0 ml), and the mixture was stirred for 44 h at 120° WITH. After cooling to RT, the mixture was filtered and the filtrate was concentrated. The residue was adsorbed into DMSO and purified by preparative HPLC (method 6). The combined desired fractions were concentrated and the residue was dried in vacuo. 70 mg (100% pure, 21% thor.) of the title compound were obtained.

- 72 040220

LC-MS (method 1): Rt = 2.70 min; MS (ESIpos): m/z = 614/616 [M+H]+.

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.150 (0.08), -0.023 (0.15), 0.007 (0.69), 0.146 (0.08), 1.233 (0.28), 1.312 (0.08), 1.330 (0.11), 1.370 (16.00), 1.826 (0.20), 2.051 (0.24), 2.079 (1.25), 2.090 (0.67), 2.106 (0.25), 2.188 (0.96) (0.21) (0.27) (0.21), 8.844 (0.42).

Example 116A.

tert-Butyl 5-[({6-bromo-2-[3-fluoropiperidin-1-yl]-3-methylquinolin-4-yl}carbonyl)amino]-4-(2chlorophenyl)pentanoate (mixture of diastereoisomers)

To a mixture of (+/-)-tert-butyl-5-{[(6-bromo-2-chloro-3-methylquinolin-4-yl)carbonyl]amino}-4-(2chlorophenyl)pentanoate (3.00 g, 98 % purity, 5.19 mmol, example 37A) in NMP (48 ml) was added (+/-)-3fluoropiperidine-hydrochloride (3.99 g, 28.6 mmol) and DIPEA (5.0 ml, 29 mmol), and the mixture was stirred for two days at 120° WITH. After cooling to RT, the mixture was mixed with water (200 ml) and ethyl acetate (100 ml) and shaken. After phase separation, the aqueous phase was extracted several times with ethyl acetate (corresponding to 100 ml). The combined organic phases were dried over sodium sulfate, filtered and concentrated, and the residue was purified by flash column chromatography (100 g Biotage Snap-Cartridge Ultra silica gel, 95:5^7:3 cyclohexane/ethyl acetate gradient, Isolera One). The combined desired fractions were concentrated and the residue was dried in vacuo. 2.61 g (98% pure, 78% th. y.) of the title compound were obtained.

LC-MS (method 1): R _t = 2.69 min; MS (ESIpos): m/z = 632/634 [M+H]+.

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.209 (0.07), 1.333 (0.09), 1.369 (16.00), 1.398 (5.31), 1.526 (0.07), 1.644 (0.17), 1.813 (0.31) , 1.898 (0.28), 2.054 (0.19), 2.074 (1.20), 2.087 (0.67), 2.103 (0.27), 2.144 (1.42), 2.327 (0.06), 2.670 (0.06), 3.093 (0.19), 3.160 (0.20) 3.376 (0.18), 3.406 (0.10), 3.433 (0.17), 3.466 (0.11), 3.586 (0.20), 3.677 (0.36), 4.815 (0.13), 4.938 (0.13), 7.254 (0.17), 7.272 (0.41) . , 7.676 (0.96), 7.681 (0.83), 7.699 (0.17), 7.704 (0.18), 8.712 (0.21), 8.726 (0.43), 8.740 (0.20).

Example 117A.

tert-Butyl-5-[({6-bromo-3-methyl-2-[(2S)-2-methylpyrrolidin-1-yl]quinolin-4-yl}carbonyl)amino]4-(2-chlorophenyl)pentanoate (mixture of epimers)

To a mixture of (+/-)-tert-butyl-5-{[(6-bromo-2-chloro-3-methylquinolin-4-yl)carbonyl]amino}-4-(2chlorophenyl)pentanoate (450 mg, 795 µmol, example 37A) in NMP (4.0 ml) was added (2S)-2methylpyrrolidine (650 µl, 6.4 mmol) and DIPEA (1.4 ml, 7.9 mmol) and the mixture was stirred for 3 h at

100°C. After cooling to RT, the mixture was filtered and purified by preparative HPLC (method 6). The combined desired fractions were concentrated and the residue was dried in vacuo. 391 mg (100% pure, 80% thor.) of the title compound were obtained.

LC-MS (method 1): R _t = 2.70 min; MS (ESIpos): m/z = 614/616 [M+H]+.

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (0.42), 0.008 (0.37), 1.142 (2.75), 1.157 (2.75), 1.208 (0.09), 1.234 (0.15), 1.301 (0.11 ), 1.330 (0.16), 1.366 (16.00), 1.369 (14.87), 1.541 (0.23), 1.557 (0.27), 1.579 (0.27), 1.607 (0.18), 1.687 (0.22), 1.812 (0.28), 1.897 (0.31 ), 2.045 (0.38), 2.072 (1.98), 2.084 (1.41), 2.103 (1.71), 2.327 (0.10), 2.366 (0.10), 2.669 (0.09), 2.710 (0.09), 3.610 (0.34), 3.694 (0.29 ), 3.716 (0.45), 3.736 (0.45), 4.361 (0.23), 4.376 (0.38), 4.398 (0.35), 4.414 (0.21), 7.241 (0.17), 7.259 (0.47), 7.278 (0.52), 7.296 (0.22 ), 7.341 (0.28), 7.360 (0.62), 7.379 (0.55), 7.398 (0.22), 7.434 (0.98), 7.454 (0.83), 7.474 (0.62), 7.499 (0.87), 7.503 (0.82), 7.521 (1.03 ), 7.526 (1.04), 7.569 (0.53), 7.575 (0.94), 7.580 (0.52), 7.591 (0.30), 7.597

- 73 040220 (0.51), 7.603 (0.30), 8.698 (0.57).

Separation of a mixture of epimers.

The title title compound (376 mg) was dissolved in methanol (30 ml) and separated into enantiomers/epimers by preparative SLC on chiral phase (see Examples 118A and 119A) [column: Daicel Chiralcel OX-H, 5 μm, 250 mm x 20 mm; flow: 80 ml/min; sample injection: 1.0 ml; eluent: 17% ethanol/83% carbon dioxide; duration of action 11 min, isocratic, UV detection 210 nm, temperature 40°C]. The combined target fractions were concentrated and the corresponding residue was lyophilized.

Example 118A.

(-)-tert-Butyl-5-[({6-bromo-3-methyl-2-[(2S)-2-methylpyrrolidin-1-yl]quinolin-4yl}carbonyl)amino]-4-(2- chlorophenyl)pentanoate (epimer 1).

Epimer separation as described in Example 117A gave 150 mg (100% pure, >99% ee) of the title compound as the previously eluted epimer/enantiomer.

[a] _D20 = -29.3°, 589 nm, c = 0.37 ^g /100 ml, methanol;

LC-MS (method 1): Rt = 2.67 min; MS (ESIpos): m/z = 614/616 [M+H]+.

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.140 (1.67), 1.155 (1.68), 1.205 (0.07), 1.300 (0.10), 1.333 (0.09), 1.365 (16.00), 1.540 (0.14) , 1.556 (0.16), 1.562 (0.16), 1.578 (0.16), 1.606 (0.10), 1.662 (0.14), 1.688 (0.14), 1.708 (0.09), 1.794 (0.13), 1.812 (0.18), 1.895 (0.18) , 2.050 (0.22), 2.072 (1.24), 2.085 (1.14), 2.124 (0.28), 2.327 (0.03), 2.669 (0.03), 3.285 (0.15), 3.580 (0.24), 3.625 (0.16), 3.691 (0.14) . , 7.295 (0.25), 7.360 (0.26), 7.379 (0.43), 7.397 (0.25), 7.434 (0.62), 7.436 (0.60), 7.454 (0.50) , 7.521 (1.12), 7.568 (0.59), 7.573 (0.55), 7.590 (0.32), 7.596 (0.32), 8.683 (0.19), 8.697 (0.32).

Example 119A.

(-)-tert-Butyl-5-[({6-bromo-3-methyl-2-[(2S)-2-methylpyrrolidin-1-yl]quinolin-4yl}carbonyl)amino]-4-(2- chlorophenyl)pentanoate (epimer 2).

Epimer separation as described in Example 117A gave 147 mg (100% pure, 97% ee) of the title compound as a later eluted epimer/enantiomer.

[a] _D20 = -10.3°, 589 nm, c = 0.46 g ^/ 100 ml, methanol;

LC-MS (method 1): Rt = 2.64 min; MS (ESIpos): m/z = 614/616 [M+H]+.

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 1.142 (2.01), 1.157 (2.03), 1.209 (0.07), 1.318 (0.08), 1.329 (0.15), 1.369 (16.00), 1.512 (0.06 ), 1.527 (0.12), 1.540 (0.15), 1.556 (0.18), 1.563 (0.17), 1.579 (0.17), 1.591 (0.13), 1.607 (0.12), 1.659 (0.14), 1.684 (0.14), 1.793 (0.15 ), 1.813 (0.19), 1.896 (0.20), 1.910 (0.19), 2.045 (0.28), 2.073 (1.27), 2.105 (1.49), 2.156 (0.20), 2.202 (0.04), 2.327 (0.03), 2.669 (0.03 ), 3.605 (0.29), 3.695 (0.27), 3.712 (0.27), 3.720 (0.35), 3.736 (0.31), 3.744 (0.19), 3.760 (0.13), 4.362 (0.15), 4.377 (0.24), 4.392 (0.20 ), 4.399 (0.23), 4.414 (0.14), 7.240 (0.20), 7.259 (0.44), 7.275 (0.32), 7.278 (0.32), 7.340 (0.29), 7.359 (0.53), 7.376 (0.28), 7.432 (0.65 ), 7.435 (0.65), 7.452 (0.59), 7.470 (0.64), 7.474 (0.65), 7.490 (0.49), 7.504 (0.76), 7.526 (1.26), 7.575 (0.72), 7.580 (0.63), 7.597 (0.39 ), 7.602 (0.36), 8.685 (0.22), 8.699 (0.41).

Example 120A.

tert-Butyl-5-[({6-bromo-3-methyl-2-[(2R)-2-methylpyrrolidin-1-yl]quinolin-4-yl}carbonyl)amino]4-(2-chlorophenyl)pentanoate (mixture of epimers)

To a mixture of (+/-)-tert-butyl-5-{[(6-bromo-2-chloro-3-methylquinolin-4-yl)carbonyl]amino}-4-(2chlorophenyl)pentanoate (450 mg, 795 µmol, example 37A) in NMP (4.0 ml) was added (2R)-2methylpyrrolidine (650 µl, 6.4 mmol) and DIPEA (1.4 ml, 7.9 mmol) and the mixture was stirred for 3 h at

100°C. After cooling to RT, the mixture was filtered and purified by preparative HPLC (method 6). The combined desired fractions were concentrated and the residue was dried in vacuo. 391 mg (100% pure, 80% thor.) of the title compound were obtained.

LC-MS (method 1): Rt = 2.69 min; MS (ESIpos): m/z = 614/616 [M+H]+.

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.141 (2.84), 1.156 (2.86), 1.207 (0.09), 1.234 (0.15), 1.300 (0.09), 1.329 (0.14), 1.365 (16.00) , 1.369 (15.64), 1.540 (0.25), 1.557 (0.29), 1.579 (0.29), 1.607 (0.20), 1.662 (0.25), 1.812 (0.31), 1.896 (0.33), 2.044 (0.39), 2.072 (2.12) , 2.084 (1.52), 2.103 (1.85), 2.327 (0.07), 2.365

- 74 040220 (0.06), 2.669 (0.08), 2.709 (0.06), 3.610 (0.37), 3.694 (0.31), 3.718 (0.49), 3.735 (0.50), 4.361 (0.23), 4.376 (0.39), 4.398 (0.37 ), 4.413 (0.23), 7.240 (0.18), 7.259 (0.50), 7.278 (0.56), 7.295 (0.24), 7.340 (0.30), 7.359 (0.66), 7.378 (0.59), 7.397 (0.23), 7.434 (1.03 ), 7.454 (0.88), 7.474 (0.66), 7.499 (0.93), 7.503 (0.87), 7.521 (1.07), 7.525 (1.10), 7.568 (0.54), 7.574 (0.96), 7.580 (0.54), 7.591 (0.31 ), 7.596 (0.54), 7.602 (0.31), 8.698 (0.61).

Separation of a mixture of epimers.

The title title compound (376 mg) was dissolved in a mixture of methanol and acetonitrile (5 ml) and separated into enantiomers/epimers by preparative SLC on chiral phase (see Examples 121A and 122A) [column: Daicel Chiralcel OX-H, 5 microns, 250 mmx20 mm; flow: 80 ml/min; sample injection: 0.3 ml; eluent: 17% isopropanol/83% carbon dioxide; duration of action 15 min, isocratic, UV detection 210 nm, temperature 40°C]. The combined target fractions were concentrated and the corresponding residue was lyophilized.

Example 121A.

(+)-tert-Bumul-5-[({6-bromo-3-methyl-2-[(2R)-2-methylpyrrolidin-1-yl]quinolin-4yl}carbonyl)amino]-4-(2- chlorophenyl)pentanoate (epimer 1).

In the separation of epimers described in Example 120A, 144 mg (95% pure, >99% ee) of the title compound as the previously eluted epimer/enantiomer.

[a] _D20 = +7.9°, 589 nm ^, c = 0.49 g/100 mL, methanol;

LC-MS (method 2): Rt = 1.37 min; MS (ESIpos): m/z = 614/616 [M+H]+.

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.142 (2.00), 1.157 (2.00), 1.209 (0.08), 1.231 (0.05), 1.317 (0.09), 1.329 (0.16), 1.369 (16.00) 1.511 (0.06), 1.526 (0.13), 1.540 (0.16), 1.556 (0.19), 1.562 (0.19), 1.578 (0.18), 1.606 (0.12), 1.658 (0.15), 1.684 (0.16), 1.702 (0.10) , 1.794 (0.17), 1.812 (0.21), 1.895 (0.22), 1.909 (0.21), 2.033 (0.19), 2.045 (0.32), 2.073 (1.39), 2.105 (1.59), 2.156 (0.22), 2.202 (0.04) , 2.327 (0.03), 2.365 (0.03), 2.669 (0.02), 2.709 (0.02), 3.605 (0.32), 3.694 (0.29), 3.711 (0.29), 3.719 (0.36), 3.735 (0.32), 3.760 (0.13) . , 7.376 (0.30) , 7.602 (0.35), 7.845 (0.02), 8.685 (0.23), 8.699 (0.42).

Example 122A.

(+)-tert-Butyl-5-[({6-bromo-3-methyl-2-[(2R)-2-methylpyrrolidin-1-yl]quinolin-4yl}carbonyl)amino]-4-(2- chlorophenyl)pentanoate (epimer 2).

Epimer separation as described in Example 120A gave 142 mg (100% pure, 96% ee) of the title compound as a later eluted epimer/enantiomer.

[a] _D20 = +25.9°, 589 nm, c = 0.36 g/100 mL ^, methanol;

LC-MS (method 2): R _t = 1.36 min; MS (ESIpos): m/z = 614/616 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.141 (1.99), 1.155 (1.99), 1.205 (0.10), 1.232 (0.06), 1.301 (0.11), 1.334 (0.13), 1.365 (16.00) , 1.540 (0.17), 1.556 (0.22), 1.579 (0.21), 1.606 (0.13), 1.663 (0.20), 1.687 (0.20), 1.794 (0.20), 1.812 (0.27), 1.896 (0.26), 2.072 (1.75) , 2.085 (1.56) . , 7.454 (0.66), 7.481 (0.59), 7.499 (1.04), 7.521 (1.19), 7.569 (0.66), 7.591 (0.36), 8.697 (0.45).

Example 123A.

(+/-)-tert-Butyl-5-({[2-(azepan-1-yl)-6-bromo-3-methylquinolin-4-yl]carbonyl}amino)-4-(2chlorophenyl)pentanoate (racemate )

To a mixture of (+/-)-tert-butyl-5-{[(6-bromo-2-chloro-3-methylquinolin-4-yl)carbonyl]amino}-4-(2chlorophenyl)pentanoate (1.50 g, 2.65 mmol, example 37A) in NMP (15 ml) was added azepane (2.4 ml, 21 mmol) and DIPEA (4.6 ml, 26 mmol), and the mixture was stirred for 3 h at 100°C. After cooling to RT, the mixture was concentrated and the residue was adsorbed into DMSO and purified by preparative HPLC (method 6). The combined desired fractions were concentrated and the residue was dried in vacuo. 1.40 g (97% pure, 84% th. y.) of the title compound was obtained.

LC-MS (method 1): Rt = 2.89 min; MS (ESIpos): m/z = 628/630 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.234 (0.16), 1.368 (16.00), 1.602 (1.61), 1.779 (1.14), 2.046

- 75 040220 (0.30), 2.073 (1.46), 2.085 (0.83), 2.126 (1.55), 2.731 (2.95), 2.890 (3.44), 3.489 (1.34), 3.503 (1.82), 3.518 (1.20), 3.582 (0.26) ), 3.662 (0.35), 7.251 (0.21), 7.270 (0.46), 7.289 (0.33), 7.352 (0.30), 7.371 (0.51), 7.389 (0.29), 7.436 (0.80), 7.456 (0.65), 7.479 (0.61 ), 7.498 (0.44), 7.526 (0.69), 7.548 (1.23), 7.593 (0.70), 7.598 (0.62), 7.615 (0.37), 7.621 (0.34), 7.952 (0.45), 8.696 (0.47).

Separation of enantiomers.

The title target compound (1.4 g) was dissolved in methanol-acetonitrile (70 ml) and separated into enantiomers by preparative HPLC on a chiral phase (see examples

124A and 125A) [column: Daicel Chiralcel OX-H, 5 µm, 250 mm x 20 mm; flow: 80 ml/min; sample injection: 1.50 ml; UV detection: 210 nm, temperature: 40°C; eluent: 17% ethanol/83% carbon dioxide; duration of action 14 min, isocratic]. The combined target fractions were concentrated and the residue was lyophilized.

Example 124A.

(-)-tert-Butyl-5-({[2-(azepan-1-yl)-6-bromo-3-methylquinolin-4-yl]carbonyl}amino)-4-(2chlorophenyl)pentanoate (enantiomer 1) .

The separation of enantiomers described in Example 123A gave 496 mg (100% pure, >99% ee) of the title compound as the previously eluted enantiomer.

[a] _D20 = -7.2°, 589 nm, c ⁼ 0.36 g/100 ml, methanol;

LC-MS (method 1): R _t = 2.90 min; MS (ESIpos): m/z = 628/630 [M+H]+.

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 1.208 (0.07), 1.309 (0.09), 1.330 (0.12), 1.368 (16.00), 1.524 (0.07), 1.602 (1.44), 1.779 (0.99 ), 1.838 (0.14), 2.046 (0.35), 2.127 (1.42), 3.489 (1.18), 3.503 (1.67), 3.517 (0.42), 7.288 (0.31), 7.352 (0.26), 7.371 (0.47), 7.389 (0.40 ), 7.526 (0.66), 7.548 (1.22), 7.592 (0.66), 7.598 (0.23), 2.055 (0.20), 2.074 (1.33), 2.085 (0.74), 2.107 (1.15), 3.583 (0.22), 3.661 (θ .3Ο), 7.252 (θ.18), 7.270 (0.26), 7.437 (0.73), 7.455 (0.58), 7.480 (0.56), 7.497 (0.62), 7.615 (0.35), 7.620 (0.34), 8.682 (0.22) .8.696 (0.43), 8.710 (0.21).

Example 125A.

(+)-tert-Butyl-5-({[2-(azepan-1-yl)-6-bromo-3-methylquinolin-4-yl]carbonyl}amino)-4-(2chlorophenyl)pentanoate (enantiomer 2) .

The separation of enantiomers described in Example 123A gave 490 mg (100% pure, 97% ee) of the title compound as the later eluted enantiomer.

[a] _D20 = +8.6°, 589 nm ^, c = 0.35 g/100 mL, methanol;

LC-MS (method 1): Rt = 2.90 min; MS (ESIpos): m/z = 628/630 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 1.208 (0.07), 1.309 (0.09), 1.331 (0.14), 1.368 (16.00), 1.524 (0.08), 1.601 (1.71), 1.779 (1.22 ), 1.838 (0.16), 2.046 (0.29), 2.074 (1.56), 2.085 (0.86), 2.108 (0.48), 2.127 (1.68), 2.327 (0.03), 2.669 (0.03), 3.488 (1.38), 3.503 (1.93 ), 3.517 (1.26), 3.584 (0.28), 3.661 (0.37), 7.251 (0.22), 7.270 (0.48), 7.288 (0.33), 7.351 (0.31), 7.370 (0.54), 7.388 (0.30), 7.436 (0.82 ), 7.456 (0.67), 7.479 (0.65), 7.498 (0.47), 7.526 (0.69), 7.548 (1.24), 7.593 (0.69), 7.597 (0.62), 7.615 (0.36), 7.620 (0.34), 8.682 (0.28 ), 8.696 (0.50), 8.710 (0.25).

Example 126A.

(+/-)-tert-Butyl-5-({[6-bromo-3-methyl-2-(piperidin-1-yl)quinolin-4-yl]carbonyl}amino)-4-[2(trifluoromethyl) phenyl]pentanoate (racemate)

To a mixture of (+/-)-tert-butyl-5-{[(6-bromo-2-chloro-3-methylquinolin-4-yl)carbonyl]amino}-4-[2(trifluoromethyl)phenyl]pentanoate ( 1.00 g, 1.67 mmol, example 38A) in NMP (6 ml) was added piperidine (1.3 ml, 13 mmol) and DIPEA (2.3 ml, 13 mmol) and the mixture was stirred for two days at 110°C. After cooling to RT, the mixture was purified by flash column chromatography (100 g Biotage Snap-Cartridge Ultra silica gel, 97:3^8:2 cyclohexane/ethyl acetate gradient, Isolera One). The combined desired fractions were concentrated and the residue was dried in vacuo. 648 mg (100% pure, 60% thor.) of the title compound were obtained.

LC-MS (method 1): Rt = 2.84 min; MS (ESIpos): m/z = 648/650 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: -0.008 (0.31), 0.008 (0.32), 0.924 (0.26), 0.939 (1.95), 0.955 (1.87), 1.186 (0.07), 1.346 ( 16.00), 1.398 (0.63), 1.503 (0.09), 1.613 (0.43), 1.679 (0.81), 1.919 (0.14), 1.949 (0.10), 1.971 (0.09), 1.989 (0.24), 2.012 (0.34), 0.27), 2.033 (0.32), 2.054 (0.25), 2.074 (0.09), 2.094 (0.21), 2.166 (1.19), 2.328 (0.07), 2.366 (0.07), 2.417 (0.11), 2.435 (0.11), 0.07), 2.968 (0.10), 3.151

- 76 040220 (1.04), 3.225 (0.08), 3.680 (0.18), 7.462 (0.25), 7.481 (0.41), 7.500 (0.24), 7.636 (0.22), 7.658 (1.37), 7.663 (1.06), 7.668 (0.86 ), 7.685 (0.27), 7.706 (0.42), 7.722 (0.85), 7.733 (0.64), 8.761 (0.20), 8.776 (0.41), 8.791 (0.19).

Separation of enantiomers.

The title title compound (560 mg) was dissolved in a mixture of isopropanol and heptane (respectively 4 ml) and separated into enantiomers by preparative HPLC on a chiral phase (see Examples 127A and 128A) [column: Daicel Chiralpak IA, 5 µm, 250 mmx20 mm; flow: 15 ml/min; sample injection: 0.14 ml; UV detection: 220 nm, temperature: 40°C; eluent: 15% isopropanol/85% heptane; duration of action 11 min, isocratic]. The combined target fractions were respectively concentrated and the corresponding residue was lyophilized from acetonitrile/water.

Example 127A.

(-)-tert-Butyl-5-({[6-bromo-3-methyl-2-(piperidin-1-yl)quinolin-4-yl]carbonyl}amino)-4-[2(trifluoromethyl)phenyl] pentanoate (enantiomer 1).

The separation of enantiomers described in Example 126A gave 241 mg (100% pure, ee 99%) of the title compound as the previously eluted enantiomer.

[a] _D20 = -14.5°, 589 nm, c = ^0.38 g/100 ml, methanol;

LC-MS (method 2): R _t = 1.50 min; MS (ESIpos): m/z = 648/650 [M+H]+.

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 1.187 (0.07), 1.243 (0.06), 1.258 (0.07), 1.273 (0.05), 1.312 (0.11), 1.324 (0.17), 1.347 (16.00 ), 1.503 (0.08), 1.613 (0.49), 1.679 (0.96), 1.888 (0.16), 1.897 (0.16), 1.909 (0.16), 1.920 (0.16), 1.949 (0.12), 1.972 (0.10), 1.990 (0.27 ), 2.003 (0.20), 2.013 (0.39), 2.025 (0.32), 2.034 (0.36), 2.056 (0.28), 2.075 (0.11), 2.096 (0.24), 2.110 (0.18), 2.128 (0.24), 2.167 (1.40 ), 2.328 (0.03), 2.671 (0.02), 3.151 (1.24), 3.640 (0.20), 3.662 (0.18), 3.680 (0.22), 3.696 (0.17), 7.462 (0.30), 7.481 (0.47), 7.499 (0.29 ), 7.636 (0.21), 7.658 (1.49), 7.663 (1.15), 7.668 (0.90), 7.686 (0.29), 7.706 (0.48), 7.721 (0.97), 7.734 (0.78), 7.751 (0.24), 8.763 (0.23 ), 8.778 (0.46), 8.792 (0.22).

Example 128A.

(+)-tert-Butyl-5-({[6-bromo-3-methyl-2-(piperidin-1-yl)quinolin-4-yl]carbonyl}amino)-4-[2(trifluoromethyl)phenyl] pentanoate (enantiomer 2).

The separation of enantiomers described in Example 126A gave 249 mg (100% pure, ee 99%) of the title compound as the later eluted enantiomer.

[a] _D20 = +14.3°, 589 nm, c = 0.38 ^g /100 ml, methanol;

LC-MS (method 2): Rt = 1.50 min; MS (ESIpos): m/z = 648/650 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 1.187 (0.07), 1.243 (0.08), 1.258 (0.09), 1.273 (0.06), 1.312 (0.09), 1.324 (0.16), 1.347 (16.00 ), 1.503 (0.08), 1.612 (0.48), 1.679 (0.94), 1.897 (0.15), 1.908 (0.16), 1.920 (0.16), 1.949 (0.12), 1.971 (0.09), 1.990 (0.26), 2.012 (0.38 ), 2.025 (0.31), 2.034 (0.36), 2.055 (0.28), 2.074 (0.10), 2.095 (0.24), 2.109 (0.17), 2.128 (0.23), 2.167 (1.39), 2.328 (0.04), 2.670 (0.03 ), 3.151 (1.22), 3.639 (0.20), 3.662 (0.18), 3.680 (0.21), 3.696 (0.17), 7.462 (0.30), 7.481 (0.47), 7.499 (0.29), 7.636 (0.21), 7.658 (1.47 ), 7.663 (1.14), 7.667 (0.91), 7.685 (0.29), 7.706 (0.48), 7.721 (0.97), 7.734 (0.76), 7.750 (0.24), 8.762 (0.23), 8.777 (0.46), 8.792 (0.22 ).

Example 129A.

(+/-)-tert-Butyl-5-({[6-bromo-3-methyl-2-(pyrrolidin-1-yl)quinolin-4-yl]carbonyl}amino)-4-[2(trifluoromethyl) phenyl]pentanoate (racemate)

To a mixture of (+/-)-tert-butyl-5-{[(6-bromo-2-chloro-3-methylquinolin-4-yl)carbonyl]amino}-4-[2(trifluoromethyl)phenyl]pentanoate ( 600 mg, 1.00 mmol, example 38A) in NMP (4 ml) was added pyrrolidine (670 μl, 8.0 mmol) and DIPEA (1.4 ml, 8.0 mmol) and the mixture was stirred for two days at 110°C. After cooling to RT, the mixture was purified by flash column chromatography (100 g Biotage Snap-Cartridge Ultra silica gel, 97:3^8:2 cyclohexane/ethyl acetate gradient, Isolera One). The combined desired fractions were concentrated and the residue was dried in vacuo. 551 mg (100% pure, 87% thor.) of the title compound were obtained.

LC-MS (method 1): Rt = 2.27 min; MS (ESIpos): m/z = 634/636 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: -0.008 (0.58), 0.008 (0.56), 0.923 (0.30), 0.938 (2.40), 0.955 (2.28), 1.344 (16.00), 1.398 ( 1.68), 1.879 (1.44), 1.942 (0.15), 1.965 (0.11), 1.983 (0.24), 2.006 (0.30), 2.018 (0.37), 2.034 (0.32), 2.056 (0.27), 2.074 (0.12), 2.093 ( 0.27), 2.182 (0.53), 2.327 (0.08), 2.416 (0.14), 2.434

- 77 040220 (0.14), 2.967 (0.12), 3.584 (1.09), 3.689 (0.17), 7.457 (0.19), 7.478 (0.97), 7.501 (1.24), 7.553 (0.65), 7.558 (0.60), 7.575 (0.36) ), 7.580 (0.35), 7.684 (0.16), 7.703 (0.47), 7.713 (0.66), 7.731 (1.08), 7.747 (0.20), 8.719 (0.37).

Separation of enantiomers.

The title target compound (463 mg) was dissolved in methanol (30 ml) and separated into enantiomers by chiral phase preparative HPLC (see Examples 130A and 131A) [column: Daicel Chiralcel OD-H, 5 μm, 250 mm x 20 mm; flow: 80 ml/min; sample injection: 1.0 ml; UV detection: 210 nm, temperature: 40°C; eluent: 15% ethanol/85% carbon dioxide; duration of action 10 min, isocratic]. The combined target fractions were respectively concentrated and the corresponding residue was lyophilized from acetonitrile/water.

Example 130A.

(+)-tert-Butyl-5-({[6-bromo-3-methyl-2-(pyrrolidin-1-yl)quinolin-4-yl]carbonyl}amino)-4-[2(trifluoromethyl)phenyl] pentanoate (enantiomer 1).

The separation of enantiomers described in Example 129A gave 177 mg (100% pure, >99% ee) of the title compound as the previously eluted enantiomer.

[a] _D20 = +13.9°, 589 nm, c = 0.43 ^g /100 mL, methanol;

LC-MS (method 1): R _t = 2.26 min; MS (ESIpos): m/z = 634/636 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 1.184 (0.07), 1.312 (0.12), 1.323 (0.19), 1.344 (16.00), 1.501 (0.07), 1.880 (1.62), 1.944 (0.17 ), 1.967 (0.12), 1.985 (0.28), 1.998 (0.19), 2.007 (0.35), 2.019 (0.42), 2.035 (0.37), 2.057 (0.31), 2.076 (0.14), 2.094 (0.31), 2.122 (0.25 ), 2.138 (0.26), 2.183 (0.61), 2.281 (0.04), 2.327 (0.04), 2.670 (0.03), 3.585 (1.24), 3.689 (0.20), 7.344 (0.07), 7.457 (0.21), 7.480 (0.76 ), 7.503 (0.95), 7.554 (0.56), 7.559 (0.55), 7.577 (0.32), 7.582 (0.32), 7.684 (0.18), 7.704 (0.52), 7.714 (0.75), 7.731 (1.21), 7.748 (0.24 ), 8.707 (0.21), 8.721 (0.41), 8.736 (0.21).

Example 131A.

(-)-tert-Butyl-5-({[6-bromo-3-methyl-2-(pyrrolidin-1-yl)quinolin-4-yl]carbonyl}amino)-4-[2(trifluoromethyl)phenyl] pentanoate (enantiomer 2).

The separation of enantiomers described in Example 129A gave 183 mg (100% pure, ee 96%) of the title compound as the later eluted enantiomer.

[a] _D20 = -11.9°, 589 nm, c = ^0.41 g/100 ml, methanol;

LC-MS (method 1): R _t = 2.27 min; MS (ESIpos): m/z = 634/636 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.183 (0.07), 1.311 (0.28), 1.343 (16.00), 1.499 (0.07), 1.878 (1.68), 1.942 (0.18), 1.966 (0.13) , 1.984 (0.29), 2.006 (0.37), 2.018 (0.44), 2.034 (0.38), 2.056 (0.32), 2.075 (0.15), 2.093 (0.32), 2.121 (0.27), 2.137 (0.30), 2.180 (0.64) , 2.279 (0.05) . , 8.734 (0.21).

Example 132A.

(+/-)-tert-Butyl-5 -({[6-bromo-2-(3,3-difluoropiperidin-1 -yl)-3-methylquinolin-4yl]carbonyl}amino)-4-[2-( trifluoromethyl)phenyl]pentanoate (racemate)

To a mixture of (+/-)-tert-butyl-5-{[(6-bromo-2-chloro-3-methylquinolin-4-yl)carbonyl]amino}-4-[2(trifluoromethyl)phenyl]pentanoate ( 600 mg, 1.00 mmol, example 38A) in NMP (4 ml) was added 3,3 difluoropiperidine hydrochloride (1.26 g, 8.00 mmol) and DIPEA (1.7 ml, 10 mmol) and the mixture was stirred for two days at 110°C. After cooling to RT, the mixture was purified by flash column chromatography (100 g Biotage Snap-Cartridge Ultra silica gel, cyclohexane/ethyl acetate gradient 97:3^8:2, Isolera One). The combined desired fractions were concentrated and the residue was dried in vacuo. 415 mg (98% pure, 59% theoretical) of the title compound were obtained.

LC-MS (method 1): R _t = 2.72 min; MS (ESIpos): m/z = 684/686 [M+H]+.

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: -0.009 (0.79), 0.919 (0.53), 0.934 (4.45), 0.950 (4.42), 1.345 (16.00), 1.397 (0.88), 1.889 ( 0.53), 1.992 (0.25), 2.014 (0.44), 2.033 (0.37), 2.054 (0.35), 2.093 (0.42), 2.187 (1.12), 2.327 (0.16), 2.391 (0.18), 2.408 (0.52), 0.52), 2.444 (0.19), 2.944 (0.28), 2.960 (0.37), 2.976 (0.28), 3.183 (0.51), 3.462 (0.31), 3.491 (0.60), 3.519 (0.29), 3.689 (0.17), 5.753 ( 1.38), 7.483 (0.46), 7.502 (0.29), 7.686 (0.32), 7.708 (1.77), 7.716 (1.09), 7.738 (1.04), 8.785 (0.41).

- 78 040220

Separation of enantiomers.

The title title compound (327 mg) was dissolved in methanol (30 ml) and separated into enantiomers by chiral phase preparative HPLC (see Examples 133A and 134A) [column: Daicel Chiralcel OX-H, 5 µm, 250 mm x 30 mm ; flow: 100 ml/min; sample injection: 3.0 ml; UV detection: 210 nm, temperature: 40°C; eluent: 15% methanol/85% carbon dioxide; duration of action 15 min, isocratic]. The combined target fractions were respectively concentrated and the corresponding residue was lyophilized.

Example 133A.

(-)-tert-Butyl-5-({[6-bromo-2-(3,3-difluoropiperidin-1-yl)-3-methylquinolin-4-yl]carbonyl}amino)4-[2-(trifluoromethyl )phenyl]pentanoate (enantiomer 1).

The separation of enantiomers described in Example 132A gave 104 mg (100% pure, >99% ee) of the title compound as the previously eluted enantiomer.

[a] _D20 = -12.1°, 589 nm, c = 0.39 g/100 ml ^, methanol;

LC-MS (method 1): Rt = 2.71 min; MS (ESIpos): m/z = 684/686 [M+H]+.

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 1.185 (0.06), 1.305 (0.17), 1.311 (0.11), 1.322 (0.16), 1.345 (16.00), 1.502 (0.06), 1.889 (0.64 ), 1.946 (0.12), 1.974 (0.09), 1.993 (0.27), 2.016 (0.49), 2.034 (0.42), 2.055 (0.40), 2.095 (0.51), 2.119 (0.41), 2.141 (0.36), 2.188 (1.32 ), 2.327 (0.03), 2.669 (0.03), 3.183 (0.62), 3.463 (0.37), 3.492 (0.71), 3.520 (0.36), 3.648 (0.19), 3.689 (0.20), 7.463 (0.27), 7.482 (0.52 ), 7.500 (0.33), 7.686 (0.34), 7.708 (2.09), 7.715 (1.26), 7.721 (0.97), 7.738 (1.17), 7.755 (0.24), 8.772 (0.24), 8.787 (0.48), 8.801 (0.23 ).

Example 134A.

(+)-tert-Butyl-5-({[6-bromo-2-(3,3-difluoropiperidin-1-yl)-3-methylquinolin-4-yl]carbonyl}amino)4-[2-(trifluoromethyl )phenyl]pentanoate (enantiomer 2).

The separation of enantiomers described in Example 132A gave 75 mg (100% pure, ee 97%) of the title compound as the later eluted enantiomer.

[a] _D20 = +13.5°, 589 nm ^, c = 0.45 g/100 ml, methanol;

LC-MS (method 1): Rt = 2.70 min; MS (ESIpos): m/z = 684/686 [M+H]+.

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: -0.009 (0.18), 1.185 (0.06), 1.311 (0.08), 1.322 (0.14), 1.345 (16.00), 1.502 (0.06), 1.889 ( 0.54), 1.945 (0.10), 1.974 (0.08), 1.993 (0.24), 2.016 (0.43), 2.034 (0.37), 2.055 (0.35), 2.095 (0.44), 2.119 (0.35), 2.188 (1.15), 2.327 ( 0.04), 3.184 (0.52), 3.463 (0.33), 3.492 (0.63), 3.520 (0.31), 3.648 (0.16), 3.689 (0.17), 7.463 (0.24), 7.482 (0.47), 7.501 (0.30), 7.686 ( 0.32), 7.708 (1.90), 7.715 (1.12), 7.721 (0.84), 7.738 (1.08), 7.755 (0.22), 8.772 (0.21), 8.787 (0.43), 8.802 (0.20).

Example 135A.

(+/-)-tert-Butyl-5-({[2-(azepan-1-yl)-6-bromo-3-methylquinolin-4-yl]carbonyl}amino)-4-[2(trifluoromethyl)phenyl ]pentanoate (racemate)

To a mixture of (+/-)-tert-butyl-5-{[(6-bromo-2-chloro-3-methylquinolin-4-yl)carbonyl]amino}-4-[2(trifluoromethyl)phenyl]pentanoate ( 600 mg, 1.00 mmol, example 38A) in NMP (4 ml) was added azepan (900 μl, 8.0 mmol) and DIPEA (1.4 ml, 8.0 mmol) and the mixture was stirred for two days at 110°C. After cooling to RT, the mixture was purified by flash column chromatography (100 g Biotage Snap-Cartridge Ultra silica gel, 97:3^8:2 cyclohexane/ethyl acetate gradient, Isolera One). The combined desired fractions were concentrated and the residue was dried in vacuo. 303 mg (100% pure, 46% thor.) of the title compound were obtained.

LC-MS (method 1): Rt = 2.91 min; MS (ESIpos): m/z = 662/664 [M+H]+.

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: -0.150 (0.09), -0.009 (0.77), 0.007 (0.77), 0.146 (0.09), 0.926 (0.28), 0.941 (2.02), 0.957 (1.89), 1.184 (0.07), 1.345 (16.00), 1.501 (0.07), 1.609 (1.32) (0.34) (0.08) (0.60), 7.560 (1.16), 7.601 (0.65), 7.607 (0.60), 7.624 (0.33), 7.629 (0.33), 7.686 (0.16), 7.705 (0.45) (0.20), 8.734 (0.20), 8.749 (0.41), 8.764 (0.19).

Separation of enantiomers.

The title title compound (215 mg) was dissolved in methanol (30 ml) and separated into enantiomers by chiral phase preparative HPLC (see Examples 136A and 137A) [colon

- 79 040220 ka: Daicel Chiralcel OX-H, 5 µm, 250 mmx20 mm; flow: 80 ml/min; sample injection: 1.0 ml; UV detection: 210 nm, temperature: 40°C; eluent: 17% methanol/83% carbon dioxide; duration of action 9 min, isocratic]. The combined target fractions were respectively concentrated and the corresponding residue was lyophilized.

Example 136A.

(-)-tert-Butyl-5 -({[2-(azepan-1 -yl)-6-bromo-3-methylquinolin-4-yl]carbonyl}amino)-4-[2(trifluoromethyl)phenyl]pentanoate (enantiomer 1).

The separation of enantiomers described in Example 135A gave 86 mg (99% pure, >99% ee) of the title compound as the previously eluted enantiomer.

[a] _D20 = -12.1°, 589 nm, c = 0.36 g ^/ 100 ml, methanol;

LC-MS (method 2): R _t = 1.53 min; MS (ESIpos): m/z = 662/664 [M+H]+.

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.185 (0.07), 1.311 (0.12), 1.346 (16.00), 1.502 (0.08), 1.610 (1.59), 1.790 (1.05), 1.908 (0.19) , 1.947 (0.16), 1.970 (0.11), 1.988 (0.30), 2.011 (0.46), 2.023 (0.36), 2.031 (0.42), 2.052 (0.32), 2.072 (0.13), 2.094 (0.24), 2.109 (0.24) . . , 7.718 (0.85), 7.736 (1.20), 7.751 (0.26), 8.735 (0.24), 8.751 (0.48), 8.765 (0.24).

Example 137A.

(+)-tert-Butyl-5-({[2-(azepan-1-yl)-6-bromo-3-methylquinolin-4-yl]carbonyl}amino)-4-[2(trifluoromethyl)phenyl]pentanoate (enantiomer 2).

The separation of enantiomers described in Example 135A gave 83 mg (100% pure, ee 97%) of the title compound as the later eluted enantiomer.

[a] _D20 = +12.6°, 589 nm, c = 0.37 ^g /100 mL, methanol;

LC-MS (method 2): R _t = 1.53 min; MS (ESIpos): m/z = 662/664 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 1.185 (0.06), 1.310 (0.09), 1.322 (0.15), 1.344 (16.00), 1.501 (0.07), 1.609 (1.35), 1.789 (0.88 ), 1.907 (0.16), 1.946 (0.14), 1.969 (0.09), 1.987 (0.26), 2.010 (0.38), 2.023 (0.30), 2.030 (0.36), 2.052 (0.28), 2.071 (0.11), 2.094 (0.20 ), 2.154 (0.96), 3.504 (1.11), 3.519 (1.52), 3.533 (1.10), 3.623 (0.15), 3.681 (0.17), 7.390 (0.09), 7.460 (0.20), 7.479 (0.41), 7.497 (0.26 ), 7.538 (0.62), 7.560 (1.18), 7.601 (0.65), 7.606 (0.63), 7.623 (o.33), 7.629 (0.33), 7.686 (0.17), 7.705 (0.47), 7.717 (0.73), 7.734 (1.07), 7.751 (0.22), 8.735 (0.20), 8.750 (0.41), 8.765 (0.20).

Example 138A.

tert-Butyl-5-[({6-bromo-2-[3-fluoropiperidin-1-yl]-3-methylquinolin-4-yl}carbonyl)amino]-4-[2(trifluoromethyl)phenyl]pentanoate (mixture diastereoisomers)

To a mixture of (+/-)-tert-butyl-5-{[(6-bromo-2-chloro-3-methylquinolin-4-yl)carbonyl]amino}-4-[2(trifluoromethyl)phenyl]pentanoate ( 600 mg, 1.00 mmol, example 38A) in NMP (4.0 ml) was added (+/-)-3fluoropiperidine-hydrochloride (1.12 g, 8.00 mmol) and DIPEA (1.7 ml, 10 mmol), and the mixture was stirred for two days at 110° WITH. After cooling to RT, the mixture was filtered and purified by flash column chromatography (100 g Biotage Snap-Cartridge Ultra silica gel, 97:3^8:2 cyclohexane/ethyl acetate gradient, Isolera One). The combined desired fractions were concentrated and the residue was dried in vacuo. 452 mg (100% pure, 68% thor.) of the title compound were obtained.

LC-MS (method 1): R _t = 2.69 min; MS (ESIpos): m/z = 666/668 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.007 (0.52), 0.923 (0.29), 0.939 (2.28), 0.955 (2.16), 1.345 (16.00), 1.397 (1.13), 1.652 (0.17) , 1.906 (0.40), 1.990 (0.32), 2.013 (0.41), 2.033 (0.34), 2.054 (0.26), 2.093 (0.24), 2.178 (1.15), 2.435 (0.12), 2.669 (0.12), 3.115 (0.19) . , 7.681 (1.39), 7.685 (1.19), 7.690 (0.93), 7.707 (0.53), 7.721 (0.80), 7.738 (0.86), 8.780 (0.39).

Example 139A.

(+/-)-tert-Butyl-5-[({6-bromo-2-[3-ethylpiperidin-1-yl]-3-methylquinolin-4-yl}carbonyl)amino]-4[2-(trifluoromethyl )phenyl]pentanoate (mixture of diastereoisomers)

- 80 040220

To a mixture of (+/-)-tert-butyl-5-{[(6-bromo-2-chloro-3-methylquinolin-4-yl)carbonyl]amino}-4-[2(trifluoromethyl)phenyl]pentanoate ( 600 mg, 1.00 mmol, example 38A) in NMP (4.0 ml) was added (+/-)-3 ethylpiperidine (906 mg, 8.00 mmol) and DIPEA (1.4 ml, 8.0 mmol) and the mixture was stirred for two days at

110°C. After cooling to RT, the mixture was filtered and purified by flash column chromatography (100 g Biotage Snap-Cartridge Ultra silica gel, 97:3^8:2 cyclohexane/ethyl acetate gradient, Isolera One). The combined desired fractions were concentrated and the residue was dried in vacuo. Received 546 mg (100% pure, 81% theoretical. out.) indicated in the title compound.

LC-MS (method 1): Rt = 3.04 min; MS (ESIpos): m/z = 676/678 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.895 (0.88), 0.913 (2.18), 0.934 (3.62), 0.950 (2.84), 1.072 (0.17), 1.102 (0.18), 1.185 (0.09) , 1.263 (0.33), 1.281 (0.44), 1.346 (16.00), 1.397 (2.53), 1.569 (0.21), 1.641 (0.17), 1.753 (0.24), 1.884 (0.32), 1.990 (0.26), 2.012 (0.49) , 2.027 (0.45), 2.051 (0.24), 2.140 (0.56), 2.166 (0.81), 2.327 (0.08), 2.390 (0.14), 2.408 (0.42), 2.426 (0.43) , 2.727 (0.13), 2.755 (0.23), 2.784 (0.13), 2.927 (0.08), 2.943 (0.19), 2.960 (0.24), 2.976 (0.18), 2.993 (0.07), 3.514 (0.34), 3.536 (0.31) , 3.635 (0.20), 3.696 (0.21), 5.753 (0.93), 7.461 (0.28), 7.479 (0.46), 7.497 (0.27), 7.637 (0.13) , 7.720 (0.60), 7.735 (1.01), 7.753 (0.22), 8.753 (0.22), 8.768 (0.44), 8.782 (0.21).

Example 140A.

tert-Butyl-5-[({6-bromo-3-methyl-2-[3-methylpiperidin-1-yl]quinolin-4-yl}carbonyl)amino]-4-[2(trifluoromethyl)phenyl]pentanoate ( mixture of diastereoisomers)

To a mixture of (+/-)-tert-butyl-5-{[(6-bromo-2-chloro-3-methylquinolin-4-yl)carbonyl]amino}-4-[2(trifluoromethyl)phenyl]pentanoate ( 600 mg, 1.00 mmol, example 38A) in NMP (4.0 ml) was added (+/-)-3methylpiperidine (940 μl, 8.0 mmol) and DIPEA (1.4 ml, 8.0 mmol) and the mixture was stirred for two days at 110°C. After cooling to RT, the mixture was purified by flash column chromatography (100 g Biotage Snap-Cartridge Ultra silica gel, 97:3^8:2 cyclohexane/ethyl acetate gradient, Isolera One). The combined desired fractions were concentrated and the residue was dried in vacuo. Received 543 mg (100% pure, 82% theoretical. yield.) indicated in the title compound.

LC-MS (method 1): R _t = 2.93 min; MS (ESIpos): m/z = 662/664 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 0.007 (0.26), 0.927 (1.58), 0.936 (2.24), 0.942 (1.80), 0.953 (1.81), 1.086 (0.16), 1.109 (0.17 ), 1.186 (0.07), 1.305 (0.09), 1.322 (0.14), 1.346 (16.00), 1.397 (0.61), 1.502 (0.07), 1.633 (0.14), 1.662 (0.17), 1.737 (0.28), 1.797 (0.34 ), 1.828 (0.22), 1.908 (0.15), 1.948 (0.11), 1.970 (0.08), 1.989 (0.25), 2.011 (0.46), 2.029 (0.38), 2.051 (0.26), 2.070 (0.09), 2.096 (0.14 ), 2.110 (0.17), 2.169 (1.03), 2.327 (0.06), 2.365 (0.05), 2.413 (0.12), 2.431 (0.18), 2.466 (0.24), 2.694 (0.12), 2.722 (0.23), 2.750 (0.12 ), 2.948 (0.07), 2.964 (0.08), 2.980 (0.06), 3.453 (0.24), 3.480 (0.44), 3.510 (0.21), 3.679 (0.18), 7.461 (0.26), 7.481 (0.42), 7.500 (0.25 ), 7.638 (0.13), 7.660 (2.06), 7.665 (1.00), 7.687 (0.26), 7.706 (0.45), 7.721 (0.82), 7.737 (0.80), 7.751 (0.21), 8.757 (0.21), 8.771 (0.42 ), 8.786 (0.20).

Example 141A.

(+/-)-tert-Butyl-5-({[6-bromo-3-methyl-2-(piperidin-1-yl)quinolin-4-yl]carbonyl}amino)-4-[2(trifluoromethoxy) phenyl]pentanoate (racemate)

- 81 040220

To a mixture of (+/-)-tert-butyl-5-{[(6-bromo-2-chloro-3-methylquinolin-4-yl)carbonyl]amino}-4-[2(trifluoromethoxy)phenyl]pentanoate ( 1.00 g, 1.62 mmol, example 41A) in NMP (6 ml) was added piperidine (1.3 ml, 13 mmol) and DIPEA (2.3 ml, 13 mmol) and the mixture was stirred for two days at 110°C. After cooling to RT, the mixture was purified by flash column chromatography (100 g Biotage Snap-Cartridge Ultra silica gel, 97:3^8:2 cyclohexane/ethyl acetate gradient, Isolera One). The combined desired fractions were concentrated and the residue was dried in vacuo. 351 mg (92% pure, 30% theoretical) of the title compound were obtained.

LC-MS (method 1): R _t = 2.86 min; MS (ESIpos): m/z = 664/666 [M+H]+.

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.009 (0.40), 0.007 (0.37), 0.922 (0.14), 0.937 (1.10), 0.953 (1.05), 1.200 (0.07), 1.301 (0.27 ), 1.325 (0.11), 1.360 (16.00), 1.373 (0.47), 1.381 (0.28), 1.397 (0.20), 1.516 (0.08), 1.610 (0.44), 1.674 (0.84), 1.805 (0.19), 1.829 (0.19 ), 1.855 (0.11), 2.033 (0.24), 2.066 (1.13), 2.088 (0.27), 2.142 (0.91), 2.208 (0.15), 2.327 (0.08), 2.366 (0.07), 2.430 (0.08), 2.669 (0.08 ), 2.709 (0.07), 2.965 (0.07), 3.143 (1.07), 3.386 (0.18), 3.612 (0.21), 3.628 (0.40), 3.643 (0.37), 3.661 (0.20), 7.362 (0.35), 7.386 (0.19 ), 7.398 (0.69), 7.403 (0.52), 7.410 (0.51), 7.416 (0.48), 7.422 (0.61), 7.472 (0.12), 7.544 (0.44), 7.557 (0.35), 7.568 (0.30), 7.631 (0.24 ), 7.653 (1.28), 7.661 (0.88), 7.665 (0.76), 7.683 (0.18), 7.688 (0.17), 8.729 (0.19), 8.744 (0.39), 8.758 (0.19).

Separation of enantiomers.

The title title compound (262 mg) was dissolved in a mixture of ethanol (3 ml) and acetonitrile (2 ml) and separated into enantiomers by preparative HPLC on a chiral phase (see Examples 142A and 143A) [column: Daicel Chiralcel OZ-H , 5 microns, 250 mmx20 mm; flow: 20 ml/min; sample injection: 0.04 ml; UV detection: 220 nm, temperature: 40°C; eluent: 20% ethanol/80% heptane; duration of action 7 min, isocratic]. The combined target fractions were respectively concentrated and the corresponding residue was lyophilized.

Example 142A.

(-)-tert-Butyl-5-({[6-bromo-3-methyl-2-(piperidin-1-yl)quinolin-4-yl]carbonyl}amino)-4-[2(trifluoromethoxy)phenyl] pentanoate (enantiomer 1).

The separation of enantiomers described in Example 141A gave 104 mg (89% pure, ee 100%) of the title compound as the previously eluted enantiomer.

[a] _D20 = -11.9°, 589 nm, c = 0.36 ^g /100 ml, methanol;

LC-MS (method 1): R _t = 2.86 min; MS (ESIpos): m/z = 664/666 [M+H]+.

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: -0.150 (0.03), 0.857 (0.03), 1.038 (0.14), 1.055 (0.28), 1.073 (0.15), 1.199 (0.09), 1.210 ( 0.06), 1.242 (0.24), 1.257 (0.25), 1.272 (0.18), 1.301 (0.54), 1.316 (0.11),1.325 (0.13), 1.360 (16.00), 1.381 (0.51), 1.516 (0.09), 0.55), 1.673 (1.07), 1.787 (0.10), 1.805 (0.23), 1.830 (0.22), 1.855 (0.13), 2.015 (0.07), 2.034 (0.27), 2.045 (0.33), 2.066 (1.36), 2.089 ( 0.32), 2.142 (1.11),2.208 (0.29), 2.327 (0.04), 2.669 (0.04), 2.974 (0.07), 3.143 (1.36), 3.369 (0.25), 3.386 (0.24), 3.431 (0.10),3.449 ( 0.09), 3.466 (0.04), 3.612 (0.26), 3.628 (0.49), 3.644 (0.46), 3.661 (0.25), 7.362 (0.41), 7.378 (0.22), 7.385 (0.25), 7.398 (0.84), 0.60), 7.416 (0.56), 7.421 (0.67), 7.434 (0.15), 7.474 (0.15), 7.544 (0.52), 7.557 (0.40), 7.568 (0.33), 7.631 (0.26), 7.653 (1.42), 0.97), 7.665 (0.83), 7.683 (0.20), 7.687 (0.17), 8.730 (0.23), 8.744 (0.46), 8.758 (0.23).

Example 143A.

(+)-tert-Butyl-5-({[6-bromo-3-methyl-2-(piperidin-1-yl)quinolin-4-yl]carbonyl}amino)-4-[2(trifluoromethoxy)phenyl] pentanoate (enantiomer 2).

The separation of enantiomers described in Example 141A gave 95 mg (97% pure, ee 97%) of the title compound as the later eluted enantiomer.

[a] _D20 = +13.8°, 589 nm, c = 0.37 g/100 mL ^, methanol;

LC-MS (method 1): R _t = 2.86 min; MS (ESIpos): m/z = 664/666 [M+H]+.

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 0.857 (0.06), 1.101 (0.05), 1.119 (0.05), 1.199 (0.08), 1.242 (0.43), 1.257 (0.43), 1.272 (0.28 ), 1.325 (0.11), 1.359 (16.00), 1.373 (0.55), 1.516 (0.08), 1.609 (0.49), 1.673 (0.95), 1.805 (0.22), 1.830 (0.22), 1.856 (0.12), 2.034 (0.28 ), 2.066 (1.32), 2.089 (0.30), 2.143 (1.07), 3.144 (1.24), 3.369 (0.27), 3.613 (0.26), 3.628 (0.48), 3.644 (0.43), 3.662 (0.21), 7.362 (0.40 ), 7.385 (0.18), 7.398 (0.76), 7.410 (0.57), 7.416 (0.55), 7.421 (0.67), 7.474 (0.16), 7.544 (0.45), 7.557 (0.38), 7.568 (0.32), 7.631 (0.26 ), 7.653 (1.39), 7.660 (0.96), 7.665 (0.82), 7.683 (0.16), 7.687 (0.17), 8.730 (0.22), 8.744 (0.44), 8.759 (0.21).

- 82 040220

Example 144A.

(+/-)-tert-Butyl-5-({[6-bromo-3-methyl-2-(pyrrolidin-1-yl)quinolin-4-yl]carbonyl}amino)-4-[2(trifluoromethoxy) phenyl]pentanoate (racemate)

To a mixture of (+/-)-tert-butyl-5-{[(6-bromo-2-chloro-3-methylquinolin-4-yl)carbonyl]amino}-4-[2(trifluoromethoxy)phenyl]pentanoate ( 600 mg, 974 µmol, example 41A) in NMP (4 ml) was added pyrrolidine (650 µl, 7.8 mmol) and DIPEA (1.4 ml, 7.8 mmol) and the mixture was stirred for two days at 110°C. After cooling to RT, the mixture was purified by flash column chromatography (100 g Biotage Snap-Cartridge Ultra silica gel, cyclohexane/ethyl acetate gradient 97:3^8:2, Isolera One). The combined desired fractions were concentrated and the residue was dried in vacuo. 564 mg (95% pure, 85% thor.) of the title compound were obtained.

LC-MS (method 1): R _t = 2.41 min; MS (ESIpos): m/z = 650/652 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 0.920 (0.21), 0.935 (1.75), 0.951 (1.69), 1.198 (0.08), 1.301 (0.37), 1.314 (0.09), 1.326 (0.12 ), 1.358 (16.00), 1.380 (0.40), 1.397 (0.73), 1.514 (0.07), 1.805 (0.23), 1.827 (0.26), 1.875 (1.57), 2.033 (0.27), 2.043 (0.32), (0.06) , 2.365 (0.05), 2.391 (0.06), 2.409 (0.17), (0.13), 2.977 (0.10), 3.367 (0.22), 3.384 (0.23), (0.49), 7.379 (0.30), 7.394 (0.81), 7.405 (0.62),

2.064 (1.48), 2.085 (0.30), 2.160 (0.54), 2.239 (0.17), 2.327

2.427 (0.17), 2.444 (0.07), 2.669 (0.05), 2.944 (0.10), 2.961

3.575 (1.25), 3.627 (0.32), 3.645 (0.31), 3.663 (0.24), 7.355

7.417 (0.64), 7.475 (0.67), 7.497 (1.15), 7.541 (0.49), 7.552 (0.93), 7.557 (0.88), 7.564 (0.41), 7.574 (0.40), 7.579 (0.37), 8.679 (0.21), 8.693 (0.40), 8.707 (0.21).

Separation of enantiomers.

The title title compound (475 mg) was dissolved in methanol (30 ml) and separated into enantiomers by chiral phase preparative HPLC (see Examples 145A and 146A) [column: Daicel Chiralcel OH-X, 5 µm, 250 mm x 30 mm ; flow: 100 ml/min; sample injection: 1.00 ml; UV detection: 210 nm, temperature: 40°C; eluent: 20% methanol/80% carbon dioxide; duration of action 9 min, isocratic]. The combined target fractions were respectively concentrated and the corresponding residue was lyophilized.

Example 145A.

(-)-tert-Butyl-5 -({[6-bromo-3-methyl-2-(pyrrolidin-1 -yl)quinolin-4-yl]carbonyl}amino)-4-[2(trifluoromethoxy)phenyl] pentanoate (enantiomer 1).

The separation of enantiomers described in Example 144A gave 159 mg (100% pure, >99% ee) of the title compound as the previously eluted enantiomer.

[a] _D20 = -13.2°, 589 nm, c = 0.33 g ^/ 100 ml, methanol;

LC-MS (method 1): R _t = 2.34 min; MS (ESIpos): m/z = 650/652 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 0.145 (0.03), 1.198 (0.07), 1.301 (0.28), 1.314 (0.08), 1.327 (0.12), 1.358 (16.00), 1.380 (0.29 ), 1.514 (0.07), 1.786 (0.10), 1.805 (0.22), 1.828 (0.25), 1.875 (1.49), 2.034 (0.25), 2.043 (0.31), 2.065 (1.44), 2.085 (0.29), 2.161 (0.52 ), 2.240 (0.07), 2.327 (0.04), 2.669 (0.03), 3.311 (6.84), 3.367 (0.22), 3.384 (0.23), 3.627 (0.31), 3.646 (0.28), 3.663 (0.22), 7.355 (0.47 ), 7.379 (0.27), 7.394 (0.78), 7.405 (0.61), 7.417 (0.63), 7.429 (0.15), 7.475 (0.66), 7.497 (1.12), 7.541 (0.48), 7.552 (0.91), 7.557 (0.87 ), 7.564 (0.39), 7.574 (0.38), 7.579 (0.36), 8.680 (0.20), 8.694 (0.39), 8.708 (0.20).

Example 146A.

(+)-tert-Butyl-5-({[6-bromo-3-methyl-2-(pyrrolidin-1-yl)quinolin-4-yl]carbonyl}amino)-4-[2(trifluoromethoxy)phenyl] pentanoate (enantiomer 2).

The separation of enantiomers described in Example 144A gave 146 mg (100% pure, ee 98%) of the title compound as the later eluted enantiomer.

[a] _D20 = +14.4°, 589 nm ^, c = 0.35 g/100 mL, methanol;

LC-MS (method 1): R _t = 2.33 min; MS (ESIpos): m/z = 650/652 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 1.198 (0.07), 1.315 (0.08), 1.327 (0.12), 1.358 (16.00), 1.515 (0.07), 1.806 (0.24), 1.828 (0.28 ), 1.876 (1.60), 2.034 (0.28), 2.044 (0.34), 2.065 (1.61), 2.086 (0.32), 2.161 (0.57), 2.327 (0.04), 3.311 (7.94), 3.367 (0.24), 3.385 (0.25 ), 3.628 (0.33), 3.646 (0.31), 3.663 (0.23), 7.356 (0.52), 7.380 (0.27), 7.394 (0.84), 7.405 (0.66), 7.417 (0.71), 7.430 (0.17), 7.475 (0.70 ), 7.498 (1.19), 7.541 (0.51), 7.553 (1.00), 7.557 (0.92), 7.564 (0.44), 7.574 (0.41), 7.579 (0.38), 8.680 (0.23), 8.694 (0.43), 8.708 (0.23 ).

Example 147A.

(+/-)-tert-Butyl-5 -({[6-bromo-2-(3,3-difluoropiperidin-1 -yl)-3 -methylquinolin-4- 83 040220 yl]carbonyl}amino)-4- [2-(trifluoromethoxy)phenyl]pentanoate (racemate)

To a mixture of (+/-)-tert-butyl-5-{[(6-bromo-2-chloro-3-methylquinolin-4-yl)carbonyl]amino}-4-[2(trifluoromethoxy)phenyl]pentanoate ( 600 mg, 974 µmol, example 41A) in NMP (4 ml) was added 3,3 difluoropiperidine hydrochloride (1.23 g, 7.79 mmol) and DIPEA (1.4 ml, 7.8 mmol) and the mixture was stirred for two days at 110°C. After cooling to RT, the mixture was purified by flash column chromatography (100 g Biotage Snap-Cartridge Ultra silica gel, cyclohexane/ethyl acetate gradient 97:3^8:2, Isolera One). The combined desired fractions were concentrated and the residue was dried in vacuo. 493 mg (92% pure, 66% thor.) of the title compound were obtained.

LC-MS (method 1): Rt = 2.73 min; MS (ESIpos): m/z = 700/702 [M+H]+.

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 0.937 (0.80), 0.953 (0.74), 1.301 (0.37), 1.360 (16.00), 1.398 (0.44), 1.808 (0.24), 1.831 (0.25 ), 1.884 (0.57), 2.067 (1.68), 2.098 (0.61), 2.161 (1.10), 2.227 (0.16), 2.327 (0.12), 2.366 (0.11), 3.176 (0.67), 3.370 (0.24), 3.455 (0.39 ), 3.484 (0.73), 3.512 (0.38), 3.638 (0.46), 3.654 (0.43), 7.363 (0.43), 7.401 (0.82), 7.413 (0.62), 7.424 (0.67), 7.549 (0.49), 7.561 (0.43 ), 7.572 (0.35), 7.683 (0.24), 7.704 (1.40), 7.710 (1.04), 7.732 (0.18), 8.755 (0.46).

Separation of enantiomers.

The title target compound (405 mg) was dissolved in methanol (30 ml) and separated into enantiomers by chiral phase preparative HPLC (see examples 148A and 149A) [column: Daicel Chiralcel OX-H, 5 μm, 250 mm x 30 mm; flow: 100 ml/min; sample injection: 0.7 ml; UV detection: 210 nm, temperature: 40°C; eluent: 12% methanol/88% carbon dioxide; duration of action 11 min, isocratic]. The combined target fractions were respectively concentrated and the corresponding residue was lyophilized.

Example 148A.

(-)-tert-Butyl-5-({[6-bromo-2-(3,3-difluoropiperidin-1-yl)-3-methylquinolin-4-yl]carbonyl}amino)4-[2-(trifluoromethoxy )phenyl]pentanoate (enantiomer 1).

The separation of enantiomers described in Example 147A gave 134 mg (98% pure, >99% ee) of the title compound as the previously eluted enantiomer.

[a] _D20 = -12.4°, 589 nm, c = 0.41 g ^/ 100 ml, methanol;

LC-MS (method 1): Rt = 2.73 min; MS (ESIpos): m/z = 700/702 [M+H]+.

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 1.199 (0.07), 1.269 (0.03), 1.301 (0.37), 1.314 (0.07), 1.325 (0.09), 1.360 (16.00), 1.380 (0.42 ), 1.516 (0.07), 1.789 (0.09), 1.808 (0.23), 1.832 (0.24), 1.885 (0.53), 2.017 (0.08), 2.036 (0.30), 2.067 (1.63), 2.098 (0.58), 2.162 (1.09 ), 2.327 (0.04), 2.669 (0.03), 3.177 (0.64), 3.371 (0.23), 3.388 (0.23), 3.455 (0.39), 3.484 (0.74), 3.513 (0.37), 3.623 (0.25), 3.639 (0.46 ), 3.654 (0.42), 3.673 (0.21), 7.363 (0.41), 7.387 (0.19), 7.400 (0.78), 7.412 (0.60), 7.418 (0.56), 7.424 (0.67), 7.436 (0.13), 7.511 (0.14 ), 7.549 (0.50), 7.561 (0.43), 7.572 (0.36), 7.682 (0.23), 7.704 (1.46), 7.709 (1.06), 7.714 (0.88), 7.732 (0.14), 7.736 (0.16), 8.740 (0.24 ), 8.755 (0.48), 8.769 (0.24).

Example 149A.

(+)-tert-Butyl-5-({[6-bromo-2-(3,3-difluoropiperidin-1-yl)-3-methylquinolin-4-yl]carbonyl}amino)4-[2-(trifluoromethoxy )phenyl]pentanoate (enantiomer 2).

The separation of enantiomers described in Example 147A gave 122 mg (100% pure, ee 98%) of the title compound as the later eluted enantiomer.

[a] _D20 = +13.3°, 589 nm, c = 0.36 g/100 mL ^, methanol;

LC-MS (method 1): R _t = 2.73 min; MS (ESIpos): m/z = 700/702 [M+H]+.

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 1.200 (0.07), 1.315 (0.08), 1.325 (0.11), 1.360 (16.00), 1.516 (0.07), 1.790 (0.09), 1.809 (0.23 ), 1.833 (0.24), 1.885 (0.51), 2.018 (0.08), 2.037 (0.30), 2.068 (1.61), 2.099 (0.56), 2.162 (1.07), 2.326 (0.04), 3.177 (0.62), 3.371 (0.22 ), 3.388 (0.22), 3.456 (0.38), 3.485 (0.72), 3.513 (0.36), 3.624 (0.24), 3.639 (0.45), 3.655 (0.41), 3.673 (0.20), 7.363 (0.42), 7.387 (0.18 ), 7.400 (0.78), 7.412 (0.59), 7.418 (0.56), 7.424 (0.67), 7.436 (0.13), 7.509 (0.14), 7.549 (0.49), 7.561 (0.42), 7.572 (0.35), 7.682 (0.24 ), 7.704 (1.48), 7.709 (1.07), 7.714 (0.88), 7.736 (0.16), 8.741 (0.24), 8.755 (0.48), 8.770 (0.24).

Example 150A.

(+/-)-tert-Butyl-5-({[2-(azepan-1-yl)-6-bromo-3-methylquinolin-4-yl]carbonyl}amino)-4-[2(trifluoromethoxy)phenyl ]pentanoate (racemate)

- 84 040220

To a mixture of (+/-)-tert-butyl-5-{[(6-bromo-2-chloro-3-methylquinolin-4-yl)carbonyl]amino}-4-[2(trifluoromethoxy)phenyl]pentanoate ( 600 mg, 974 µmol, example 41A) in NMP (4 ml) were added azepan (880 µl, 7.8 mmol) and DIPEA (1.4 ml, 7.8 mmol) and the mixture was stirred for 30 h at 110°C. After cooling to RT, the mixture was mixed with dichloromethane (150 ml) and washed once with water (120 ml) and once with a mixture of 1 M hydrochloric acid (20 ml) in water (100 ml). The organic phase was dried, filtered and concentrated, and the residue was adsorbed in dichloromethane and purified by flash column chromatography (50 g Biotage Snap-Cartridge Ultra silica gel, 97:3^7:3 cyclohexane/ethyl acetate gradient, Isolera One). The combined desired fractions were concentrated and the residue was dried in vacuo. 557 mg (100% pure, 84% thor.) of the title compound were obtained.

LC-MS (method 1): Rt = 2.94 min; MS (ESIpos): m/z = 678/680 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.009 (0.15), 0.007 (0.15), 1.199 (0.06), 1.234 (0.05), 1.301 (0.35), 1.313 (0.08), 1.324 (0.10 ), 1.359 (16.00), 1.373 (0.45), 1.382 (0.35), 1.397 (1.92), 1.515 (0.07), 1.606 (1.33), 1.786 (0.91), 1.829 (0.22), 1.856 (0.12), 2.014 (0.06 ), 2.033 (0.25), 2.044 (0.27), 2.065 (1.16), 2.089 (0.32), 2.097 (0.28), 2.128 (0.68), 2.201 (0.10), 2.327 (0.04), 2.669 (0.03), 3.369 (0.18 ), 3.387 (0.19), 3.496 (1.06), 3.511 (1.44), 3.525 (1.04), 3.602 (0.18), 3.618 (0.24), 3.631 (0.24), 3.646 (0.24), 3.663 (0.18), 7.358 (0.37 ), 7.362 (0.34), 7.384 (0.23), 7.397 (0.75), 7.401 (0.60), 7.408 (0.60), 7.414 (0.57), 7.420 (0.68), 7.432 (0.18), 7.534 (0.65), 7.545 (0.46 ), 7.557 (1.42), 7.569 (0.32), 7.600 (0.64), 7.606 (0.60), 7.623 (0.34), 7.628 (0.33), 8.704 (0.19), 8.718 (0.37), 8.733 (0.19).

Separation of enantiomers.

The title target compound (450 mg) was dissolved in methanol (30 ml) and separated into enantiomers by chiral phase preparative HPLC (see examples 151A and 152A) [column: Daicel Chiralcel OH-X, 5 μm, 250 mm x 20 mm; flow: 80 ml/min; sample injection: 0.40 ml; UV detection: 210 nm, temperature: 40°C; eluent: 20% methanol/80% carbon dioxide; duration of action 5 min, isocratic]. The combined target fractions were respectively concentrated and the corresponding residue was lyophilized.

Example 151A.

(-)-tert-Butyl-5-({[2-(azepan-1-yl)-6-bromo-3-methylquinolin-4-yl]carbonyl}amino)-4-[2(trifluoromethoxy)phenyl]pentanoate (enantiomer 1).

The separation of enantiomers described in Example 150A gave 154 mg (100% pure, >99% ee) of the title compound as the previously eluted enantiomer.

[a] _D20 = -12.0°, 589 nm, c = 0.47 g ^/ 100 ml, methanol;

LC-MS (method 1): R _t = 2.95 min; MS (ESIpos): m/z = 678/680 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 1.200 (0.08), 1.301 (0.35), 1.313 (0.09), 1.324 (0.11), 1.359 (16.00), 1.381 (0.38), 1.515 (0.08 ), 1.606 (1.70), 1.786 (1.21), 1.856 (0.15), 2.033 (0.31), 2.066 (1.56), 2.089 (0.40), 2.129 (0.92), 2.201 (0.09), 3.369 (0.24), 3.387 (0.25 ), 3.496 (1.27), 3.511 (1.87), 3.525 (1.28), 3.602 (0.24), 3.618 (0.33), 3.631 (0.32), 3.646 (0.31), 3.663 (0.23), 7.358 (0.47), 7.397 (0.94 ), 7.408 (0.75), 7.420 (0.83), 7.534 (0.71), 7.546 (0.53), 7.557 (1.60), 7.569 (0.39), 7.601 (0.64), 7.605 (0.67), 7.623 (0.35), 7.627 (0.36 ), 8.704 (0.25), 8.718 (0.49), 8.733 (0.25).

Example 152A.

(+)-tert-Butyl-5-({[2-(azepan-1-yl)-6-bromo-3-methylquinolin-4-yl]carbonyl}amino)-4-[2(trifluoromethoxy)phenyl]pentanoate (enantiomer 2).

The separation of enantiomers described in Example 150A gave 149 mg (100% pure, 97% ee) of the title compound as the later eluted enantiomer.

[a] _D20 = +13.3°, 589 nm, c = 0.40 g/100 mL ^, methanol;

LC-MS (method 1): R _t = 2.95 min; MS (ESIpos): m/z = 678/680 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.150 (0.03), 0.145 (0.03), 1.199 (0.06), 1.313 (0.08), 1.324 (0.10), 1.359 (16.00), 1.515 (0.07 ), 1.606 (1.36), 1.786 (0.95), 1.829 (0.23), 1.856 (0.12), 2.014 (0.07), 2.033 (0.27), 2.044 (0.29), 2.065 (1.27), 2.089 (0.32), 2.096 (0.28 ), 2.128 (0.72), 2.327 (0.04), 2.669 (0.04), 3.369 (0.20), 3.386 (0.20), 3.496 (1.10), 3.511 (1.53), 3.525 (1.08), 3.602 (0.20), 3.618 (0.27 ), 3.630 (0.26), 3.645 (0.24), 3.663 (0.18), 7.358 (0.39), 7.384 (0.20), 7.397 (0.78), 7.408 (0.64), 7.414 (0.61), 7.420 (0.72), 7.432 (0.19 ), 7.534 (0.65), 7.546 (0.46), 7.556 (1.45), 7.569 (0.34), 7.600 (0.62), 7.606 (0.59), 7.623 (0.33), 7.628 (0.32), 8.703 (0.21), 8.718 (0.40 ), 8.732 (0.20).

- 85 040220

Example 153A.

tert-Butyl 5-[({6-bromo-2-[3-fluoropiperidin-1-yl]-3-methylquinolin-4-yl}carbonyl)amino]-4-[2(trifluoromethoxy)phenyl]pentanoate (mixture diastereoisomers)

To a mixture of (+/-)-tert-butyl-5-{[(6-bromo-2-chloro-3-methylquinolin-4-yl)carbonyl]amino}-4-[2(trifluoromethoxy)phenyl]pentanoate ( 600 mg, 974 µmol, example 41 A) in NMP (3.9 ml) was added (+/-)-3fluoropiperidine-hydrochloride (1.09 g, 7.79 mmol) and DIPEA (1.7 ml, 9.7 mmol) and the mixture was stirred for 30 h at 110 °C. After cooling to RT, the mixture was mixed with dichloromethane (150 ml) and washed once with water (120 ml) and once with a mixture of 1 M hydrochloric acid (25 ml) in water (100 ml). The organic phase was dried, filtered and concentrated, and the residue was adsorbed in dichloromethane and purified by flash column chromatography (50 g Biotage Snap-Cartridge Ultra silica gel, 97:3^7:3 cyclohexane/ethyl acetate gradient, Isolera One). The combined desired fractions were concentrated and the residue was dried in vacuo. 463 mg (92% pure, 64% thor.) of the title compound were obtained.

LC-MS (method 1): Rt = 2.74 min; MS (ESIpos): m/z = 682/684 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 1.199 (0.07), 1.233 (0.05), 1.301 (0.32), 1.314 (0.07), 1.325 (0.09), 1.360 (16.00), 1.381 (0.37 ), 1.397 (3.74), 1.516 (0.07), 1.646 (0.18), 1.807 (0.33), 1.831 (0.31), 1.855 (0.18), 1.902 (0.27), 1.952 (0.17), 2.036 (0.24), 2.067 (1.20 ), 2.089 (0.27), 2.156 (0.93), 2.222 (0.14), 2.327 (0.04), 3.104 (0.18), 3.181 (0.18), 3.333 (0.26), 3.353 (0.21), 3.387 (0.36), 3.412 (0.15 ), 3.444 (0.16), 3.472 (0.10), 3.618 (0.21), 3.634 (0.38), 3.650 (0.35), 4.818 (0.14), 4.938 (0.14), 7.362 (0.37), 7.386 (0.19), 7.399 (0.69 ), 7.410 (0.52), 7.417 (0.49), 7.422 (0.59), 7.434 (0.12), 7.491 (0.13), 7.546 (0.43), 7.559 (0.38), 7.570 (0.30), 7.656 (0.23), 7.677 (1.30 ), 7.683 (0.96), 7.688 (0.80), 7.706 (0.17), 7.711 (0.16), 7.901 (0.04), 8.735 (0.20), 8.750 (0.39), 8.765 (0.19).

Example 154A.

tert-Butyl 5-[({6-bromo-2-[3-ethylpiperidin-1-yl]-3-methylquinolin-4-yl}carbonyl)amino]-4-[2(trifluoromethoxy)phenyl]pentanoate (mixture diastereoisomers)

To a mixture of (+/-)-tert-butyl-5-{[(6-bromo-2-chloro-3-methylquinolin-4-yl)carbonyl]amino}-4-[2(trifluoromethoxy)phenyl]pentanoate ( 600 mg, 974 µmol, example 41A) in NMP (4.0 ml) was added (+/-)-3ethylpiperidine (882 mg, 7.79 mmol) and DIPEA (1.4 ml, 7.8 mmol) and the mixture was stirred for two days at

110°C. After cooling to RT, the mixture was purified by flash column chromatography (100 g Biotage Snap-Cartridge Ultra silica gel, 97:3^8:2 cyclohexane/ethyl acetate gradient, Isolera One). The combined desired fractions were concentrated and the residue was dried in vacuo. Received 501 mg (98% pure, 73% theoretical. out.) specified in the title compound.

LC-MS (method 1): Rt = 3.07 min; MS (ESIpos): m/z = 692/694 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.964 (0.91), 0.983 (2.24), 1.002 (1.37), 1.023 (0.48), 1.141 (0.18), 1.170 (0.19), 1.271 (0.09) , 1.333 (0.37), 1.350 (0.49), 1.372 (0.61), 1.432 (16.00), 1.452 (0.35), 1.469 (0.15), 1.636 (0.22), 1.822 (0.26), 1.855 (0.25) , 1.898 (0.22), 1.924 (0.31), 1.952 (0.22), 2.103 (0.27), 2.137 (1.26), 2.188 (0.46), 2.215 (0.65), 2.272 (0.11), 2.398 (0.08), 2.437 (0.09) . , 7.430 (0.34), 7.468 (0.71), 7.480 (0.54), 7.492 (0.61), 7.549 (0.12), 7.620 (0.40), 7.632 (0.34), 7.643 (0.28), 7.705 (0.17), 7.727 (1.51) , 7.757 (0.11), 8.795 (0.22), 8.810 (0.42), 8.825 (0.21).

Example 155A.

tert-Butyl 5-[({6-bromo-3-methyl-2-[3-methylpiperidin-1-yl]quinolin-4-yl}carbonyl)amino]-4-[2(trifluoromethoxy)phenyl]pentanoate ( mixture of diastereoisomers)

- 86 040220

To a mixture of (+/-)-tert-butyl-5-{[(6-bromo-2-chloro-3-methylquinolin-4-yl)carbonyl]amino}-4-[2(trifluoromethoxy)phenyl]pentanoate ( 600 mg, 974 µmol, example 41A) in NMP (3.9 ml) was added (+/-)-3methylpiperidine (910 µl, 7.8 mmol) and DIPEA (1.4 ml, 7.8 mmol) and the mixture was stirred for 30 h at 110°C. After cooling to RT, the mixture was mixed with dichloromethane (150 ml) and washed once with water (120 ml) and once with a mixture of 1 M hydrochloric acid (20 ml) in water (100 ml). The organic phase was dried, filtered and concentrated, and the residue was adsorbed in dichloromethane and purified by flash column chromatography (50 g Biotage Snap-Cartridge Ultra silica gel, 97:3^7:3 cyclohexane/ethyl acetate gradient, Isolera One). The combined desired fractions were concentrated and the residue was dried in vacuo. 646 mg (100% pure, 98% thor.) of the title compound were obtained.

LC-MS (method 1): R _t = 2.97 min; MS (ESIpos): m/z = 678/680 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 0.833 (0.04), 0.849 (0.05), 0.922 (1.43), 0.938 (1.46), 1.082 (0.16), 1.111 (0.18), 1.200 (0.08 ), 1.233 (0.08), 1.301 (0.35), 1.324 (0.10), 1.360 (16.00), 1.381 (0.36), 1.397 (3.29), 1.516 (0.07), 1.628 (0.15), 1.657 (0.17), 1.733 (0.30 ), 1.765 (0.31), 1.804 (0.43), 1.830 (0.37), 2.014 (0.07), 2.033 (0.25), 2.066 (1.17), 2.092 (0.29), 2.146 (0.69), 2.210 (0.14), 2.327 (0.03 ), 2.435 (0.12), 2.461 (0.19), 2.687 (0.12), 2.717 (0.21), 2.747 (0.12), 3.369 (0.19), 3.386 (0.20), 3.442 (0.24), 3.471 (0.44), 3.502 (0.21 ), 3.611 (0.21), 3.629 (0.35), 3.647 (0.31), 3.666 (0.20), 7.361 (0.38), 7.378 (0.15), 7.385 (0.20), 7.398 (0.74), 7.403 (0.56), 7.410 (0.55 ), 7.416 (0.51), 7.421 (0.63), 7.434 (0.15), 7.472 (0.14), 7.546 (0.43), 7.558 (0.35), 7.570 (0.29), 7.634 (0.17), 7.657 (1.59), 7.663 (0.95 ), 7.681 (0.13), 7.685 (0.12), 8.725 (0.20), 8.739 (0.40), 8.754 (0.20).

Example 156A.

(+/-)-tert-Butyl-5-({[6-bromo-3-methyl-2-(piperidin-1-yl)quinolin-4-yl]carbonyl}amino)-4-(2-chloro3- fluorophenyl)pentanoate (racemate)

To a mixture of (+/-)-tert-butyl-5-{[(6-bromo-2-chloro-3-methylquinolin-4-yl)carbonyl]amino}-4-(2-chloro-3-fluorophenyl)pentanoate (204 mg, 349 μmol, example 44A) in NMP (3.4 ml) was added piperidine (280 μl, 2.8 mmol) and DIPEA (490 μl, 2.8 mmol) and the mixture was stirred overnight at 100°C. After cooling to RT, the mixture was filtered and purified by preparative HPLC (method 6). The combined desired fractions were concentrated and the residue was dried in vacuo. 175 mg (100% pure, 79% thor.) of the title compound were obtained.

LC-MS (method 1): R _t = 2.81 min; MS (ESIpos): m/z = 632/634 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: -0.150 (0.06), -0.023 (0.27), 0.007 (0.41), 0.145 (0.05), 1.208 (0.07), 1.233 (0.57), 1.303 (0.08), 1.327 (0.10), 1.368 (16.00), 1.525 (0.07), 1.606 (0.45), 1.670 (0.88) (1.12) (0.18) (1.35), 7.653 (0.89), 7.658 (0.80), 7.675 (0.17), 7.680 (0.19), 8.716 (0.21), 8.730 (0.45), 8.744 (0.22).

Example 157A.

(+/-)-tert-Butyl-5-({[6-bromo-3-methyl-2-(piperidin-1-yl)quinolin-4-yl]carbonyl}amino)-4-(6-chloro2, 3-difluorophenyl)pentanoate (racemate)

- 87 040220

To a mixture of (+/-)-tert-butyl-5-{[(6-bromo-2-chloro-3-methylquinolin-4-yl)carbonyl]amino}-4-(6-chloro2,3-difluorophenyl) pentanoate (154 mg, 87% pure, 222 µmol, example 45A) in NMP (2 ml) was added piperidine (180 µl, 1.8 mmol) and DIPEA (310 µl, 1.8 mmol) and the mixture was stirred overnight at 100°C . After cooling to RT, the mixture was filtered and purified by preparative HPLC (method 6). The combined desired fractions were concentrated and the residue was dried in vacuo. 126 mg (100% pure, 87% thor.) of the title compound were obtained.

LC-MS (method 1): R _t = 2.82 min; MS (ESIpos): m/z = 650/652 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.150 (0.07), -0.023 (0.47), 1.202 (0.10), 1.233 (0.72), 1.362 (16.00), 1.518 (0.09), 1.606 ( 0.59), 1.670 (1.09), 1.981 (0.14), 2.064 (0.26), 2.143 (3.28), 2.169 (0.73), 2.327 (0.09), 2.365 (0.09), 2.670 (0.08), 2.709 (0.07), 3.134 ( 1.42), 3.689 (0.24), 3.766 (0.34), 7.377 (0.42), 7.389 (0.49), 7.412 (0.33), 7.433 (0.29), 7.627 (0.40), 7.649 (1.50), 7.659 (0.92), 0.81), 7.681 (0.21), 7.686 (0.21), 8.811 (0.45).

Example 158A.

(+/-)-tert-Butyl-5-({[6-bromo-3-methyl-2-(piperidin-1-yl)quinolin-4-yl]carbonyl}amino)-4-(5-fluoro2- methylphenyl)pentanoate (racemate)

To a mixture of (+/-)-tert-butyl-5-{[(6-bromo-2-chloro-3-methylquinolin-4-yl)carbonyl]amino}-4-(5-fluoro-2methylphenyl)pentanoate ( 200 mg, 355 μmol, example 46A) in NMP (2 ml) was added piperidine (280 μl, 2.8 mmol) and DIPEA (620 μl, 3.5 mmol) and the mixture was stirred overnight at 100°C. After cooling to RT, the mixture was filtered and purified by preparative HPLC (method 6). The combined desired fractions were concentrated and the residue was dried in vacuo. 190 mg (100% pure, 87% thor.) of the title compound were obtained.

LC-MS (method 1): R _t = 2.83 min; MS (ESIpos): m/z = 612/614 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.023 (0.35), 0.852 (0.06), 1.211 (0.08), 1.233 (0.83), 1.317 (0.07), 1.337 (0.10), 1.371 (16.00 ), 1.528 (0.08), 1.606 (0.47), 1.669 (0.92), 1.754 (0.13), 1.787 (0.20), 1.811 (0.16), 2.000 (0.19), 2.016 (0.18), 2.036 (0.20), 2.061 (0.06 ), 2.669 (0.07), 2.709 (0.06), 3.135 (1.22), 3.478 (0.23), 3.671 (0.21), 3.686 (0.17), 3.706 (0.10), 6.928 (0.36), 7.142 (0.37), 7.163 (0.37 ), 7.169 (0.36), 7.198 (0.78), 2.077 (0.97), 2.099 (0.17), 3.497 (0.20), (0.17), 6.943 (0.33), (0.35), 7.213 (0.40), (0.26), 7.650 (1.44), 7.657 (0.95), 7.662 (0.83), 7.679 (0.16), 7.684 (0.18), (0.23).

(1.51), 2.291 (2.74), 2.365 (0.23), 3.635 (0.15), 3.653 (0.37), 6.971 (0.20), 7.136 (0.31), 7.455 (0.20)

3.512

6.949

7.234

8.702

Example 159A.

(+/-)-tert-Butyl-5-({[6-bromo-2-(3,3-difluoropiperidin-1-yl)-3-methylquinolin-4yl]carbonyl}amino)-4-(5-fluoro -2-methylphenyl)pentanoate (racemate)

To a mixture of (+/-)-tert-butyl-5-{[(6-bromo-2-chloro-3-methylquinolin-4-yl)carbonyl]amino}-4-(5-fluoro-2methylphenyl)pentanoate ( 336 mg, 596 µmol, example 46A) in NMP (4.0 ml) was added 3,3 difluoropiperidine hydrochloride (751 mg, 4.77 mmol) and DIPEA (1.0 ml, 6.0 mmol) and the mixture was stirred for 44 h at 100°C. The temperature was then raised to 120° C. and the mixture was stirred for an additional 24 hours.

- 88 040220 after cooling to RT, the mixture was filtered and purified by preparative HPLC (method 6). The combined desired fractions were concentrated and the residue was dried in vacuo. 265 mg (100% pure, 69% th. y.) of the title compound were obtained.

LC-MS (method 1): R _t = 2.70 min; MS (ESIpos): m/z = 648/650 [M+H]+.

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.212 (0.07), 1.316 (0.06), 1.337 (0.10), 1.372 (16.00), 1.528 (0.07), 1.757 (0.13), 1.790 (0.21) , 1.814 (0.18), 1.829 (0.12), 1.878 (0.50), 1.988 (0.16), 2.002 (0.21), 2.018 (0.21), 2.064 (0.98), 2.080 (1.25), 2.099 (0.84), 2.119 (1.49) . . , 7.215 (0.43), 7.236 (0.33), 7.492 (0.19), 7.679 (0.24), 7.701 (1.55), 7.706 (1.07), 7.711 (0.88) , 8.744 (0.25).

Example 160A.

(+/-)-tert-Butyl-5-({[6-bromo-3-methyl-2-(piperidin-1-yl)quinolin-4-yl]carbonyl}amino)-4-(2-chloro3, 6-difluorophenyl)pentanoate (racemate)

To a mixture of (+/-)-tert-butyl-5-{[(6-bromo-2-chloro-3-methylquinolin-4-yl)carbonyl]amino}-4-(2-chloro3,6-difluorophenyl) pentanoate (314 mg, 521 µmol, example 47A) in NMP (3.1 ml) was added piperidine (410 µl, 4.2 mmol) and DIPEA (730 µl, 4.2 mmol) and the mixture was stirred overnight at 100°C. After cooling to RT, the mixture was filtered and purified by preparative HPLC (method 6). The combined desired fractions were concentrated and the residue was dried in vacuo. 272 mg (100% pure, 80% thor.) of the title compound were obtained.

LC-MS (method 1): R _t = 2.80 min; MS (ESIpos): m/z = 650/652 [M+H]+.

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.022 (0.18), -0.008 (0.77), 0.008 (0.66), 1.234 (0.33), 1.361 (16.00), 1.608 (0.43), 1.673 ( 0.83), 2.142 (2.24), 2.366 (0.22), 2.710 (0.22), 3.138 (1.09), 3.759 (0.22), 7.303 (0.24), 7.317 (0.19), 7.421 (0.24), 7.630 (0.32), 1.33), 7.662 (0.94), 7.667 (0.81), 7.684 (0.21), 7.690 (0.22), 8.814 (0.34).

Example 161A.

(+/-)-tert-Butyl-5-({[6-bromo-3-methyl-2-(pyrrolidin-1-yl)quinolin-4-yl]carbonyl}amino)-4-(2chloro-3, 6-difluorophenyl)pentanoate (racemate)

To a mixture of (+/-)-tert-butyl-5-{[(6-bromo-2-chloro-3-methylquinolin-4-yl)carbonyl]amino}-4-(2-chloro3,6-difluorophenyl) pentanoate (600 mg, 996 µmol, example 47A) in NMP (4.0 ml) was added pyrrolidine (670 µl, 8.0 mmol) and DIPEA (1.4 ml, 8.0 mmol) and the mixture was stirred for 5 h at 110°C. After cooling to RT, the mixture was mixed with dichloromethane (150 ml) and washed successively with water and 1M hydrochloric acid (respectively 100 ml). The organic phase was dried, filtered and concentrated, and the residue was adsorbed in dichloromethane and purified by flash column chromatography (50 g Biotage Snap-Cartridge Ultra silica gel, 97:3^7:3 cyclohexane/ethyl acetate gradient, Isolera One). The combined desired fractions were concentrated and the residue was dried in vacuo. 90 mg (100% pure, 14% thor.) of the title compound were obtained.

LC-MS (method 1): R _t = 2.25 min; MS (ESIpos): m/z = 636/638 [M+H]+.

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.007 (0.21), 1.211 (0.07), 1.300 (0.11), 1.332 (0.11), 1.372 (16.00), 1.397 (2.79), 1.755 (0.12) , 1.789 (0.19), 1.812 (0.17), 1.969 (0.16), 1.982 (0.20), 1.999 (0.20) . . , 8.851 (0.31).

- 89 040220

Example 162A.

(+/-)-tert-Butyl-5-({[6-bromo-2-(3,3-difluoropiperidin-1-yl)-3-methylquinolin-4yl]carbonyl}amino)-4-(2-chloro -3,6-difluorophenyl)pentanoate (racemate)

To a mixture of (+/-)-tert-butyl-5-{[(6-bromo-2-chloro-3-methylquinolin-4-yl)carbonyl]amino}-4-(2-chloro3,6-difluorophenyl) pentanoate (536 mg, 890 µmol, example 47A) in NMP (3.6 ml) was added 3,3 difluoropiperidine hydrochloride (1.12 g, 7.12 mmol) and DIPEA (1.6 ml, 8.9 mmol) and the mixture was stirred for three days at 110°C. After cooling to RT, the mixture with dichloromethane (150 ml) was mixed and washed once with water (120 ml) and once with a mixture of 1 M hydrochloric acid (25 ml) in water (100 ml). The organic phase was dried, filtered and concentrated, and the residue was adsorbed in dichloromethane and purified by flash column chromatography (50 g Biotage Snap-Cartridge Ultra silica gel, 97:3^7:3 cyclohexane/ethyl acetate gradient, Isolera One). The combined desired fractions were concentrated and the residue was dried in vacuo. 204 mg (100% pure, 33% thor.) of the title compound were obtained.

LC-MS (method 1): Rt = 2.67 min; MS (ESIpos): m/z = 686/688 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 1.156 (0.07), 1.174 (0.12), 1.200 (0.08), 1.233 (0.12), 1.269 (0.09), 1.315 (0.44), 1.360 (16.00 ), 1.377 (0.68), 1.406 (0.22), 1.517 (0.07), 1.883 (0.55), 1.987 (0.32), 2.082 (0.53), 2.097 (0.54), 2.136 (0.81), 2.163 (2.62), 2.327 (0.07 ), 2.669 (0.05), 3.171 (0.66), 3.450 (0.40), 3.479 (0.77), 3.508 (0.39), 3.696 (0.24), 3.771 (0.26), 4.020 (0.06), 4.038 (0.05), 7.270 (0.14 ), 7.281 (0.16), 7.294 (0.28), 7.305 (0.29), 7.319 (0.22), 7.330 (0.20), 7.410 (0.28), 7.421 (0.27), 7.681 (0.32), 7.703 (1.51), 7.711 (1.02 ), 7.716 (0.87), 7.734 (0.20), 7.738 (0.21), 8.828 (0.41).

Example 163A.

tert-Butyl 5-[({6-bromo-2-[3-fluoropiperidin-1-yl]-3-methylquinolin-4-yl}carbonyl)amino]-4-(2chloro-3,6-difluorophenyl)pentanoate (mixture of diastereoisomers)

To a mixture of (+/-)-tert-butyl-5-{[(6-bromo-2-chloro-3-methylquinolin-4-yl)carbonyl]amino}-4-(2-chloro3,6-difluorophenyl) pentanoate (600 mg, 996 µmol, example 47A) in NMP (4.0 ml) was added (+/-)-3fluoropiperidine hydrochloride (1.11 g, 7.97 mmol) and DIPEA (1.7 ml, 10 mmol) and the mixture was stirred for 30 h at 110°C. After cooling to RT, the mixture was mixed with dichloromethane (150 ml) and washed once with water (120 ml) and once with a mixture of 1 M hydrochloric acid (25 ml) in water (100 ml). The organic phase was dried, filtered and concentrated, and the residue was adsorbed in dichloromethane and purified by flash column chromatography (50 g Biotage Snap-Cartridge Ultra silica gel, 97:3^7:3 cyclohexane/ethyl acetate gradient, Isolera One). The combined desired fractions were concentrated and the residue was dried in vacuo. 463 mg (100% pure, 69% thor.) of the title compound were obtained.

LC-MS (method 1): Rt = 2.68 min; MS (ESIpos): m/z = 668/670 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: -0.008 (0.17), 1.157 (0.10), 1.175 (0.20), 1.193 (0.11), 1.201 (0.08), 1.235 (0.07), 1.268 ( 0.07), 1.316 (0.43), 1.361 (16.00), 1.378 (0.68), 1.398 (2.22), 1.518 (0.07), 1.646 (0.20), 1.808 (0.18), 1.901 (0.32), 1.920 (0.30), 0.27), 1.989 (0.53), 2.067 (0.21), 2.084 (0.21), 2.103 (0.18), 2.137 (0.65), 2.157 (2.66), 2.260 (0.06), 2.670 (0.04), 3.099 (0.21), 0.22), 3.349 (0.16), 3.380 (0.21), 3.410 (0.11), 3.437 (0.19), 3.468 (0.12), 3.698 (0.22), 3.767 (0.25), 4.003 (0.04), 4.021 (0.09) 0.09), 4.057 (0.04), 4.820 (0.15), 4.940 (0.15), 7.269 (0.13), 7.280 (0.15), 7.293 (0.26), 7.304 (0.28), 7.318 (0.21), 7.329 (0.19), 0.26), 7.421 (0.26), 7.499 (0.08), 7.655 (0.32), 7.677 (1.46), 7.686 (0.97), 7.691 (0.89), 7.709 (0.21), 7.713 (0.23), 7.906 (0.04), 0.37).

Example 164A.

tert-Butyl-5-[({6-bromo-3-methyl-2-[3-methylpiperidin-1-yl]quinolin-4-yl}carbonyl)amino]-4-(2-90 040220 chloro-3, 6-difluorophenyl)pentanoate (mixture of diastereoisomers)

To a mixture of (+/-)-tert-butyl-5-{[(6-bromo-2-chloro-3-methylquinolin-4-yl)carbonyl]amino}-4-(2-chloro3,6-difluorophenyl) pentanoate (600 mg, 996 µmol, example 47A) in NMP (4.0 ml) was added (+/-)-3methylpiperidine (940 µl, 8.0 mmol) and DIPEA (1.4 ml, 8.0 mmol), and the mixture was stirred for 30 h at 110° WITH. After cooling to RT, the mixture was mixed with dichloromethane (150 ml) and washed once with water (120 ml) and once with a mixture of 1 M hydrochloric acid (20 ml) in water (100 ml). The organic phase was dried, filtered and concentrated, and the residue was adsorbed in dichloromethane and purified by flash column chromatography (50 g Biotage Snap-Cartridge Ultra silica gel, 97:3^7:3 cyclohexane/ethyl acetate gradient, Isolera One). The combined desired fractions were concentrated and the residue was dried in vacuo. Received 550 mg (100% pure, 83% theoretical. Y.) specified in the title compound.

LC-MS (method 1): Rt = 2.90 min; MS (ESIpos): m/z = 664/666 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.867 (0.06), 0.884 (0.06), 0.954 (1.62), 0.970 (1.65), 1.114 (0.19), 1.142 (0.20), 1.165 (0.08) 1.235 (0.08), 1.267 (0.11), 1.303 (0.07), 1.348 (0.51), 1.395 (16.00), 1.411 (0.72), 1.431 (5.54), 1.551 (0.07), 1.663 (0.17), 1.686 (0.19) , 1.765 (0.35), 1.796 (0.33), 1.826 (0.41), 1.857 (0.26), 2.017 (0.12), 2.102 (0.22), 2.118 (0.22), 2.138 (0.22), 2.181 (2.31), 2.280 (0.06) . , 7.325 (0.27), 7.336 (0.28), 7.351 (0.22), 7.362 (0.20), 7.421 (0.18) , 7.667 (0.24), 7.689 (1.52), 7.694 (1.18), 7.698 (0.95), 7.716 (0.16), 7.721 (0.18), 8.828 (0.22), 8.842 (0.38), 11.235 (0.02).

Example 165A.

tert-Butyl 5-[({6-bromo-2-[3-ethylpiperidin-1-yl]-3-methylquinolin-4-yl}carbonyl)amino]-4-(2chloro-3,6-difluorophenyl)pentanoate (mixture of diastereoisomers)

To a mixture of (+/-)-tert-butyl-5-{[(6-bromo-2-chloro-3-methylquinolin-4-yl)carbonyl]amino}-4-(2-chloro3,6-difluorophenyl) pentanoate (600 mg, 996 µmol, example 47A) in NMP (4.0 ml) was added (+/-)-3ethylpiperidine (1.1 ml, 8.0 mmol) and DIPEA (1.4 ml, 8.0 mmol), and the mixture was stirred for 30 h at 110° WITH. After cooling to RT, the mixture was mixed with dichloromethane (150 ml) and washed once with water (150 ml) and once with a mixture of 1 M hydrochloric acid (20 ml) in water (100 ml). The organic phase was dried, filtered and concentrated, and the residue was adsorbed in dichloromethane and purified by flash column chromatography (50 g Biotage Snap-Cartridge Ultra silica gel, cyclohexane/ethyl acetate gradient 97:3^7:3, Isolera One). The combined desired fractions were concentrated and the residue was dried in vacuo. Received 558 mg (100% pure, 83% theoretical. yield.) specified in the title compound.

LC-MS (method 1): Rt = 3.00 min; MS (ESIpos): m/z = 678/680 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 0.890 (0.96), 0.909 (2.20), 0.927 (1.16), 1.065 (0.24), 1.095 (0.25), 1.200 (0.09), 1.259 (0.54 ), 1.276 (0.70), 1.294 (0.48), 1.313 (0.75), 1.360 (16.00), 1.377 (0.79), 1.396 (1.93), 1.566 (0.29), 1.747 (0.34), 1.779 (0.23), 1.847 (0.29 ), 1.877 (0.29), 1.973 (0.15), 2.066 (0.28), 2.082 (0.29), 2.139 (2.33), 2.241 (0.08), 2.424 (0.20), 2.695 (0.12), 2.752 (0.22), 3.490 (0.54 ), 3.519 (0.51), 3.694 (0.28), 3.763 (0.32), 7.276 (0.19), 7.290 (0.33), 7.300 (0.34), 7.314 (0.25), 7.325 (0.22), 7.404 (0.35), 7.415 (0.35 ), 7.632 (0.27), 7.654 (1.72), 7.686 (0.19), 8.809 (0.48).

Example 166A.

(+/-)-tert-Butyl-5-({[2-(azepan-1-yl)-6-bromo-3-methylquinolin-4-yl]carbonyl}amino)-4-(2-chloro-3 ,6difluorophenyl)pentanoate (racemate)

- 91 040220

To a mixture of (+/-)-tert-butyl-5-{[(6-bromo-2-chloro-3-methylquinolin-4-yl)carbonyl]amino}-4-(2-chloro3,6-difluorophenyl) pentanoate (600 mg, 996 µmol, example 47A) in NMP (4.0 ml) was added azepane (900 µl, 8.0 mmol) and DIPEA (1.4 ml, 8.0 mmol) and the mixture was stirred for 5 h at 110°C. After cooling to RT, the mixture was mixed with dichloromethane (150 ml) and washed once with a mixture of 1 M hydrochloric acid (20 ml) in water (100 ml) and once with water (150 ml). The organic phase was dried, filtered and concentrated, and the residue was adsorbed in dichloromethane and purified by flash column chromatography (50 g Biotage Snap-Cartridge Ultra silica gel, cyclohexane/ethyl acetate gradient 97:3^7:3, Isolera One). The combined desired fractions were concentrated and the residue was dried in vacuo. Received 599 mg (100% pure, 90% theoretical. yield.) specified in the title compound.

LC-MS (method 1): Rt = 2.85 min; MS (ESIpos): m/z = 664/666 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 0.851 (0.05), 1.200 (0.08), 1.234 (0.20), 1.267 (0.10), 1.312 (0.62), 1.360 (16.00), 1.377 (0.75 ), 1.397 (4.30), 1.517 (0.09), 1.602 (1.91), 1.780 (1.21), 1.882 (0.08), 1.901 (0.11), 1.920 (0.13), 1.972 (0.15), 2.065 (0.25), 2.082 (0.27 ), 2.133 (2.63), 2.150 (1.06), 2.195 (0.12), 2.236 (0.07), 2.328 (0.05), 2.670 (0.04), 2.695 (0.40), 3.285 (0.13), 3.492 (1.43), 3.506 (2.16 ), 3.520 (1.38), 3.708 (0.30), 7.266 (0.15), 7.277 (0.18), 7.290 (0.31), 7.301 (0.33), 7.315 (0.24), 7.326 (0.22), 7.407 (0.35), 7.418 (0.34 ), 7.532 (0.71), 7.554 (1.27), 7.602 (0.76), 7.607 (0.67), 7.624 (0.42), 7.629 (0.39), 8.789 (0.43).

Example 167A.

(+/-)-tert-Butyl-5-({[6-bromo-3-methyl-2-(piperidin-1-yl)quinolin-4-yl]carbonyl}amino)-4-[2-fluoro6- (trifluoromethyl)phenyl] pentanoate (racemate)

To a mixture of (+/-)-tert-butyl-5-{[(6-bromo-2-chloro-3-methylquinolin-4-yl)carbonyl]amino}-4-[2-fluoro-6(trifluoromethyl) phenyl]pentanoate (300 mg, 97% pure, 471 µmol, example 50A) in NMP (4.0 ml) was added in a thick-walled glass vial (microwave) piperidine (230 µl, 2.4 mmol) and DIPEA (410 µl, 2.4 mmol). The vessel was rinsed with argon, closed and shaken overnight with a thermal shaker at 100°C. Then shaken for an additional 24 hours at 130°C. After cooling to RT, the mixture was directly (without further workup) purified by preparative HPLC (method 14). The combined target fractions were concentrated and the residue was adsorbed in dichloromethane, concentrated again and dried in vacuo. 258 mg (100% pure, 82% thor.) of the title compound were obtained.

LC-MS (method 4): Rt = 1.80 min; Ionization without target mass detection.

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.149 (0.10), -0.008 (0.85), 0.008 (0.95), 0.146 (0.10), 1.307 (0.15), 1.340 (16.00), 1.613 ( 0.43), 1.678 (0.85), 2.042 (0.25), 2.073 (0.48), 2.093 (0.35), 2.114 (0.48), 2.141 (0.39), 2.168 (1.23), 2.328 (0.11), 2.670 (0.11), 1.11), 3.700 (0.12), 3.849 (0.11), 5.754 (0.33), 7.561 (0.48), 7.571 (0.44), 7.594 (0.69), 7.622 (0.44), 7.634 (0.51), 7.656 (1.32), 0.97), 7.666 (0.84), 7.688 (0.17), 8.803 (0.21), 8.818 (0.42), 8.833 (0.21).

Separation of enantiomers.

The title target compound (188 mg) was separated into its enantiomers by preparative chiral phase SLC (see Examples 168A and 169A) [column: Daicel Chiralcel OZ-H, 5 μm, 250 mm x 20 mm; flow: 60 ml/min; UV detection: 260 nm, temperature: 25°C; eluent: 10% methanol/90% carbon dioxide; outlet pressure 150 bar, isocratic]. The combined target fractions were respectively concentrated and the corresponding residue was dried in vacuo.

Example 168A.

tert-Butyl-5-({[6-bromo-3-methyl-2-(piperidin-1-yl)quinolin-4-yl]carbonyl}amino)-4-[2-fluoro-6(trifluoromethyl)phenyl] pentanoate (enantiomer 1).

Separation of enantiomers as described in Example 167A yielded 85 mg (100% pure, ee

- 92 040220 value 99%) of the title compound as the previously eluted enantiomer.

R _t = 11.5 min (chiral analytical HPLC; Saule Chiralpak IE, 5 µm, 250 mm x 4.6 mm, eluent heptane/isopropanol/diethylamine 80:20:0.1; flow 1 ml/min; temperature 25°C; detection 225 nm) .

LC-MS (method 2): R _t = 1.48 min; MS (ESIpos): m/z = 666/668 [M+H]+.

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.348 (16.00), 1.621 (0.41), 1.687 (0.81), 2.080 (0.44), 2.122 (0.46), 2.177 (1.18), 3.158 (1.06) , 7.569 (0.47), 7.579 (0.44), 7.603 (0.69), 7.631 (0.44), 7.642 (0.51), 7.664 (1.33), 7.669 (1.00), 7.674 (0.86), 8.826 (0.40).

Example 169A.

tert-Butyl-5-({[6-bromo-3-methyl-2-(piperidin-1-yl)quinolin-4-yl]carbonyl}amino)-4-[2-fluoro-6(trifluoromethyl)phenyl] pentanoate (enantiomer 2).

The separation of enantiomers described in Example 167A gave 93 mg (100% pure, ee 97%) of the title compound as the later eluted enantiomer.

R _t = 10.3 min (chiral analytical HPLC; Saule Chiralpak IE, 5 µm, 250 mm x 4.6 mm, eluent heptane/isopropanol/diethylamine 80:20:0.1; flow 1 ml/min; temperature 25°C; detection 225 nm) .

LC-MS (method 2): Rt = 1.48 min; MS (ESIpos): m/z = 666/668 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: -0.009 (0.46), 0.007 (0.43), 1.029 (0.54), 1.044 (0.55), 1.235 (0.26), 1.307 (0.15), 1.340 ( 16.00), 1.613 (0.42), 1.678 (0.83), 2.041 (0.24), 2.072 (0.47), 2.092 (0.34), 2.114 (0.47), 2.140 (0.39), 2.167 (1.21), 2.327 (0.11), 0.11), 3.154 (1.12), 3.714 (0.12), 3.847 (0.11), 7.561 (0.47), 7.570 (0.43), 7.594 (0.69), 7.622 (0.44), 7.633 (0.49), 7.655 (1.31), 0.93), 7.666 (0.80), 7.688 (0.16), 8.802 (0.20), 8.817 (0.41), 8.832 (0.20).

Example 170A.

(+/-)-tert-Butyl-5-({[6-bromo-3-methyl-2-(pyrrolidin-1-yl)quinolin-4-yl]carbonyl}amino)-4-[2fluoro-6- (trifluoromethyl)phenyl]pentanoate (racemate)

To a mixture of (+/-)-tert-butyl-5-{[(6-bromo-2-chloro-3-methylquinolin-4-yl)carbonyl]amino}-4-[2-fluoro-6(trifluoromethyl) phenyl]pentanoate (300 mg, 97% pure, 471 µmol, example 50A) in NMP (4.0 ml) in a thick-walled glass vial (microwave) were added pyrrolidine (200 µl, 2.4 mmol) and DIPEA (410 µl, 2.4 mmol). The vessel was rinsed with argon, closed and shaken overnight with a thermal shaker at 100°C. After cooling to RT, the mixture was directly (without further workup) purified by preparative HPLC (method 14). The combined target fractions were concentrated and the residue was adsorbed in dichloromethane, concentrated again and dried in vacuo. 239 mg (100% pure, 78% thor.) of the title compound were obtained.

LC-MS (method 4): R _t = 1.46 min; MS (ESIpos): m/z = 652/654 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.149 (0.10), -0.008 (0.85), 0.008 (0.95), 0.146 (0.10), 1.290 (0.07), 1.308 (0.14), 1.337 ( 16.00), 1.879 (1.23), 2.038 (0.27), 2.067 (0.53), 2.093 (0.41), 2.115 (0.61), 2.144 (0.39), 2.178 (0.48), 2.328 (0.11), 2.669 (0.10), 0.86), 3.867 (0.11), 5.754 (0.65), 7.476 (0.63), 7.499 (1.10), 7.552 (0.74), 7.557 (0.95), 7.574 (0.65), 7.580 (0.59), 7.590 (0.62), 0.41), 8.745 (0.19), 8.760 (0.38), 8.775 (0.20).

Separation of enantiomers.

The title target compound (163 mg) was separated into its enantiomers by preparative SLC on chiral phase (see Examples 171A and 172A) [column: Daicel Chiralpak IG, 5 μm, 250 mm x 20 mm; flow: 60 ml/min; UV detection: 230 nm, temperature: 25°C; eluent: 20% (methanol + 1% diethylamine)/80% carbon dioxide; outlet pressure 150 bar, isocratic]. The combined target fractions were respectively concentrated and the corresponding residue was dried in vacuo.

Example 171A.

tert-Butyl-5-({[6-bromo-3-methyl-2-(pyrrolidin-1-yl)quinolin-4-yl]carbonyl}amino)-4-[2-fluoro-6(trifluoromethyl)phenyl] pentanoate (enantiomer 1).

The separation of enantiomers described in Example 170A gave 75 mg (98% pure, ee 98%) of the title compound as the previously eluted enantiomer.

R _t = 10.8 min (chiral analytical HPLC; Saule Chiralpak IC, 5 µm, 250 mm x 4.6 mm, eluent heptane/isopropanol/diethylamine 70:30:0.1; flow 1 ml/min; temperature 25°C; detection 260 nm) .

LC-MS (method 2): R _t = 1.11 min; MS (ESIpos): m/z = 652/654 [M+H] ⁺ .

- 93 040220

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 1.029 (0.47), 1.045 (0.47), 1.337 (16.00), 1.879 (1.24), 2.038 (0.29), 2.067 (0.55), 2.092 (0.43 ), 2.115 (0.62), 2.144 (0.40), 2.179 (0.49), 2.327 (0.16), 2.669 (0.15), 3.581 (0.87), 7.476 (0.64), 7.498 (1.12), 7.552 (0.76), 7.557 (0.98 ), 7.574 (0.67), 7.580 (0.60), 7.590 (0.64), 7.613 (0.42), 8.760 (0.38).

Example 172A.

tert-Butyl-5-({[6-bromo-3-methyl-2-(pyrrolidin-1-yl)quinolin-4-yl]carbonyl}amino)-4-[2-fluoro-6(trifluoromethyl)phenyl] pentanoate (enantiomer 2).

The separation of enantiomers described in Example 170A gave 79 mg (97% pure, ee 98%) of the title compound as the later eluted enantiomer.

R _t = 13.4 min (chiral analytical HPLC; Saule Chiralpak IC, 5 µm, 250 mm x 4.6 mm, eluent heptane/isopropanol/diethylamine 70:30:0.1; flow 1 ml/min; temperature 25°C; detection 260 nm) .

LC-MS (method 2): R _t = 1.11 min; MS (ESIpos): m/z = 652/654 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.030 (1.27), 1.045 (1.26), 1.235 (0.11), 1.308 (0.16), 1.337 (16.00), 1.879 (1.30), 1.960 (0.11) 2.037 (0.29), 2.067 (0.56), 2.093 (0.44), 2.115 (0.64), 2.144 (0.41), 2.178 (0.52), 2.327 (0.12), 3.580 (0.92), 3.864 (0.12), 7.476 (0.67) , 7.498 (1.16), 7.552 (0.83), 7.557 (1.01), 7.574 (0.69), 7.580 (0.63), 7.589 (0.66), 7.613 (0.43), 8.760 (0.40).

Example 173A.

(+/-)-tert-Butyl-5-({[6-bromo-2-(3,3-difluoropiperidin-1-yl)-3-methylquinolin-4yl]carbonyl}amino)-4-[2-fluoro -6-(trifluoromethyl)phenyl]pentanoate (racemate)

To a mixture of (+/-)-tert-butyl-5-{[(6-bromo-2-chloro-3-methylquinolin-4-yl)carbonyl]amino}-4-[2-fluoro-6(trifluoromethyl) phenyl]pentanoate (300 mg, 98% pure, 476 µmol, example 50A) in NMP (4.0 ml) in a thick-walled glass vial (microwave) was added 3,3-difluoropiperidine hydrochloride (387 mg, 97% pure, 2.38 mmol) and DIPEA (410 µl, 2.4 mmol). The vessel was rinsed with argon, closed and shaken overnight with a thermal shaker at 100°C. Then an additional 24 h at 130°C was shaken. After cooling to RT, the mixture was directly (without further workup) purified by preparative HPLC (method 14). The combined target fractions were concentrated and the residue was adsorbed in dichloromethane, concentrated again and dried in vacuo. 248 mg (100% pure, 74% thor.) of the title compound were obtained.

LC-MS (method 1): R _t = 2.72 min; MS (ESIpos): m/z = 702/704 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: -0.149 (0.05), -0.008 (0.42), 0.008 (0.38), 0.146 (0.05), 1.180 (0.06), 1.290 (0.07), 1.307 (0.14), 1.340 (16.00), 1.497 (0.06), 1.889 (0.41), 2.049 (0.30), 2.078 (0.59), 2.100 (0.65), 2.117 (0.70) (0.07) (0.43) (0.15), 8.815 (0.20), 8.831 (0.42), 8.846 (0.20).

Separation of enantiomers.

The title target compound (179 mg) was separated into its enantiomers by preparative SLC on chiral phase (see examples 174A and 175A) [column: Daicel Chiralpak AD-H, 5 μm, 250 mm x 30 mm; flow: 120 ml/min; UV detection: 260 nm, temperature: 25°C; eluent: 10% isopropanol/90% carbon dioxide; outlet pressure 150 bar, isocratic]. The combined target fractions were respectively concentrated and the corresponding residue was dried in vacuo.

Example 174A.

tert-Butyl-5-({[6-bromo-2-(3,3-difluoropiperidin-1-yl)-3-methylquinolin-4-yl]carbonyl}amino)-4-[2fluoro-6-(trifluoromethyl) phenyl]pentanoate (enantiomer 1).

The separation of enantiomers described in Example 173A gave 91 mg (100% pure, >99% ee) of the title compound as the previously eluted enantiomer.

R _t = 18.1 min (chiral analytical HPLC; Saule Chiralpak IC, 5 µm, 250 mm x 4.6 mm, eluent heptane/isopropanol/diethylamine 90:10:0.1; flow 1 ml/min; temperature 25°C; detection 225 nm) .

LC-MS (method 2): R _t = 1.43 min; MS (ESIpos): m/z = 702/704 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (0.91), 0.008 (0.87), 1.030 (1.67), 1.045 (1.69), 1.237 (0.39), 1.340 (16.00), 1.888 (0.40 ), 2.100 (0.64), 2.117 (0.68), 2.141 (0.43), 2.189 (1.08), 2.328 (0.16), 2.670 (0.17), 3.187 (0.45), 3.462 (0.32), 3.491 (0.62), 3.520 (0.31 ), 4.323 (0.21), 4.334 (0.21), 7.565 (0.44), 7.575

- 94 040220 (0.42), 7.598 (0.64), 7.625 (0.42), 7.684 (0.20), 7.706 (1.29), 7.710 (1.00), 7.715 (0.82), 7.737 (0.15), 8.830 (0.40).

Example 175A.

tert-Butyl-5-({[6-bromo-2-(3,3-difluoropiperidin-1-yl)-3-methylquinolin-4-yl]carbonyl}amino)-4-[2fluoro-6-(trifluoromethyl) phenyl]pentanoate (enantiomer 2).

The separation of enantiomers described in Example 173A gave 93 mg (100% pure, >99% ee) of the title compound as the later eluted enantiomer.

R _t = 21.4 min (chiral analytical HPLC; Saule Chiralpak IC, 5 µm, 250 mm x 4.6 mm, eluent heptane/isopropanol/diethylamine 90:10:0.1; flow 1 ml/min; temperature 25°C; detection 225 nm) .

LC-MS (method 2): R _t = 1.43 min; MS (ESIpos): m/z = 702/704 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 0.007 (0.93), 1.029 (1.51), 1.044 (1.53), 1.236 (0.47), 1.340 (16.00), 1.889 (0.45), 2.100 (0.71 ), 2.115 (0.76), 2.140 (0.47), 2.188 (1.18), 2.327 (0.16), 2.669 (0.17), 3.183 (0.50), 3.462 (0.34), 3.490 (0.67), 3.519 (0.33), 4.322 (0.21 ), 4.333 (0.20), 7.564 (0.46), 7.574 (0.46), 7.597 (0.67), 7.624 (0.45), 7.683 (0.20), 7.705 (1.37), 7.709 (1.07), 7.714 (0.86), 7.737 (0.15 ), 8.830 (0.43).

Example 176A.

tert-Butyl-5-[({6-bromo-2-[3-fluoropiperidin-1-yl]-3-methylquinolin-4-yl}carbonyl)amino]-4-[2fluoro-6-(trifluoromethyl)phenyl] pentanoate (mixture of diastereoisomers)

To a mixture of (+/-)-tert-butyl-5-{[(6-bromo-2-chloro-3-methylquinolin-4-yl)carbonyl]amino}-4-[2-fluoro-6(trifluoromethyl) phenyl]pentanoate (400 mg, 98% pure, 634 µmol, example 50A) in NMP (4.0 ml) in a thick-walled glass vial (microwave) was added (+/-)-3-fluoropiperidine hydrochloride (457 mg, 97% pure , 3.17 mmol) and DIPEA (550 μl, 3.2 mmol). The vessel was rinsed with argon, closed and shaken overnight with a thermal shaker at 130°C. After cooling to RT, the mixture was directly (without further workup) purified by preparative HPLC (method 14). The combined target fractions were concentrated and the residue was adsorbed in dichloromethane, concentrated again and dried in vacuo. 351 mg (100% pure, 81% thor.) of the title compound were obtained.

LC-MS (method 1): R _t = 2.71 min; MS (ESIpos): m/z = 684/686 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (0.42), 0.008 (0.45), 1.307 (0.13), 1.340 (16.00), 1.654 (0.14), 1.813 (0.14), 1.906 (0.24 ), 2.075 (0.45), 2.097 (0.36), 2.116 (0.48), 2.142 (0.31), 2.181 (1.06), 2.328 (0.11), 2.670 (0.12), 3.113 (0.17), 3.179 (0.17), 3.391 (0.18 ), 3.449 (0.16), 3.482 (0.10), 3.705 (0.11), 3.861 (0.11), 4.825 (0.12), 4.945 (0.12), 5.754 (0.82), 7.562 (0.45), 7.573 (0.42), 7.595 (0.65 ), 7.623 (0.43), 7.636 (0.28), 7.657 (0.21), 7.679 (1.15), 7.712 (0.12), 8.824 (0.35).

Example 177A.

tert-Butyl-5-[({6-bromo-2-[3-ethylpiperidin-1-yl]-3-methylquinolin-4-yl}carbonyl)amino]-4-[2fluoro-6-(trifluoromethyl)phenyl] pentanoate (mixture of diastereoisomers)

To a mixture of (+/-)-tert-butyl-5-{[(6-bromo-2-chloro-3-methylquinolin-4-yl)carbonyl]amino}-4-[2-fluoro-6(trifluoromethyl) phenyl]pentanoate (400 mg, 98% pure, 634 µmol, example 50A) in NMP (4.0 ml) in a heavy-walled glass vial (microwave) was added (+/-)-3-ethylpiperidine (378 mg, 95% pure, 3.17 mmol) and DIPEA (550 µl, 3.2 mmol). The vessel was rinsed with argon, closed and shaken overnight with a thermal shaker at 130°C. After cooling to RT, the mixture was directly (without further workup) purified by preparative HPLC (method 14). The combined target fractions were concentrated and the residue was adsorbed in dichloromethane, concentrated again and dried in vacuo. 383 mg (100% pure, 87% thor.) of the title compound were obtained.

- 95 040220

LC-MS (method 1): Rt = 3.01 min; MS (ESIpos): m/z = 684/686 [M+H]+.

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: -0.009 (0.42), 0.007 (0.45), 1.306 (0.13), 1.339 (16.00), 1.653 (0.14), 1.812 (0.14), 1.905 ( 0.24), 2.075 (0.45), 2.096 (0.36), 2.116 (0.48), 2.141 (0.31), 2.180 (1.06), 2.327 (0.11), 2.669 (0.12), 3.112 (0.17), 3.178 (0.17), 3.390 ( 0.18), 3.448 (0.16), 3.482 (0.10), 3.704 (0.11), 3.860 (0.11), 4.825 (0.12), 4.944 (0.12), 5.753 (0.82), 7.562 (0.45), 7.572 (0.42), 7.595 ( 0.65), 7.622 (0.43), 7.635 (0.28), 7.656 (0.21), 7.679 (1.15), 7.711 (0.12), 8.823 (0.35).

Example 178A.

(+/-)-tert-Butyl-5-({[6-bromo-3-methyl-2-(piperidin-1-yl)quinolin-4-yl]carbonyl}amino)-4-(2.3, 6trichlorophenyl)pentanoate (racemate)

To a mixture of (+/-)-tert-butyl-5-{[(6-bromo-2-chloro-3-methylquinolin-4-yl)carbonyl]amino}-4-(2,3,6trichlorophenyl)pentanoate ( 300 mg, 472 μmol, example 51 A) in NMP (4.0 ml) in a thick glass vessel (microwave vessel) was added piperidine (230 μl, 2.4 mmol) and DIPEA (410 μl, 2.4 mmol). The vessel was rinsed with argon, closed and shaken overnight with a thermal shaker at 130°C. After cooling to RT, the mixture was directly (without further workup) purified by preparative HPLC (method 14). The combined target fractions were concentrated and the residue was adsorbed in dichloromethane, concentrated again and dried in vacuo. 242 mg (100% pure, 75% thor.) of the title compound were obtained.

LC-MS (method 4): R _t = 1.87 min; Ionization without target mass detection.

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (1.20), 0.008 (1.31), 1.351 (14.79), 1.355 (16.00), 1.610 (0.78), 1.674 (1.51), 2.073 (3.11) ), 2.138 (2.16), 2.156 (0.92), 2.169 (3.50), 2.327 (0.31), 2.670 (0.18), 3.141 (1.94), 3.819 (0.29), 4.033 (0.51), 7.473 (0.58), 7.495 (0.81 ), 7.532 (0.71), 7.554 (1.23), 7.593 (0.84), 7.614 (0.57), 7.631 (0.37), 7.637 (0.35), 7.653 (1.38), 7.659 (1.35), 7.669 (1.22), 7.674 (0.69 ), 7.691 (0.30), 8.806 (0.51).

Separation of enantiomers.

The title target compound (194 mg) was separated into its enantiomers by chiral phase preparative SLC (see Examples 179A and 180A) [column: Daicel Chiralpak IG, 5 μm, 250 mm x 20 mm; flow: 60 ml/min; UV detection: 260 nm, temperature: 25°C; eluent: 35% (isopropanol + 1% diethylamine)/65% carbon dioxide; outlet pressure 150 bar, isocratic]. The combined target fractions were respectively concentrated and the corresponding residue was dried in vacuo. Peak 2 was re-separated by chiral HPLC [column: Daicel Chiralpak IG, 5 μm, 250 mm x 20 mm; flow: 20 ml/min; UV detection: 260 nm, temperature: 25°C; eluent: 20% ethyl acetate/80% heptane, isocratic].

Example 179A.

tert-Butyl 5-({[6-bromo-3-methyl-2-(piperidin-1-yl)quinolin-4-yl]carbonyl}amino)-4-(2,3,6trichlorophenyl)pentanoate (enantiomer 1 ).

The separation of enantiomers described in Example 178A gave 92 mg (100% pure, ee 98%) of the title compound as the previously eluted enantiomer.

R _t = 8.3 min (chiral analytical HPLC; Saule Chiralpak IG, 5 µm, 250 mm x 4.6 mm, eluent heptane/isopropanol/diethylamine 70:30:0.1; flow 1 ml/min; temperature 25°C; detection 225 nm) .

LC-MS (method 2): Rt = 1.58 min; MS (ESIpos): m/z = 682/684/686 [M+H]+.

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: -0.008 (0.84), 0.008 (0.66), 1.029 (4.38), 1.045 (4.40), 1.236 (0.62), 1.351 (15.34), 1.355 ( 16.00), 1.609 (0.80), 1.673 (1.53), 2.083 (0.46), 2.098 (0.48), 2.112 (0.60), 2.137 (2.18), 2.156 (0.97), 2.169 (3.55), 2.523 (0.44), 1.98), 4.032 (0.52), 4.323 (0.54), 4.334 (0.53), 7.473 (0.56), 7.495 (0.78), 7.532 (0.67), 7.554 (1.18), 7.593 (0.80), 7.599 (0.70), 0.56), 7.653 (1.35), 7.659 (1.31), 7.662 (1.07), 7.669 (1.19), 7.674 (0.67), 8.792 (0.44), 8.806 (0.51).

Example 180A.

tert-Butyl 5-({[6-bromo-3-methyl-2-(piperidin-1-yl)quinolin-4-yl]carbonyl}amino)-4-(2,3,6trichlorophenyl)pentanoate (enantiomer 2 ).

The separation of enantiomers described in Example 178A gave 96 mg (100% pure, >99% ee) of the title compound as the later eluted enantiomer.

R _t = 11.0 min (chiral analytical HPLC; Saule Chiralpak IG, 5 µm, 250 mm x 4.6 mm, eluent heptane/isopropanol/diethylamine 70:30:0.1; flow 1 ml/min; temperature 25°C; detection 225 nm) .

LC-MS (method 2): R _t = 1.58 min; MS (ESIpos): m/z = 682/684/686 [M+H]+.

- 96 040220

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (0.62), 0.008 (0.63), 0.854 (0.49), 0.858 (0.46), 1.237 (2.83), 1.249 (1.11), 1.258 (0.60 ), 1.336 (0.75), 1.351 (15.06), 1.355 (16.00), 1.610 (0.78), 1.673 (1.51), 2.083 (0.45), 2.098 (0.47), 2.111 (0.58), 2.137 (2.17), 2.156 (0.95 ), 2.169 (3.50), 3.141 (1.96), 4.032 (0.52), 7.473 (0.54), 7.495 (0.77), 7.532 (0.67), 7.554 (1.15), 7.593 (0.79), 7.599 (0.69), 7.615 (0.55 ), 7.653 (1.32), 7.658 (1.27), 7.662 (1.06), 7.668 (1.15), 7.674 (0.65), 8.791 (0.43), 8.806 (0.50).

Example 181A.

(+/-)-tert-Butyl-5-({[6-bromo-3-methyl-2-(pyrrolidin-1-yl)quinolin-4-yl]carbonyl}amino)-4-(2.3, 6trichlorophenyl)pentanoate (racemate)

To a mixture of (+/-)-tert-butyl-5-{[(6-bromo-2-chloro-3-methylquinolin-4-yl)carbonyl]amino}-4-(2,3,6trichlorophenyl)pentanoate ( 300 mg, 472 μmol, example 51A) in NMP (4.0 ml) in a thick-walled glass vessel (microwave vessel) was added pyrrolidine (200 μl, 2.4 mmol) and DIPEA (410 μl, 2.4 mmol). The vessel was rinsed with argon, closed and shaken overnight with a thermal shaker at 130°C. After cooling to RT, the mixture was directly (without further workup) purified by preparative HPLC (method 14). The combined target fractions were concentrated and the residue was adsorbed in dichloromethane, concentrated again and dried in vacuo.

261 mg (100% pure, 82% thor.) of the title compound were obtained.

LC-MS (method 1): R _t = 2.45 min; MS (ESIpos): m/z = 668/670/672 [M+H]+.

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: -0.149 (0.69), -0.008 (5.80), 0.008 (5.56), 0.146 (0.67), 1.349 (16.00), 1.353 (15.98), 1.875 (2.13), 2.073 (0.92), 2.095 (0.52), 2.121 (0.82), 2.134 (1.09), 2.158 (1.22), 2.174 (0.95) (1.49), 4.035 (0.47), 7.473 (1.07), 7.480 (0.77), 7.495 (1.59), 7.502 (1.19), 7.522 (0.70) (0.60), 7.576 (0.52), 7.587 (0.94), 7.608 (0.50), 8.754 (0.54).

Separation of enantiomers.

The title target compound (199 mg) was separated into its enantiomers by preparative SLC on chiral phase (see examples 182A and 183A) [column: Daicel Chiralpak IG, 5 μm, 250 mm x 20 mm; flow: 60 ml/min; UV detection: 230 nm, temperature: 25°C; eluent: 40% (isopropanol + 1% diethylamine)/60% carbon dioxide; outlet pressure 150 bar, isocratic]. The combined target fractions were respectively concentrated and the corresponding residue was dried in vacuo.

Example 182A.

tert-Butyl 5-({[6-bromo-3-methyl-2-(pyrrolidin-1-yl)quinolin-4-yl]carbonyl}amino)-4-(2,3,6trichlorophenyl)pentanoate (enantiomer 1 ).

The separation of enantiomers described in Example 181A gave 92 mg (100% pure, >99% ee) of the title compound as the previously eluted enantiomer.

R _t = 12.0 min (chiral analytical HPLC; Saule Chiralpak IG, 5 µm, 250 mm x 4.6 mm, eluent heptane/isopropanol/diethylamine 70:30:0.1; flow 1 ml/min; temperature 25°C; detection 225 nm) .

LC-MS (method 2): Rt = 1.21 min; MS (ESIpos): m/z = 668/670/672 [M+H]+.

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: -0.008 (0.88), 0.008 (0.72), 1.030 (1.55), 1.045 (1.56), 1.236 (1.18), 1.349 (15.95), 1.353 ( 16.00), 1.875 (2.18), 2.080 (0.50), 2.095 (0.55), 2.108 (0.59), 2.121 (0.86), 2.135 (1.11), 2.158 (1.23), 2.174 (0.99), 2.193 (2.17), 0.41), 3.574 (1.54), 4.037 (0.49), 7.473 (1.01), 7.480 (0.76), 7.495 (1.53), 7.502 (1.18), 7.522 (0.66), 7.544 (1.14), 7.554 (0.74), 0.96), 7.566 (0.59), 7.576 (0.51), 7.588 (0.95), 7.609 (0.51), 8.755 (0.50).

Example 183A.

tert-Butyl 5-({[6-bromo-3-methyl-2-(pyrrolidin-1-yl)quinolin-4-yl]carbonyl}amino)-4-(2,3,6trichlorophenyl)pentanoate (enantiomer 2 ).

The separation of enantiomers described in Example 181A gave 98 mg (100% pure, ee 99%) of the title compound as the later eluted enantiomer.

R _t = 16.7 min (chiral analytical HPLC; Saule Chiralpak IG, 5 µm, 250 mm x 4.6 mm, eluent heptane/isopropanol/diethylamine 70:30:0.1; flow 1 ml/min; temperature 25°C; detection 225 nm) .

LC-MS (method 2): R _t = 1.21 min; MS (ESIpos): m/z = 668/670/672 [M+H]+.

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (0.95), 0.008 (0.59), 0.854 (0.51), 1.030 (1.60), 1.045 (1.59), 1.092 (0.52), 1.236 (2.83 ), 1.259 (0.57), 1.331 (0.85), 1.349 (16.00), 1.353 (15.73), 1.875 (2.07), 1.961 (0.65), 2.081 (0.48), 2.095 (0.54), 2.108 (0.58), 2.120 (0.84 ), 2.134 (1.06), 2.158 (1.19), 2.174 (0.97), 2.193

- 97 040220 (2.12), 2.327 (0.40), 3.574 (1.44), 4.037 (0.47), 7.473 (1.00), 7.480 (0.76), 7.495 (1.52), 7.502 (1.18), 7.522 (0.67), 7.544 (1.15) ), 7.554 (0.74), 7.560 (0.97), 7.567 (0.59), 7.576 (0.49), 7.588 (0.93), 7.609 (0.51), 8.756 (0.50).

Example 184A.

(+/-)-tert-Butyl-5 -({[6-bromo-2-(3,3-difluoropiperidin-1 -yl)-3-methylquinolin-4yl]carbonyl}amino)-4-(2,3 ,6-trichlorophenyl)pentanoate (racemate)

To a mixture of (+/-)-tert-butyl-5-{[(6-bromo-2-chloro-3-methylquinolin-4-yl)carbonyl]amino}-4-(2,3,6trichlorophenyl)pentanoate ( 300 mg, 472 µmol, example 51 A) in NMP (4.0 ml) in a thick-walled glass vessel (microwave vessel) was added 3,3-difluoropiperidine hydrochloride (372 mg, 2.36 mmol) and DIPEA (410 µl, 2.4 mmol). The vessel was rinsed with argon, closed and shaken overnight with a thermal shaker at 130°C. Then it was shaken for 24 h at 140°C. After cooling to RT, the mixture was directly (without further workup) purified by preparative HPLC (method 14). The combined target fractions were concentrated and the residue was adsorbed in dichloromethane, concentrated again and dried in vacuo. 241 mg (100% pure, 71% thor.) of the title compound were obtained.

LC-MS (method 1): Rt = 2.83 min; MS (ESIpos): m/z = 718/720/722 [M+H]+.

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (2.55), 0.008 (2.50), 1.331 (0.53), 1.351 (14.99), 1.355 (16.00), 1.883 (0.79), 2.100 (0.98) ), 2.115 (0.97), 2.128 (1.23), 2.159 (1.91), 2.189 (3.51), 2.328 (0.53), 3.177 (0.91), 3.453 (0.61), 3.483 (1.16), 3.511 (0.61), 4.035 (0.51 ), 7.476 (0.52), 7.498 (0.75), 7.534 (0.65), 7.556 (1.20), 7.595 (0.89), 7.617 (0.61), 7.704 (1.44), 7.711 (1.65), 7.718 (1.30), 7.724 (0.76 ), 8.819 (0.53).

Separation of enantiomers.

The title target compound (172 mg) was separated into its enantiomers by preparative SLC on chiral phase (see examples 185A and 186A) [column: Daicel Chiralpak IG, 5 μm, 250 mm x 20 mm; flow: 60 ml/min; UV detection: 260 nm, temperature: 25°C; eluent: 25% isopropanol/75% carbon dioxide; outlet pressure 150 bar, isocratic]. The combined target fractions were respectively concentrated and the corresponding residue was dried in vacuo. Peak 2 was re-separated by chiral HPLC [column: Daicel Chiralpak IG, 5 μm, 250 mm x 20 mm; flow: 20 ml/min; UV detection: 260 nm, temperature: 25°C; eluent: 20% ethyl acetate/80% heptane, isocratic].

Example 185A.

tert-Butyl-5-({[6-bromo-2-(3,3-difluoropiperidin-1-yl)-3-methylquinolin-4-yl]carbonyl}amino)-4(2,3,6-trichlorophenyl) pentanoate (enantiomer 1).

The separation of enantiomers described in Example 184A gave 79 mg (100% pure, ee 97%) of the title compound as the previously eluted enantiomer.

Rt = 7.9 min (chiral analytical HPLC; Saule Chiralpak IG, 5 µm, 250 mm x 4.6 mm, eluent heptane/isopropanol/diethylamine 70:30:0.1; flow 1 ml/min; temperature 25°C; detection 225 nm).

LC-MS (method 2): Rt = 1.49 min; MS (ESIpos): m/z = 718/720/722 [M+H]+.

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (1.18), 0.008 (1.05), 1.029 (2.87), 1.045 (2.90), 1.236 (1.65), 1.330 (0.53), 1.351 (15.41 ), 1.355 (16.00), 1.884 (0.77), 2.085 (0.83), 2.100 (0.95), 2.115 (0.96), 2.128 (1.21), 2.159 (1.89), 2.173 (0.76), 2.189 (3.45), 3.176 (0.89 ), 3.453 (0.59), 3.482 (1.14), 3.511 (0.60), 4.036 (0.49), 7.476 (0.50), 7.498 (0.72), 7.534 (0.62), 7.556 (1.17), 7.595 (0.80), 7.617 (0.56 ), 7.704 (1.34), 7.711 (1.51), 7.718 (1.22), 7.724 (0.71), 8.805 (0.43), 8.819 (0.52).

Example 186A.

tert-Butyl-5-({[6-bromo-2-(3,3-difluoropiperidin-1-yl)-3-methylquinolin-4-yl]carbonyl}amino)-4(2,3,6-trichlorophenyl) pentanoate (enantiomer 2).

The separation of enantiomers described in Example 184A gave 100 mg (100% pure, >99% ee) of the title compound as the later eluted enantiomer.

Rt = 10.1 min (chiral analytical HPLC; Saule Chiralpak IG, 5 µm, 250 mm x 4.6 mm, eluent heptane/isopropanol/diethylamine 70:30:0.1; flow 1 ml/min; temperature 25°C; detection 225 nm).

LC-MS (method 2): Rt = 1.49 min; MS (ESIpos): m/z = 718/720/722 [M+H]+.

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (1.56), 0.008 (1.36), 0.836 (0.55), 0.854 (1.20), 0.858 (0.83), 0.870 (0.53), 1.237 (6.54 ), 1.249 (2.69), 1.259 (1.82), 1.298 (1.07), 1.335 (1.81), 1.351 (15.42), 1.355 (16.00), 1.883 (0.75), 2.085 (0.81), 2.100 (0.95), 2.115 (0.92 ), 2.128 (1.16), 2.159 (1.85), 2.189 (3.47), 2.322

- 98 040220 (0.42), 2.327 (0.45), 3.176 (0.87), 3.453 (0.60), 3.482 (1.12), 3.511 (0.57), 4.036 (0.49), 7.476 (0.51), 7.498 (0.72), 7.534 (0.62 ), 7.556 (1.16), 7.595 (0.80), 7.617 (0.57), 7.704 (1.36), 7.711 (1.52), 7.718 (1.22), 7.724 (0.72), 8.806 (0.41), 8.819 (0.51).

Example 187A.

tert-Butyl 5-[({6-bromo-2-[3-fluoropiperidin-1-yl]-3-methylquinolin-4-yl}carbonyl)amino]-4-(2,3,6trichlorophenyl)pentanoate (mixture diastereoisomers)

To a mixture of (+/-)-tert-butyl-5-{[(6-bromo-2-chloro-3-methylquinolin-4-yl)carbonyl]amino}-4-(2,3,6trichlorophenyl)pentanoate ( 400 mg, 630 µmol, example 51A) in NMP (4.0 ml) in a thick-walled glass vessel (microwave vessel) was added (+/-)-3-fluoropiperidine hydrochloride (440 mg, 3.15 mmol) and DIPEA (550 µl, 3.1 mmol ). The vessel was rinsed with argon, closed and shaken overnight with a thermal shaker at 130°C. After cooling to RT, the mixture was directly (without further workup) purified by preparative HPLC (method 14). The combined target fractions were concentrated and the residue was adsorbed in dichloromethane, concentrated again and dried in vacuo. 355 mg (100% pure, 80% theoretical) of the title compound were obtained.

LC-MS (method 4): R _t = 1.80 min; Ionization without target mass detection.

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 1.330 (0.83), 1.351 (14.93), 1.354 (16.00), 1.899 (0.53), 2.085 (0.47), 2.099 (0.52), 2.126 (0.99 ), 2.139 (1.04), 2.155 (2.15), 2.182 (3.06), 2.327 (0.43), 4.036 (0.55), 5.754 (0.98), 7.475 (0.50), 7.496 (0.70), 7.533 (0.63), 7.554 (1.12 ), 7.593 (0.76), 7.615 (0.53), 7.677 (1.36), 7.683 (1.42), 7.692 (1.25), 8.800 (0.49), 8.814 (0.55).

Example 188A.

tert-Butyl 5-[({6-bromo-2-[3-ethylpiperidin-1-yl]-3-methylquinolin-4-yl}carbonyl)amino]-4-(2,3,6trichlorophenyl)pentanoate (mixture diastereoisomers)

To a mixture of (+/-)-tert-butyl-5-{[(6-bromo-2-chloro-3-methylquinolin-4-yl)carbonyl]amino}-4-(2,3,6trichlorophenyl)pentanoate ( (+/-)-3-ethylpiperidine (356 mg, 3.15 mmol) and DIPEA (550 µl, 3.1 mmol). The vessel was rinsed with argon, closed and shaken overnight with a thermal shaker at 130°C. After cooling to RT, the mixture was directly (without further workup) purified by preparative HPLC (method 14). The combined target fractions were concentrated and the residue was adsorbed in dichloromethane, concentrated again and dried in vacuo. 383 mg (100% pure, 85% thor.) of the title compound were obtained.

LC-MS (method 4): R _t = 1.80 min; Ionization without target mass detection.

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (1.66), 0.008 (1.50), 0.893 (1.23), 0.912 (2.91), 0.930 (1.51), 1.263 (0.60), 1.281 (0.76 ), 1.303 (0.62), 1.352 (15.56), 1.356 (16.00), 2.086 (0.46), 2.099 (0.52), 2.133 (1.62), 2.158 (2.77), 2.163 (1.99), 3.494 (0.64), 3.525 (0.59 ), 4.025 (0.41), 4.037 (0.41), 5.754 (1.33), 7.473 (0.59), 7.495 (0.85), 7.527 (0.71), 7.549 (1.21), 7.588 (0.74), 7.596 (0.78), 7.610 (0.51 ), 7.617 (0.44), 7.656 (1.49), 7.660 (2.02), 7.665 (1.35), 8.790 (0.44).

Example 189A.

(+/-)-tert-Butyl-5-({[6-bromo-3-methyl-2-(piperidin-1-yl)quinolin-4-yl]carbonyl}amino)-4-[2(difluoromethoxy) -6-fluorophenyl]pentanoate (racemate)

- 99 040220

To a mixture of (+/-)-tert-butyl-5-{[(6-bromo-2-chloro-3-methylquinolin-4-yl)carbonyl]amino}-4-[2(difluoromethoxy)-6-fluorophenyl ]pentanoate (1.00 g, 1.62 mmol, example 52A) in NMP (5.8 ml) was added piperidine (1.3 ml, 13 mmol) and DIPEA (2.3 ml, 13 mmol), and the mixture was stirred for 5 h at 110°C. After cooling to RT, the mixture was mixed with dichloromethane (150 ml) and washed once with water (150 ml) and once with a mixture of 1 M hydrochloric acid (40 ml) in water (100 ml). The organic phase was dried, filtered and concentrated, and the residue was adsorbed in dichloromethane and purified by flash column chromatography (50 g Biotage Snap-Cartridge Ultra silica gel, 97:3^7:3 cyclohexane/ethyl acetate gradient, Isolera One). The combined desired fractions were concentrated and the residue was dried in vacuo. 933 mg (96% pure, 83% thor.) of the title compound were obtained.

LC-MS (method 1): Rt = 2.73 min; MS (ESIpos): m/z = 664/666 [M+H]+.

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 0.833 (0.05), 0.850 (0.06), 1.196 (0.08), 1.234 (0.17), 1.289 (0.08), 1.307 (0.33), 1.311 (0.43 ), 1.356 (16.00), 1.369 (0.64), 1.397 (5.74), 1.512 (0.08), 1.607 (0.50), 1.672 (0.95), 1.881 (0.06), 1.901 (0.09), 1.920 (0.12), 1.937 (0.14 ), 1.954 (0.18), 2.027 (0.16), 2.042 (0.21), 2.056 (0.20), 2.079 (1.01), 2.093 (0.71), 2.114 (0.39), 2.133 (1.36), 2.175 (0.13), 2.195 (0.07 ), 2.240 (0.10), 2.294 (0.03), 2.327 (0.03), 2.669 (0.03), 2.694 (0.32), 3.137 (1.23), 3.284 (0.10), 3.516 (0.18), 3.661 (0.08), 3.676 (0.13 ), 3.693 (0.24), 3.709 (0.30), 3.727 (0.24), 3.746 (0.21), 3.765 (0.17), 3.799 (0.06), 7.019 (0.42), 7.039 (0.45), 7.060 (0.33), 7.089 (0.29 ), 7.111 (0.42), 7.135 (0.31), 7.244 (0.63), 7.357 (0.17), 7.378 (0.33), 7.395 (0.31), 7.415 (0.15), 7.428 (0.34), 7.485 (0.11), 7.627 (0.32 ), 7.650 (1.43), 7.659 (0.90), 7.664 (0.80), 7.682 (0.20), 7.686 (0.21), 8.772 (0.23), 8.787 (0.45), 8.801 (0.22).

Separation of enantiomers.

The title target compound (810 mg) was dissolved in methanol (30 ml) and separated into enantiomers by chiral phase preparative HPLC (see examples 190A and 191A) [column: Daicel Chiralcel OX-H, 5 μm, 250 mm x 30 mm; flow: 90 ml/min; sample injection: 0.3 ml; UV detection: 210 nm, temperature: 40°C; eluent: 15% methanol/85% carbon dioxide; duration of action 6 min, isocratic]. The combined target fractions were respectively concentrated and the corresponding residue was lyophilized.

Example 190A.

(-)-tert-Butyl-5-({[6-bromo-3-methyl-2-(piperidin-1-yl)quinolin-4-yl]carbonyl}amino)-4-[2(difluoromethoxy)-6 -fluorophenyl]pentanoate (enantiomer 1).

The separation of enantiomers described in Example 189A gave 810 mg (96% pure, >99% ee) of the title compound as the previously eluted enantiomer.

[a] _D20 = -23.0°, 589 nm, c = 0.36 g ^/ 100 ml, methanol;

LC-MS (method 2): Rt = 1.47 min; MS (ESIpos): m/z = 664/666 [M+H]+.

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.889 (5.96), 0.908 (13.53), 0.926 (6.80), 1.034 (0.52), 1.062 (1.29), 1.085 (1.31), 1.114 (0.57) 1.240 (1.11), 1.256 (2.40), 1.274 (3.14), 1.283 (2.64), 1.291 (2.25), 1.301 (1.76), 1.558 (1.43), 1.604 (1.33), 1.635 (1.24), 1.665 (0.54) . . . . , 8.726 (1.55), 12.043 (3.31).

Example 191A.

(+)-tert-Butyl-5-({[6-bromo-3-methyl-2-(piperidin-1-yl)quinolin-4-yl]carbonyl}amino)-4-[2(difluoromethoxy)-6 -fluorophenyl]pentanoate (enantiomer 2).

The separation of enantiomers described in Example 189A gave 159 mg (100% pure, ee 94%) of the title compound as the later eluted enantiomer.

[a] _D20 = +24.9°, 589 nm, c = 0.38 g/100 mL ^, methanol;

LC-MS (method 2): Rt = 1.47 min; MS (ESIneg): m/z = 664/666 [M+H] ^- .

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 1.197 (0.07), 1.290 (0.06), 1.311 (0.12), 1.356 (16.00), 1.513 (0.08), 1.608 (0.51), 1.672 (0.99 ), 1.955 (0.20), 2.043 (0.23), 2.056 (0.21), 2.079 (1.09), 2.093 (0.76), 2.134 (1.45), 3.138 (1.29), 3.518 (0.20), 3.676 (0.14), 3.694 (0.25 ), 3.709 (0.31), 3.727 (0.26), 3.747 (0.24), 3.765 (0.19), 7.019 (0.44), 7.040 (0.49), 7.061 (0.33), 7.089 (0.29), 7.112 (0.45), 7.136 (0.33 ), 7.245 (0.65), 7.358 (0.17), 7.378 (0.34), 7.395 (0.32), 7.416 (0.16), 7.429 (0.36), 7.489 (0.12), 7.628 (0.33), 7.650 (1.42), 7.659

- 100 040220 (0.88), 7.664 (0.86), 7.682 (0.19), 7.686 (0.22), 8.772 (0.24), 8.787 (0.47), 8.802 (0.24).

Example 192A.

(-)-tert-Butyl-5-[({6-bromo-2-[3-fluoropiperidin-1 -yl] -3-methylquinolin-4-yl}carbonyl)amino]-4-(2chlorophenyl)pentanoate (diastereoisomer 1) [for the structural formula, see example 116A (mixture of diastereoisomers)].

Separation of diastereoisomers/enantiomers from Example 116A:

tert-butyl-5-[({6-bromo-2-[3-fluoropiperidin-1-yl]-3-methylquinolin-4-yl}carbonyl)amino]-4-(2chlorophenyl)pentanoate (mixture of diastereoisomers, 2.53 g , example 116A) adsorbed in ethanol (60 ml), filtered, and first pre-separated by preparative SLC on a chiral phase [column: Daicel Chiralpak OX-H, 5 µm, 250 mm x 30 mm; flow: 125 ml/min; sample injection: 0.6 ml; temperature 38°C, UV detection 210 nm, eluent: 80% carbon dioxide/20% ethanol; duration of action 19 min, isocratic]. A mixed fraction (peak 1) and two fairly pure fractions (peak 2 and peak 3, see examples 194A and 195A) were obtained. The mixed fraction (peak 1) was purified by preparative SLC [column: Daicel Chiralpak IC, 5 μm, 250 mm x 20 mm; flow: 80 ml/min; sample injection: 0.35 ml; temperature 40°C, UV detection 210 nm, eluent: 76% carbon dioxide/24% ethanol; duration of action 10.5 min, isocratic] (see examples 192A and 193A). The combined target fractions were suitably concentrated and the residue was suitably lyophilized.

(-)-tert-Butyl-5-[({6-bromo-2-[3-fluoropiperidin-1 -yl] -3-methylquinolin-4-yl}carbonyl)amino]-4-(2chlorophenyl)pentanoate (diastereoisomer 1).

Separation of the diastereoisomers of the mixed fraction (peak 1, s.o.) as described gave 485 mg (100% pure, >99% ee) of the title compound as the first eluting diastereoisomer (peak 1-1).

[a] _D20 = -6.3°, 589 nm, c = 0.40 ^g /100 ml, methanol;

LC-MS (method 1): Rt = 2.66 min; MS (ESIpos): m/z = 632/634 [M+H]+.

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.370 (16.00), 1.639 (0.22), 1.795 (0.34), 1.815 (0.41), 1.837 (0.27), 1.898 (0.35), 1.917 (0.31) , 1.948 (0.22), 2.027 (0.17), 2.047 (0.24), 2.055 (0.24), 2.075 (1.54), 2.087 (0.82), 2.104 (0.33), 2.110 (0.30), 2.145 (1.93), 3.092 (0.24) . , 7.252 (0.21) , 7.648 (0.27), 7.670 (1.50), 7.677 (1.05), 7.681 (0.86), 7.699 (0.17), 7.704 (0.18), 8.712 (0.27), 8.727 (0.54), 8.741 (0.26).

Example 193A.

(-)-tert-Butyl-5-[({6-bromo-2-[3-fluoropiperidin-1 -yl] -3-methylquinolin-4-yl}carbonyl)amino]-4-(2chlorophenyl)pentanoate (diastereoisomer 2).

Separation of mixed fraction diastereoisomers (peak 1, s.o.) as described in Example 192A gave 437 mg (100% pure, >99% ee) of the title compound as the second eluted diastereoisomer (peak 1-2).

[a] _D20 = -11.5°, 589 nm, c = 0.44 g ^/ 100 ml, methanol;

LC-MS (method 1): Rt = 2.66 min; MS (ESIpos): m/z = 632/634 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.369 (16.00), 1.644 (0.19), (0.23), 1.900 (0.32), 1.921 (0.26), 1.947 (0.16), 2.046 (0.20), 2.055 (0.21), (0.30), 2.110 (0.28), 2.144 (1.53), 3.102 (0.22), 3.148 (0.23), 3.164 (0.22) (0.21), 3.434 (0.19), 3.586 (0.23), 0.39), 7.254 (0.19), 7.273 (0.44), (0.49), 7.391 (0.25), 7.439 (0.64), 7.441 (0.64), 7.459 (0.54), 7.484 (0.60),

1.802 (0.30), 1.814 (0.35), 1.837

2.075

3.295

7.292

7.503 (1.37), 2.087 (0.76), 2.104 (0.18), 3.324 (0.30), 3.377 (0.31), 7.354 (0.27), 7.373 (0.51), 7.648 (0.25), 7.670 (1.41), 7.676 (0.97), 7.681 (0.83), 7.703 (0.17), 8.712 (0.24), 8.726 (0.46), 8.740 (0.23).

Example 194A.

(+)-tert-Butyl-5-[({6-bromo-2-[3-fluoropiperidin-1-yl]-3-methylquinolin-4-yl}carbonyl)amino]-4-(2chlorophenyl)pentanoate (diastereoisomer 3).

Separation of diastereoisomers as described in Example 192A gave 593 mg (100% pure) of the title compound as the third eluting diastereoisomer (peak 3).

[a] _D20 = +7.2°, 436 nm, c = 0.36 ^g /100 ml, methanol;

LC-MS (method 1): Rt = 2.69 min; MS (ESIpos): m/z = 632/634 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (0.40), 0.008 (0.38), 1.369 (16.00), 1.640 (0.16), 1.795 (0.24), 1.813 (0.29), 1.836 (0.19 ), 1.897 (0.25), 1.918 (0.22), 2.047 (0.17), (0.61), 2.103 (0.24), 2.109 (0.23), 2.144 (1.45), 2.523 (0.16), 3.092 (0.17), (0.18), 3.438 (0.16), 3.589 (0.19), 3.677 (0.36), 7.254 (0.17), 7.272 (0.38), (0.24), 7.372 (0.43), 7.391 (0.22), 7.439 (0.59), 7.441 (0.58), 7.458 (0.50), (0.52), 7.500 (0.43), 7.503 (0.42), 7.648 (0.26), 7.670 (1.32), 7.677 (0.92), (0.21), 8.726 (0.42), 8.741 (0.20).

2.053

3.161

7.289

7.462

7.682 (0.17), 2.074 (1.13), (0.19), 3.178 (0.18), (0.27), 7.292 (0.27), (0.48), 7.480 (0.51), (0.81), 7.704 (0.18),

2.086

3.380

7.354

7.484

8.712

- 101 040220

Example 195A.

(+)-tert-Butyl-5-[({6-bromo-2-[3-fluoropiperidin-1-yl]-3-methylquinolin-4-yl}carbonyl)amino]-4-(2chlorophenyl)pentanoate (diastereoisomer 4).

Separation of diastereoisomers as described in Example 192A gave 621 mg (100% pure) of the title compound as the fourth eluting diastereoisomer (peak 4).

[a]D ²⁰ = +20.8°, 589 nm, c = 0.49 g/100 mL, DMSO;

LC-MS (method 1): Rt = 2.69 min; MS (ESIpos): m/z = 632/634 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.038 (0.20), 1.056 (0.41), 1.073 (0.21), 1.369 (16.00), 1.644 (0.19), 1.795 (0.28), 1.814 (0.34) , 1.837 (0.22), 1.900 (0.32), 1.921 (0.26), 1.948 (0.16), 2.045 (0.19), 2.054 (0.21), 2.075 (1.31), 2.087 (0.75), 2.103 (0.29) . . , 7.501 (0.50), 7.648 (0.26), 7.670 (1.41), 7.676 (0.95), 7.681 (0.82), 7.699 (0.16), 7.703 (0.17), 8.711 (0.24), 8.726 (0.47), 8.740 (0.23) .

Example 196A.

(+)-tert-Butyl-5-[({6-bromo-2-[3-fluoropiperidin-1-yl]-3-methylquinolin-4-yl}carbonyl)amino]-4-[2(trifluoromethyl)phenyl ]pentanoate (diastereoisomer 1) [for structural formula, see example 138A (mixture of diastereoisomers)].

Separation of diastereoisomers/enantiomers from example 13 8A:

tert-butyl 5-[({6-bromo-2-[3-fluoropiperidin-1-yl]-3-methylquinolin-4-yl}carbonyl)amino]-4-[2(trifluoromethyl)phenyl]pentanoate (mixture diastereoisomers, 364 mg, example 138A) was dissolved in a mixture of methanol and acetonitrile (5 ml) and purified by preparative SLC on a chiral phase [column: Daicel Chiralpak OX-H, 5 μm, 250 mm x 20 mm; flow: 80 ml/min; sample injection: 0.35 ml; temperature 40°C, UV detection 210 nm, eluent: 86% carbon dioxide/14% ethanol; duration of action 15 min, isocratic]. A mixed fraction (peak 1) and two reasonably pure fractions (peak 2 and peak 3, see examples 196A and 197A) were obtained. The combined target fractions were suitably concentrated and the residue was suitably lyophilized. The mixed fraction (peak 1) was used directly in the reaction described in Example 191.

(+)-tert-Butyl-5-[({6-bromo-2-[3-fluoropiperidin-1-yl]-3-methylquinolin-4-yl}carbonyl)amino]-4-[2(trifluoromethyl)phenyl ]pentanoate (diastereoisomer 1).

The separation of the diastereoisomers as described gave 72 mg (100% pure, >99% ee) of the title compound as peak 2.

[a] _D20 = +10.9°, 589 nm ^, c = 0.34 g/100 mL, methanol;

LC-MS (method 2): Rt = 1.45 min; MS (ESIpos): m/z = 666/668 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.323 (0.17), 1.347 (16.00), 1.650 (0.21), 1.813 (0.20), 1.875 (0.22), 1.907 (0.50), 1.921 (0.44) , 1.953 (0.29), 1.973 (0.18), 1.992 (0.39), 2.005 (0.26), 2.015 (0.49), 2.027 (0.37), 2.035 (0.42), 2.057 (0.32), 2.095 (0.29), 2.108 (0.18) . . , 7.661 (0.24), 7.683 (1.73), 7.707 (0.62), 7.722 (1.07), 7.738 (0.99), 7.753 (0.27), 8.768 (0.26), 8.783 (0.53), 8.797 (0.25).

Example 197A.

(+)-tert-Butyl-5-[({6-bromo-2-[3-fluoropiperidin-1-yl]-3-methylquinolin-4-yl}carbonyl)amino]-4-[2(trifluoromethyl)phenyl ]pentanoate (diastereoisomer 2).

Separation of diastereoisomers as described in Example 196A gave 72 mg (100% pure, >99% ee) of the title compound as peak 3.

[a] _D20 = +16.2°, 589 nm, c = 0.37 g/100 mL ^, methanol;

LC-MS (method 2): Rt = 1.45 min; MS (ESIpos): m/z = 666/668 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.324 (0.18), 1.347 (16.00), 1.652 (0.22), 1.812 (0.20), 1.830 (0.18), 1.907 (0.53), 1.920 (0.46) , 1.944 (0.28), 1.953 (0.30), 1.974 (0.19), 1.992 (0.41), 2.016 (0.56), 2.027 (0.39), 2.034 (0.45), 2.056 (0.33), 2.095 (0.29), 2.108 (0.20) . . , 7.660 (0.21), 7.682 (1.69), 7.708 (0.67), 7.722 (0.98), 7.738 (1.19), 7.754 (0.28), 8.766 (0.26), 8.780 (0.52), 8.795 (0.26).

Example 198A.

(+)-tert-Butyl-5-[({6-bromo-2-[3-ethylpiperidin-1-yl]-3-methylquinolin-4-yl}carbonyl)amino]-4-[2(trifluoromethyl)phenyl ]pentanoate (diastereoisomer 1) [for structural formula, see Example 139A (mixture of diastereoisomers)].

Separation of diastereoisomers/enantiomers from Example 139A:

tert-Butyl-5-[({6-bromo-2-[3-ethylpiperidin-1-yl]-3-methylquinolin-4-yl}carbonyl)amino]-4-[2- 102 040220 (trifluoromethyl)phenyl] pentanoate (mixture of diastereoisomers, 548 mg, 677 µmol, example 139A) was dissolved in a mixture of methanol (20 ml) and acetonitrile (20 ml) and separated into diastereoisomers by preparative SLC on a chiral phase [column: Daicel Chiralcel OZ-H, 5 µm , 250 mmx30 mm; flow: 100 ml/min; sample injection: 0.3 ml; temperature 40°C, UV detection 210 nm, eluent: 80% carbon dioxide/20% methanol; duration of action 9.8 min, isocratic]. Four fractions were obtained (peak 1-peak 4, see examples 198A and 201A). The combined target fractions were suitably concentrated and the residue was suitably lyophilized.

(+)-tert-Butyl-5-[({6-bromo-2-[3-ethylpiperidin-1-yl]-3-methylquinolin-4-yl}carbonyl)amino]-4-[2(trifluoromethyl)phenyl ]pentanoate (diastereoisomer 1).

The separation of diastereoisomers described gave 63 mg (100% pure) of the title compound as the primarily eluting diastereoisomer (peak 1).

[a] _D20 = +19.1°, 436 nm, c = 0.32 ^g /100 mL, methanol;

LC-MS (method 1): Rt = 3.02 min; MS (ESIpos): m/z = 676/678 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.895 (0.93), 0.914 (2.23), 0.932 (1.13), 1.070 (0.18), 1.101 (0.20), 1.264 (0.37), 1.281 (0.50) , 1.299 (0.36), 1.321 (0.27), 1.347 (16.00), 1.570 (0.23), 1.608 (0.22), 1.639 (0.18), 1.754 (0.27), 1.786 (0.18), 1.884 (0.36), 1.991 (0.29) . . , 7.714 (0.73), 7.724 (0.54), 7.735 (1.21), 7.755 (0.27), 8.755 (0.24), 8.770 (0.47), 8.785 (0.24).

Example 199A.

(-)-tert-Butyl-5-[({6-bromo-2-[3-ethylpiperidin-1 -yl] -3-methylquinolin-4-yl}carbonyl)amino]-4-[2(trifluoromethyl)phenyl ]pentanoate (diastereoisomer 2).

Separation of diastereoisomers as described in Example 198A gave 57 mg (100% pure) of the title compound as the second eluting diastereoisomer (peak 2).

[a] _D20 = -25.0°, 589 nm, c = 0.34 g ^/ 100 ml, methanol;

LC-MS (method 1): Rt = 3.03 min; MS (ESIpos): m/z = 676/678 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.895 (0.88), 0.914 (2.18), 0.932 (1.09), 1.073 (0.17), 1.102 (0.18), 1.263 (0.32), 1.281 (0.45) , 1.293 (0.39), 1.310 (0.31), 1.346 (16.00), 1.570 (0.20), 1.612 (0.19), 1.643 (0.17), 1.753 (0.24), 1.786 (0.16), 1.853 (0.24), 1.886 (0.33) , 1.917 (0.16), 1.993 (0.27), 2.014 (0.51), 2.029 (0.56), 2.050 (0.27), 2.113 (0.18), 2.133 (0.26), 2.168 (1.42), 2.444 (0.23) , 2.753 (0.22) , 7.660 (2.23), 7.687 (0.27), 7.707 (0.49), 7.720 (0.80), 7.737 (1.06), 7.754 (0.23), 8.754 (0.23), 8.769 (0.47), 8.784 (0.22).

Example 200A.

tert-Butyl 5-[({6-bromo-2-[3-ethylpiperidin-1-yl]-3-methylquinolin-4-yl}carbonyl)amino]-4-[2(trifluoromethyl)phenyl]pentanoate (diastereoisomer 3).

Separation of diastereoisomers as described in Example 198A gave 72 mg (100% pure) of the title compound as the third eluting diastereoisomer (peak 3).

LC-MS (method 1): Rt = 3.02 min; MS (ESIpos): m/z = 676/678 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.895 (0.90), 0.913 (2.13), 0.932 (1.03), 1.071 (0.16), 1.093 (0.17), 1.246 (0.17), 1.263 (0.36) , 1.281 (0.46), 1.287 (0.39), 1.298 (0.36), 1.306 (0.38), 1.312 (0.35), 1.322 (0.43), 1.347 (16.00), 1.570 (0.21), 1.596 (0.19) , 1.753 (0.23) . . , 8.755 (0.22), 8.770 (0.40), 8.785 (0.19).

Example 201A.

(+)-tert-Butyl-5-[({6-bromo-2-[3-ethylpiperidin-1-yl]-3-methylquinolin-4-yl}carbonyl)amino]-4-[2(trifluoromethyl)phenyl ]pentanoate (diastereoisomer 4).

Separation of diastereoisomers as described in Example 198A gave 62 mg (100% pure) of the title compound as the fourth eluting diastereoisomer (peak 4).

[a] _D20 = +27.0°, 589 nm, ^c = 0.33 g/100 ml, methanol;

LC-MS (method 2): Rt = 1.63 min; MS (ESIpos): m/z = 676/678 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.895 (0.96), 0.914 (2.24), 0.932 (1.16), 1.072 (0.21), 1.101 (0.22), 1.246 (0.17), 1.263 (0.37) 1.280 (0.53), 1.292 (0.48), 1.310 (0.38), 1.346 (16.00), 1.569 (0.24), 1.612 (0.23), 1.643 (0.21), 1.753 (0.29), 1.784 (0.20), 1.862 (0.29) , 1.884 (0.41), 1.992 (0.32), 2.013 (0.61), 2.028 (0.66), 2.049 (0.32), 2.098 (0.17), 2.112 (0.22), 2.132 (0.29), 2.167 (1.77), 2.415 (0.18) . , 3.699 (0.21), 7.461 (0.32), 7.480 (0.54), 7.499 (0.33), 7.659 (2.38), 7.686 (0.30), 7.706 (0.57) , 8.754 (0.27), 8.768 (0.55), 8.783 (0.27).

- 103 040220

Example 202A.

(+)-tert-Butyl-5-[({6-bromo-3-methyl-2-[3-methylpiperidin-1-yl]quinolin-4-yl}carbonyl)amino]-4[2-(trifluoromethyl) phenyl]pentanoate (diastereoisomer 1) [see Example 140A for structural formula (mixture of diastereoisomers)].

Separation of diastereoisomers/enantiomers from example 140A: tert-butyl-5-[({6-bromo-3-methyl-2[3-methylpiperidin-1-yl]quinolin-4-yl}carbonyl)amino]-4-[2 -(trifluoromethyl)phenyl]pentanoate (mixture of diastereoisomers, 455 mg, Example 140A) was dissolved in a mixture (6 ml) of methanol and acetonitrile and purified by chiral phase preparative SLC [column: Daicel Chiralpak OX-H, 5 μm, 250 mm x 20 mm; flow: 80 ml/min; sample injection: 0.25 ml; temperature 40°C, UV detection 210 nm, eluent: 89% carbon dioxide/11% ethanol; duration of action 19 min, isocratic]. A mixed fraction (peak 1) and two fairly pure fractions (peak 2 and peak 3, see examples 202A and 203A) were obtained. The combined target fractions were suitably concentrated and the residue was suitably lyophilized. The mixed fraction (peak 1) was used directly in the described example.

199 reactions.

(+)-tert-Butyl-5-[({6-bromo-3-methyl-2-[3-methylpiperidin-1-yl]quinolin-4-yl}carbonyl)amino]-4[2-(trifluoromethyl) phenyl]pentanoate (diastereoisomer 1).

The separation of diastereoisomers as described gave 80 mg (100% pure) of the title compound as peak 2.

[a] _D20 = +17.0°, 589 nm, c = 0.35 g/100 mL ^, methanol;

LC-MS (method 2): Rt = 1.59 min; MS (ESIpos): m/z = 662/664 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.927 (1.56), 0.943 (1.58), 1.085 (0.17), 1.116 (0.17), 1.324 (0.18), 1.347 (16.00), 1.662 (0.17) , 1.737 (0.30), 1.772 (0.30), 1.798 (0.37), 1.828 (0.23), 1.908 (0.16), 1.990 (0.27), 2.013 (0.47), 2.031 (0.39), 2.052 (0.28), 2.097 (0.16) . . , 7.752 (0.24), 8.757 (0.21), 8.772 (0.44), 8.787 (0.21).

Example 203A.

(+)-tert-Butyl-5-[({6-bromo-3-methyl-2-[3-methylpiperidin-1-yl]quinolin-4-yl}carbonyl)amino]-4[2-(trifluoromethyl) phenyl]pentanoate (diastereoisomer 2).

Separation of diastereoisomers as described in Example 202A gave 82 mg (100% pure) of the title compound as peak 3.

[a] _D20 = +7.3°, 589 nm ^, c = 0.36 g/100 mL, methanol;

LC-MS (method 2): Rt = 1.59 min; MS (ESIpos): m/z = 662/664 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.928 (1.80), 0.944 (1.86), 1.087 (0.22), 1.115 (0.23), 1.324 (0.21), 1.347 (16.00), 1.635 (0.20) , 1.665 (0.23), 1.738 (0.39), 1.771 (0.38), 1.798 (0.48), 1.829 (0.30), 1.889 (0.20), 1.898 (0.20), 1.909 (0.18), 2.114 (0.23), 2.133 (0.16) , 3.455 (0.35), 3.482 (0.34), 7.482 (0.56), 7.501 (0.22), 1.920 (0.21), 1.990 (0.28), 2.174 (1.76), 2.440 (0.62), 3.513 (0.29), 3.619 (0.34) , 7.661 (2.34), 7.688 (0.29), 8.759 (0.29), 8.774 (0.57), 8.788 (0.28).

2.052 (0.35), 2.099 (0.17), 2.722 (0.30), 2.751 (0.26), 3.698 (0.21), 7.463 (1.10), 7.737 (1.07), 7.752 (0.33), 2.013 (0.63), 2.030 (0.22), 2.469 (0.35), 2.694 (0.21), 3.634 (0.24), 3.683 (0.31), 7.707 (0.59), 7.722

Example 204A.

(-)-tert-Butyl-5-[({6-bromo-2-[3-fluoropiperidin-1 -yl] -3-methylquinolin-4-yl}carbonyl)amino]-4-[2(trifluoromethoxy)phenyl ]pentanoate (diastereoisomer 1) [for structural formula, see Example 153A (mixture of diastereoisomers)].

Separation of diastereoisomers/enantiomers from Example 153A:

tert-butyl 5-[({6-bromo-2-[3-fluoropiperidin-1-yl]-3-methylquinolin-4-yl}carbonyl)amino]-4-[2(trifluoromethoxy)phenyl]pentanoate (mixture diastereoisomers, 359 mg, 486 µmol, example 153A) were separated into diastereoisomers by preparative HPLC in the chiral phase [method 1: Column: Dai cel Chiralcel OZ-H, 5 µm, 250 mm x 20 mm; flow: 20 ml/min; temperature 25°C, eluent: 90% heptane/10% ethanol; UV detection 255 nm, isocratic; Method 2: Column: Daicel Chiralcel OZ-H, 5 µm, 250 mm x 20 mm; flow: 20 ml/min; temperature 25°C, eluent: 90% heptane/10% isopropanol, UV detection 255 nm, isocratic]. Four fractions were obtained (peak 1-peak 4, see examples 204A and 207A). The combined target fractions were suitably concentrated (conditions: 25° C., 40 mbar).

(-)-tert-Butyl-5-[({6-bromo-2-[3-fluoropiperidin-1 -yl] -3-methylquinolin-4-yl}carbonyl)amino]-4-[2(trifluoromethoxy)phenyl ]pentanoate (diastereoisomer 1).

The separation of the diastereoisomers described gave 85 mg (90% pure, >98% ee) of the title compound as the primarily eluting diastereoisomer (peak 1).

[a] _D20 = -9.4°, 436 nm, c ⁼ 0.38 g/100 ml, methanol;

LC-MS (method 2): Rt = 1.43 min; MS (ESIpos): m/z = 682/684 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.234 (0.80), 1.258 (0.70), 1.301 (0.94), 1.336 (0.21), 1.360 (16.00), 1.381 (0.64), 1.646 (0.25) , 1.808 (0.42), 1.831 (0.39), 1.855 (0.23), 1.903 (0.37), 1.922 (0.32), 1.954

- 104 040220 (0.23), 2.036 (0.29), 2.068 (1.52), 2.089 (0.32), 2.156 (1.22), 2.222 (0.27), 3.106 (0.24), 3.168 (0.25), 3.186 (0.25), 3.333 (0.33) ), 3.352 (0.27), 3.388 (0.45), 3.413 (0.20), 3.445 (0.21), 3.619 (0.28), 3.634 (0.50), 3.650 (0.49), 3.666 (0.27), 4.820 (0.18), 4.940 (0.19 ), 7.363 (0.48), 7.379 (0.23), 7.386 (0.26), 7.399 (0.90), 7.411 (0.64), 7.417 (0.60), 7.422 (0.70), 7.495 (0.17), 7.547 (0.52), 7.559 (0.48 ), 7.570 (0.36), 7.656 (0.27), 7.678 (1.54), 7.685 (1.05), 7.689 (0.93), 7.707 (0.21), 8.736 (0.25), 8.751 (0.50), 8.765 (0.25).

Example 205A.

(-)-tert-Butyl-5-[({6-bromo-2-[3-fluoropiperidin-1 -yl] -3-methylquinolin-4-yl}carbonyl)amino]-4-[2(trifluoromethoxy)phenyl ]pentanoate (diastereoisomer 2).

Separation of diastereoisomers as described in Example 204A gave 85 mg (100% pure, ee 97%) of the title compound as the second eluting diastereoisomer (peak 2).

[a] _D20 = -14.3°, 589 nm, c = ^0.39 g/100 ml, methanol;

LC-MS (method 2): Rt = 1.42 min; MS (ESIpos): m/z = 682/684 [M+H]+.

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.853 (0.18), 1.234 (1.31), 1.249 (0.44), 1.259 (1.44), 1.299 (1.16), 1.326 (0.17), 1.336 (0.40) , 1.360 (16.00), 1.381 (0.22), 1.646 (0.21), 1.808 (0.39), 1.831 (0.36), 1.856

(0.20), 1.903 (0.32), 1.924 (0.27), 1.951 (0.18), 2.036 (0.27), 2.067 (1.41), 2.090 (0.29), 2.156 (1.05), 3.109 (0.21), 3.164 (0.22), 3.179 (0.21), 3.337 (0.29), 3.356 (0.26), 3.387 (0.42), 3.412 (0.16), 3.444 (0.19), 3.618 (0.24), 3.635 (0.44), 3.651 (0.38), 3.671 (0.21), 4.938 (0.16), 7.363 (0.45), 7.388 (0.19), 7.400 (0.79), 7.412 (0.61), 7.418 (0.58), 7.424 (0.68), 7.548 (0.45), 7.560 (0.40), 7.571 (0.33), 7.656 (0.24), 7.678 (1.42), 7.684

(1.00), 7.689 (0.87), 7.707 (0.18), 7.711 (0.19), 8.736 (0.22), 8.751 (0.44), 8.765 (0.23).

Example 206A.

(+)-tert-Butyl-5-[({6-bromo-2-[3-fluoropiperidin-1-yl]-3-methylquinolin-4-yl}carbonyl)amino]-4-[2(trifluoromethoxy)phenyl ]pentanoate (diastereoisomer 3).

The separation of diastereoisomers described in Example 204A gave 79 mg (98% pure, >98% ee) of the title compound as the third eluting diastereoisomer (peak 3).

[a] _D20 = +14.1°, 589 nm, c = 0.37 ^g /100 mL, methanol;

LC-MS (method 2): Rt = 1.43 min; MS (ESIpos): m/z = 682/684 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.360 (16.00), 1.644 (0.23), 1.808 (0.45), 1.830 (0.42), 1.854 (0.24), 1.901 (0.38), 1.922 (0.32) , 1.953 (0.23), 2.036 (0.38), 2.067 (1.64), (0.25), 3.168 (0.28), 3.185 (0.26), 3.332 (0.40), 3.353 (0.30), 3.388 (0.49), (0.33), 3.634 (0.56), 3.649 (0.52), 3.666 (0.26), 4.820 (0.18), 4.939 (0.19), (0.89), 7.410 (0.66), 7.417 (0.62), 7.422 (0.72), 7.495 (0.17), 7.547 ( 0.53),

2.089

3.413

7.363

7.559 (0.34), 2.156 (1.32), 3.100 (0.21), 3.445 (0.23), 3.620 (0.47), 7.386 (0.25), 7.399 (0.45), 7.570 (0.37), 7.656 (0.31), 7.678 (1.54), 7.684 (0.98), 7.688 (0.86), 7.711 (0.16), 8.737 (0.29), 8.751 (0.53), 8.765 (0.25).

Example 207A.

(+)-tert-Butyl-5-[({6-bromo-2-[3-fluoropiperidin-1-yl]-3-methylquinolin-4-yl}carbonyl)amino]-4-[2(trifluoromethoxy)phenyl ]pentanoate (diastereoisomer 4).

Separation of diastereomers as described in Example 204A gave 79 mg (100% pure, >99% ee) of the title compound as the fourth eluting diastereoisomer (peak 4).

[a] _D20 = +55.1°, 436 nm, c = 0.081 ^g /100 ml, methanol;

LC-MS (method 2): Rt = 1.42 min; MS (ESIpos): m/z = 682/684 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.234 (0.20), 1.258 (0.18), 1.360 (16.00), 1.646 (0.22), 1.789 (0.23), 1.808 (0.43), 1.831 (0.41) , 1.855 (0.23), 1.903 (0.36), 1.923 (0.30), 1.953 (0.20), 2.036 (0.30), 2.068 (1.63), 2.090 (0.33), 2.156 (1.21), 3.110 (0.24), 3.169 (0.27) . , 4.938 (0.17), 7.363 (0.46), 7.388 (0.20), 7.400 (0.86), 7.412 (0.65), 7.418 (0.63), 7.423 (0.73), 7.435 (0.16), 7.486 (0.17), 7.548 (0.49) , 7.560 (0.44), 7.571 (0.36), 7.656 (0.26), 7.678 (1.51), 7.684 (1.05), 7.688 (0.92), 7.711 (0.17), 8.737 (0.26), 8.752 (0.50), 8.766 (0.25) .

Example 208A.

(+)-tert-Butyl-5-[({6-bromo-2-[3-ethylpiperidin-1-yl]-3-methylquinolin-4-yl}carbonyl)amino]-4-[2(trifluoromethoxy)phenyl ]pentanoate (diastereoisomer 1) [for structural formula, see example 154A (mixture of diastereoisomers)].

Separation of diastereoisomers/enantiomers from example 154A:

tert-butyl 5-[({6-bromo-2-[3-ethylpiperidin-1-yl]-3-methylquinolin-4-yl}carbonyl)amino]-4-[2(trifluoromethoxy)phenyl]pentanoate (mixture diastereoisomers, 458 mg, 648 µmol, example 154A) was dissolved in a mixture of methanol (12 ml) and acetonitrile (5 ml) and separated into diastereoisomers by preparative SLC on a chiral phase [column: Daicel Chiralcel OZ-H, 5 µm, 250 mm x 20 mm; flow: 80 ml/min; sample injection: 0.3 ml; temperature 40°C, UV detection 210 nm, eluent: 88% carbon dioxide/12% methanol; duration of action 9.5 min, isocratic]. Four fractions were obtained (peak 1-peak 4, see examples 208A and 211A). The combined target fractions are respectively concentrated

- 105 040220 were taken and the residue was lyophilized accordingly.

(+)-tert-Butyl-5-[({6-bromo-2-[3-ethylpiperidin-1-yl]-3-methylquinolin-4-yl}carbonyl)amino]-4-[2(trifluoromethoxy)phenyl ]pentanoate (diastereoisomer 1).

The separation of the diastereoisomers described gave 64 mg (99% pure, >95% ee) of the title compound as the primarily eluting diastereoisomer (peak 1).

[a] _D20 = +17.0°, 436 nm, c = 0.35 g/100 mL ^, methanol;

LC-MS (method 1): Rt = 3.05 min; MS (ESIpos): m/z = 692/694 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.893 (0.87), 0.912 (2.16), 0.930 (1.06), 1.069 (0.16), 1.098 (0.17), 1.260 (0.35), 1.278 (0.46) 1.301 (0.60), 1.315 (0.18), 1.360 (16.00), 1.382 (0.29), 1.565 (0.20), 1.600 (0.18), 1.751 (0.23), 1.784 (0.23), 1.802 (0.23), 1.827 (0.20) , 1.854 (0.28), 1.881 (0.19), 2.033 (0.24), 2.065 (1.20), 2.089 (0.38), 2.118 (0.69), 2.422 (0.17), 2.755 (0.23), 3.370 (0.19), 3.388 (0.19) . , 7.408 (0.57), 7.414 (0.51), 7.420 (0.62), 7.549 (0.44), 7.555 (0.28), 7.562 (0.37), 7.573 (0.32) , 8.725 (0.20), 8.740 (0.38), 8.754 (0.20).

Example 209A.

(-)-tert-Butyl-5-[({6-bromo-2-[3-ethylpiperidin-1 -yl] -3-methylquinolin-4-yl}carbonyl)amino]-4-[2(trifluoromethoxy)phenyl ]pentanoate (diastereoisomer 2).

Separation of diastereomers as described in Example 208A gave 48 mg (100% pure, >95% ee) of the title compound as the second eluting diastereoisomer (peak 2).

[a] _D20 = -25.7°, 589 nm, c = ^0.34 g/100 ml, methanol;

LC-MS (method 1): Rt = 3.05 min; MS (ESIpos): m/z = 692/694 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.893 (0.84), 0.912 (2.08), 0.930 (1.04), 1.070 (0.16), 1.101 (0.17), 1.261 (0.31), 1.270 (0.28) , 1.279 (0.42), 1.287 (0.37), 1.297 (0.32), 1.325 (0.18), 1.361 (16.00), 1.564 (0.19), 1.607 (0.18), 1.640 (0.17), 1.749 (0.23) . . . , 7.663 (0.91), 8.725 (0.22), 8.739 (0.44), 8.754 (0.22).

Example 210A.

(-)-tert-Butyl-5-[({6-bromo-2-[3-ethylpiperidin-1 -yl] -3-methylquinolin-4-yl}carbonyl)amino]-4-[2(trifluoromethoxy)phenyl ]pentanoate (diastereoisomer 3).

Separation of diastereoisomers as described in Example 208A gave 59 mg (98% pure, >93% ee) of the title compound as the third eluting diastereoisomer (peak 3).

[a] _D20 = -17.5°, 436 nm, c = 0.32 g ^/ 100 ml, methanol;

LC-MS (method 1): Rt = 3.05 min; MS (ESIpos): m/z = 692/694 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.893 (0.89), 0.912 (2.18), 0.930 (1.08), 1.069 (0.17), 1.091 (0.17), 1.261 (0.36), 1.278 (0.48) , 1.296 (0.34), 1.315 (0.18), 1.361 (16.00), 1.565 (0.21), 1.601 (0.20), 1.633 (0.16), 1.750 (0.23), 1.784 (0.23) . . . , 8.740 (0.41), 8.754 (0.20).

Example 211A.

(+)-tert-Butyl-5-[({6-bromo-2-[3-ethylpiperidin-1-yl]-3-methylquinolin-4-yl}carbonyl)amino]-4-[2(trifluoromethoxy)phenyl ]pentanoate (diastereoisomer 4).

Separation of diastereoisomers as described in Example 208A gave 65 mg (100% pure, >95% ee) of the title compound as the fourth eluting diastereoisomer (peak 4).

[a] _D20 = +26.9°, 589 nm, c = 0.34 ^g /100 mL, methanol;

LC-MS (method 1): Rt = 3.05 min; MS (ESIpos): m/z = 692/694 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.893 (0.99), 0.912 (2.18), 0.930 (1.09), 1.071 (0.20), 1.092 (0.21), 1.261 (0.41), 1.269 (0.39) , 1.279 (0.52), 1.287 (0.46), 1.297 (0.39), 1.305 (0.36), 1.325 (0.40), 1.361 (16.00), 1.565 (0.24), 1.607 (0.22), 1.639 (0.20), 1.749 (0.29) , 1.784 (0.27), 1.803 (0.29), 1.828 (0.28), 1.854 (0.36), 1.884 (0.23), 2.033 (0.35), 2.048 (0.45), 2.066 (1.46), 2.092 (0.36), 2.144 (1.32) , 2.408 (0.17), 2.436 (0.27), 2.747 (0.25), 3.369 (0.25), 3.387 (0.25), 3.498 (0.46), 3.529 (0.40), 3.618 (0.36), 3.632 (0.57) . , 7.560 (0.42), 7.571 (0.34), 7.633 (0.22), 7.656 (1.87), 8.725 (0.29), 8.740 (0.51), 8.754 (0.24).

- 106 040220

Example 212A.

tert-Butyl 5-[({6-bromo-3-methyl-2-[3-methylpiperidin-1-yl]quinolin-4-yl}carbonyl)amino]-4-[2(trifluoromethoxy)phenyl]pentanoate ( diastereoisomer 1) [for structural formula, see example 155A (mixture of diastereoisomers)].

Separation of diastereoisomers/enantiomers from Example 155A:

tert-butyl 5-[({6-bromo-2-[3-ethylpiperidin-1-yl]-3-methylquinolin-4-yl}carbonyl)amino]-4-[2(trifluoromethoxy)phenyl]pentanoate (mixture diastereoisomers, 539 mg, 781 µmol, example 155A) were separated into diastereoisomers by preparative HPLC in the chiral phase [column: Daicel Chiralcel AD-H, 5 µm, 250 mm x 20 mm; flow: 7 ml/min; temperature 25°C, UV detection 240 nm, eluent: 95% heptane/5% isopropanol; isocratic]. Four fractions were obtained (peak 1-peak 4, see examples 212A and 215A). The combined target fractions were respectively concentrated and each one to three times further purified by the same Method, then re-concentrated (rotary evaporator at 40° C.) and dried in vacuo.

tert-Butyl 5-[({6-bromo-3-methyl-2-[3-methylpiperidin-1-yl]quinolin-4-yl}carbonyl)amino]-4-[2(trifluoromethoxy)phenyl]pentanoate ( diastereoisomer 1).

The separation of the diastereoisomers described gave 55 mg (100% pure) of the title compound as the primarily eluting diastereoisomer (peak 1).

LC-MS (method 1): Rt = 2.99 min; MS (ESIpos): m/z = 678/680 [M+H]+.

Example 213A.

tert-Butyl 5-[({6-bromo-3-methyl-2-[3-methylpiperidin-1-yl]quinolin-4-yl}carbonyl)amino]-4-[2(trifluoromethoxy)phenyl]pentanoate ( diastereoisomer 2).

Separation of diastereomers as described in Example 212A gave 54 mg (100% pure) of the title compound as the second eluting diastereoisomer (peak 2).

LC-MS (method 1): Rt = 2.99 min; MS (ESIpos): m/z = 678/680 [M+H] ⁺ .

Example 214A.

tert-Butyl 5-[({6-bromo-3-methyl-2-[3-methylpiperidin-1-yl]quinolin-4-yl}carbonyl)amino]-4-[2(trifluoromethoxy)phenyl]pentanoate ( diastereoisomer 3).

Separation of diastereoisomers as described in Example 212A gave 43 mg (100% pure) of the title compound as the third eluting diastereoisomer (peak 3).

LC-MS (method 1): Rt = 2.99 min; MS (ESIpos): m/z = 678/680 [M+H] ⁺ .

Example 215A.

tert-Butyl 5-[({6-bromo-3-methyl-2-[3-methylpiperidin-1-yl]quinolin-4-yl}carbonyl)amino]-4-[2(trifluoromethoxy)phenyl]pentanoate ( diastereoisomer 4).

Separation of diastereoisomers as described in Example 212A gave 53 mg (100% pure) of the title compound as the fourth eluting diastereoisomer (peak 4).

LC-MS (method 1): Rt = 2.99 min; MS (ESIpos): m/z = 678/680 [M+H] ⁺ .

Example 216A.

(+)-tert-Butyl-5-({[6-bromo-2-(3,3-difluoropiperidin-1-yl)-3-methylquinolin-4-yl]carbonyl}amino)4-(2-chloro- 3,6-difluorophenyl)pentanoate (enantiomer 1) [see Example 162A (racemate) for structural formula].

Separation of enantiomers from Example 162A:

(+/-)-tert-butyl-5-({[6-bromo-2-(3,3-difluoropiperidin-1-yl)-3-methylquinolin-4yl]carbonyl}amino)-4-(2-chloro -3,6-difluorophenyl)pentanoate (racemate, 185 mg, 269 µmol, example 162A) was separated into enantiomers by preparative SLC on a chiral phase [column: Daicel Chiralpak AD-H, 5 µm, 250 mm x 30 mm; flow: 120 ml/min; temperature 25°C, UV detection 230 nm, eluent: 85% heptane/15% isopropanol; isocratic]. The combined target fractions were respectively concentrated at 30° C./30 mbar.

(+)-tert-Butyl-5-({[6-bromo-2-(3,3-difluoropiperidin-1-yl)-3-methylquinolin-4-yl]carbonyl}amino)4-(2-chloro- 3,6-difluorophenyl)pentanoate (enantiomer 1).

Separation of the enantiomers as described gave 85 mg (98% pure, >99% ee) of the title compound as the previously eluted enantiomer.

[a] _D20 = +32.2°, 589 nm, c = 0.32 g/100 ml ^, methanol;

LC-MS (method 2): Rt = 1.40 min; MS (ESIpos): m/z = 686/688 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.235 (0.22), 1.311 (0.16), 1.362 (16.00), 1.884 (0.53), 2.066 (0.38), 2.083 (0.51), 2.099 (0.52) , 2.115 (0.43), 2.137 (0.79), 2.165 (2.62), 3.172 (0.64), 3.451 (0.40) . , 7.717 (0.88), 7.735 (0.19), 7.739 (0.20), 8.815 (0.22), 8.830 (0.41), 8.844 (0.21).

Example 217A.

(-)-tert-Butyl-5-({[6-bromo-2-(3,3-difluoropiperidin-1-yl)-3-methylquinolin-4-yl]carbonyl}amino)4-(2-chloro- 3,6-difluorophenyl)pentanoate (enantiomer 2).

- 107 040220

The separation of enantiomers described in Example 216A gave 85 mg (100% pure, >98% ee) of the title compound as the later eluted enantiomer.

[a] _D20 = -28.0°, 589 nm, c = 0.38 g/100 ml ^, methanol;

LC-MS (method 2): Rt = 1.40 min; MS (ESIpos): m/z = 686/688 [M+H]+.

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.235 (0.31), 1.361 (16.00), 1.884 (0.70), 1.975 (0.18), 2.082 (0.68), 2.098 (0.69), 2.115 (0.58) , 2.137 (1.03), 2.164 (3.20), 3.172 (0.85), 3.451 (0.49), 3.480 (0.92) . , 7.712 (1.11), 7.716 (0.97), 7.735 (0.21), 7.739 (0.22), 8.829 (0.52).

Example 218A.

tert-Butyl 5-({[2-(azepan-1-yl)-6-bromo-3-methylquinolin-4-yl]carbonyl}amino)-4-(2-chloro-3,6difluorophenyl)pentanoate (enantiomer 1) [structural formula, see example 166A (racemate)].

Separation of enantiomers from example 166A:

(+/-)-tert-butyl-5-({[2-(azepan-1-yl)-6-bromo-3-methylquinolin-4-yl]carbonyl}amino)-4-(2-chloro-3 ,6difluorophenyl)pentanoate (racemate, 489 mg, 735 µmol, Example 166A) was separated into enantiomers by preparative SLC on chiral phase [column: Daicel Chiralpak AD-H, 5 µm, 250 mm x 20 mm; flow: 80 ml/min; sample injection: 0.3 ml; temperature 40°C, UV detection 210 nm, eluent: 85% heptane/15% isopropanol; duration of action 13 min, isocratic]. The combined target fractions were respectively concentrated and the corresponding residue was lyophilized from acetonitrile/water.

tert-Butyl 5-({[2-(azepan-1-yl)-6-bromo-3-methylquinolin-4-yl]carbonyl}amino)-4-(2-chloro-3,6difluorophenyl)pentanoate (enantiomer 1).

Separation of the enantiomers as described gave 39 mg (93% pure, >99% ee) of the title compound as the previously eluted enantiomer.

LC-MS (method 2): Rt = 1.50 min; MS (ESIpos): m/z = 664/666 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.360 (16.00), 1.371 (1.06), 1.603 (1.40), 1.780 (0.84), 2.080 (0.23), 2.133 (1.95), 2.150 (0.79) . , 7.420 (0.29), 7.532 (0.64), 7.554 (1.12), 7.602 (0.66), 7.607 (0.60), 7.624 (0.35), 7.629 (0.34), 8.788 (0.31).

Example 219A.

tert-Butyl 5-({[2-(azepan-1-yl)-6-bromo-3-methylquinolin-4-yl]carbonyl}amino)-4-(2-chloro-3,6difluorophenyl)pentanoate (enantiomer 2).

The separation of enantiomers described in Example 218A gave 32 mg (93% pure, 89% ee) of the title compound as the later eluted enantiomer.

LC-MS (method 2): Rt = 1.50 min; MS (ESIpos): m/z = 664/666 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.309 (0.17), 1.361 (16.00), 1.603 (1.35), 1.780 (0.81), 2.066 (0.24), 2.082 (0.22), 2.103 (0.22) . , 7.327 (0.19), 7.386 (0.20), 7.398 (0.24), 7.408 (0.31), 7.419 (0.29), 7.532 (0.60), 7.555 (1.06), 7.602 (0.61), 7.607 (0.55), 7.624 (0.34) , 7.630 (0.32), 8.775 (0.18), 8.789 (0.32).

Example 220A.

tert-Butyl 5-[({6-bromo-2-[3-fluoropiperidin-1-yl]-3-methylquinolin-4-yl}carbonyl)amino]-4-(2,3,6trichlorophenyl)pentanoate (diastereoisomer 1) [for structural formula, see example 187A (mixture of diastereoisomers)].

Separation of diastereoisomers/enantiomers from Example 187A:

tert-butyl 5-[({6-bromo-2-[3-fluoropiperidin-1-yl]-3-methylquinolin-4-yl}carbonyl)amino]-4-(2,3,6trichlorophenyl)pentanoate (mixture diastereoisomers, 294 mg, 419 µmol, example 187A), separated into diastereoisomers by preparative HPLC using three different preparative separation methods on the chiral phase [method 1: Column: Daicel Chiralpak AD-H, 5 µm, 250 mm x 20 mm; flow: 14 ml/min; temperature 25°C, UV detection 240 nm, eluent: 90% heptane/10% isopropanol; isocratic; Method 2: Column: Daicel Chiralpak AD-H, 5 µm, 250 mm x 20 mm; flow: 9 ml/min; temperature 25°C, UV detection 240 nm, eluent: 100% ethanol; Method 3: Column: Daicel Chiralcel OD-H, 5 µm, 250 mm x 20 mm; flow: 9 ml/min; temperature 25°C, UV detection 240 nm, eluent: 90% heptane/10% isopropanol; isocratic]. Four fractions were obtained (see Examples 219A and 222A), the order of the peaks depending in part on the separation method used. The order of examples 219A-222A correlates with the elution order of peaks 1-4 in the following analytical HPLC method: Column: Daicel Chiralpak OD-H, 5 µm, 250 mm x 4.6 mm; flow: 0.3 ml/min; temperature 25°C, UV detection 240 nm, eluent: 90% heptane/10% isopropanol; isocratic. The combined desired fractions were suitably concentrated (rotary evaporator at 40° C.) and then dried in vacuo.

tert-Butyl-5-[({6-bromo-2-[3-fluoropiperidin-1-yl]-3-methylquinolin-4-yl}carbonyl)amino]-4-(2,3,6

- 108 040220 trichlorophenyl) pentanoate (diastereoisomer 1).

The separation of the diastereoisomers as described gave 14 mg (100% pure) of the title compound (peak 1 analytical HPLC, s.o.).

LC-MS (method 1): R _t = 2.83 min; MS (ESIpos): m/z = 700/702/704 [M+H]+.

Example 221A.

tert-Butyl 5-[({6-bromo-2-[3-fluoropiperidin-1-yl]-3-methylquinolin-4-yl}carbonyl)amino]-4-(2,3,6trichlorophenyl)pentanoate (diastereoisomer 2).

Separation of diastereoisomers as described in Example 220A gave 17 mg (100% pure) of the title compound (Analytical HPLC peak 2, see Example 220A).

LC-MS (method 1): Rt = 2.84 min; MS (ESIpos): m/z = 700/702/704 [M+H] ⁺ .

Example 222A.

tert-Butyl 5-[({6-bromo-2-[3-fluoropiperidin-1-yl]-3-methylquinolin-4-yl}carbonyl)amino]-4-(2,3,6trichlorophenyl)pentanoate (diastereoisomer 3).

The separation of diastereomers described in example 220A gave 32 mg (100% pure) of the title compound (peak 3 analytical HPLC, see example 220A).

LC-MS (method 1): R _t = 2.83 min; MS (ESIpos): m/z = 700/702/704 [M+H] ⁺ .

Example 223A.

tert-Butyl 5-[({6-bromo-2-[3-fluoropiperidin-1-yl]-3-methylquinolin-4-yl}carbonyl)amino]-4-(2,3,6trichlorophenyl)pentanoate (diastereoisomer 4).

Separation of diastereoisomers as described in example 220A gave 27 mg (94% pure) of the title compound (peak 4 analytical HPLC, see example 220A).

LC-MS (method 1): Rt = 2.83 min; MS (ESIpos): m/z = 700/702/704 [M+H] ⁺ .

Example 224A.

(+/-)-tert-Butyl-4-cyano-4-(2,5-difluorophenyl)butanoate (racemate)

gt o sn ₃

Under argon, diisopropylamine (10 ml, 74 mmol) in THF (44 ml) at -78° C. was provided to prepare an LDA solution and mixed slowly with a solution of n-butyllithium (1.6 M in hexane, 44 ml, 70 mmol). After completion of the addition, the solution was further stirred for 10 min at 0°C. This LDA solution was slowly added dropwise to a -78° C. cooled solution of (2,5difluorophenyl)acetonitrile (8.1 ml, 98% pure, 64 mmol) in THF (120 ml). After complete addition, the cold bath was removed, the reaction mixture was brought to 0°C and re-cooled to -78°C after 15 min. A solution of tert-butyl-3-bromopropanoate (13 ml, 97% pure, 77 mmol) in 44 ml THF was then slowly added dropwise and the mixture was stirred an additional 1 h at -78°C, allowed to warm to RT and further stirred overnight at CT. Ammonium chloride solution (300 ml, 10% in water) was added for working up. The mixture was stirred vigorously for 5 minutes and then extracted twice with ethyl acetate. The combined organic phases were washed twice in succession with 1 M hydrochloric acid each, saturated sodium bicarbonate solution and saturated sodium chloride solution. The organic phase was then dried over sodium sulfate and concentrated on a rotary evaporator. The residue was dissolved in a small amount of DMSO and purified in 4 portions by preparative HPLC (method 29). The fractions containing the product were combined and concentrated on a rotary evaporator. 8.05 g (100% pure, 45% th. y.) of the title compound was obtained.

LC-MS (method 1): R _t = 2.11 min; MS (ESIpos): m/z = 282 [M+H] ⁺ .

'H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 1.381 (16.00), 2.313 (0.86), 2.332 (1.28), 2.350 (0.44), 4.414 (0.63), 7.353 (0.40), 7.366 ( 0.62), 7.374 (0.51), 7.377 (0.49).

Example 225A.

(+/-)-tert-Butyl-5-amino-4-(2,5-difluorophenyl)pentanoate (racemate)

The (+/-)-tert-butyl-4-cyano-4-(2,5-difluorophenyl)butanoate prepared in Example 224A (racemate, 8.05 g, 100% pure, 28.6 mmol) was provided in tert-butanol (210 mL, 2.2 mol) and methanol (9.3 ml) and mixed with Raney nickel (1.68 g, 28.6 mmol). The reaction mixture was stirred for 9 days under normal hydrogen pressure. Despite incomplete implementation, the reaction was interrupted. The catalyst was filtered through diatomaceous earth and washed three times with methanol (30 ml, respectively). The filtrate was evaporated and the residue was adsorbed in ethyl acetate (200 ml). The organic phase was extracted twice with 1 M hydrochloric acid

- 109 040220 (corresponding to 200 ml). The combined aqueous phases were adjusted to pH 8 by slow addition of sodium bicarbonate and extracted twice with dichloromethane (respectively 200 ml). The combined organic phases were dried over sodium sulfate, filtered and concentrated. 3.84 g (100% pure, 47% th. y.) of the title compound was obtained.

LC-MS (method 1): R _t = 1.12 min; MS (ESIpos): m/z = 286 [M+H]+.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 7.29-7.04 (m, 3H), 2.92-2.84 (m, 1H), 2.79-2.67 (m, 2H), 2.051.91 ( m, 3H), 1.74-1.61 (m, 1H), 1.35 (s, 9H).

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.111 (0.42), 1.354 (16.00), 2.012 (1.26), 2.025 (0.85), 2.728 (0.47), 2.736 (0.51), 2.747 (0.69) , 2.751 (0.69).

Example 226A.

(+/-)-tert-Butyl-5 - {[(6-bromo-2-chloro-3 -methylquinolin-4-yl)carbonyl] amino}-4-(2,5difluorophenyl)pentanoate (racemate) ' o I ^Nz η—CH ₃

Ο^ΝΗ O CH ₃

Βγ^1όΗ ₃

XXI

The (+/-)-tert-butyl-5-amino-4-(2,5-difluorophenyl)pentanoate prepared in Example 225A (racemate, 3.00 g, 10.5 mmol) was provided in dichloromethane (80 mL) and mixed with DIPEA at RT (4.6 ml, 26 mmol), then with a solution of 6-bromo-2-chloro-3-methylquinoline-4-carbonyl chloride (2.79 g, 8.76 mmol, example 3A) in dichloromethane (20 ml). The reaction mixture was stirred 2 h, then diluted with dichloromethane (100 ml) and twice with 1 M hydrochloric acid, then washed twice with saturated sodium bicarbonate solution. The organic phase was dried, filtered and concentrated. The residue was dried in vacuo. 4.92 g (99% pure, 98% theoretical) of the title compound were obtained.

LC-MS (method 1): Rt = 2.48 min; MS (ESIneg): m/z = 565/567 [M-H] ^- .

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 8.89 (t, 1H), 7.94-7.86 (m, 2H), 7.82-7.40 (br. m, 1H), 7.347.29 ( m, 1H), 7.24 (td, 1H), 7.19-7.07 (m, 1H), 3.81-3.62 (m, 2H), 3.41-3.34 (m, 1H), 2.30-2.15 (m, 3H), 2.142. 06 (m, 2H), 2.05-1.98 (m, 1H), 1.88-1.73 (m, 1H), 1.37 (s, 9H).

Example 227A.

tert-Butyl 5-[({6-bromo-2-[3-ethylpiperidin-1-yl]-3-methylquinolin-4-yl}carbonyl)amino]-4-(2,5difluorophenyl)pentanoate (mixture of diastereoisomers)

Provided tert-butyl 5-{[(6-bromo-2-chloro-3-methylquinolin-4-yl)carbonyl]amino}-4-(2,5difluorophenyl)pentanoate (400 mg, 704 µmol, Example 226A) in thick-walled microwave vessel in NMP (4.5 ml) and mixed successively with 3-ethylpiperidine (399 mg, 3.52 mmol) and DIPEA (610 μl, 3.5 mmol). The vessel was closed and shaken overnight at 130°C. The reaction solution was cooled to RT and directly (without further processing) purified by preparative HPLC (method 14). Product-containing fractions were concentrated and dried in vacuo. The resulting residue was dissolved in a small amount of dichloromethane and foamed in vacuo. 375 mg (100% pure, 83% thor.) of the title compound were obtained.

LC-MS (method 1): R _t = 2.90 min; MS (ESIpos): m/z = 644/646 [M+H] ⁺ .

¹ H-NMR (400 MHz, DMSO-d6): δ [ppm] = 8.73 (br t, 1H), 7.70-7.60 (m, 2H), 7.44 (br s, 1H), 7.33-7.27 (m, 1H ), 7.26-7.19 (m, 1H), 7.16-7.09 (m, 1H), 3.74-3.59 (m, 2H), 3.55-3.42 (m, 2H), 3.40-3.34 (m, 1H), 2.802.69 (m, 1H), 2.48-2.37 (m, 1H), 2.16-1.98 (m, 6H), 1.91-1.72 (m, 3H), 1.68-1.51 (m, 2H), 1.37 (s, 9H), 1.341 .21 (m, 2H), 1.13–1.02 (m, 1H), 0.91 (t, 3H).

Separation of diastereoisomers/enantiomers:

The title target compound (316 mg, 490 µmol) was dissolved in methanol (12 ml) and diastereoisomerized by preparative SLC on chiral phase [column: Daicel Chiralcel OX-H, 5 µm, 250 mm x 20 mm; sample injection: 0.30 ml; eluent: 82% carbon dioxide/18% methanol; flow: 80 ml/min; temperature 40°C, UV detection 210 nm, duration 6.1 min, isocratic]. Three fractions were obtained (peak 1-3), of which peak 1 was obtained as a mixture

- 110 040220 two diastereoisomers/enantiomers (see example 228A) and peak 2 and peak 3 respectively as separate diastereoisomers (see examples 229A and 230A). The combined target fractions were suitably concentrated and the residue was suitably lyophilized.

Example 228A.

tert-Butyl 5-[({6-bromo-2-[3-ethylpiperidin-1-yl]-3-methylquinolin-4-yl}carbonyl)amino]-4-(2,5difluorophenyl)pentanoate (mixture of two diastereoisomers ).

Separation of diastereoisomers as described in Example 227A gave 125 mg (100% pure) of the title compound as fraction 1 (mixture of two diastereoisomers).

LC-MS (method 1): Rt = 2.92 min; MS (ESIpos): m/z = 644/646 [M+H]+.

1H-NMR (500 MHz, DMSO-d ₆ ) δ [ppm]: 0.893 (0.86), 0.908 (1.93), 0.923 (0.96), 1.084 (0.16), 1.090 (0.16), 1.244 (0.19), 1.258 (0.30 ), 1.272 (0.40), 1.281 (0.30), 1.286 (0.31), 1.294 (0.24), 1.372 (16.00), 1.560 (0.17), 1.748 (0.23), 1.754 (0.20), 1.774 (0.26), 1.799 (0.17 ), 1.848 (0.19), 1.873 (0.18), 2.010 (0.19), 2.025 (0.20), 2.085 (0.63), 2.099 (1.07), 2.104 (0.83), 2.113 (1.02), 2.741 (0.18), 3.340 (1.17 ), 3.358 (0.24), 3.360 (0.22), 3.494 (0.35), 3.512 (0.29), 3.642 (0.21), 3.651 (0.22), 7.122 (0.24), 7.203 (0.20), 7.212 (0.21), 7.222 (0.33 ), 7.231 (0.32), 7.240 (0.17), 7.289 (0.20), 7.296 (0.27), 7.304 (0.20), 7.632 (0.23), 7.649 (1.27), 7.655 (0.79), 7.658 (0.68), 8.725 (0.21 ), 8.736 (0.36), 8.747 (0.20).

Example 229A.

tert-Butyl 5-[({6-bromo-2-[3-ethylpiperidin-1-yl]-3-methylquinolin-4-yl}carbonyl)amino]-4-(2,5difluorophenyl)pentanoate (diastereoisomer 1) .

Separation of diastereoisomers as described in Example 227A gave 43 mg (100% pure) of the title compound as peak 2.

LC-MS (method 1): Rt = 2.92 min; MS (ESIpos): m/z = 644/646 [M+H] ⁺ .

¹ H-NMR (500 MHz, DMSO-d6) δ [ppm]: 0.894 (0.95), 0.909 (2.24), 0.924 (1.09), 1.084 (0.16), 1.090 (0.16), 1.244 (0.20), 1.258 (0.30 ), 1.272 (0.42), 1.286 (0.35), 1.294 (0.23), 1.372 (16.00), 1.560 (0.18), 1.567 (0.16), 1.748 (0.23), 1.754 (0.20), 1.773 (0.27), 1.786 (0.20 ), 1.792 (0.16), 1.800 (0.18), 1.806 (0.16), 1.849 (0.19), 1.873 (0.18), 2.010 (0.20), 2.024 (0.21), 2.051 (0.17), 2.085 (0.68), 2.098 (1.17 ), 2.111 (0.81), 2.743 (0.21), 3.494 (0.35), 3.511 (0.26), 3.631 (0.20), 3.642 (0.27), 3.689 (0.16), 7.122 (0.23), 7.203 (0.19), 7.212 (0.21 ), 7.221 (0.32), 7.231 (0.31), 7.240 (0.16), 7.277 (0.17), 7.283 (0.21), 7.288 (0.21), 7.295 (0.29), 7.302 (0.21), 7.306 (0.20), 7.313 (0.16 ), 7.632 (0.26), 7.650 (1.35), 7.655 (0.95), 7.659 (0.81), 7.673 (0.16), 7.677 (0.17), 8.723 (0.23), 8.734 (0.39), 8.746 (0.22).

Example 230A.

tert-Butyl 5-[({6-bromo-2-[3-ethylpiperidin-1-yl]-3-methylquinolin-4-yl}carbonyl)amino]-4-(2,5difluorophenyl)pentanoate (diastereoisomer 2) .

Separation of diastereoisomers as described in Example 227A gave 48 mg (100% pure) of the title compound as peak 3.

LC-MS (method 1): Rt = 2.92 min; MS (ESIpos): m/z = 644/646 [M+H] ⁺ .

1H-NMR (500 MHz, DMSO-d6) δ [ppm]: 0.892 (1.06), 0.907 (2.36), 0.922 (1.19), 1.066 (0.21), 1.084 (0.22), 1.245 (0.24), 1.260 (0.41) , 1.274 (0.54), 1.287 (0.40), 1.372 (16.00), 1.558 (0.23), 1.580 (0.20), 1.606 (0.21), 1.631 (0.22), 1.748 (0.31), 1.773 (0.34), 1.783 (0.30) , 1.797 (0.25), 1.804 (0.22), 1.817 (0.20), 1.848 (0.26), 1.872 (0.25), 1.999 (0.20), 2.010 (0.25), 2.024 (0.25), 2.041 (0.18), 2.050 (0.19) . . . , 7.657 (0.93), 7.671 (0.18), 7.675 (0.18), 8.725 (0.30), 8.737 (0.53), 8.748 (0.28).

Example 231A.

(+/-)-tert-Butyl-4-cyano-4-(2-methylphenyl)butanoate (racemate)

o CH ₃ (2-Methylphenyl)acetonitrile (7.08 g, 54.0 mmol) was dissolved in DMF, mixed slowly with sodium hydride, and stirred for an additional 10 min at RT. Then, tert-butyl-3-bromopropanoate (9.0 mL, 54 mmol) was added slowly dropwise, with slight foaming and warming of approx. at 35°C. The reaction vessel was cooled in a water bath during further addition. Then the water bath was removed and the mixture was stirred for an additional 2.5 h at RT. The reaction mixture was added to water, extracted with dichloromethane, dried (sodium sulfate) and concentrated on a rotary evaporator. The starting material was purified by flash column chromatography (Isolera, KP-Sil, eluent: hexane/acetic ester, gradient: 1-30% ethyl acetate). 8.32 g (74% pure, 44% th. y.) of the title compound was obtained.

LC-MS (method 25): Rt = 1.39 min; MS (ESIpos): m/z = 260 [M+H] ⁺ .

- 111 040220

1H-NMR (400 MHz, chloroform-d) δ [ppm]: 1.494 (16.00), 2.146 (0.44), 2.148 (0.40), 2.382 (0.77), 2.411 (3.67), 2.491 (0.43), 2.522 (0.58) , 3.702 (0.51), 7.241 (0.45), 7.279 (0.68), 7.288 (0.62).

Example 232A.

(+/-)-tert-Butyl-5-amino-4-(2-methylphenyl)pentanoate (racemate)

Provided (+/-)-tert-butyl-4-cyano-4-(2-methylphenyl)butanoate (racemate, 8.32 g, 74% pure, 23.8 mmol, Example 231A) in tert-butanol (200 ml) and mixed with Raney nickel (1.88 g, 32.1 mmol). Hydrogenated for 6 h with hydrogen at normal pressure. Raney nickel (1.88 g, 32.1 mmol) was then added again and hydrogenated for an additional 8 h. Then the same amount of catalyst was added once more and hydrogenated for an additional 5 h. using column chromatography (Isolera, RP18, solvent: water + 0.1 vol.% formic acid/acetonitrile, gradient: 5-95% acetonitrile). 5.74 g (98% pure, 90% tho.) of the title compound were obtained.

LC-MS (method 25): R _t = 0.71 min; MS (ESIpos): m/z = 264 [M+H]+.

1H-NMR (400 MHz, chloroform-d) δ [ppm]: 1.517 (16.00), 2.171 (1.18), 2.178 (0.59), 2.432 (3.54), 3.574 (2.02), 7.250 (0.67), 7.254 (0.75) , 7.256 (0.51), 7.400 (1.05), 8.286 (0.70).

Example 233A.

(+/-)-tert-Butyl-5-{[(6-bromo-2-chloro-3-methylquinolin-4-yl)carbonyl]amino}-4-(2methylphenyl)pentanoate (racemate)

(+/-)-tert-Butyl-5-amino-4-(2-methylphenyl)pentanoate (5.74 g, 98% pure, 21.4 mmol, Example 232A) and 6-bromo-2-chloro-3-methylquinoline-4 -carbonyl chloride (6.32 g, 19.8 mmol, example 3A) was dissolved in dichloromethane, mixed with aqueous sodium hydrogen carbonate solution (240 ml, 1.0 M, 240 mmol) and the reaction mixture was vigorously stirred for 1.5 h at RT. The reaction mixture was added to water, extracted with dichloromethane, the organic phase was washed with 1 M hydrochloric acid and saturated aqueous sodium chloride, dried over sodium sulfate, filtered and concentrated on a rotary evaporator. The starting material was purified by column chromatography (Isolera, KP-Sil, eluent: hexane/ethyl acetate, gradient: 0-100% ethyl acetate). 7.72 g (84% pure, 61% th. y.) of the title compound were obtained.

LC-MS (method 26): R _t = 1.59 min; MS (ESIpos): m/z = 545/547 [M+H]+.

Example 234A.

(+/-)-5-{[(6-Bromo-2-chloro-3-methylquinolin-4-yl)carbonyl]amino}-4-(2-methylphenyl)valeric acid (racemate)

(+/-)-tert-Butyl-5-{[(6-bromo-2-chloro-3-methylquinolin-4-yl)carbonyl]amino}-4-(2methylphenyl)pentanoate (racemate, 7.72 g, 84% purity, 11.9 mmol, example 233A) was dissolved in dichloromethane (25 ml). TFA (22 ml, 280 mmol) was then added and stirred overnight at RT. The reaction mixture was concentrated and the residue was purified by column chromatography (Isolera, LiChroprep RP-18 (40-63 µm), eluent: water + 0.1 vol% ammonia/acetonitrile, gradient: 10-90% acetonitrile). 6.71 g (86% pure, 99% th. y.) of the title compound were obtained.

LC-MS (method 26): Rt = 0.76 min; MS (ESIneg): m/z = 487/489 [M-H] ^- .

Example 235A.

(+/-)-tert-Butyl-4-cyano-4-(2-methoxyphenyl)butanoate (racemate)

- 112 040220

Method A.

To a solution of (2-methoxyphenyl)acetonitrile (2.00 g, 13.6 mmol) in THF (17 ml) in argon at -78°C was added a 2 M solution of LDA in THF (10 ml, 20 mmol) slowly with stirring. The mixture was brought to 0°C and after 15 min re-cooled to -78°C. Then, tert-butyl-3-bromopropanoate (2.6 ml, 16 mmol) was slowly added dropwise with stirring at -78°C. The mixture was further stirred overnight while the cooling bath (dry ice/acetone) was slowly brought to RT. The mixture was then slowly mixed with water and extracted twice with ethyl acetate. The combined organic phases were washed once with saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated, and the residue was previously purified by flash column chromatography (100 g Biotage Snap-Cartridge KP-Sil, cyclohexane/ethyl acetate gradient 93:7^6: 4, Isolera One). Then further purified by preparative HPLC (method 12). The combined desired fractions were concentrated and the residue was dried in vacuo. 495 mg (98% pure, 13% thor.) of the title compound were obtained.

LC-MS (method 1): R _t = 2.13 min; MS (ESIpos): m/z = 276 [M+H]+.

Method B.

(2-Methoxyphenyl)acetonitrile (7.98 g, 54.2 mmol) was dissolved in DMF (200 ml), mixed slowly with sodium hydride, and the mixture was stirred for 10 min at RT. Then, while cooling (water bath), tert-butyl-3-bromopropanoate (11.3 g, 54.2 mmol) was slowly added dropwise, the reaction solution warming to approx. 35°C. After 3 h stirring at RT, the reaction mixture was added to water and extracted with dichloromethane. The organic phase was dried, filtered and concentrated, and the residue was purified by flash column chromatography (silica gel, gradient 1-30% ethyl acetate in hexanes).

9.79 g (62% pure, 40% theoretical) of the title compound was obtained.

LC-MS (method 25): R _t = 1.32-1.35 min; MS (ESIpos): m/z = 276 [M+H] ⁺ .

Example 236A.

(+/-)-tert-Butyl-5-amino-4-(2-methoxyphenyl)pentanoate (racemate)

nh ₂ o sn ₃

Method A.

A solution of (+/-)-tert-butyl-4-cyano-4-(2-methoxyphenyl)butanoate (495 mg, 1.80 mmol, example 235A, method A) in tert-butanol (11 ml) was mixed with Raney nickel ( 106 mg, 1.80 mmol) and hydrogenated overnight at normal pressure. The catalyst was then filtered through kieselguhr and the mother liquor was concentrated. 269 mg (85% pure, 46% thor.) of the title compound were obtained.

LC-MS (method 2): R _t = 0.68 min; MS (ESIpos): m/z = 280 [M+H] ⁺ .

Method B.

A solution of (+/-)-tert-butyl-4-cyano-4-(2-methoxyphenyl)butanoate (9.79 g, 62% pure 22.4 mmol, example 235A, method B) in tert-butanol (350 ml) was mixed with Raney nickel (2.09 g, 35.6 mmol) and hydrogenated for 6 h at normal pressure. The mixture was then mixed again with Raney nickel (2.09 g, 35.6 mmol) and hydrogenated for an additional 8 h. After repeated addition of Raney nickel (2.09 g, 35.6 mmol), hydrogenated once more for 5 h. The solids were filtered through diatomaceous earth, washed further with ethyl acetate and the filtrate was concentrated. The starting material was purified by flash column chromatography (LiChroprep RP-18 40-63 µm; gradient: 5-95% acetonitrile in 0.1% aqueous formic acid). 2.69 g (99% pure, 42% th. y.) of the title compound were obtained.

LC-MS (method 25): R _t = 0.74 min; MS (ESIpos): m/z = 280 [M+H] ⁺ .

Separation of enantiomers.

The title target compound (2.69 g, 99% pure, from method B), purified by preparative HPLC, was separated into enantiomers in the chiral phase [column: Cellulose SC 10μ 250x50mm; flow: 120 ml/min; eluent: 20% isopropanol/(80% hexane + 0.1% diethylamine), isocratic]. The combined desired fractions were suitably concentrated and the residues dried in vacuo.

Example 237A.

tert-Butyl-5-amino-4-(2-methoxyphenyl)pentanoate (enantiomer 1).

- 113 040220

Separation of enantiomers as described in Example 236A gave 1.16 g (45% pure, ee 99%) of the title compound as the previously eluted enantiomer (separation gave an impurity).

LC-MS (method 25): Rt = 0.74 min; MS (ESIpos): m/z=280 [M+H]+.

Example 238A.

tert-Butyl-5-amino-4-(2-methoxyphenyl)pentanoate (enantiomer 2).

Separation of enantiomers as described in Example 236A gave 1.19 g (33% pure, ee 99%) of the title compound as a later eluted enantiomer (separation gave an impurity).

LC-MS (method 25): Rt = 0.75 min; MS (ESIpos): m/z = 280 [M+H] ⁺ .

Example 239A.

tert-Butyl-5-{[(6-bromo-2-chloro-3-methylquinolin-4-yl)carbonyl]amino}-4-(2methoxyphenyl)pentanoate (enantiomer 1)

To a mixture of 6-bromo-2-chloro-3-methylquinoline-4-carbonyl chloride (1.21 g, 3.78 mmol, example 3A) and tert-butyl 5-amino-4-(2-methoxyphenyl)pentanoate (1.16 g, 45 % purity, 1.87 mmol, enantiomer 7, example 237A) in dichloromethane (25 ml) was added 1 M aqueous sodium hydrogen carbonate solution (25 ml) and the reaction mixture was vigorously shaken at RT for 2 h. The organic phase was separated, dried over sodium sulfate, filtered and concentrated, and the residue was purified by flash column chromatography (LiChroprep RP-18 40-63 µm; gradient: 50-100% acetonitrile in water). 1.27 g (73% pure, 88% th. y.) of the title compound was obtained.

LC-MS (method 25): Rt = 1.54 min; MS (ESIpos): m/z = 561/563 [M+H] ⁺ .

Example 240A.

tert-Butyl-5-{[(6-bromo-2-chloro-3-methylquinolin-4-yl)carbonyl]amino}-4-(2methoxyphenyl)pentanoate (enantiomer 2).

To a mixture of 6-bromo-2-chloro-3-methylquinoline-4-carbonyl chloride (1.24 g, 3.90 mmol, example 3A) and tert-butyl 5-amino-4-(2-methoxyphenyl)pentanoate (1.19 g, 33 % purity, 1.41 mmol, enantiomer 2, example 238A) in dichloromethane (25 ml) was added 1 M aqueous sodium hydrogen carbonate solution (25 ml) and the reaction mixture was vigorously shaken at RT for 2 h. The organic phase was separated, dried over sodium sulfate, filtered and concentrated, and the residue was purified by flash column chromatography (LiChroprep RP-18 40-63 µm; gradient: 50-100% acetonitrile in water). 693 mg (97% pure, 85% thor.) of the title compound were obtained.

LC-MS (method 25): Rt = 1.54 min; MS (ESIpos): m/z = 561/563 [M+H] ⁺ .

1H-NMR (400 MHz, chloroform-d) δ [ppm]: 1.390 (0.43), 1.428 (16.00), 2.160 (0.41), 2.190 (0.50), 2.280 (1.48), 3.751 (5.16), 6.858 (0.50) , 6.878 (0.54), 6.994 (0.51), 7.218 (0.55), 7.237 (0.47), 7.243 (0.46), 7.720 (0.49), 7.725 (0.70), 7.761 (1.42), 7.783 (0.51).

Example 241A.

5-{[(6-Bromo-2-chloro-3-methylquinolin-4-yl)carbonyl]amino}-4-(2-methoxyphenyl)valeric acid (enantiomer 1)

To a solution of tert-butyl 5-{[(6-bromo-2-chloro-3-methylquinolin-4-yl)carbonyl]amino}-4-(2methoxyphenyl)pentanoate (1.27 g, 73% purity, 1.65 mmol, enantiomer 7, example 239A) in dichloromethane (15 ml) was added TFA (3.5 ml) and the mixture was stirred overnight at RT. The reaction mixture was then concentrated and the residue was purified by flash column chromatography (LiChroprep RP-18 40-63 µm; gradient: 20-90% acetonitrile in water). 800 mg (85% pure, 81% thor.) of the title compound were obtained.

LC-MS (method 25): Rt = 1.19 min; MS (ESIpos): m/z = 505/507 [M+H] ⁺ .

Example 242A.

5-{[(6-Bromo-2-chloro-3-methylquinolin-4-yl)carbonyl]amino}-4-(2-methoxyphenyl)valeric acid

- 114 040220 slots (enantiomer 2).

To a solution of tert-butyl 5-{[(6-bromo-2-chloro-3-methylquinolin-4-yl)carbonyl]amino}-4-(2methoxyphenyl)pentanoate (690 mg, 97% pure, 1.19 mmol, enantiomer 2, example 240A) in dichloromethane (7 ml) was added TFA (1.9 ml) and the mixture was stirred overnight at RT. The reaction mixture was then concentrated and the residue was purified by flash column chromatography (LiChroprep RP-18 40-63 µm; gradient: 20-80% acetonitrile in water). 482 mg (87% pure, 70% thor.) of the title compound were obtained.

LC-MS (method 25): R _t = 1.19 min; MS (ESIpos): m/z = 505/507 [M+H] ⁺ .

1H-NMR (400 MHz, chloroform-d) δ [ppm]: 1.262 (0.78), 2.044 (0.43), 2.049 (0.43), 2.132 (0.59), 2.144 (0.71), 2.152 (0.41), 2.165 (0.59) , 2.279 (4.28), 2.291 (1.50), 2.301 (1.46), 2.306 (1.22), 2.311 (1.15), 2.320 (1.60), 2.340 (0.70), 2.472 (0.42), 3.480 (0.50), 3.492 (0.62) . . , 7.218 (1.09), 7.221 (1.57), 7.233 (1.33), 7.237 (1.62), 7.240 (1.40), 7.254 (1.31), 7.693 (0.80) , 7.750 (3.37), 7.761 (1.28), 7.772 (1.63).

Example 243A.

(+/-)-tert-Butyl-4-cyano-4-(2,6-dichlorophenyl)butanoate (racemate) (2,6-dichlorophenyl)acetonitrile (10.0 g, 54.0 mmol) was dissolved in DMF (200 ml, 2.6 mol), mixed slowly with NaH (2.59 g, 60% pure, 64.8 mmol) and stirred for an additional 10 min at RT. Then, tert-butyl-3-bromopropanoate (9.0 mL, 54 mmol) was slowly added dropwise, with slight foaming and a warming of approximately 35°C. The reaction vessel was cooled in a water bath during further addition, then the water bath was removed and stirred for 2.5 h at RT. The reaction mixture was added to water and extracted with dichloromethane. The organic phase was dried and concentrated on a rotary evaporator. The starting material was purified by column chromatography (Isolera, KP-Sil, eluent: hexane/acetic ester, gradient: 1-30% ethyl acetate). 13.2 g (75% pure, 59% th. y.) of the title compound were obtained.

LC-MS (method 25): R, = 1.43 min; MS (ESIpos): m/z = 314 [M+H] ⁺ .

'H-NMR (400 MHz, chloroform-d) δ [ppm]: 1.170 (0.43), 1.369 (16.00), 1.957 (0.77), 2.323 (0.44), 2.343 (0.91), 2.354 (0.40), 4.770 (0.57 ), 7.128 (0.41), 7.147 (0.55), 7.150 (0.58), 7.169 (0.69).

Example 244A.

(+/-)-tert-Butyl-5-amino-4-(2,6-dichlorophenyl)pentanoate (racemate)

Provided (+/-)-tert-Butyl-4-cyano-4-(2,6-dichlorophenyl)butanoate (racemate, 2.00 g, 75% pure, 4.78 mmol, Example 243A) in tert-butanol (3.9 ml, 67 mmol) and mixed with Raney nickel. The reaction mixture was hydrogenated with hydrogen for 6 hours at normal pressure. The catalyst was then added again and hydrogenated for an additional 8 hours. The catalyst was filtered through kieselguhr and the filtrate was concentrated on a rotary evaporator. The residue was purified by column chromatography (Isolera, LiChroprep RP-18, eluent: water + 0.1 vol% formic acid/acetonitrile, gradient: 5-95% acetonitrile). 660 mg (99% pure, 44% thor.) of the title compound were obtained.

LC-MS (method 25): R, = 0.76 min; MS (ESIpos): m/z = 318 [M+H] ⁺ .

'H-NMR (400 MHz, chloroform-d) δ [ppm]: 1.403 (16.00), 7.115 (0.42), 7.135 (1.08), 7.155 (0.65), 7.287 (0.47), 7.290 (0.46), 7.321 (0.70 ), 7.324 (0.62), 7.341 (0.67), 7.344 (0.61).

Example 245A.

(+/-)-tert-Butyl-5-{[(6-bromo-2-chloro-3-methylquinolin-4-yl)carbonyl]amino}-4-(2,6dichlorophenyl)pentanoate (racemate)

6-Bromo-2-chloro-3-methylquinoline-4-carbonyl chloride (4.31 g, 13.5 mmol, example 3A) and (+/-)-tert

- 115 040220 butyl 5-amino-4-(2,6-dichlorophenyl)pentanoate (racemate, 4.74 g, 14.9 mmol, example 244A) was dissolved in dichloromethane (25 ml, 390 mmol) and the solution was mixed with aqueous sodium hydrogen carbonate solution (25 ml, 1.0 M, 25 mmol). The reaction mixture was vigorously shaken for 1.5 h at RT. Then the reaction mixture was added to water, extracted with dichloromethane, the organic phase was washed with 1 M hydrochloric acid and saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated on a rotary evaporator. The starting material was purified by column chromatography (Isolera, LiChroprep RP-18, eluent: water/acetonitrile, gradient: 40-100% acetonitrile). 2.33 g of the title compound (contaminated) was obtained, which was used in the next step without further purification.

LC-MS (method 25): Rt = 1.60 min; MS (ESIneg): m/z = 597/599 [M-H] ^- .

Example 246A.

(+/-)-5-{[(6-Bromo-2-chloro-3-methylquinolin-4-yl)carbonyl]amino }-4-(2,6-dichlorophenyl)valeric acid (racemate)

(+/-)-tert-Butyl-5-{[(6-bromo-2-chloro-3-methylquinolin-4-yl)carbonyl]amino}-4-(2,6dichlorophenyl)pentanoate (racemate, 2.33 g, example 245A) was dissolved in dichloromethane (29 ml, 460 mmol). TFA (6.0 ml, 77 mmol) was added at RT and stirred 16 h at RT. The reaction mixture was then concentrated on a rotary evaporator and re-adsorbed several times in dichloromethane and concentrated again. The starting material was purified by column chromatography (Isolera, LiChroprep RP-18, eluent: water + 0.1 vol% ammonia/acetonitrile, gradient: 5-40% acetonitrile, then subjected to an additional wash with methanol to wash the product completely). The combined desired fractions were concentrated and the residue was dried in vacuo. 950 mg (72% pure, 26% theoretical yield over two steps) of the title compound were obtained.

LC-MS (method 26): Rt = 0.74 min; MS (ESIpos): m/z = 543/545 [M+H] ⁺ .

Example 247A.

(+/-)-tert-Butyl-4-cyano-4-(2,6-difluorophenyl)butanoate (racemate)

o sn ₃

Method A.

To a solution of (2,6-difluorophenyl)acetonitrile (5.00 g, 32.7 mmol) in THF (30 ml) in argon at -78°C, a 2 M solution of LDA in THF (20 ml, 39 mmol) was added slowly with stirring. The mixture was brought to 0°C and after 15 min re-cooled to -78°C. A solution of tert-butyl-3-bromopropanoate (6.2 ml, 39 mmol) in THF (10 ml) was then slowly added dropwise with stirring at -78°C. The mixture was further stirred overnight while the cooling bath (dry ice/acetone) was slowly brought to RT. The mixture was then slowly mixed at approximately 0° C. with water and ethyl acetate (respectively 100 ml) and shaken. After phase separation, the aqueous phase was extracted once with ethyl acetate (100 ml). The combined organic phases were washed once with saturated sodium chloride solution (150 ml), dried over sodium sulfate, filtered and concentrated, and the residue was adsorbed in dichloromethane and purified by flash column chromatography (100 g Biotage Snap-Cartridge Ultra silica gel, cyclohexane/ethyl acetate- gradient 93:7 ^ 7:3, Isolera One). The combined desired fractions were concentrated and the residue was dried in vacuo. 4.87 g (76% pure, 40% th. y.) of the title compound was obtained.

LC-MS (method 1): R _t = 2.06 min; MS (ESIpos): m/z = 282 [M+H] ⁺ .

Method B.

Under argon, diisopropylamine (10 ml, 71 mmol) was provided at -15° C. in THF (43 ml) to prepare an LDA solution and mixed slowly with a solution of n-butyllithium (1.6 M in hexane, 43 ml, 68 mmol). After completion of the addition, the solution was further stirred for 10 min at 0°C. This LDA solution was slowly added dropwise to a -78° C. cooled solution of (2,6-difluorophenyl)acetonitrile (9.90 g, 96% pure, 62.1 mmol) in THF (119 ml). After complete addition, the reaction mixture was brought to 0°C and after 15 min re-cooled to -78°C. A solution of tert-butyl-3-bromopropanoate (13 ml, 97% pure, 74 mmol) in 45 ml THF was then slowly added dropwise. The mixture was stirred 1 h at -78°C and then further stirred overnight at RT. Chloro solution was added for processing

- 116 040220 ammonium chloride (400 ml, 10% in water). The mixture was stirred vigorously for 5 minutes and then extracted twice with ethyl acetate. The combined organic phases were washed successively twice with 1 M hydrochloric acid, saturated sodium bicarbonate solution and saturated sodium chloride solution. The organic phase was then dried over sodium sulfate and concentrated on a rotary evaporator. The oily residue was dissolved in dichloromethane, mixed with diatomaceous earth and concentrated on a rotary evaporator. The accumulated residue was purified by flash column chromatography (silica gel, Isolera, 100 g Ultra Snap Kartuschen; cyclohexane/ethyl acetate gradient 100:070:30) in several passes. Product-containing fractions were concentrated together. 12.9 g (100% pure, 74% th. y.) of the title compound were obtained.

LC-MS (method 1): Rt = 2.08 min; MS (ESIpos): m/z = 282 [M+H]+.

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.374 (16.00), 2.313 (0.89), 2.331 (1.31), 2.349 (0.45), 4.499 (0.52), 7.197 (0.60), 7.219 (1.24) , 7.240 (0.68), 7.519 (0.45).

Example 248A.

(+/-)-tert-Butyl-5-amino-4-(2,6-difluorophenyl)pentanoate (racemate)

nh ₂ o sn ₃

Method A.

A solution of (+/-)-tert-butyl-4-cyano-4-(2,6-difluorophenyl)butanoate (4.80 g, 17.1 mmol, example 247A, method A) in tert-butanol (100 ml) was mixed with nickel Raney (1.00 g, 17.1 mmol) and hydrogenated overnight at normal pressure. The catalyst was then filtered through kieselguhr and the mother liquor was concentrated. 4.06 g (81% pure, 67% th. y.) of the title compound was obtained.

LC-MS (method 2): Rt = 0.64 min; MS (ESIpos): m/z = 286 [M+H]+.

Method B.

Provided (+/-)-tert-butyl-4-cyano-4-(2,6-difluorophenyl)butanoate (12.9 g, 100% pure, 46.0 mmol, Example 247A, method B) in tert-butanol mixture. (340 ml) and methanol (15 ml) and mixed with Raney nickel (2.00 g, 34.1 mmol). The reaction mixture was stirred overnight under normal hydrogen pressure. Thereafter, another 2 g of Raney nickel was added to the reaction mixture, and the reaction was stirred for an additional two nights under normal hydrogen pressure. The catalyst was filtered through diatomaceous earth and washed three times with methanol (respectively 50 ml). The filtrate was concentrated and the residue was dissolved in 400 ml of ethyl acetate. The solution was extracted twice with 1 M hydrochloric acid (respectively 400 ml). The combined aqueous phases were divided into three Erlenmeyer flasks. One of the three portions was adjusted to pH 8-9 with sodium bicarbonate (powder) and extracted twice with 200 ml of ethyl acetate. Due to the large amount of sodium bicarbonate required, the next two aqueous portions of lithium hydroxide were adjusted to pH 8-10 and each was extracted twice with 200 ml of ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and concentrated. The residue was taken up in ethyl acetate and water. After phase separation, the aqueous phase was extracted twice with ethyl acetate. The combined organic phases were concentrated and the residue was dried in vacuo. 7.76 g (76% pure, 45% th. y.) of the title compound were obtained.

LC-MS (method 1): Rt = 1.05 min; MS (ESIpos): m/z = 286 [M+H]+.

1H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 7.35-7.24 (m, 1H), 7.08-6.98 (m, 2H), 3.10-2.95 (m, 1H), 2.912.73 (m , 2H), 2.09–1.99 (m, 3H), 1.85–1.70 (m, 1H), 1.60–1.40 (m, 2H), 1.34 (s, 9H).

Example 249A.

(+/-)-tert-Butyl-5-{[(6-bromo-2-chloro-3-methylquinolin-4-yl)carbonyl]amino}-4-(2,6difluorophenyl)pentanoate (racemate)

Provided (+/-)-tert-Butyl-5-amino-4-(2,6-difluorophenyl)pentanoate (racemate, 3.12 g, 76% pure, 8.31 mmol, Example 248A, method B) in dichloromethane (65 mL) at CT. DIPEA (3.6 ml, 21 mmol) was added, followed by a solution of 6-bromo-2-chloro-3-methylquinoline-4-carbonyl chloride (2.21 g, 6.93 mmol, Example 3A) in dichloromethane (15 ml). The reaction mixture was stirred overnight and then mixed with water and dichloromethane (respectively 200 ml). The phases were separated and the aqueous phase was extracted with dichloromethane (200 ml). The combined organic phases were washed with brine for

- 117 040220 triium (200 ml), dried over sodium sulfate, filtered and concentrated. The residue was dissolved in a small amount of DMSO and purified in two portions by preparative HPLC (method 30). The combined desired fractions were concentrated and the residue was dried in vacuo. 3.77 g (98% pure, 94% th. y.) of the title compound were obtained.

LC-MS (method 2): Rt = 1.30 min; MS (ESIneg): m/z = 565/567 [M-H] ^- .

1H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 8.97 (t, 1H), 7.94-7.86 (m, 2H), 7.84-7.46 (very broad m, 1H), 7.43-7.29 (m , 1H), 7.09 (t, 2H), 3.83-3.68 (m, 2H), 3.57-3.41 (m, 1H), 2.35-1.99 (m, 6H), 1.96-1.83 (m, 1H), 1.37 (s , 9H).

Example 250A.

(+/-)-tert-Butyl-5-({[6-bromo-3-methyl-2-(piperidin-1-yl)quinolin-4-yl]carbonyl}amino)-4-(2,6difluorophenyl) pentanoate (racemate)

Provided (+/-)-tert-butyl-5-{[(6-bromo-2-chloro-3-methylquinolin-4-yl)carbonyl]amino}-4-(2,6difluorophenyl)pentanoate (300mg, 98 % purity, 518 µmol, example 249A) in a thick walled microwave vial in NMP (4.4 ml) and mixed successively with piperidine (260 µl, 2.6 mmol) and DIPEA (450 µl, 2.6 mmol). The vessel was closed and filled with argon through the cannula. The reaction solution was shaken overnight at 100°C and then an additional 20 h at 130°C. After cooling to RT, the reaction solution was purified by preparative HPLC (method 14). Product-containing fractions were concentrated and dried in vacuo. The residue was dissolved in dichloromethane and foamed in vacuo. 252 mg (100% pure, 79% th. y.) of the title compound were obtained.

LC-MS (method 1): R _t = 2.76 min; MS (ESIpos): m/z = 616/618 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 8.81 (t, 1H), 7.71-7.61 (m, 2H), 7.57-7.42 (m, 1H), 7.42-7.30 (m, 1H ), 7.08 (t, 2H), 3.83-3.63 (m, 2H), 3.56-3.42 (m, 1H), 3.13 (br. d, 4H), 2.22-2.00 (m, 6H), 1.97-1.84 (m , 1H), 1.73-1.54 (m, 6H), 1.36 (s, 9H)

Separation of enantiomers.

The title target compound (169 mg) purified by preparative HPLC was separated into enantiomers in the chiral phase (see Examples 251A and 252A) [column: Daicel Chiralpak IG, 5 μm, 250 mm x 20 mm; eluent n-heptane/isopropanol 90:10; flow: 25 ml/min; UV detection: 225 nm, temperature: 25°C]. The combined target fractions were suitably concentrated (22° C., 40 mbar).

Example 251A.

tert-Butyl 5-({[6-bromo-3-methyl-2-(piperidin-1-yl)quinolin-4-yl]carbonyl}amino)-4-(2,6difluorophenyl)pentanoate (enantiomer 1).

The separation of enantiomers described in Example 250A gave 88 mg (99% pure, >95% ee) of the title compound as the previously eluted enantiomer.

Chiral analytical HPLC [column: Daicel Chiralpak IG, 5 µm, 250 mm x 4.6 mm; eluent ngeptane/isopropanol 90:10; flow: 1 ml/min; UV detection: 225 nm, temperature: 25°C]: R _t = 28.9 min.

LC-MS (method 1): Rt = 2.73 min; MS (ESIpos): m/z = 616/618 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.236 (0.76), 1.259 (0.48), 1.364 (16.00), 1.607 (0.49), 1.671 (0.94), 2.096 (0.45), 2.113 (0.86) , 2.135 (1.82), 3.134 (1.22), 3.707 (0.42), 7.057 (0.50), 7.079 (0.89), 7.102 (0.58), 7.647 (1.36), 7.658 (0.88), 7.663 (0.81), 8.811 (0.46) .

Example 252A.

tert-Butyl 5-({[6-bromo-3-methyl-2-(piperidin-1-yl)quinolin-4-yl]carbonyl}amino)-4-(2,6difluorophenyl)pentanoate (enantiomer 2).

The separation of enantiomers described in Example 250A gave 66 mg (95% pure, ee 98%) of the title compound as the later eluted enantiomer.

Chiral analytical HPLC [column: Daicel Chiralpak IG, 5 µm, 250 mm x 4.6 mm; eluent ngeptane/isopropanol 90:10; flow: 1 ml/min; UV detection: 225 nm, temperature: 25°C]: R _t = 34.9 min.

LC-MS (method 1): Rt = 2.73 min; MS (ESIpos): m/z = 616/618 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 1.236 (0.63), 1.259 (0.47), 1.364 (16.00), 1.606 (0.44), 1.670 (0.85), 2.095 (0.41), 2.112 (0.81 ), 2.135 (1.69), 3.133 (1.12), 7.057 (0.47), 7.079 (0.84), 7.101 (0.55), 7.647 (1.32), 7.658 (0.86), 7.663 (0.75), 8.811 (0.44).

- 118 040220

Example 253A.

(+/-)-tert-Butyl-(5-({[6-bromo-3-methyl-2-(pyrrolidin-1-yl)quinolin-4-yl]carbonyl}amino)-4-(2,6difluorophenyl )pentanoate (racemate)

Provided (+/-)-tert-butyl-5-{[(6-bromo-2-chloro-3-methylquinolin-4-yl)carbonyl]amino}-4-(2,6difluorophenyl)pentanoate (300mg, 98 % purity, 518 µmol, example 249A) in a microwave vial in NMP (4.4 ml) and mixed successively with pyrrolidine (220 µl, 2.6 mmol) and DIPEA (450 µl, 2.6 mmol). The vessel was closed and filled with argon through the cannula. The reaction solution was shaken overnight at 100°C. After cooling to RT, the reaction solution was purified by preparative HPLC (method 14). Product-containing fractions were concentrated and dried in vacuo. The residue was dissolved in a small amount of dichloromethane and foamed in vacuo. 193 mg (100% pure, 62% th. y.) of the title compound were obtained.

LC-MS (method 4): Rt = 1.37 min; MS (ESIpos): m/z = 602/604 [M+H]+.

1H-NMR (400 MHz, DMSO-d6): δ [ppm] = 8.76 (t, 1H), 7.56 (dd, 1H), 7.48 (d, 1H), 7.42-7.27 (m, 2H), 7.07 (t , 2H), 3.73-3.66 (m, 2H), 3.57 (br s, 4H), 3.52-3.40 (m, 1H), 2.22-2.01 (m, 6H), 1.95-1.82 (m, 5H), 1.36 ( s, 9H).

Separation of enantiomers.

119 mg of the title compound was separated by chiral phase preparative HPLC into enantiomers (see examples 254A and 255A) [column: Daicel Chiralpak IC, 5 μm, 250 mm x 30 mm; eluent n-heptane/isopropanol 80:20; flow: 42.5 ml/min; UV detection: 225 nm, temperature: 25°C]. The combined target fractions were suitably concentrated (22° C., 40 mbar).

Example 254A.

tert-Butyl-(5-({[6-bromo-3-methyl-2-(pyrrolidin-1-yl)quinolin-4-yl]carbonyl}amino)-4-(2,6difluorophenyl)pentanoate (enantiomer 1) .

The separation of enantiomers described in Example 253A gave 57 mg (95% pure, ee 96%) of the title compound as the previously eluted enantiomer.

Chiral analytical HPLC [column: Daicel Chiralpak IC, 5 µm, 250 mm x 4.6 mm; eluent ngeptane/isopropanol 80:20; flow: 1 ml/min; UV detection: 260 nm, temperature: 25°C]: R _t = 23.1 min.

LC-MS (method 1): Rt = 2.14 min; MS (ESIpos): m/z = 602/604 [M+H]+.

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 1.235 (0.87), 1.258 (0.56), 1.298 (0.40), 1.362 (16.00), 1.871 (1.37), 2.095 (0.48), 2.111 (0.81 ), 2.129 (0.63), 2.160 (0.80), 3.566 (0.86), 7.050 (0.50), 7.072 (0.90), 7.094 (0.57), 7.467 (0.69), 7.489 (1.13), 7.549 (0.60), 7.554 (0.55 ), 8.763 (0.47).

Example 255A.

tert-Butyl-(5-({[6-bromo-3-methyl-2-(pyrrolidin-1-yl)quinolin-4-yl]carbonyl}amino)-4-(2,6difluorophenyl)pentanoate (enantiomer 2) .

The separation of enantiomers described in Example 253A gave 50 mg (95% pure, ee 99%) of the title compound as the later eluted enantiomer.

Chiral analytical HPLC [column: Daicel Chiralpak IC, 5 µm, 250 mm x 4.6 mm; eluent ngeptane/isopropanol 80:20; flow: 1 ml/min; UV detection: 260 nm, temperature: 25°C]: R _t = 28.2 min.

LC-MS (method 1): Rt = 2.14 min; MS (ESIpos): m/z = 602/604 [M+H]+.

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: -0.008 (1.15), 0.008 (0.74), 0.859 (0.62), 1.245 (0.48), 1.362 (16.00), 1.872 (1.21), 2.096 ( 0.42), 2.111 (0.72), 2.129 (0.57), 2.160 (0.70), 2.523 (0.69), 3.566 (0.77), 7.050 (0.45), 7.072 (0.79), 7.095 (0.51), 7.468 (0.69), 7.490 1.11), 7.549 (0.62), 7.555 (0.57), 8.763 (0.41).

Example 256A.

(+/-)-tert-Butyl-5-({[6-bromo-2-(3,3-difluoropiperidin-1-yl)-3-methylquinolin-4yl]carbonyl}amino)-4-(2,6 -difluorophenyl)pentanoate (racemate)

- 119 040220

Provided (+/-)-tert-butyl-5-{[(6-bromo-2-chloro-3-methylquinolin-4-yl)carbonyl]amino}-4-(2,6difluorophenyl)pentanoate (racemate, 300 mg , 98% pure, 518 µmol, Example 249A) in a heavy wall microwave vial in NMP (4.4 mL) and mixed successively with 3,3-difluoropiperidine hydrochloride (421 mg, 97% pure, 2.59 mmol) and DIPEA (450 µL, 2.6 mmol) . The vessel was closed and filled with argon through the cannula. The reaction solution was overnight at 100°C and then shaken for an additional 20 hours at 130°C. After cooling to RT, the reaction solution was purified by preparative HPLC (method 14). Product-containing fractions were concentrated and dried in vacuo. The residue was dissolved in dichloromethane and foamed in vacuo. 234 mg (100% pure, 69% th. y.) of the title compound were obtained.

LC-MS (method 1): R _t = 2.64 min; MS (ESIpos): m/z = 652/654 [M+H] ⁺ .

'H-NMR (400 MHz, DMSO-d6): δ [ppm] = 8.83 (t, 1H), 7.76-7.65 (m, 2H), 7.61-7.43 (m, 1H), 7.42-7.30 (m, 1H ), 7.08 (t, 2H), 3.83-3.64 (m, 2H), 3.53-3.42 (m, 3H), 3.22-3.11 (m, 2H), 2.22-1.99 (m, 8H), 1.97-1.82 (m , 3H), 1.36 (s, 9H).

Separation of enantiomers.

170 mg of the title compound were separated by preparative HPLC in chiral phase into enantiomers (see examples 257A and 258A) [column: Daicel Chiralpak OX-H, 5 μm, 250 mm x 20 mm; eluent n-heptane/isopropanol 82:18; flow: 30 ml/min; UV detection: 220 nm, temperature: RT]. The combined target fractions were suitably concentrated on a rotary evaporator.

Example 257A.

tert-Butyl 5-({[6-bromo-2-(3,3-difluoropiperidin-1-yl)-3-methylquinolin-4-yl]carbonyl}amino)-4(2,6-difluorophenyl)pentanoate ( enantiomer 1).

The separation of enantiomers described in Example 256A gave 82 mg (98% pure, ee 98%) of the title compound as the previously eluted enantiomer.

Chiral analytical HPLC [column: Daicel Chiralpak OX-H, 5 µm, 250 mm x 4.6 mm; eluent ngeptane/isopropanol 80:20; flow: 1 ml/min; UV detection: 220 nm, temperature: 30°C]: Rt = 2.13 min.

LC-MS (method 1): R _t = 2.65 min; MS (ESIpos): m/z = 652/654 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (0.49), 0.008 (0.47), 1.105 (0.66), 1.120 (0.67), 1.364 (16.00), 1.887 (0.54), 2.071 (0.51 ), 2.097 (0.69), 2.114 (0.87), 2.135 (0.66), 2.154 (1.54), 3.166 (0.53), 3.448 (0.62), 3.478 (1.91), 7.059 (0.45), 7.081 (0.83), 7.104 (0.53 ), 7.698 (1.28), 7.707 (0.88), 7.712 (0.77), 8.825 (0.44).

Example 258A.

tert-Butyl 5-({[6-bromo-2-(3,3-difluoropiperidin-1-yl)-3-methylquinolin-4-yl]carbonyl}amino)-4(2,6-difluorophenyl)pentanoate ( enantiomer 2).

The separation of enantiomers described in Example 256A gave 73 mg (98% pure, ee 95%) of the title compound as the later eluted enantiomer.

Chiral analytical HPLC [column: Daicel Chiralpak OX-H, 5 µm, 250 mm x 4.6 mm; eluent ngeptane/isopropanol 80:20; flow: 1 ml/min; UV detection: 220 nm, temperature: 30°C]: R _t = 3.23 min.

LC-MS (method 1): R _t = 2.65 min; MS (ESIpos): m/z = 652/654 [M+H] ⁺ .

'H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (0.50), 0.008 (0.51), 1.105 (0.61), 1.120 (0.60), 1.364 (16.00), 1.888 (0.54), 2.072 ( 0.50), 2.097 (0.68), 2.114 (0.86), 2.136 (0.64), 2.154 (1.50), 3.166 (0.52), 3.475 (1.28), 3.504 (0.56), 7.059 (0.46), 7.081 (0.80), 7.104 ( 0.52), 7.698 (1.25), 7.707 (0.84), 7.712 (0.75), 8.825 (0.43).

Example 259A.

tert-Butyl 5-[({6-bromo-2-(3-fluoropiperidin-1-yl)-3-methylquinolin-4-yl}carbonyl)amino]-4-(2,6difluorophenyl)pentanoate (mixture of diastereoisomers)

- 120 040220

Provided (+/-)-tert-butyl-5-{[(6-bromo-2-chloro-3-methylquinolin-4-yl)carbonyl]amino}-4-(2,6difluorophenyl)pentanoate (racemate, 400 mg , 98% pure, 690 µmol, Example 249A) in a heavy wall microwave vial in NMP (4.0 mL) and mixed successively with 3-fluoropiperidine hydrochloride (497 mg, 97% pure, 3.45 mmol) and DIPEA (600 µL, 3.5 mmol) . The vessel was closed and shaken overnight at 130°C. After cooling to RT, the reaction solution was purified by preparative HPLC (method 14). Product-containing fractions were concentrated and dried in vacuo. The residue was dissolved in a small amount of dichloromethane and foamed in vacuo. 343 mg (100% pure, 78% thor.) of the title compound were obtained.

LC-MS (method 1): R _t = 2.60 min; MS (ESIpos): m/z = 634/636 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 8.82 (t, 1H), 7.72-7.64 (m, 2H), 7.61-7.43 (m, 1H), 7.41-7.30 (m, 1H ), 7.08 (d, 2H), 4.98-4.76 (m, 1H), 3.82-3.63 (m, 2H), 3.56-3.30 (m, 3H), 3.24-3.02 (m, 2H), 2.23-1.72 (m , 10H), 1.70-1.57 (m, 1H), 1.36 (s, 9H).

Example 260A.

tert-Butyl 5-[({6-bromo-2-(3-ethylpiperidin-1-yl)-3-methylquinolin-4-yl}carbonyl)amino]-4-(2,6difluorophenyl)pentanoate (mixture of diastereoisomers)

Provided (+/-)-tert-butyl-5-{[(6-bromo-2-chloro-3-methylquinolin-4-yl)carbonyl]amino}-4-(2,6difluorophenyl)pentanoate (racemate, 400 mg , 98% pure, 690 µmol, Example 249A) in a heavy wall microwave vial in NMP (4.0 mL) and mixed successively with 3-ethylpiperidine (411 mg, 95% pure, 3.45 mmol) and DIPEA (600 µL, 3.5 mmol). The vessel was closed and shaken overnight at 130°C. After cooling to RT, the reaction solution was purified by preparative HPLC (method 14). Product-containing fractions were concentrated and dried in vacuo. The residue was dissolved in a small amount of dichloromethane and foamed in vacuo. 365 mg (100% pure, 82% th. y.) of the title compound were obtained.

1H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 8.81 (t, 1H), 7.71-7.59 (m, 2H), 7.56-7.42 (m, 1H), 7.42-7.29 (m, 1H ), 7.08 (t, 2H), 3.80-3.64 (m, 2H), 3.57-3.42 (m, 3H), 2.83-2.69 (m, 1H), 2.48-2.36 (m, 1H), 2.24-1.99 (m , 6H), 1.98-1.81 (m, 2H), 1.81-1.70 (m, 1H), 1.68-1.48 (m, 2H), 1.36 (s, 9H), 1.32-1.20 (m, 2H), 1.16-1.00 (m, 1H), 0.97–0.83 (m, 3H).

Example 261A.

(+/-)-tert-Butyl-5-({[6-bromo-3-methyl-2-(piperidin-1-yl)quinolin-4-yl]carbonyl}amino)-4-(2,5difluorophenyl) pentanoate (racemate)

Provided (+/-)-tert-butyl-5-{[(6-bromo-2-chloro-3-methylquinolin-4-yl)carbonyl]amino}-4-(2,5difluorophenyl)pentanoate (racemate, 300 mg , 528 µmol, example 226A) in a thick wall microwave vessel in NMP (4.0 ml) and mixed successively with piperidine (260 µl, 2.6 mmol) and DIPEA (460 µl, 2.6 mmol). The vessel was closed and shaken overnight at 130°C. After cooling to RT, the reaction solution was purified by preparative HPLC (method 14). Product-containing fractions were concentrated and dried in vacuo. The residue was dissolved in a small amount of dichloromethane and foamed in vacuo. Received 265 mg (100% purity, 81% theoretical yield) specified in the

- 121 040220 clever connections.

LC-MS (method 1): Rt = 2.72 min; MS (ESIpos): m/z = 616/618 [M+H]+.

1H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 8.81-8.67 (m, 1H), 7.73-7.58 (m, 2H), 7.55-7.36 (m, 1H), 7.337.27 (m , 1H), 7.27-7.19 (m, 1H), 7.18-7.06 (m, 1H), 3.76-3.56 (m, 2H), 3.40-3.33 (m, 1H), 3.19-3.07 (m, 4H), 2.16 -2.07 (m, 5H), 2.06-1.96 (m, 1H), 1.86-1.73 (m, 1H), 1.73-1.55 (m, 6H), 1.37 (s, 9H).

Separation of enantiomers.

The title target compound (268 mg) purified by preparative HPLC was separated into enantiomers in the chiral phase (see intermediates 262 and 263) [column: Daicel Chiralpak OX-H, 5 μm, 250 mm x 20 mm; eluent n-heptane/ethanol 80:20; flow: 20 ml/min; UV detection: 210 nm, temperature: 23°C]. The combined target fractions were suitably concentrated on a rotary evaporator. The appropriate residues were mixed with 2 ml of acetonitrile and 15 ml of water and lyophilized.

Example 262A.

tert-Butyl 5-({[6-bromo-3-methyl-2-(piperidin-1-yl)quinolin-4-yl]carbonyl}amino)-4-(2,5difluorophenyl)pentanoate (enantiomer 1).

The separation of enantiomers described in Example 261A gave 82 mg (99% pure, ee 100%) of the title compound as the previously eluted enantiomer.

Chiral analytical HPLC [column: Daicel Chiralpak OX-3, 3 µm, 50 mm x 4.6 mm; eluent isoHexan/ethanol 80:20; flow: 1 ml/min; UV detection: 220 nm, temperature: 25°C]: R _t = 2.24 min.

LC-MS (method 1): R _t = 2.74 min; MS (ESIpos): m/z = 616/618 [M+H] ⁺ .

'H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: -0.008 (0.46), 0.008 (0.40), 1.371 (16.00), 1.607 (0.40), 1.670 (0.79), 2.079 (0.65), 2.096 (0.94), 2.115 (1.18), 3.132 (1.05), 7.646 (1.28), 7.655 (0.84), 7.660 (0.76).

Example 263A.

tert-Butyl 5-({[6-bromo-3-methyl-2-(piperidin-1-yl)quinolin-4-yl]carbonyl}amino)-4-(2,5difluorophenyl)pentanoate (enantiomer 2).

The separation of enantiomers described in Example 261A gave 90 mg (98% pure, ee 97%) of the title compound as the later eluted enantiomer.

Chiral analytical HPLC [column: Daicel Chiralpak OX-3, 3 µm, 50 mm x 4.6 mm; eluent isoHexan/ethanol 80:20; flow: 1 ml/min; UV detection: 220 nm, temperature: 25°C]: R _t = 2.60 min.

LC-MS (method 1): Rt = 2.74 min; MS (ESIpos): m/z = 616/618 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (0.44), 1.372 (16.00), 1.605 (0.43), 1.670 (0.83), 2.080 (0.67), 2.096 (0.97), 2.115 (1.24 ), 3.133 (1.10), 7.646 (1.31), 7.655 (0.88), 7.660 (0.81), 8.740 (0.40).

Example 264A.

(+/-)-tert-Butyl-5-({[6-bromo-3-methyl-2-(pyrrolidin-1-yl)quinolin-4-yl]carbonyl}amino)-4-(2,5difluorophenyl) pentanoate (racemate)

Provided (+/-)-tert-butyl-5-{[(6-bromo-2-chloro-3-methylquinolin-4-yl)carbonyl]amino}-4-(2,5difluorophenyl)pentanoate (racemate, 300 mg , 528 µmol, example 226A) in a thick-walled microwave vessel in NMP (4.0 ml) and sequentially mixed with pyrrolidine (220 µl, 2.6 mmol) and DIPEA (460 µl, 2.6 mmol). The vessel was closed and shaken overnight at 130°C. After cooling to RT, the reaction solution was purified by preparative HPLC (method 14). Product-containing fractions were concentrated and dried in vacuo. 245 mg (100% pure, 77% thor.) of the title compound were obtained.

LC-MS (method 1): R _t = 2.13 min; MS (ESIpos): m/z = 602/604 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 8.69 (t, 1H), 7.56 (dd, 1H), 7.48 (d, 1H), 7.44-7.18 (m, 3H), 7.17- 7.08 (m, 1H), 3.73-3.50 (m, 6H), 3.39-3.33 (m, 1H), 2.20-1.97 (m, 6H), 1.91-1.84 (m, 4H), 1.85-1.73 (m, 1H ), 1.37(s, 9H).

Separation of enantiomers.

The title target compound (173 mg) purified by preparative HPLC was separated into enantiomers in the chiral phase (see examples 265A and 266A) [column: Daicel Chiralpak IC, 5 μm, 250 mm x 30 mm; eluent n-heptane/isopropanol 80:20; flow: 42.5 ml/min; UV detection: 260 nm, temperature: 25°C]. The combined target fractions are respectively concentrated

- 122 040220 was triaged (25°C, 40 mbar).

Example 265A.

tert-Butyl 5-({[6-bromo-3-methyl-2-(pyrrolidin-1-yl)quinolin-4-yl]carbonyl}amino)-4-(2,5difluorophenyl)pentanoate (enantiomer 1).

Separation of enantiomers as described in Example 264A gave 83 mg (90% pure, solvent-containing, ee-value 96%) of the title compound as the previously eluted enantiomer.

Chiral analytical HPLC [column: Daicel Chiralpak IC, 5 µm, 250 mm x 4.6 mm; eluent ngeptane/isopropanol 80:20; flow: 1 ml/min; UV detection: 260 nm, temperature: 25°C]: R _t = 19.2 min.

LC-MS (method 1): R _t = 2.13 min; MS (ESIpos): m/z = 602/604 [M+H]+.

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: -0.008 (0.81), 0.008 (0.79), 1.236 (0.96), 1.259 (0.72), 1.298 (0.54), 1.370 (16.00), 1.871 ( 1.18), 2.078 (0.65), 2.095 (0.85), 2.115 (0.44), 2.142 (0.50), 2.523 (0.56), 3.565 (0.80), 7.466 (0.63), 7.488 (1.07), 7.545 (0.55), 0.50).

Example 266A.

tert-Butyl 5-({[6-bromo-3-methyl-2-(pyrrolidin-1-yl)quinolin-4-yl]carbonyl}amino)-4-(2,5difluorophenyl)pentanoate (enantiomer 2).

The separation of enantiomers described in Example 264A gave 86 mg (90% pure containing solvent, ee-value 96%) of the title compound as the later eluted enantiomer.

Chiral analytical HPLC [column: Daicel Chiralpak IC, 5 µm, 250 mm x 4.6 mm; eluent ngeptane/isopropanol 80:20; flow: 1 ml/min; UV detection: 260 nm, temperature: 25°C]: R _t = 23.1 min.

LC-MS (method 1): R _t = 2.13 min; MS (ESIpos): m/z = 602/604 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: -0.008 (0.66), 0.008 (0.62), 0.839 (0.47), 1.235 (1.44), 1.259 (1.15), 1.298 (0.84), 1.352 ( 0.50), 1.370 (16.00), 1.871 (1.21), 2.078 (0.67), 2.095 (0.87), 2.115 (0.46), 2.141 (0.51), 2.523 (0.47), 3.567 (0.83), 7.466 (0.64), 7.488 ( 1.07), 7.545 (0.55), 7.551 (0.51).

Example 267A.

(+/-)-tert-Butyl-5 -({[6-bromo-2-(3,3-difluoropiperidin-1 -yl)-3-methylquinolin-4yl]carbonyl}amino)-4-(2.5 -difluorophenyl)pentanoate (racemate)

Provided (+/-)-tert-butyl-5-{[(6-bromo-2-chloro-3-methylquinolin-4-yl)carbonyl]amino}-4-(2,5difluorophenyl)pentanoate (racemate, 300 mg , 528 µmol, example 226A) in a thick-walled microwave vessel in NMP (4.0 ml) and mixed successively with 3,3-difluoropiperidine hydrochloride (416 mg, 2.64 mmol) and DIPEA (460 µl, 2.6 mmol). The vial was closed and overnight at 130°C and shaken for an additional 20 hours at 140°C. After cooling to RT, the reaction solution was purified by preparative HPLC (method 14). Product-containing fractions were concentrated and dried in vacuo. The residue was dissolved in a small amount of dichloromethane and foamed in vacuo. 253 mg (100% pure, 73% thor.) of the title compound were obtained.

LC-MS (method 1): R _t = 2.60 min; MS (ESIpos): m/z = 652/654 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6): δ [ppm] = 8.75 (t, 1H), 7.74-7.67 (m, 2H), 7.48 (br s, 1H), 7.39-7.20 (m, 2H), 7.17-7.09 (m, 1H), 3.78-3.56 (m, 2H), 3.48 (t, 2H), 3.40-3.29 (m, 1H), 3.17 (br s, 2H), 2.20-1.97 (m, 8H) , 1.92-1.75 (m, 3H), 1.39-1.29 (m, 9H).

Separation of enantiomers.

The title target compound (202 mg) purified by preparative HPLC was separated into enantiomers in the chiral phase (see intermediates 268A and 269A) [column: Daicel Chiralpak OX-H, 5 μm, 250 mm x 30 mm; eluent n-heptane/ethanol 85:15; flow: 42.5 ml/min; UV detection: 220 nm, temperature: 20°C]. The combined target compounds were suitably concentrated and the residue was suitably dried in vacuo.

Example 268A.

tert-Butyl 5-({[6-bromo-2-(3,3-difluoropiperidin-1-yl)-3-methylquinolin-4-yl]carbonyl}amino)-4(2,5-difluorophenyl)pentanoate ( enantiomer 1).

Separation of enantiomers as described in Example 267A yielded 71 mg (99% pure, ee

- 123 040220 value 99%) of the title compound as the previously eluted enantiomer.

Chiral analytical HPLC [column: Daicel Chiralpak OX-3, 3 µm, 50 mm x 4.6 mm; eluent iHexan/ethanol 80:20; flow: 1 ml/min; UV detection: 220 nm, temperature: 25°C]: R _t = 1.10 min.

LC-MS (method 1): R _t = 2.60 min; MS (ESIpos): m/z = 652/654 [M+H]+.

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: -0.008 (0.84), 0.008 (0.94), 1.358 (0.70), 1.371 (16.00), 1.880 (0.44), 2.081 (0.90), 2.098 ( 1.18), 2.120 (0.74), 2.134 (1.11), 3.164 (0.56), 3.475 (0.68), 7.697 (1.31), 7.704 (0.89), 7.709 (0.81), 8.752 (0.43).

Example 269A.

tert-Butyl 5-({[6-bromo-2-(3,3-difluoropiperidin-1-yl)-3-methylquinolin-4-yl]carbonyl}amino)-4(2,5-difluorophenyl)pentanoate ( enantiomer 2).

The separation of enantiomers described in Example 261A gave 71 mg (95% pure, ee 93%) of the title compound as the later eluted enantiomer.

Chiral analytical HPLC [column: Daicel Chiralpak OX-3, 3 µm, 50 mm x 4.6 mm; eluent iHexan/ethanol 80:20; flow: 1 ml/min; UV detection: 220 nm, temperature: 25°C]: R _t = 1.10 min.

LC-MS (method 1): R _t = 2.60 min; MS (ESIpos): m/z = 652/654 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (1.68), 0.008 (1.48), 1.372 (16.00), 1.879 (0.41), 2.081 (0.84), 2.098 (1.10), 2.119 (0.69 ), 2.134 (1.02), 3.165 (0.52), 3.475 (0.62), 7.697 (1.27), 7.704 (0.89), 7.709 (0.79), 8.752 (0.41).

Example 270A.

tert-Butyl 5-[({6-bromo-2-(3-fluoropiperidin-1-yl)-3-methylquinolin-4-yl}carbonyl)amino]-4-(2,5difluorophenyl)pentanoate (mixture of diastereoisomers)

^XXF OS. O ? ⁿ *n ^SNz

Ο^ΝΗ O CH ₃ Br .xlcH ₃

Provided (+/-)-tert-butyl-5-{[(6-bromo-2-chloro-3-methylquinolin-4-yl)carbonyl]amino}-4-(2,5difluorophenyl)pentanoate (racemate, 400 mg , 704 µmol, example 226A) in a thick wall microwave vial in NMP (4.5 ml) and mixed successively with 3-fluoropiperidine hydrochloride (492 mg, 3.52 mmol) and DIPEA (610 µl, 3.5 mmol). The vessel was closed and shaken overnight at 130°C. After cooling to RT, the reaction solution was purified by preparative HPLC (method 14). Product-containing fractions were concentrated and dried in vacuo. 293 mg (100% pure, 66% thor.) of the title compound were obtained.

LC-MS (method 1): Rt = 2.59 min; MS (ESIpos): m/z = 634/636 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6): δ [ppm] = 8.75 (t, 1H), 7.71-7.64 (m, 2H), 7.60-7.36 (m, 1H), 7.33-7.20 (m, 2H) , 7.17-7.08 (m, 1H), 4.98-4.76 (m, 1H), 3.77-3.57 (m, 2H), 3.50-3.35 (m, 2H), 3.23-3.14 (m, 1H), 3.133.03 ( m, 1H), 2.16-1.87 (m, 8H), 1.86-1.73 (m, 2H), 1.71-1.57 (m, 1H), 1.37 (s, 9H), 1H hidden.

Example 271A.

(+/-)-tert-Butyl-5-[(tert-butoxycarbonyl)amino]-4-(2-chlorophenyl)pentanoate (racemate)

Triethylamine ( 3.0 ml, 21.5 mmol) and di-tert-butyl dicarbonate (4.70 g, 21.5 mmol) (gas formation), and the mixture was first stirred at RT and then left for five days. The mixture was then mixed with dichloromethane (60 ml) and washed once with sodium hydrogen carbonate solution and once with saturated sodium chloride solution. The organic phase was dried, filtered and concentrated. The residue was purified by flash column chromatography (100 g Biotage Snap-Cartridge Ultra silica gel, cyclohexane/ethyl acetate gradient 97:3^7:3, Isolera One). The combined target fractions were concentrated on a rotary evaporator at 20° C. and the residue was dried in vacuo. Two fractions of the title compound were obtained, with slightly different purities: fraction 1: 4.33 g (100% pure, 59% th. y., see Analysis section) and fraction 2: 1.66 g (94% pure, 21% th. y. .).

- 124 040220

LC-MS (method 2): Rt = 1.26 min; MS (ESIpos): m/z = 384 [M+H]+.

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 1.333 (9.46), 1.353 (16.00), 1.398 (0.17), 1.692 (0.21), 1.708 (0.24), 1.716 (0.21), 1.731 (0.18 ), 1.933 (0.16), 1.947 (0.27), 1.957 (0.23), 1.976 (0.92), 1.999 (0.31), 2.012 (0.23), 3.038 (0.18), 3.055 (0.25), 3.072 (0.28), 3.087 (0.19 ), 3.183 (0.25), 3.200 (0.23), 3.335 (0.25), 3.352 (0.23), 3.363 (0.16), 6.843 (0.18), 6.857 (0.33), 6.871 (0.17), 7.220 (0.26), 7.227 (0.32 ), 7.238 (0.32), 7.248 (0.27), 7.311 (0.94), 7.320 (1.08), 7.395 (0.60), 7.415 (0.50).

Separation of enantiomers.

Both pooled fractions of the title compound (5.9 g) were adsorbed in ethanol (100 ml), filtered and separated into enantiomers by chiral phase preparative HPLC (see examples 272A and 273A) [column: Daicel Chiralcel OX, 20 μm, 380 mm x 50 mm; flow: 300 ml/min; sample injection: 1.2 ml; UV detection: 210 nm, temperature: 40°C; eluent: 90% carbon dioxide/10% ethanol; duration of action 10 min, isocratic]. The combined target fractions were respectively concentrated and dried in vacuo.

Example 272A.

(+)-tert-Butyl-5-[(tert-butoxycarbonyl)amino]-4-(2-chlorophenyl)pentanoate (enantiomer 1).

The separation of enantiomers described in Example 271A gave 2.59 g (99% pure, ee >99%) of the title compound as the previously eluted enantiomer.

[a] _D20 = +8.5°, 589 nm, c = 0.41 ^g /100 mL, methanol;

LC-MS (method 1): Rt = 2.42 min; MS (ESIpos): m/z = 384 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 1.332 (9.45), 1.352 (16.00), 1.691 (0.22), 1.706 (0.24), 1.715 (0.21), 1.730 (0.18), 1.946 (0.27 ), 1.955 (0.24), 1.975 (0.91), 2.011 (0.23), 3.037 (0.17), 3.054 (0.24), 3.071 (0.28), 3.086 (0.19), 3.182 (0.25), 3.198 (0.23), 3.334 (0.28 ), 3.351 (0.24), 6.843 (0.19), 6.857 (0.33), 6.871 (0.18), 7.219 (0.26), 7.227 (0.33), 7.238 (0.32), 7.247 (0.27), 7.311 (0.98), 7.320 (1.08 ), 7.395 (0.60), 7.415 (0.51).

Example 273A.

(-)-tert-Butyl-5-[(tert-butoxycarbonyl)amino]-4-(2-chlorophenyl)pentanoate (enantiomer 2).

The separation of enantiomers described in Example 271A gave 2.47 g (100% pure, >99% ee) of the title compound as the later eluted enantiomer.

[a] _D20 = -8.2°, 589 nm, c ⁼ 0.65 g/100 ml, methanol;

LC-MS (method 1): Rt = 2.42 min; MS (ESIpos): m/z = 384 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (0.33), 0.008 (0.34), 1.332 (8.75), 1.352 (16.00), 1.691 (0.19), 1.706 (0.22), 1.715 (0.19 ), 1.730 (0.16), 1.946 (0.22), 1.955 (0.20), 1.975 (0.81), 2.012 (0.21), 3.053 (0.22), 3.071 (0.25), 3.086 (0.17), 3.162 (0.18), 3.175 (0.18 ), 3.181 (0.23), 3.198 (0.20), 3.333 (0.28), 3.351 (0.22), 6.858 (0.30), 7.219 (0.23), 7.227 (0.30), 7.238 (0.30), 7.248 (0.25), 7.311 (0.89 ), 7.320 (0.99), 7.396 (0.57), 7.415 (0.48).

Example 274A.

(-)-tert-Butyl-5-amino-4-(2-chlorophenyl)pentanoate hydrochloride (enantiomer 1)

To a mixture of (+)-tert-butyl-5-[(tert-butoxycarbonyl)amino]-4-(2-chlorophenyl)pentanoate (2.55 g, 6.64 mmol, example 272A) in dioxane (13 ml) at RT slowly dropwise a 4 M solution of hydrogen chloride in dioxane (3.3 ml, 13.28 mmol) was added and the mixture was stirred for 22 h at RT. Then a 4 M solution of hydrogen chloride in dioxane (830 µl, 3.32 mmol) was again added dropwise, and the mixture was stirred for another 1 h at RT. Then again a 4 M solution of hydrogen chloride in dioxane (830 µl, 3.32 mmol) was added dropwise and the mixture was stirred for an additional 2 h at RT. The mixture was then concentrated and mixed several times with dichloromethane and re-concentrated. The residue was dried in vacuo. 2.29 g (67% pure, 72% th. y.) of the title compound were obtained.

[a] _D20 = -4.4°, 589 nm, c ⁼ 0.72 g/100 ml, methanol;

LC-MS (method 1): Rt = 1.14 min; MS (ESIpos): m/z = 284 [M+H] ⁺ .

Example 275A.

(+)-tert-Butyl-5-amino-4-(2-chlorophenyl)pentanoate hydrochloride (enantiomer 2).

To a mixture of (-)-tert-butyl-5-[(tert-butoxycarbonyl)amino]-4-(2-chlorophenyl)pentanoate (2.42 g, 6.30 mmol, example 273A) in dioxane (12 ml) at RT slowly dropwise a 4 M solution of hydrogen chloride in dioxane (3.2 ml, 12.61 mmol) was added and the mixture was stirred for 22 h at RT. Then again a 4 M solution of hydrogen chloride in dioxane (790 μl, 3.16 mmol) was added dropwise, and the mixture was stirred for another 1 h at RT. Then again a 4 M solution of hydrogen chloride in dioxane (790 μl, 3.16 mmol) was added dropwise and the mixture was stirred for an additional 2 h at RT. The mixture was then concentrated and mixed several times with dichloromethane and re-concentrated. The residue was dried in

- 125 040220 kuume. 2.15 g (68% pure, 73% th. y.) of the title compound was obtained.

[a] _D20 = +5.9°, 589 nm ^, c = 0.66 g/100 mL, methanol;

LC-MS (method 1): Rt = 1.12 min; MS (ESIpos): m/z = 284 [M+H] ⁺ .

Example 276A.

(+)-tert-Butyl-5-{[(6-bromo-2-chloro-3-methylquinolin-4-yl)carbonyl]amino}-4-(2chlorophenyl)pentanoate (enantiomer 1) [see structural formula in example 37A (racemate)].

DIPEA ( 2.3 ml, 13.22 mmol). Then 6-bromo-2-chloro-3-methylquinoline-4-carbonyl chloride (1.41 g, 4.41 mmol, example 3A) was added and the mixture was stirred for 16 h at RT. The mixture was then mixed with water (100 ml) and shaken. After phase separation, the aqueous phase was extracted once with dichloromethane (100 ml). The combined organic phases were dried over sodium sulfate, filtered and concentrated, and the residue was adsorbed in dichloromethane and purified by flash column chromatography (100 g Biotage SnapCartridge Ultra silica gel, cyclohexane/ethyl acetate gradient 97:3^7:3, Isolera One). The combined desired fractions were concentrated and the residue was dried in vacuo. 2.26 g (100% pure, 91% th. y.) of the title compound was obtained.

[a] _D20 = +12.8°, 589 nm, c = 0.59 ^g /100 mL, methanol;

LC-MS (method 2): Rt = 1.33 min; MS (ESIpos): m/z = 565/567/569 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.157 (0.24), 1.175 (0.47), 1.193 (0.24), 1.371 (16.00), 1.816 (0.18), 1.820 (0.18), 1.989 (0.88) , 2.028 (0.18), 2.033 (0.17), 2.045 (0.19), 2.051 (0.17), 2.065 (0.28), 2.077 (0.96), 2.093 (0.81), 2.110 (0.29), 2.114 (0.28), 2.213 (0.28) . . , 8.874 (0.20).

Example 277A.

(-)-tert-Butyl-5-{[(6-bromo-2-chloro-3-methylquinolin-4-yl)carbonyl]amino}-4-(2chlorophenyl)pentanoate (enantiomer 2).

DIPEA ( 2.2 ml, 12.70 mmol). Then 6-bromo-2-chloro-3-methylquinoline-4-carbonyl chloride (1.35 g, 4.23 mmol, example 3A) was added and the mixture was stirred for 16 h at RT. The mixture was then mixed with water (100 ml) and shaken. After phase separation, the aqueous phase was extracted once with dichloromethane (100 ml). The combined organic phases were dried over sodium sulfate, filtered and concentrated, and the residue was adsorbed in dichloromethane and purified by flash column chromatography (100 g Biotage SnapCartridge Ultra silica gel, cyclohexane/ethyl acetate gradient 97:3^7:3, Isolera One). The combined desired fractions were concentrated and the residue was dried in vacuo. 2.21 g (99% pure, 91% theoretical) of the title compound was obtained.

[a] _D20 = -12.2°, 589 nm, c = 0.43 g ^/ 100 ml, methanol;

LC-MS (method 2): Rt = 1.33 min; MS (ESIpos): m/z = 565/567/569 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (0.24), 0.008 (0.21), 1.157 (0.30), 1.175 (0.59), 1.193 (0.30), 1.371 (16.00), 1.815 (0.17 ), 1.989 (1.13), 2.027 (0.17), 2.045 (0.18), 2.050 (0.16), 2.064 (0.27), 2.076 (0.96), 2.092 (0.80), 2.109 (0.28), 2.210 (0.28), 3.588 (0.19 ), 3.712 (0.28), 4.021 (0.26), 4.039 (0.26), 7.279 (0.27), 7.298 (0.19), 7.359 (0.17), 7.377 (0.29), 7.396 (0.16), 7.448 (0.59), 7.451 (0.63 ), 7.468 (0.50), 7.470 (0.52), 7.491 (0.44), 7.509 (0.33), 7.894 (2.22), 8.846 (0.20), 8.860 (0.39), 8.874 (0.20).

Example 278A.

(+)-tert-Butyl-5-[({6-bromo-3-methyl-2-[( ² H ₁₀ )nineridin-1 -yl]quinolin-4-yl}carbonyl)amino]-4-(2chlorophenyl )pentanoate (enantiomer 1)

SI ΉΗ about SN ₃

Λθ ^Η 3 η dd

D D-D

To a solution of (+)-tert-butyl-5-{[(6-bromo-2-chloro-3-methylquinolin-4-yl)carbonyl]amino}-4-(2chlorophenyl)pentanoate (283 mg, 0.5 mmol, example 276A) in NMP (2 ml) was added piperidine-D11 (148 μl, 1.50 mmol) and the mixture was stirred for 2 h at 110°C. After cooling to RT, the mixture was mixed with water (75 ml) and the solid present was filtered off and washed twice with water (respectively 4 ml).

- 126 040220

After drying in vacuo, 284 mg (92% pure, 83% theoretical) of the title compound were obtained.

[a] ^D20 = +9.2°, 589 nm, c = 0.39 g/100 mL, methanol;

LC-MS (method 1): R _t = 2.79 min; MS (ESIpos): m/z = 624/626 [M+H] ⁺ .

1H-NMR (500 MHz, DMSO-d ₆ ) δ [ppm]: 1.087 (1.47), 1.369 (16.00), 1.814 (0.16), 2.055 (0.21), 2.075 (1.01), 2.085 (0.55), 2.099 (0.27 ), 2.104 (0.27), 2.129 (1.02), 2.695 (0.24), 3.585 (0.18), 3.671 (0.28), 7.255 (0.18), 7.271 (0.36), 7.285 (0.23), 7.356 (0.22), 7.371 (0.39 ), 7.385 (0.20), 7.440 (0.61), 7.442 (0.58), 7.456 (0.53), 7.458 (0.48), 7.479 (0.49), 7.482 (0.50), 7.495 (0.41), 7.624 (0.34), 7.641 (1.25 ), 7.651 (0.85), 7.655 (0.79), 7.669 (0.21), 7.673 (0.23), 8.709 (0.23), 8.720 (0.41), 8.732 (0.19).

Example 279A.

(-)-tert-Butyl-5-[({6-bromo-3-methyl-2-[( ² H ₁₀ )piperidin-1-yl]quinolin-4-yl}carbonyl)amino]-4-(2chlorophenyl )pentanoate (enantiomer 2).

To a solution of (-)-tert-butyl-5-{[(6-bromo-2-chloro-3-methylquinolin-4-yl)carbonyl]amino}-4-(2chlorophenyl)pentanoate (283 mg, 0.5 mmol, example 277A) in NMP (2 ml) was added piperidine-DH (148 μl, 1.50 mmol) and the mixture was stirred for 4 h at 110°C. After cooling to RT, the mixture was mixed with water (75 ml) and the solid present was filtered off and washed twice with water (respectively 4 ml). After drying in vacuo, 276 mg (100% pure, 88% thor.) of the title compound were obtained.

[a] _D20 = -9.3°, 589 nm, c ⁼ 0.33 g/100 ml, methanol;

LC-MS (method 1): R _t = 2.78 min; MS (ESIpos): m/z = 624/626 [M+H] ⁺ .

1H-NMR (600 MHz, DMSO-d6) δ [ppm]: 1.087 (0.22), 1.369 (16.00), 1.807 (0.17), 2.041 (0.18), 2.045 (0.16), 2.053 (0.21), 2.056 (0.23) , 2.073 (1.08), 2.083 (0.72), 2.095 (0.33), 2.098 (0.34), 2.126 (0.65) , 7.286 (0.21) , 7.628 (0.47), 7.643 (1.32), 7.656 (0.76), 7.660 (0.72), 7.671 (0.26), 7.674 (0.27), 8.734 (0.24), 8.744 (0.45), 8.753 (0.23).

Example 280A.

(-)-tert-Butyl-5-[({6-bromo-3-methyl-2-[( ² H ₁₀ )piperidin-1-yl]quinolin-4-yl}carbonyl)amino]-4-[2 (trifluoromethyl)phenyl]pentanoate (enantiomer 1)

To a solution of (-)-tert-butyl-5-{[(6-bromo-2-chloro-3-methylquinolin-4-yl)carbonyl]amino}-4-[2(trifluoromethyl)phenyl]pentanoate (234 mg , 391 µmol, example 39A) in NMP (1.6 ml) was added piperidine-DII (116 µl, 1.17 mmol) and the mixture was stirred for 4 h at 110°C. After cooling to RT, the mixture was mixed with water (75 ml) and the solid present was filtered off and washed twice with water (respectively 4 ml). After drying in vacuo, 228 mg (86% pure, 97% theoretical) of the title compound were obtained.

[a] ^D20 = -14.0°, 589 nm, c = 0.48 g/100 ml, methanol;

LC-MS (method 1): R _t = 2.80 min; MS (ESIpos): m/z = 658/660 [M+H] ⁺ .

1H-NMR (600 MHz, DMSO-d ₆ ) δ [ppm]: 1.346 (16.00), 1.889 (0.17), 1.903 (0.18), 1.913 (0.17), 1.991 (0.23), 2.001 (0.18), 2.006 (0.26 ), 2.015 (0.21), 2.022 (0.23), 2.034 (0.30), 2.049 (0.29), 2.116 (0.17), 2.128 (0.26), 2.140 (0.30), 2.163 (0.54), 2.696 (0.21), 3.303 (0.21 ), 3.315 (0.26), 7.470 (0.21), 7.483 (0.41), 7.495 (0.24), 7.640 (0.39), 7.655 (1.29), 7.665 (0.77), 7.669 (0.70), 7.680 (0.22), 7.684 (0.24 ), 7.697 (0.18), 7.709 (0.43), 7.726 (0.60), 7.739 (0.99), 7.752 (0.27), 8.790 (0.23), 8.800 (0.46), 8.809 (0.23).

Example 281A.

(+)-tert-butyl-5-[({6-bromo-3-methyl-2-[( ² H ₁₀ )piperidin-1-yl]quinolin-4-yl}carbonyl)amino]-4-[2 (trifluoromethyl)phenyl]pentanoate (enantiomer 2).

To a solution of (+)-tert-butyl-5-{[(6-bromo-2-chloro-3-methylquinolin-4-yl)carbonyl]amino}-4-[2(trifluoromethyl)phenyl]pentanoate (234 mg , 391 µmol, example 40A) in NMP (1.6 ml) was added piperidine-DII (116 µl, 1.17 mmol) and the mixture was stirred for 4 h at 110°C. After cooling to RT, the mixture was mixed with water (75 ml) and the solid present was filtered off and washed twice with water (respectively 4 ml). After drying in vacuo, 221 mg (100% pure, 86% thor.) of the title compound were obtained.

[a] ^D20 = +13.9°, 589 nm, c = 0.49 g/100 mL, methanol;

- 127 040220

LC-MS (method 1): R _t = 2.80 min; MS (ESIpos): m/z = 658/660 [M+H]+.

1H-NMR (600 MHz, DMSO-d ₆ ) δ [ppm]: 1.346 (16.00), 1.890 (0.18), 1.898 (0.18), 1.905 (0.19), 1.913 (0.18), 1.991 (0.24), 2.001 (0.19 ), 2.006 (0.28), 2.016 (0.22), 2.023 (0.25), 2.034 (0.32), 2.049 (0.31), 2.116 (0.19), 2.129 (0.28), 2.140 (0.33), 2.163 (0.58), 3.303 (0.19 ), 3.314 (0.26), 3.322 (0.25), 7.470 (0.23), 7.482 (0.45), 7.495 (0.27), 7.641 (0.40), 7.655 (1.33), 7.665 (0.80), 7.669 (0.72), 7.680 (0.23 ), 7.683 (0.24), 7.696 (0.20), 7.709 (0.47), 7.726 (0.64), 7.739 (1.05), 7.752 (0.29), 8.790 (0.25), 8.800 (0.49), 8.810 (0.24).

Example 282A.

(+)-tert-Butyl-5-[({6-bromo-3-methyl-2-[( ² H ₁₀ )piperidin-1 -yl]quinolin-4-yl}carbonyl)amino]-4-[2 (trifluoromethoxy)phenyl]pentanoate (enantiomer 1)

To a solution of (+)-tert-butyl-5-{[(6-bromo-2-chloro-3-methylquinolin-4-yl)carbonyl]amino}-4-[2(trifluoromethoxy)phenyl]pentanoate (241 mg , 391 µmol, example 42A) in NMP (1.6 ml) was added piperidine-DII (116 µl, 1.17 mmol) and the mixture was stirred for 4 h at 110°C. After cooling to RT, the mixture was mixed with water (75 ml) and the solid present was filtered off and washed twice with water (respectively 4 ml). After drying in vacuo, 211 mg (100% pure, 80% theoretical) of the title compound were obtained.

[a]D ²⁰ = +12.4°, 589 nm, c = 0.45 g/100 ml, DMSO;

LC-MS (method 1): R _t = 2.82 min; MS (ESIpos): m/z = 674/676 [M+H] ⁺ .

1H-NMR (600 MHz, DMSO-d ₆ ) δ [ppm]: 1.360 (16.00), 1.374 (0.22), 1.809 (0.20), 1.824 (0.21), 2.038 (0.29), 2.052 (0.31), 2.055 (0.30 ), 2.065 (1.21), 2.085 (0.35), 2.089 (0.32), 2.097 (0.18), 2.138 (0.38), 3.383 (0.27), 3.615 (0.18), 3.626 (0.22), 3.636 (0.22), 3.648 (0.20 ), 3.659 (0.16), 7.352 (0.25), 7.364 (0.40), 7.394 (0.18), 7.407 (0.67), 7.413 (0.58), 7.419 (0.65), 7.554 (0.41), 7.564 (0.31), 7.569 (0.31 ), 7.637 (0.43), 7.652 (1.21), 7.665 (0.69), 7.668 (0.64), 7.679 (0.23), 7.683 (0.23), 8.758 (0.21), 8.767 (0.40), 8.777 (0.21).

Example 283A.

(-)-tert-Butyl-5-[({6-bromo-3-methyl-2-[( ² H ₁₀ )piperidin-1-yl]quinolin-4-yl}carbonyl)amino]-4-[2 (trifluoromethoxy)phenyl]pentanoate (enantiomer 2).

To a solution of (-)-tert-butyl-5-{[(6-bromo-2-chloro-3-methylquinolin-4-yl)carbonyl]amino}-4-[2(trifluoromethoxy)phenyl]pentanoate (241 mg , 391 µmol, example 43A) in NMP (1.6 ml) was added piperidine-DII (116 µl, 1.17 mmol) and the mixture was stirred for 4 h at 110°C. After cooling to RT, the mixture was mixed with water (75 ml) and the solid present was filtered off and washed twice with water (respectively 4 ml). After drying in vacuo, 196 mg (94% pure, 69% theoretical) of the title compound were obtained.

[a] ^D20 = -11.9°, 589 nm, c = 0.49 g/100 ml, DMSO;

LC-MS (method 1): R _t = 2.83 min; MS (ESIpos): m/z = 674/676 [M+H] ⁺ .

1H-NMR (600 MHz, DMSO-d ₆ ) δ [ppm]: 1.360 (16.00), 1.817 (1.14), 2.064 (3.81), 2.137 (2.64), 2.694 (0.27), 3.635 (1.64), 7.362 (1.83 ), 7.410 (3.01), 7.562 (1.69), 7.657 (2.27), 8.767 (1.34).

Example 284A.

(+)-tert-Butyl-5-[({6-bromo-3-methyl-2-[( ² H ₁₀ )pyrrolidin-1-yl]quinolin-4-yl}carbonyl)amino]-4-(2chlorophenyl )pentanoate (enantiomer 1)

To a solution of (+)-tert-butyl-5-{[(6-bromo-2-chloro-3-methylquinolin-4-yl)carbonyl]amino}-4-(2chlorophenyl)pentanoate (283 mg, 0.5 mmol, example 276A) pyrrolidine 2,2,3,3,4,4,5,5-D8 (150 μl, 1.50 mmol) was added to NMP (2 ml) and the mixture was stirred for 2 h at 110°C. After cooling to RT, the mixture was mixed with water (75 ml) and the solid present was filtered off and washed twice with water.

- 128 040220 (corresponding to 4 ml). After drying in vacuo, 254 mg (93% pure, 77% thor.) of the title compound were obtained.

[a] ^D20 = +9.0°, 589 nm, c = 0.47 g/100 mL, methanol;

LC-MS (method 1): R _t = 2.13 min; MS (ESIpos): m/z = 608/610 [M+H] ⁺ .

1H-NMR (500 MHz, DMSO-d ₆ ) δ [ppm]: 1.085 (1.40), 1.334 (0.21), 1.367 (16.00), 1.798 (0.21), 1.815 (0.28), 2.028 (0.20), 2.038 (0.23 ), 2.044 (0.23), 2.052 (0.34), 2.073 (1.32), 2.083 (0.78), 2.097 (0.37), 2.103 (0.32), 2.156 (0.92), 2.694 (0.20), 3.578 (0.30), 3.655 (0.31 ), 7.250 (0.26), 7.266 (0.49), 7.281 (0.32), 7.352 (0.34), 7.367 (0.56), 7.381 (0.34), 7.434 (0.82), 7.449 (0.69), 7.468 (0.97), 7.474 (0.78 ), 7.486 (1.43), 7.545 (0.71), 7.549 (0.68), 7.562 (0.47), 7.567 (0.44), 8.658 (0.31), 8.669 (0.50), 8.680 (0.26).

Example 285A.

(-)-tert-Butyl-5-[({6-bromo-3-methyl-2-[( ² H ₁₀ )pyrrolidin-1-yl]quinolin-4-yl}carbonyl)amino]-4-(2chlorophenyl )pentanoate (enantiomer 2).

To a solution of (-)-tert-butyl-5-{[(6-bromo-2-chloro-3-methylquinolin-4-yl)carbonyl]amino}-4-(2chlorophenyl)pentanoate (283 mg, 0.5 mmol, example 277A), pyrrolidine 2,2,3,3,4,4,5,5-D8 (150 μl, 1.50 mmol) was added to NMP (2 ml) and the mixture was stirred for 2 h at 110°C. After cooling to RT, the mixture was mixed with water (75 ml) and the solid present was filtered off and washed twice with water (respectively 4 ml). After drying in vacuo, 274 mg (100% pure, 90% theoretical) of the title compound were obtained.

[a] _D20 = -9.2°, 589 nm, c ⁼ 0.37 g/100 ml, methanol;

LC-MS (method 1): R _t = 2.11 min; MS (ESIpos): m/z = 608/610 [M+H] ⁺ .

1H-NMR (600 MHz, DMSO-d6) δ [ppm]: 1.085 (0.23), 1.367 (16.00), 1.809 (0.17), 2.039 (0.17), 2.051 (0.20), 2.055 (0.24), 2.072 (0.92) . , 7.357 (0.18) , 7.493 (0.39), 7.550 (0.57), 7.553 (0.53), 7.564 (0.40), 7.568 (0.38), 8.686 (0.18), 8.695 (0.32), 8.703 (0.18).

Example 286A.

(-)-tert-Butyl-5-[({6-bromo-3-methyl-2-[( ² H ₁₀ )pyrrolidin-1-yl]quinolin-4-yl}carbonyl)amino]-4-[2 (trifluoromethyl)phenyl]pentanoate (enantiomer 1)

To a solution of (-)-tert-butyl-5-{[(6-bromo-2-chloro-3-methylquinolin-4-yl)carbonyl]amino}-4-[2(trifluoromethyl)phenyl]pentanoate (234 mg , 391 µmol, example 39A) pyrrolidine-2,2,3,3,4,4,5,5-D8 (98 µl, 1.17 mmol) was added to NMP (1.6 ml) and the mixture was stirred for 3 h at 110°С . After cooling to RT, the mixture was mixed with water (75 ml) and the solid present was filtered off and washed twice with water (respectively 4 ml). After drying in vacuo, 218 mg (100% pure, 87% thor.) of the title compound were obtained.

[a] _D20 = -13.1°, 589 nm, c = 0.44 g ^/ 100 ml, methanol;

LC-MS (method 1): R _t = 2.16 min; MS (ESIpos): m/z = 642/644 [M+H] ⁺ .

1H-NMR (600 MHz, DMSO-d6) δ [ppm]: 1.324 (0.18), 1.345 (16.00), 1.890 (0.20), 1.898 (0.21), 1.904 (0.21), 1.913 (0.21), 1.987 (0.25) , 1.997 (0.20), 2.002 (0.28), 2.012 (0.21), 2.027 (0.24), 2.038 (0.33), 2.053 (0.33), 2.065 (0.17), 2.103 (0.18), 2.113 (0.24) . . , 7.750 (0.34), 8.746 (0.35).

Example 287A.

(+)-tert-Butyl-5-[({6-bromo-3-methyl-2-[( ² H ₁₀ )pyrrolidin-1-yl]quinolin-4-yl}carbonyl)amino]-4-[2 (trifluoromethyl)phenyl]pentanoate (enantiomer 2).

To a solution of (+)-tert-butyl-5-{[(6-bromo-2-chloro-3-methylquinolin-4-yl)carbonyl]amino}-4-[2(trifluoromethyl)phenyl]pentanoate (234 mg , 391 μmol, example 40A) in NMP (1.6 ml) was added pyrrolidine-2,2,3,3,4,4,5,5-D8 (98 μl, 1.17 mmol), and the mixture was stirred for 3 h at 110°C . After cooling to RT, the mixture was mixed with water (75 ml) and the solid present was filtered off and washed twice with water (respectively 4 ml). After drying in vacuo, 239 mg (100% pure, 95% theoretical) of the title compound were obtained.

[a] _D20 = +14.1°, 589 nm, c = 0.44 ^g /100 mL, methanol;

- 129 040220

LC-MS (method 1): Rt = 2.16 min; MS (ESIpos): m/z = 642/644 [M+H] ⁺ .

1H-NMR (600 MHz, DMSO-d6) δ [ppm]: 1.345 (16.00), 1.890 (0.16), 1.897 (0.17), 1.904 (0.17), 1.913 (0.17), 1.987 (0.22), 1.997 (0.17) . , 2.159 (0.20), 2.176 (0.21), 2.186 (0.18),2.696 (0.17), 3.302 (0.19), 3.313 (0.23), 7.465 (0.18), 7.477 (0.35), 7.484 (0.89), 7.499 (1.12) . , 8.745 (0.30).

Example 288A.

(+)-tert-Butyl-5-[({6-bromo-3-methyl-2-[( ² H ₁₀ )pyrrolidin-1-yl]quinolin-4-yl}carbonyl)amino]-4-[2 (trifluoromethoxy)phenyl]pentanoate (enantiomer 1)

To a solution of (+)-tert-butyl-5-{[(6-bromo-2-chloro-3-methylquinolin-4-yl)carbonyl]amino}-4-[2(trifluoromethoxy)phenyl]pentanoate (241 mg , 391 µmol, example 42A) pyrrolidine-2,2,3,3,4,4,5,5-D8 (98 µl, 1.17 mmol) was added to NMP (1.6 ml) and the mixture was stirred for 2 h at 110°С . After cooling to RT, the mixture was mixed with water (75 ml) and the solid present was filtered off and washed twice with water (respectively 4 ml). After drying in vacuo, 241 mg (98% pure, 91% theoretical) of the title compound were obtained.

[a] _D20 = +13.9°, 589 nm, c = 0.46 g/100 mL ^, methanol;

LC-MS (method 1): Rt = 2.22 min; MS (ESIpos): m/z = 658/660 [M+H] ⁺ .

1H-NMR (600 MHz, DMSO-d6) δ [ppm]: 1.358 (16.00), 1.372 (0.17), 1.806 (0.22), 1.823 (0.20), 2.039 (0.27), 2.049 (0.34), 2.062 (1.24) , 2.080 (0.32), 2.084 (0.26), 2.16 (0.14), 3.369 (0.20), 3.381 (0.20), 3.61 (0.14), 3.65 (0.15), 7.345 (0.26), 7.357 (0.41) 7.407 (0.47), 7.414 (0.50), 7.478 (0.71), 7.493 (0.98), 7.550 (0.42), 7.557 (0.64), 7.561 (0.73), 7.565 (0.37), 7.572 (0.36), 7.575 (0.33) , 8.715 (0.25).

Example 289A.

(-)-tert-Butyl-5-[({6-bromo-3-methyl-2-[( ² H ₁₀ )pyrrolidin-1-yl]quinolin-4-yl}carbonyl)amino]-4-[2 (trifluoromethoxy)phenyl]pentanoate (enantiomer 2).

To a solution of (-)-tert-butyl-5-{[(6-bromo-2-chloro-3-methylquinolin-4-yl)carbonyl]amino}-4-[2(trifluoromethoxy)phenyl]pentanoate (241 mg , 391 μmol, example 43A) in NMP (1.6 ml) was added pyrrolidine-2,2,3,3,4,4,5,5-D8 (98 μl, 1.17 mmol), and the mixture was stirred for 3 h at 110°C . After cooling to RT, the mixture was mixed with water (75 ml) and the solid present was filtered off and washed twice with water (respectively 4 ml). After drying in vacuo, 225 mg (100% pure, 88% thor.) of the title compound were obtained.

[a] _D20 = -13.7°, 589 nm, c = 0.43 g ^/ 100 ml, methanol;

LC-MS (method 1): Rt = 2.24 min; MS (ESIpos): m/z = 658/660 [M+H] ⁺ .

1H-NMR (600 MHz, DMSO-d6) δ [ppm]: 1.359 (16.00), 1.807 (0.21), 1.824 (0.20), 2.040 (0.26), 2.050 (0.33), 2.064 (1.21), 2.081 (0.31) , 2.086 (0.25), 2.16 (0.14), 3.383 (0.24), 3.61 (0.13), 3.65 (0.13), 7.345 (0.25), 7.355 (0.33), 7.358 (0.41), 7.402 (0.47), 7.408 (0.47) , 7.414 (0.49), 7.480 (0.71), 7.495 (0.99), 7.550 (0.40), 7.553 (0.33), 7.558 (0.60), 7.562 (0.71), 7.565 (0.38), 7.573 (0.35), 7.576 (0.33) , 8.718 (0.24).

Example 290A.

tert-Butyl-5-[({6-bromo-3-methyl-2-[( ² H ₁₀ )pyrrolidin-1-yl]quinolin-4-yl}carbonyl)amino]-4-(2chloro-3,6 -difluorophenyl)pentanoate (enantiomer 1)

To a solution of (+)-tert-butyl-5-{[(6-bromo-2-chloro-3-methylquinolin-4-yl)carbonyl]amino}-4-(2-chloro3,6-difluorophenyl)pentanoate ( 241 mg, 400 µmol, example 48A) in NMP (1.6 ml) was added pyrrolidine 2,2,3,3,4,4,5,5-D8 (100 µl, 1.20 mmol) and the mixture was stirred for 20 h at 110°C . After cooling down to RT

- 130 040220 the mixture was mixed with water (100 ml) and extracted twice with ethyl acetate (respectively 80 ml). The combined organic phases were dried over sodium sulfate, filtered and concentrated and the residue was purified by preparative HPLC (method 32). The combined target fractions were concentrated and the residue was lyophilized from acetonitrile/water. Two fractions were obtained: as fraction 1, 34 mg (100% pure) (+)-5-[({6-bromo-3-methyl-2-[( ² H ₁₀ )pyrrolidin-1-yl]quinolin-4yl }carbonyl)amino]-4-(2-chloro-3,6-difluorophenyl)valeric acid (see Example 281, Method B). As fraction 2, 42 mg (93% pure, 15% theoretical yield, see Analysis) of the title compound were obtained.

LC-MS (method 1): Rt = 2.14 min; MS (ESIpos): m/z = 644/646 [M+H] ⁺ .

1H-NMR (600 MHz, DMSO-d6) δ [ppm]: 1.231 (0.25), 1.359 (16.00), 2.053 (0.22), 2.061 (0.26), 2.074 (0.26), 2.084 (0.19), 2.139 (0.80) , 2.151 (1.21), 2.162 (0.89), 3.689 (0.28), 7.302 (0.28), 7.413 (0.24), 7.475 (1.03), 7.490 (1.40), 7.558 (0.72), 7.562 (0.66), 7.573 (0.51) , 7.576 (0.48), 8.786 (0.36).

Example 291A.

tert-Butyl-5-[({6-bromo-3-methyl-2-[( ² H ₁₀ )pyrrolidin-1-yl]quinolin-4-yl}carbonyl)amino]-4-(2chloro-3,6 -difluorophenyl)pentanoate (enantiomer 2).

To a solution of (-)-tert-butyl-5-{[(6-bromo-2-chloro-3-methylquinolin-4-yl)carbonyl]amino}-4-(2-chloro3,6-difluorophenyl)pentanoate ( 241 mg, 400 µmol, example 49A) in NMP (1.6 ml) was added pyrrolidine 2,2,3,3,4,4,5,5-D8 (100 µl, 1.20 mmol) and the mixture was stirred for 20 h at 110°C . After cooling to RT, the mixture was mixed with water (100 ml) and extracted twice with ethyl acetate (respectively 80 ml). The combined organic phases were dried over sodium sulfate, filtered and concentrated and the residue was purified by preparative HPLC (method 32). The combined target fractions were concentrated and the residue was lyophilized from acetonitrile/water. Two fractions were obtained: as fraction 1, 55 mg (100% pure) of (-)-5-[({6-bromo-3-methyl-2[( ² H ₁₀ )pyrrolidin-1-yl] described in Example 282 was obtained quinolin-4-yl}carbonyl)amino]-4-(2-chloro-3,6-difluorophenyl)valeric acid. As fraction 2, 24 mg (100% pure, 9% theoretical yield, see Analysis) of the title compound were obtained.

LC-MS (method 1): Rt = 2.09 min; MS (ESIpos): m/z = 644/646 [M+H] ⁺ .

1H-NMR (600 MHz, DMSO-d6) δ [ppm]: 1.231 (0.36), 1.359 (16.00), 1.962 (0.21), 2.054 (0.30), 2.063 (0.36), 2.075 (0.36), 2.086 (0.28) , 2.097 (0.23), 2.141 (1.07), 2.152 (1.57), 3.692 (0.39), 3.751 (0.22), 7.301 (0.37), 7.412 (0.33), 7.476 (0.97), 7.491 (1.32), 7.558 (0.76) , 7.573 (0.56), 8.786 (0.47).

Example 292A.

tert-Butyl-(4R)-5-({[6-bromo-3-methyl-2-(pyrrolidin-1-yl)quinolin-4-yl]carbonyl}amino)-4-(2chlorophenyl)pentanoate (enantiomer 1 ) [for structural formula, see Example 79A (racemate)].

To a solution of (+)-tert-butyl-5-{[(6-bromo-2-chloro-3-methylquinolin-4-yl)carbonyl]amino}-4-(2chlorophenyl)pentanoate (2.30 g, 4.06 mmol, example 276A) in NMP (34 ml) was added pyrrolidine (1.0 ml, 12.18 mmol) and the mixture was stirred for 17 h at 100°C. After cooling to RT, the mixture was concentrated and the residue was mixed with water (100 ml) and ethyl acetate (100 ml) and shaken. After phase separation, the aqueous phase was extracted once with ethyl acetate (75 ml). The combined organic phases were washed once with saturated sodium chloride solution (150 ml), dried over sodium sulfate, filtered and concentrated, and the residue was adsorbed in dichloromethane and purified by flash column chromatography (50 g Biotage Snap-Cartridge Ultra silica gel, cyclohexane/ethyl acetate gradient 93 :7 ^ 6:4, Isolera One). The combined desired fractions were concentrated and the residue was dried in vacuo. 2.19 g (100% pure, 90% th. y.) of the title compound were obtained.

[a] _D20 = +6.3°, 589 nm ^, c = 0.45 g/100 mL, methanol;

LC-MS (method 2): Rt = 1.08 min; MS (ESIpos): m/z = 600/602 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.175 (0.27), 1.367 (16.00), 1.794 (0.16), 1.814 (0.23), 1.870 (1.42), 1.988 (0.49), 2.034 (0.17) . , 7.266 (0.42), 7.285 (0.31), 7.349 (0.28), 7.368 (0.50), 7.386 (0.30), 7.432 (0.66), 7.434 (0.67), 7.452 (0.54), 7.454 (0.54), 7.467 (0.78) , 7.473 (0.61), 7.490 (1.36), 7.544 (0.64), 7.550 (0.60), 7.567 (0.38), 7.572 (0.37), 8.657 (0.22), 8.671 (0.42), 8.685 (0.22).

The absolute configuration of the compound was determined using VCD spectroscopy (cf. Kuppens et al. Determination of absolute configuration via vibrational circular dichroism, Drug Discovery Today: Technologies 2004, 7, 269-275; Stephens, P.J., Vibrational circular dichroism spectroscopy: A new tool for the stereochemical characterization of chiral molecules, Computational Medicinal Chemistry for Drug Discovery 2004, 699-725).

Thus, the title compound is in the R configuration.

Example 293A.

(-)-tert-Butyl-5-({[6-bromo-3-methyl-2-(pyrrolidin-1-yl)quinolin-4-yl]carbonyl}amino)-4-(2chlorophenyl)pentanoate (enantiomer 2 ).

To a solution of (-)-tert-butyl-5-{[(6-bromo-2-chloro-3-methylquinolin-4-yl)carbonyl]amino}-4-(2chlorophenyl)pentanoate (2.25 g, 3.97 mmol, example 277A) in NMP (34 ml) was added pyrrolidine (1.0 ml,

- 131 040220

11.92 mmol), and the mixture was stirred for 17 h at 100°C. After cooling to RT, the mixture was concentrated and the residue was mixed with water (100 ml) and ethyl acetate (100 ml) and shaken. After phase separation, the aqueous phase was extracted once with ethyl acetate (75 ml). The combined organic phases were washed once with saturated sodium chloride solution (150 ml), dried over sodium sulfate, filtered and concentrated, and the residue was adsorbed in dichloromethane and purified by flash column chromatography (50 g Biotage Snap-Cartridge Ultra silica gel, cyclohexane/ethyl acetate gradient 93 :7 ^ 6:4, Isolera One). The combined desired fractions were concentrated and the residue was dried in vacuo. 2.14 g (98% pure, 88% th. y.) of the title compound were obtained.

[a] ^D20 = -10.4°, 589 nm, c = 0.46 g/100 ml, methanol;

LC-MS (method 2): Rt = 1.08 min; MS (ESIpos): m/z = 600/602 [M+H]+.

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.157 (0.18), 1.175 (0.36), 1.192 (0.18), 1.367 (16.00), 1.814 (0.20), 1.870 (1.24), 1.988 (0.67) , 2.044 (0.20), 2.051 (0.18), 2.072 (1.15), 2.083 (0.57), 2.100 (0.24), 2.108 (0.22), 2.158 (0.85), 3.311 (8.02), 3.657 (0.27), 7.248 (0.16) , 7.266 (0.37), 7.286 (0.27), 7.349 (0.25), 7.368 (0.45), 7.386 (0.27), 7.432 (0.64), 7.434 (0.64), 7.451 (0.53), 7.454 (0.52), 7.467 (0.78) , 7.473 (0.55), 7.476 (0.54), 7.490 (1.36), 7.544 (0.64), 7.550 (0.59), 7.567 (0.37), 7.572 (0.36), 8.657 (0.20), 8.671 (0.38), 8.686 (0.19) .

Implementation examples.

Example 1

(+/-)-4-({[6-bromo-3-methyl-2-(piperidin-1-yl)quinolin-4-yl]carbonyl}amino)-3-(2-chloro-6fluorophenyl)butanoic acid (racemate)

To a solution of (+/-)-tert-butyl-4-({[6-bromo-3-methyl-2-(piperidin-1-yl)quinolin-4yl]carbonyl}amino)-3-(2-chloro -6-fluorophenyl)butanoate (150 mg, 242 µmol, racemate, example 53 A) in dichloromethane (2.3 ml) was added TFA (370 µl, 4.8 mmol) and the mixture was stirred 16 h at RT. The mixture was then concentrated and mixed several times with dichloromethane and re-concentrated. The residue was dissolved in acetonitrile and purified by preparative HPLC (method 11). The combined target fractions were concentrated and the residue was lyophilized. 125 mg (98% pure, 90% theoretical) of the title compound were obtained.

LC-MS (method 1): Rt = 2.13 min; MS (ESIpos): m/z = 562/564 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (3.57), 0.008 (2.96), 0.146 (0.41), 1.611 (4.57), 1.676 (8.94), 2.072 (0.69), 2.150 (16.00 ), 2.327 (0.68), 2.366 (0.48), 2.670 (0.79), 2.709 (0.98), 2.774 (1.22), 2.796 (3.04), 2.812 (3.09), 2.835 (1.38), 2.851 (1.09), 3.153 (11.54 ), 3.711 (1.62), 3.816 (1.22), 4.070 (2.46), 4.089 (3.00), 4.106 (2.39), 7.176 (1.51), 7.186 (1.95), 7.200 (2.59), 7.208 (2.12), 7.227 (2.29 ), 7.303 (2.07), 7.315 (8.43), 7.323 (9.04), 7.341 (2.19), 7.362 (0.73), 7.481 (0.59), 7.637 (3.03), 7.659 (13.06), 7.669 (8.47), 7.673 (7.54 ), 7.691 (1.75), 7.695 (1.86), 8.799 (2.25), 8.815 (4.44), 8.829 (2.18).

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 12.21 (s, 1H), 8.81 (t, 1H), 7.68 (dd, 1H), 7.66 (d, 1H), 7.48 (br. s, 1H), 7.37-7.29 (m, 2H), 7.24-7.16 (m, 1H), 4.14-4.06 (m, 1H), 3.82 (br. s, 1H), 3.71 (br. s, 1H), 3.19- 3.12 (m, 4H), 2.89-2.62 (m, 2H), 2.15 (s, 3H), 1.74-1.52 (m, 6H).

Separation of enantiomers.

The title target compound (100 mg) was dissolved in isopropanol (2.5 ml) and separated into enantiomers by preparative HPLC in chiral phase (see examples 2 and 3) [column: Daicel Chiralpak ID, 5 μm, 250 mm x 20 mm; flow: 20 ml/min; sample injection: 0.06 ml; eluent: 30% isopropanol/70% heptane; duration of action 15 min, isocratic]. The combined target fractions were concentrated and the residue was lyophilized. Then further purified by preparative HPLC on a chiral phase (acetonitrile/water gradient). The residue was lyophilized again.

Example 2

(-)-4-({[6-bromo-3-methyl-2-(piperidin-1-yl)quinolin-4-yl]carbonyl}amino)-3-(2-chloro-6fluorophenyl)butanoic acid (enantiomer 1).

The separation of the enantiomers described in Example 1 gave 29 mg (ee-value 99%) of the previously purified title compound as the previously eluted enantiomer. Then further purified by preparative HPLC (method 9). The combined desired fractions were concentrated and the residue was adsorbed in dichloromethane and washed with saturated aqueous sodium hydrogen carbonate. The organic phase was dried, filtered and concentrated and the residue

- 132 040220 lyophilized. 13 mg (98% pure, 13% theoretical) of the further purified title compound was obtained.

[a] _D20 = -16.9°, 589 nm, c = 0.25 ^g /100 ml, methanol;

LC-MS (method 1): R _t = 2.13 min; MS (ESIpos): m/z = 562/564 [M+H]+.

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: -0.149 (1.61), -0.008 (16.00), 0.008 (13.21), 0.146 (1.69), 0.959 (0.44), 1.040 (0.73), 1.235 (2.64) 1.374 (0.95) 1.607 (3.23) 1.673 (6.17) 2.150 (9.39) 2.327 (2.50) (2.50) (5.06), 7.624 (1.91), 7.646 (8.22), 7.657 (5.28), 7.661 (4.70), 7.684 (1.25), 8.900 (0.73).

Example 3

(+)-4-({[6-bromo-3-methyl-2-(piperidin-1-yl)quinolin-4-yl]carbonyl}amino)-3-(2-chloro-6fluorophenyl)butanoic acid (enantiomer 2).

The separation of the enantiomers described in Example 1 gave 26 mg (ee value 96%) of the prepurified title compound as the later eluted enantiomer. Then further purified by preparative HPLC (method 9). The combined desired fractions were concentrated and the residue was adsorbed in dichloromethane and washed with saturated aqueous sodium hydrogen carbonate. The organic phase was dried, filtered and concentrated and the residue was lyophilized. 12 mg (98% pure, 12% theoretical) of further purified title compound was obtained.

[a] _D20 = +15.6°, 589 nm, c = 0.25 g/100 mL ^, methanol;

LC-MS (method 1): R _t = 2.13 min; MS (ESIpos): m/z = 562/564 [M+H]+.

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: -0.150 (1.51), -0.008 (16.00), 0.008 (12.20), 0.146 (1.58), 1.234 (2.73), 1.372 (1.87), 1.610 (1.72), 1.669 (3.23), 2.149 (5.60), 2.327 (3.01), 2.366 (2.65), 2.523 (10.48), 2.669 (3.23), 2.709 (3.30) (0.93), 3.707 (0.86), 4.084 (0.86), 7.198 (1.08), 7.321 (3.01), 7.625 (1.22), 7.647 (4.74), 7.658 (3.09), 7.663 (2.58), 7.680 (1.00) (0.57).

Example 4

(+/-)-4-[({6-bromo-3-methyl-2-[(2-phenylethyl)amino]quinolin-4-yl}carbonyl)amino]-3-(2-chloro-6fluorophenyl)butanoic acid (racemate)

To a solution of (+/-)-tert-butyl-4-[({6-bromo-3-methyl-2-[(2-phenylethyl)amino]quinolin-4yl}carbonyl)amino]-3-(2- chloro-6-fluorophenyl)butanoate (150 mg, 229 µmol, racemate, example 54A) in dichloromethane (2.2 ml) TFA (350 µl, 4.6 mmol) was added and the mixture was stirred 16 h at RT. The mixture was then concentrated and mixed several times with dichloromethane and re-concentrated. The residue was dissolved in acetonitrile and purified by preparative HPLC (method 9). The combined desired fractions were concentrated and the residue was dried in vacuo. 55 mg (98% pure, 39% thor.) of the title compound were obtained.

LC-MS (method 2): R _t = 0.92 min; MS (ESIpos): m/z = 598/600 [M+H]+.

Ή-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 12.23 (br. s, 1H), 8.88 (br. s, 1H), 8.02-7.06 (m, 11H), 4.07 (br. s, partially hidden, 1H), 3.93-3.63 (m, partially hidden, 4H), 3.04-2.90 (m, 2H), 2.88-2.68 (m, 2H), 2.11-1.83 (m, 3H).

Example 5

(+/-)-5-({[6-Bromo-3-methyl-2-(piperidin-1-yl)quinolin-4-yl]carbonyl}amino)-4-(2-chloro-5fluorophenyl)valeric acid (racemate)

To a solution of (+/-)-tert-butyl-5-({[6-bromo-3-methyl-2-(piperidin-1-yl)quinolin-4yl]carbonyl}amino)-4-(2-chloro -5-fluorophenyl)pentanoate (90 mg, 98% pure, 139 µmol, racemate, example 55A) in dichloromethane (990 µl) TFA (210 µl, 2.8 mmol) was added and the mixture was stirred overnight at RT . The mixture was then concentrated and mixed several times with dichloromethane and re-concentrated. The residue was purified by preparative HPLC (method 9). The combined target fractions were concentrated and the residue was mixed with ethyl acetate and saturated aqueous sodium hydrogen carbonate (respectively 20 ml) and shaken. After phase separation, the aqueous phase was extracted twice with ethyl acetate (corresponding to 20 ml). The combined organic phases were dried over sodium sulfate, filtered and concentrated and the residue dried in vacuo. 45 mg (98% pure, 55% thor.) of the title compound were obtained.

LC-MS (method 1): Rt = 2.22 min; MS (ESIpos): m/z = 576/578 [M+H]+.

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.235 (2.02), 1.605 (3.36), 1.670 (6.76), 1.768 (0.41), 1.782 (0.67), 1.804 (1.37), 1.824 (1.54) , 1.835 (1.07), 1.865 (0.45), 1.899 (0.47), 2.020 (1.25), 2.041 (2.87), 2.068 (2.26), 2.080 (2.13), 2.090 (2.63), 2.101 (1.69), 2.128 (16.00) , 2.160 (1.18), 2.176 (0.61), 2.689 (0.94), 2.731 (0.90), 2.890 (1.03), 3.132 (8.80), 3.585 (1.45), 3.689 (3.38), 7.124 (1.14), 7.144 (2.04) . , 7.622 (1.58), 7.644 (8.32), 7.651 (5.86), 7.655 (5.07), 7.674 (1.01), 7.678 (1.08), 8.719 (1.55), 8.734 (2.96), 8.747 (1.48).

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 8.73 (t, 1H), 7.70-7.60 (m, 2H), 7.50 (dd, 1H), 7.46 (br. s, 1H, partially obscured) , 7.40 (dd, 1H), 7.14 (td, 1H), 3.78-3.51 (m, 3H), 3.13 (br. s, 4H), 2.20-1.96 (m, 6H), 1.91-1.75 (m, 1H) , 1.72-1.52 (m, 6H).

Example 6

(-)-5-({[6-Bromo-3-methyl-2-(piperidin-1-yl)quinolin-4-yl]carbonyl}amino)-4-(2-chloro-5fluorophenyl)valeric acid (enantiomer 1).

To a solution of (-)-tert-butyl-5-({[6-bromo-3-methyl-2-(piperidin-1-yl)quinolin-4yl]carbonyl}amino)-4-(2-chloro-5 -fluorophenyl)pentanoate (230 mg, 98% pure, 356 µmol, enantiomer 7, example 56A) in dichloromethane (2.5 ml) TFA (550 µl, 7.1 mmol) was added and the mixture was stirred overnight at RT. TFA (270 μl, 3.6 mmol) was then added again and the mixture was stirred one additional night at RT. The mixture was then concentrated and mixed several times with dichloromethane and re-concentrated. The residue was purified by preparative HPLC (method 8). The combined desired fractions were concentrated and the residue was dried in vacuo. 165 mg (98% pure, 99% ee, 79% thor.) of the title compound were obtained.

[a] _D20 = -18.7°, 589 nm, c = 0.38 ^g /100 ml, methanol;

LC-MS (method 1): Rt = 2.18 min; MS (ESIpos): m/z = 576/578 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (1.97), 0.008 (1.54), 1.604 (2.79), 1.670 (5.48), 1.786 (0.53), 1.808 (1.09), 1.829 (1.31 ), 1.850 (0.77), 2.012 (0.76), 2.023 (1.05), 2.041 (1.18), 2.055 (2.69), 2.082 (2.31), 2.095 (2.27), 2.102 (2.81), 2.128 (16.00), 2.149 (2.04 ), 2.172 (0.75), 3.132 (7.19), 3.590 (1.09), 3.692 (2.69), 7.119 (0.93), 7.126 (1.05), 7.140 (1.72), 7.147 (1.83), 7.160 (1.06), 7.168 (1.05 ), 7.390 (2.22), 7.397 (2.22), 7.415 (2.32), 7.422 (2.27), 7.457 (0.69), 7.485 (3.00), 7.499 (2.98), 7.508 (2.75), 7.521 (2.53), 7.622 (1.66 ), 7.644 (8.81), 7.652 (5.93), 7.657 (5.03), 7.674 (1.03), 7.679 (1.13), 8.711 (1.34), 8.726 (2.72), 8.740 (1.29), 12.066 (0.66).

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 12.07 (br. s, 1H), 8.73 (t, 1H), 7.70-7.60 (m, 2H), 7.50 (dd, 1H), 7.46 (br. s, 1H, partially hidden), 7.41 (dd, 1H), 7.14 (td, 1H), 3.74-3.64 (m, 2H), 3.63-3.54 (m, 1H), 3.17-3.09 (m, 4H ), 2.20-1.98 (m, 6H), 1.89-1.76 (m, 1H), 1.72-1.55 (m, 6H).

Example 7

(+)-5-({[6-Bromo-3-methyl-2-(piperidin-1-yl)quinolin-4-yl]carbonyl}amino)-4-(2-chloro-5fluorophenyl)valeric acid (enantiomer 2).

To a solution of (+)-tert-butyl-5-({[6-bromo-3-methyl-2-(piperidin-1-yl)quinolin-4yl]carbonyl}amino)-4-(2-chloro-5 -fluorophenyl)pentanoate (200 mg, 98% pure, 310 μmol, enantiomer 2, example 57A) in dichloromethane (2.2 ml) was added with TFA (480 μl, 6.2 mmol) and the mixture was stirred overnight at RT. TFA (240 μl, 3.1 mmol) was then added again and the mixture was stirred one additional night at RT. The mixture was then concentrated and mixed several times with dichloromethane and re-concentrated. The residue was purified by preparative HPLC (method 8). The combined desired fractions were concentrated and the residue was dried in vacuo. 150 mg (98% pure, 99% ee, 82% thor.) of the title compound were obtained.

[a] _D20 = +17.4°, 589 nm, c = 0.35 g/100 mL ^, methanol;

LC-MS (method 1): Rt = 2.18 min; MS (ESIpos): m/z = 576/578 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (1.88), 0.008 (1.49), 1.605 (2.71), 1.670 (5.29), 1.786 (0.50), 1.809 (1.07), 1.830 (1.30 ), 1.850 (0.76), 2.011 (0.75), 2.024 (0.98), 2.042 (1.13), 2.056 (2.63), 2.083 (2.20), 2.097 (2.19), 2.103 (2.78), 2.128 (16.00), 2.150 (2.00 ), 2.173 (0.74), 3.134 (6.98), 3.591 (1.11), 3.692 (2.69), 7.119 (0.86), 7.127 (1.00), 7.141 (1.66), 7.147 (1.80), 7.161 (1.03), 7.168 (1.04 ), 7.390 (2.13), 7.398 (2.20), 7.416 (2.28), 7.423 (2.26), 7.486 (2.99), 7.499 (2.96), 7.508 (2.77), 7.521 (2.58), 7.624 (1.61), 7.646 (8.66 ), 7.654 (5.91), 7.658 (5.11), 7.676 (1.01), 7.681 (1.11), 8.712 (1.32), 8.727 (2.75), 8.741 (1.30).

- 134 040220

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 12.06 (br. s, 1H), 8.73 (t, 1H), 7.70-7.61 (m, 2H), 7.50 (dd, 1H), 7.46 ( br. s, 1H, partially hidden), 7.41 (dd, 1H), 7.14 (td, 1H), 3.75-3.64 (m, 2H), 3.63-3.53 (m, 1H), 3.19-3.08 (m, 4H) , 2.21-1.98 (m, 6H), 1.88-1.75 (m, 1H), 1.72-1.52 (m, 6H).

Example 8

(+/-)-5-({[6-Bromo-2-(4,4-difluoropiperidin-1-yl)-3-methylquinolin-4-yl]carbonyl}amino)-4-(2-chloro5-fluorophenyl )valeric acid (racemate)

To a solution of (+/-)-tert-butyl-5-({[6-bromo-2-(4,4-difluoropiperidin-1-yl)-3-methylquinolin-4yl]carbonyl}amino)-4-( 2-Chloro-5-fluorophenyl)pentanoate (19 mg, 72% pure, 20.4 µmol, racemate, example 58A) in dichloromethane (140 µl) was added with TFA (32 µl, 410 µmol) and the mixture was stirred overnight at RT. TFA (32 μl, 410 μmol) was then added again and the mixture was stirred one additional night at RT. The mixture was then concentrated and mixed several times with dichloromethane and re-concentrated. The residue was purified by preparative HPLC (method 10). The combined desired fractions were concentrated and the residue was dried in vacuo. Received 8 mg (98% pure, 61% theoretical. output.) specified in the title compound.

LC-MS (method 2): Rt = 1.14 min; MS (ESIpos): m/z = 612/614 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.242 (0.50), 1.789 (0.50), 1.811 (1.11), 1.832 (1.34), 1.854 (0.80), 2.012 (0.86), 2.025 (1.09) , 2.044 (1.23), 2.058 (2.67), 2.085 (2.29), 2.105 (3.75), 2.119 (3.73) , 3.702 (2.68), 4.410 (1.45), 6.962 (0.45), 7.090 (0.51), 7.121 (0.84), 7.128 (0.99), 7.148 (1.77), 7.163 (1.04), 7.169 (1.00), 7.218 (0.48) . , 7.691 (5.10), 7.696 (4.49), 7.714 (0.99), 7.718 (1.05), 8.736 (1.40), 8.750 (2.79), 8.764 (1.38).

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 8.75 (t, 1H), 7.73-7.63 (m, 2H), 7.50 (dd, 1H), 7.46 (br. s, 1H, hidden), 7.41 (dd, 1H), 7.15 (td, 1H), 3.70 (br. s, 2H), 3.60 (br. s, 1H), 3.38-3.24 (m, 4H), 2.24-1.97 (m, 10H), 1.89-1.74 (m, 1H).

Example 9

(+/-)-5-({[6-Bromo-3-methyl-2-(morpholin-4-yl)quinolin-4-yl]carbonyl}amino)-4-(2-chloro-5fluorophenyl)valeric acid (racemate)

To a solution of (+/-)-tert-butyl-5-({[6-bromo-3-methyl-2-(morpholin-4-yl)quinolin-4yl]carbonyl}amino)-4-(2-chloro -5-fluorophenyl)pentanoate (55 mg, 98% pure, 84.9 µmol, racemate, example 59A) in dichloromethane (600 µl) TFA (130 µl, 1.7 mmol) was added and the mixture was stirred overnight at RT. The mixture was then concentrated and mixed several times with dichloromethane and re-concentrated. The residue was purified by preparative HPLC (method 9). The combined target fractions were concentrated and the residue was mixed with ethyl acetate and saturated aqueous sodium hydrogen carbonate (respectively 20 ml) and shaken. After phase separation, the aqueous phase was extracted twice with ethyl acetate (corresponding to 20 ml). The combined organic phases were dried over sodium sulfate, filtered and concentrated and the residue dried in vacuo. 37 mg (98% pure, 74% thor.) of the title compound were obtained.

LC-MS (method 1): Rt = 1.89 min; MS (ESIpos): m/z = 578/580 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.061 (0.65), 0.854 (0.64), 1.175 (0.42), 1.235 (4.42), 1.769 (0.44), 1.783 (0.75), 1.805 (1.56 ), 1.826 (1.77), 1.837 (1.11), 1.847 (0.98), 1.866 (0.49), 1.988 (0.93), 2.005 (1.13), 2.019 (1.47), 2.045 (3.35), 2.072 (2.85), 2.084 (2.55 ), 2.093 (3.17), 2.105 (1.88), 2.123 (3.22), 2.151 (16.00), 2.690 (0.60), 2.890 (0.46), 3.175 (11.00), 3.184 (8.56), 3.510 (0.50), 3.586 (1.72 ), 3.696 (3.93), 3.755

- 135 040220 (9.55), 3.766 (12.93), 3.777 (8.58), 7.119 (1.16), 7.125 (1.35), 7.140 (2.19), 7.146 (2.28), 7.160 (1.31), 7.167 (1.25), 7.390 (2.73) ), 7.397 (2.79), 7.415 (2.82), 7.423 (2.73), 7.485 (3.89), 7.499 (3.92), 7.507 (3.56), 7.521 (3.08), 7.659 (1.54), 7.682 (12.34), 7.688 (7.12 ), 7.706 (0.79), 7.711 (0.94), 8.743 (1.86), 8.757 (3.48), 8.771 (1.67).

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 12.03 (br. s, 1H), 8.76 (t, 1H), 7.73-7.63 (m, 2H), 7.50 (dd, 1H), 7.46 ( br. s, 1H, hidden), 7.41 (dd, 1H), 7.14 (td, 1H), 3.82-3.64 (m, 6H), 3.59 (br. s, 1H), 3.20-3.12 (m, 4H), 2.21-1.95 (m, 6H), 1.88-1.75 (m, 1H).

Example 10

(+/-)-5-({[6-Bromo-2-(3,6-dihydropyridin-1(2H)-yl)-3-methylquinolin-4-yl]carbonyl}amino)-4-(2chloro- 5-fluorophenyl)valeric acid (racemate)

To a solution of (+/-)-tert-bugyl-5-({[6-bromo-2-(3,6-dihydropyridin-1(2H)-yl)-3-methylquinolin-4yl]carbonyl}amino)- 4-(2-Chloro-5-fluorophenyl)pentanoate (50 mg, 79.2 µmol, racemate, example 60A) in dichloromethane (580 µl) was added with TFA (61 µl, 790 µmol) and the mixture was stirred for two days at RT. The mixture was then concentrated and mixed several times with dichloromethane and re-concentrated. The residue was dissolved in acetonitrile and purified by preparative HPLC (method 6). The combined target fractions were concentrated and the residue was lyophilized. 25 mg (98% pure, 53% thor.) of the title compound were obtained.

LC-MS (method 2): Rt = 1.12 min; MS (ESIpos): m/z = 574/576 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.369 (0.42), 1.787 (0.60), 1.809 (1.26), 1.829 (1.41), 1.841 (0.94), 1.870 (0.43), 1.989 (0.41) 2.010 (0.86), 2.027 (1.19), 2.046 (2.98), 2.073 (2.55), 2.085 (2.25), 2.093 (2.89), 2.106 (1.49), 2.124 (2.93), 2.141 (16.00), 2.163 (1.30) . . , 7.484 (3.06), 7.497 (3.07), 7.506 (2.86), 7.519 (2.63), 7.617 (2.21), 7.639 (8.00), 7.653 (5.10),7.658 (4.43), 7.675 (1.38), 7.680 (1.36) , 8.731 (1.43), 8.745 (2.71), 8.759 (1.30).

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 12.15 (br. s, 1H), 8.75 (t, 1H), 7.69-7.61 (m, 2H), 7.50 (dd, 1H), 7.46 ( br. s, 1H, partially hidden), 7.41 (dd, 1H), 7.14 (td, 1H), 5.92-5.79 (m, 2H), 3.80 (br. s, 2H), 3.75-3.65 (m, 2H) , 3.59 (br. s, 1H), 3.35-3.22 (hidden, 2H), 2.30 (br. s, 2H), 2.22-1.96 (m, 6H), 1.90-1.73 (m, 1H).

Example 11.

(+/-)-5-({[6-Bromo-3-methyl-2-(thiomorpholin-4-yl)quinolin-4-yl]carbonyl}amino)-4-(2-chloro-5fluorophenyl)valeric acid (racemate)

To a solution of (+/-)-tert-butyl-5-({[6-bromo-3-methyl-2-(thiomorpholin-4-yl)quinolin-4yl]carbonyl}amino)-4-(2-chloro -5-fluorophenyl)pentanoate (55 mg, 84.5 µmol, racemate, example 61A) in dichloromethane (620 µl) TFA (65 µl, 840 µmol) was added and the mixture was stirred for two days at RT. The mixture was then concentrated and mixed several times with dichloromethane and re-concentrated. The residue was dissolved in acetonitrile and purified by preparative HPLC (method 6). The combined target fractions were concentrated and the residue was lyophilized. 41 mg (98% pure, 80% thor.) of the title compound were obtained.

LC-MS (method 2): Rt = 1.10 min; MS (ESIpos): m/z = 594/596 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (1.05), 0.008 (0.98), 1.788 (0.49), 1.810 (1.08), 1.820 (0.71), 1.831 (1.32), 1.852 (0.79 ), 2.011 (0.78), 2.024 (1.04), 2.042 (1.18), 2.056 (2.70), 2.074 (0.77), 2.083 (2.28), 2.097 (2.36), 2.103 (2.82), 2.131 (16.00), 2.149 (2.40 ), 2.172 (0.86), 2.189 (0.44), 2.523 (0.52), 2.775

- 136 040220 (6.19), 2.787 (7.27), 2.798 (6.78), 3.413 (6.57), 3.419 (6.69), 3.426 (7.12), 3.436 (6.16), 3.590 (1.20), 3.695 (2.52), 7.120 (0.86) ), 7.127 (1.01), 7.141 (1.67), 7.147 (1.76), 7.161 (1.04), 7.169 (1.00), 7.393 (2.19), 7.401 (2.24), 7.418 (2.29), 7.426 (2.20), 7.485 (3.17 ), 7.499 (3.20), 7.507 (2.93), 7.521 (2.65), 7.656 (1.27), 7.678 (9.12), 7.683 (6.85), 7.687 (5.30), 7.705 (0.85), 7.709 (0.91), 8.720 (1.43 ), 8.734 (2.85), 8.748 (1.36), 12.055 (0.73).

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 12.06 (br. s, 1H), 8.73 (t, 1H), 7.73-7.63 (m, 2H), 7.50 (dd, 1H), 7.46 (br. s, 1H, partially hidden), 7.41 (dd, 1H), 7.14 (td, 1H), 3.69 (br. s, 2H), 3.59 (br. s, 1H), 3.46-3.39 (m, 4H ), 2.83-2.75 (m, 4H), 2.21-1.97 (m, 6H), 1.89-1.75 (m, 1H).

Example 12.

(+/-)-5-[({6-bromo-2-[cis-2,6-dimethylmorpholin-4-yl]-3-methylquinolin-4-yl}carbonyl)amino]-4-(2chloro-5 -fluorophenyl)valeric acid (racemate)

To a solution of (+/-)-tert-butyl-5-[({6-bromo-2-[cis-2,6-dimethylmorpholin-4-yl]-3-methylquinolin-4yl}carbonyl)amino]-4 -(2-chloro-5-fluorophenyl)pentanoate (70 mg, 106 µmol, racemate, example 62A) in dichloromethane (780 µl) TFA (81 µl, 1.1 mmol) was added and the mixture was stirred for two days at RT. The mixture was then concentrated and mixed several times with dichloromethane and re-concentrated. The residue was dissolved in acetonitrile and purified by preparative HPLC (method 6). The combined target fractions were concentrated and the residue was lyophilized. 47 mg (98% pure, 71% thor.) of the title compound were obtained.

LC-MS (method 2): Rt = 1.10 min; MS (ESIpos): m/z = 606/608 [M+H]+.

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 1.134 (16.00), 1.149 (15.70), 1.793 (0.43), 1.814 (0.86), 1.835 (1.00), 1.856 (0.57), 2.013 (0.68 ), 2.026 (0.87), 2.045 (1.01), 2.057 (2.01), 2.084 (1.82), 2.098 (1.82), 2.104 (2.14), 2.119 (1.55), 2.132 (2.14), 2.157 (11.42), 2.190 (0.41 ), 2.469 (1.68), 3.431 (2.87), 3.462 (2.59), 3.589 (0.93), 3.693 (1.77), 3.756 (1.66), 3.776 (2.04), 7.120 (0.71), 7.127 (0.80), 7.142 (1.27 ), 7.148 (1.30), 7.162 (0.75), 7.169 (0.70), 7.391 (1.65), 7.398 (1.65), 7.416 (1.69), 7.423 (1.58), 7.486 (2.10), 7.499 (2.07), 7.508 (1.83 ), 7.521 (1.63), 7.655 (0.55), 7.676 (9.58), 8.710 (1.15), 8.725 (2.08), 8.739 (0.98), 12.063 (4.18).

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 12.06 (s, 1H), 8.72 (t, 1H), 7.72-7.63 (m, 2H), 7.50 (dd, 1H), 7.47 (br s, 1H, partially hidden), 7.41 (dd, 1H), 7.14 (td, 1H), 3.84-3.53 (m, 5H), 3.45 (br. d, 2H), 2.53-2.45 (hidden, 2H), 2.21-1.97 (m, 6H), 1.91-1.75 (m, 1H), 1.15 (s, 3H), 1.13 (s, 3H).

Example 13

(+/-)-5-({[6-Bromo-3-methyl-2-(pyrrolidin-1-yl)quinolin-4-yl]carbonyl}amino)-4-(2-chloro-5fluorophenyl)valeric acid (racemate)

To a solution of (+/-)-tert-butyl-5-({[6-bromo-3-methyl-2-(pyrrolidin-1-yl)quinolin-4yl]carbonyl}amino)-4-(2-chloro -5-fluorophenyl)pentanoate (63 mg, 102 μmol, racemate, example 63 A) in dichloromethane (750 μl) TFA (78 μl, 1.0 mmol) was added and the mixture was stirred for two days at RT. The mixture was then concentrated and mixed several times with dichloromethane and re-concentrated. The residue was dissolved in acetonitrile and purified by preparative HPLC (method 6). The combined target fractions were concentrated and the residue was lyophilized. 36 mg (98% pure, 62% thor.) of the title compound were obtained.

LC-MS (method 2): Rt = 0.77 min; MS (ESIpos): m/z = 562/564 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 12.06 (br. s, 1H), 8.68 (t, 1H), 7.59-7.53 (m, 1H), 7.50 (dd, 2H), 7.40 (dd, 1H), 7.35 (br. s, partially hidden), 7.14 (td, 1H), 3.68 (br. s, 2H), 3.57 (br. s, 5H), 2.26-1.97 (m, 6H), 1.94-1.74 (m, 5H).

- 137 040220

Example 14

(+/-)-5-({[6-Bromo-3-methyl-2-(1,2-oxazolidin-2-yl)quinolin-4-yl]carbonyl}amino)-4-(2-chloro- 5fluorophenyl)valeric acid (racemate)

To a solution of (+/-)-tert-butyl-5-({[6-bromo-3-methyl-2-(1,2-oxazolidin-2-yl)quinolin-4yl]carbonyl}amino)-4- (2-Chloro-5-fluorophenyl)pentanoate (35 mg, 56.4 µmol, racemate, example 64A) in dichloromethane (410 µl) TFA (43 µl, 560 µmol) was added and the mixture was stirred for two days at RT. The mixture was then concentrated and mixed several times with dichloromethane and re-concentrated. The residue was dissolved in acetonitrile and purified by preparative HPLC (method 6). The combined target fractions were concentrated and the residue was lyophilized. 24 mg (95% pure, 72% thor.) of the title compound were obtained.

LC-MS (method 2): R _t = 0.96 min; MS (ESIpos): m/z = 564/566 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: -0.008 (1.04), 0.008 (0.83), 1.134 (1.33), 1.150 (1.34), 1.788 (0.58), 1.810 (1.36), 1.820 ( 0.87), 1.831 (1.64), 1.853 (1.06), 1.873 (0.44), 1.989 (0.45), 2.010 (0.97), 2.023 (1.32), 2.041 (1.43), 2.057 (3.36), 2.073 (2.58), 2.085 2.55) 5.79) 4.26), 3.844 (7.14), 3.862 (3.86), 7.121 (0.95), 7.128 (1.11), 7.142 (1.89), 7.149 (1.96), 7.163 (1.16) 2.60), 7.419 (2.65), 7.426 (2.51), 7.489 (3.30), 7.502 (3.52), 7.511 (3.35),7.525 (3.11), 7.677 (0.86), 7.712 (0.64), 7.733 (16.00), 0.50), 8.775 (1.61), 8.790 (3.19), 8.804 (1.53).

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 8.79 (t, 1H), 7.78-7.70 (m, 2H), 7.51 (dd, 1H), 7.46 (br. s, 1H, hidden), 7.41 (dd, 1H), 7.15 (td, 1H), 3.84 (t, 2H), 3.78 (br. s, 2H), 3.74-3.67 (m, 2H), 3.65-3.55 (m, 1H), 2.32- 1.95 (m, 8H), 1.90-1.74 (m, 1H).

Example 15

(+/-)-5-({[6-Bromo-2-(2,5-dihydro-1 H-pyrrol-1 -yl)-3-methylquinolin-4-yl]carbonyl} amino)-4-( 2chloro-5-fluorophenyl)valeric acid (racemate)

To a solution of (+/-)-tert-butyl-5-({[6-bromo-2-(2,5-dihydro-1H-pyrrol-1-yl)-3-methylquinolin-4yl]carbonyl}amino) -4-(2-Chloro-5-fluorophenyl)pentanoate (32 mg, 51.9 µmol, racemate, Example 65A) in dichloromethane (380 µl) TFA (40 µl, 520 µmol) was added and the mixture was stirred for two days at RT. The mixture was then concentrated and mixed several times with dichloromethane and re-concentrated. The residue was dissolved in acetonitrile and purified by preparative HPLC (method 6). The combined target fractions were concentrated and the residue was lyophilized. 20 mg (90% pure, 61% thor.) of the title compound were obtained.

LC-MS (method 2): R _t = 0.87 min; MS (ESIpos): m/z = 560/562 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.773 (0.50), 1.787 (0.88), 1.808 (1.83), 1.819 (1.42), 1.829 (2.14), 1.840 (1.55), 1.851 (1.30) , 1.870 (0.65), 2.026 (1.76), 2.048 (4.09), 2.075 (3.34), 2.087 (3.15), 2.097 (3.64), 2.108 (2.21), 2.128 (2.86), 2.145 (2.35), 2.169 (1.45) . , 7.141 (2.44) . , 7.880 (3.13), 8.688 (1.91), 8.702 (3.51), 8.716 (1.74), 8.886 (0.68).

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 12.09 (br. s, 1H), 8.70 (t, 1H), 7.56 (dd, 1H), 7.53-7.46 (m, 2H), 7.46 ( wide, hidden, 1H), 7.40 (dd, 1H), 7.18-7.10 (m, 1H), 5.96 (s, 2H), 4.53 (br. s, 4H), 3.78-3.53 (m, 3H), 2.29- 1.97 (m, 6H), 1.88-1.72 (m, 1H).

- 138 040220

Example 16

5-[({6-Bromo-2-[3-hydroxypyrrolidin-1-yl]-3-methylquinolin-4-yl}carbonyl)amino]-4-(2-chloro-5fluorophenyl)valeric acid (mixture of diastereoisomers)

To a solution of tert-butyl-5-[({6-bromo-2-[3-hydroxypyrrolidin-1-yl]-3-methylquinolin-4yl}carbonyl)amino]-4-(2-chloro-5-fluorophenyl) pentanoate (60 mg, 94.5 µmol, mixture of diastereoisomers, example 66A) in dichloromethane (690 µl) TFA (73 µl, 940 µmol) was added and the mixture was stirred for two days at RT. The mixture was then concentrated and mixed several times with dichloromethane and re-concentrated. The residue was dissolved in acetonitrile and purified by preparative HPLC (method 6). The combined target fractions were concentrated and the residue was lyophilized. 50 mg (98% pure, 90% theoretical) of the title compound were obtained.

LC-MS (method 2): Rt = 0.69 min; MS (ESIpos): m/z = 578/580 [M+H]+.

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (1.27), 0.008 (1.10), 1.772 (0.54), 1.786 (0.97), 1.808 (2.80), 1.830 (3.88), 1.850 (3.12 ), 1.920 (1.78), 1.938 (1.54), 1.988 (0.75), 2.023 (1.72), 2.040 (1.99), 2.053 (4.47), 2.081 (3.66), 2.094 (3.39), 2.102 (4.12), 2.115 (3.02 ), 2.147 (16.00), 2.171 (1.97), 2.189 (1.08), 2.327 (0.57), 2.523 (1.83), 2.669 (0.59), 2.710 (0.40), 3.356 (2.29), 3.569 (2.21), 3.667 (3.45 ), 3.678 (3.50), 3.782 (2.75), 4.331 (3.12), 4.898 (3.56), 4.905 (5.60), 4.912 (3.39), 7.130 (2.10), 7.138 (2.24), 7.149 (2.13), 7.262 (0.51 ), 7.381 (2.88), 7.388 (3.99), 7.406 (2.94), 7.414 (3.80), 7.466 (5.93), 7.480 (3.91), 7.488 (11.07), 7.500 (3.34), 7.514 (3.02), 7.544 (5.14 ), 7.566 (2.99), 8.699 (3.26), 12.057 (4.53).

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 12.06 (br. s, 1H), 8.70 (br. t, 1H), 7.58-7.53 (m, 1H), 7.52-7.45 (m, 2H), 7.40 (br. dt, 1H), 7.34 (br. s, partially hidden, 1H), 7.19-7.09 (m, 1H), 4.91 (t, 1H), 4.33 (br. s, 1H), 3.88 -3.47 (m, 7H), 2.19-1.78 (m, 9H).

Example 17.

5-[({6-Bromo-3-methyl-2-[3-methylpiperidin-1-yl]quinolin-4-yl}carbonyl)amino]-4-(2-chloro-5fluorophenyl)valeric acid (mixture of diastereoisomers)

To a solution of tert-butyl-5-[({6-bromo-3-methyl-2-[3-methylpiperidin-1-yl]quinolin-4yl}carbonyl)amino]-4-(2-chloro-5-fluorophenyl )pentanoate (75 mg, 116 μmol, mixture of diastereoisomers, example 67A) in dichloromethane (850 μl) TFA (89 μl, 1.2 mmol) was added and the mixture was stirred for two days at RT. The mixture was then concentrated and mixed several times with dichloromethane and re-concentrated. The residue was dissolved in acetonitrile and purified by preparative HPLC (method 12). The combined target fractions were concentrated and the residue was mixed with ethyl acetate and saturated aqueous sodium hydrogen carbonate solution (respectively 10 ml) and shaken. After phase separation, the aqueous phase was extracted twice with ethyl acetate (corresponding to 10 ml). The combined organic phases were dried over sodium sulfate, filtered and concentrated and the residue was lyophilized. 57 mg (98% pure, 82% thor.) of the title compound were obtained.

LC-MS (method 1): Rt = 2.34 min; MS (ESIpos): m/z = 590/592 [M+H]+.

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: -0.022 (0.66), -0.008 (1.50), 0.008 (1.14), 0.920 (8.53), 0.936 (8.61), 0.963 (0.41), 1.077 (0.96), 1.099 (1.00), 1.127 (0.40), 1.233 (1.61), 1.627 (0.77), 1.650 (0.89), 1.729 (1.77) (2.33) (2.53) 2.131 (16.00) (1.94), 3.459 (2.87), 3.487 (1.47), 3.579 (1.20), 3.686 (2.45), 7.116 (0.84), 7.123 (0.97), 7.137 (1.62) (0.98), 7.381 (2.07), 7.389 (2.10), 7.407 (2.19), 7.414 (2.11), 7.456 (0.62) (0.93), 7.647 (9.27), 7.654 (5.14), 7.672 (0.63), 7.676 (0.73), 8.719 (1.20), 8.733 (2.27), 8.746 (1.13).

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 12.26 (br. s, 1H), 8.73 (t, 1H), 7.69-7.61 (m, 2H), 7.50 (dd, 1H),

- 139 040220

7.46 (br. s, partially hidden, 1H), 7.40 (dd, 1H), 7.14 (td, 1H), 3.76-3.40 (m, 5H), 2.80-2.61 (m, 1H), 2.48-2.34 (m, 1H), 2.20-1.95 (m, 6H), 1.88-1.55 (m, 5H), 1.17-1.01 (m, 1H), 0.93 (d, 3H).

Example 18.

(+/-)-5 -({[6-Bromo-3-methyl-2-(4-methylpiperidin-1-yl)quinolin-4-yl]carbonyl}amino)-4-(2-chloro-5fluorophenyl )valeric acid (racemate)

To a solution of (+/-)-tert-butyl-5-({[6-bromo-3-methyl-2-(4-methylpiperidin-1-yl)quinolin-4yl]carbonyl}amino)-4-(2 -chloro-5-fluorophenyl)pentanoate (70 mg, 108 µmol, racemate, Example 68 A) in dichloromethane (790 µl) TFA (83 µl, 1.1 mmol) was added and the mixture was stirred for two days at RT. The mixture was then concentrated and mixed several times with dichloromethane and re-concentrated. The residue was dissolved in acetonitrile and purified by preparative HPLC (method 12). The combined target fractions were concentrated and the residue was mixed with ethyl acetate and saturated aqueous sodium hydrogen carbonate solution (respectively 10 ml) and shaken. After phase separation, the aqueous phase was extracted twice with ethyl acetate (corresponding to 10 ml). The combined organic phases were dried over sodium sulfate, filtered and concentrated and the residue was lyophilized. 35 mg (98% pure, 53% thor.) of the title compound were obtained.

LC-MS (method 1): R _t = 2.33 min; MS (ESIpos): m/z = 590/592 [M+H]+.

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.964 (10.37), 0.980 (10.93), 1.233 (0.56), 1.256 (0.68), 1.286 (1.96), 1.315 (2.22), 1.345 (0.95) , 1.552 (0.89), 1.562 (1.05), 1.578 (0.95), 1.588 (0.80), 1.718 (2.85) , 1.844 (0.79), 1.863 (0.41), 2.001 (0.79), 2.017 (1.16), 2.036 (3.01), 2.063 (2.22), 2.075 (2.05), 2.086 (2.34), 2.097 (1.62), 2.119 (16.00) , 2.156 (0.97), 2.173 (0.46), 2.730 (1.03), 2.759 (2.00), 2.774 (2.10), 2.802 (1.10), 3.302 (2.59), (3.16), 3.580 (1.37), 3.688 (2.97), 7.116 (0.92), 7.123 (1.05), 7.137 (1.77), (1.08), 7.383 (2.21), 7.390 (2.26), 7.408 (2.34), 7.415 (2.30), 7.457 (0.72), (2.61), 7.517 ( 2.39), 7.617 (1.88), 7.639 (8.36), 7.648 (5.27), 7.653 (4.59), (1.41), 8.734 (2.79), 8.748 (1.35).

(2.67), 3.508 (3.25), 3.540 (1.90), 7.157 (1.08), 7.165 (2.87), 7.495 (2.84), 7.504 (1.10), 7.676 (1.17), 8.719

3.314

7.144

7.482

7.671

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 12.16 (br. s, 1H), 8.73 (t, 1H), 7.69-7.61 (m, 2H), 7.50 (dd, 1H), 7.46 (br. s, partially hidden, 1H), 7.40 (dd, 1H), 7.14 (td, 1H), 3.74-3.48 (m, 5H), 2.82-2.69 (m, 2H), 2.19-1.96 (m, 6H ), 1.88-1.67 (m, 3H), 1.63-1.50 (m, 1H), 1.38-1.19 (m, 2H), 0.97 (d, 3H).

Example 19.

5-[({6-Bromo-2-[3-methoxypiperidin-1-yl]-3-methylquinolin-4-yl}carbonyl)amino]-4-(2-chloro-5fluorophenyl)valeric acid (mixture of diastereoisomers)

To a solution of tert-butyl-5-[({6-bromo-2-[3-methoxypiperidin-1-yl]-3-methylquinolin-4yl}carbonyl)amino]-4-(2-chloro-5-fluorophenyl) pentanoate (65 mg, 98.0 µmol, mixture of diastereoisomers, example 69A) in dichloromethane (720 µl) TFA (76 µl, 980 µmol) was added and the mixture was stirred for two days at RT. The mixture was then concentrated and mixed several times with dichloromethane and re-concentrated. The residue was dissolved in acetonitrile and purified by preparative HPLC (method 12). The combined target fractions were concentrated and the residue was mixed with ethyl acetate and saturated aqueous sodium hydrogen carbonate solution (respectively 10 ml) and shaken. After phase separation, the aqueous phase was extracted twice with ethyl acetate (corresponding to 10 ml). The combined organic phases were dried over sodium sulfate, filtered and concentrated and the residue was lyophilized. 35 mg (98% pure, 57% thor.) of the title compound were obtained.

LC-MS (method 1): R _t = 2.04 min; MS (ESIpos): m/z = 606/608 [M+H]+.

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 1.400 (0.45), 1.806 (0.89), 1.817 (0.65), 1.828 (0.90), 2.020 (0.80), 2.048 (1.24), 2.076 (0.89 ), 2.089 (0.77), 2.097 (1.04), 2.131 (6.49), 2.732 (0.44), 2.845 (0.41), 2.861

- 140 040220 (0.42), 3.301 (16.00), 3.313 (7.33), 3.425 (0.66), 3.434 (0.65), 3.588 (1.07), 3.616 (0.82), 3.694 (1.18), 7.123 (0.42), 7.138 (0.70) ), 7.144 (0.75), 7.158 (0.43), 7.165 (0.42), 7.390 (0.84), 7.398 (0.87), 7.416 (0.89), 7.423 (0.87), 7.481 (1.16), 7.495 (1.15), 7.503 (1.03 ), 7.517 (0.93), 7.633 (0.58), 7.656 (3.28), 7.662 (2.19), 7.667 (1.89), 8.714 (0.52), 8.727 (1.00), 8.741 (0.50).

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 12.09 (br. s, 1H), 8.73 (t, 1H), 7.70-7.62 (m, 2H), 7.50 (dd, 1H), 7.46 (br. s, partially hidden, 1H), 7.41 (dd, 1H), 7.14 (td, 1H), 3.75-3.66 (m, 2H), 3.65-3.54 (m, 2H), 3.47-3.39 (m, 1H ), 3.30 (s, partially hidden, 3H), 2.93-2.80 (m, 1H), 2.78-2.65 (m, 1H), 2.18-1.96 (m, 7H), 1.89-1.75 (m, 2H), 1.66- 1.51 (m, 1H), 1.46-1.32 (m, 1H).

Example 20.

5-[({6-Bromo-2-[2-(hydroxymethyl)morpholin-4-yl]-3-methylquinolin-4-yl}carbonyl)amino]-4-(2chloro-5-fluorophenyl)valeric acid (mixture diastereoisomers)

To a solution of tert-butyl-5-[({6-bromo-2-[2-(hydroxymethyl)morpholin-4-yl]-3-methylquinolin-4yl}carbonyl)amino]-4-(2-chloro-5 -fluorophenyl)pentanoate (35 mg, 52.6 µmol, mixture of diastereoisomers, example 70A) in dichloromethane (390 µl) was added with TFA (41 µl, 530 µmol) and the mixture was stirred for two days at RT. The mixture was then concentrated and mixed several times with dichloromethane and re-concentrated. The residue was dissolved in acetonitrile and purified by preparative HPLC (method 12). The combined target fractions were concentrated and the residue was mixed with ethyl acetate and saturated aqueous sodium hydrogen carbonate solution (respectively 10 ml) and shaken. After phase separation, the aqueous phase was extracted twice with ethyl acetate (corresponding to 10 ml). The combined organic phases were dried over sodium sulfate, filtered and concentrated and the residue was lyophilized. 26 mg (98% pure, 78% thor.) of the title compound were obtained.

LC-MS (method 1): R _t = 1.67 min; MS (ESIpos): m/z = 608/610 [M+H]+.

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 1.788 (0.65), 1.810 (1.36), 1.831 (1.64), 1.852 (0.96), 1.871 (0.44), 1.991 (0.46), 2.011 (0.97 ), 2.024 (1.28), 2.042 (1.48), 2.055 (3.21), 2.082 (2.67), 2.095 (2.49), 2.102 (3.16), 2.116 (1.97), 2.131 (3.02), 2.157 (16.00), 2.189 (0.75 ), 2.643 (0.63), 2.670 (1.36), 2.691 (1.24), 2.710 (0.74), 2.717 (0.78), 2.891 (1.17), 2.921 (0.67), (3.16), 3.517 (3.57), 3.529 (2.32) , 3.551 (2.26), (3.34), 3.710 (4.45), 3.739 (1.84), 3.909 (2.58), (2.03), 7.147 (2.14), 7.161 (1.24), 7.168 (1.20),

3.385

3.605

3.936

7.394 (3.18), 3.415 (2.21), 3.619 (2.02), 4.762 (2.43), 7.401 (3.71), (2.39), (0.56), (2.44),

3.428

3.644

7.120

7.419 (2.50), 3.490 (2.32), 3.502 (1.89), 3.659 (1.32), 3.688 (1.03), 7.126 (1.19), 7.141 (2.54), 7.508 (3.33), 7.521 (2.98), 7.661 (0.94), 7.683 (14.87), 7.706 (0.58), 7.710 (0.70), 8.743 (1.59), 8.756 (2.91), 8.770 (1.45).

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 12.07 (br. s, 1H), 8.76 (t, 1H), 7.72-7.64 (m, 2H), 7.50 (dd, 1H), 7.47 ( br. s, partially hidden, 1H), 7.41 (dd, 1H), 7.14 (td, 1H), 4.76 (br. s, 1H), 3.92 (br. d, 1H), 3.78-3.36 (m, 9H) , 2.97-2.80 (m, 1H), 2.77-2.60 (m, 1H), 2.21-1.95 (m, 6H), 1.90-1.71 (m, 1H).

Example 21.

5-[({6-Bromo-2-[3-(hydroxymethyl)piperidin-1-yl]-3-methylquinolin-4-yl}carbonyl)amino]-4-(2chloro-5-fluorophenyl)valeric acid (mixture diastereoisomers)

To a solution of tert-butyl-5-[({6-bromo-2-[3-(hydroxymethyl)piperidin-1-yl]-3-methylquinolin-4yl}carbonyl)amino]-4-(2-chloro-5 -fluorophenyl)pentanoate (63 mg, 95.0 µmol, mixture of diastereoisomers, example 71A) in dichloromethane (700 µl) was added with TFA (73 µl, 950 µmol) and the mixture was stirred for two days at RT. The mixture was then concentrated and mixed several times with dichloromethane and re-concentrated. The residue was dissolved in acetonitrile and purified by preparative HPLC (method 12). The combined target fractions were concentrated and the residue was lyophilized. 20 mg (98% pure, 34% thor.) of the title compound were obtained.

- 141 040220

LC-MS (method 1): R _t = 1.80 min; MS (ESIpos): m/z = 606/608 [M+H]+.

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 1.089 (0.50), 1.117 (1.29), 1.140 (1.38), 1.622 (1.10), 1.648 (1.20), 1.676 (0.84), 1.746 (5.89 ), 1.773 (5.29), 1.812 (1.66), 1.833 (1.70), 1.857 (2.04), 1.871 (1.27), 1.885 (1.70), 1.904 (1.40), 1.917 (1.31), 1.924 (1.32), 1.959 (0.47 ), 2.151 (16.00), 2.566 (0.62), 2.723 (1.19), 2.747 (1.22), 2.776 (0.57), 3.336 (11.62), 3.450 (2.50), 3.481 (3.01), 7.083 (1.12), 7.090 (1.27 ), 7.105 (2.10), 7.111 (2.23), 7.125 (1.26), 7.132 (1.23), 7.298 (2.44), 7.305 (2.40), 7.323 (2.44), 7.330 (2.25), 7.458 (3.55), 7.471 (3.44 ), 7.479 (3.00), 7.493 (2.57), 7.621 (1.06), 7.643 (11.76), 7.672 (0.74), 8.997 (1.74).

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 9.00 (br. s, 1H), 7.69-7.60 (m, 1H), 7.48 (dd, 1H), 7.43 (br. s, partially obscured, 1H), 7.31 (dd, 1H), 7.11 (td, 1H), 4.63 (br. s, 1H), 3.74-3.18 (m, partially hidden, 8H), 2.822.62 (m, 1H), 2.15 (s , 3Н), 1.99-1.55 (m, 8H), 1.21-1.04 (m, 1H).

Example 22.

(+/-)-5-({[6-Bromo-3-methyl-2-(piperidin-1-yl)quinolin-4-yl]carbonyl}amino)-4-(2chlorophenyl)valeric acid (racemate)

A

Λύ° ^η

Ο^ΝΗ O ^Br ^^A^ ^CH 3

Ta x

To a solution of (+/-)-tert-butyl-5-({[6-bromo-3-methyl-2-(piperidin-1-yl)quinolin-4yl]carbonyl}amino)-4-(2-chlorophenyl )pentanoate (100 mg, 163 μmol, racemate, example 72A) in dichloromethane (2.9 ml) TFA (130 μl, 1.6 mmol) was added and the mixture was stirred 66 h at RT. The mixture was then concentrated and mixed several times with dichloromethane and re-concentrated. The residue was dissolved in acetonitrile and purified by preparative HPLC (method 6). The combined target fractions were concentrated. The residue was adsorbed several times in dichloromethane and re-concentrated and then dried in vacuo. 62 mg (100% pure, 68% thor.) of the title compound were obtained.

LC-MS (method 1): Rt = 2.18 min; MS (ESIpos): m/z = 558/560 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.149 (0.58), -0.008 (7.08), 0.008 (4.63), 0.146 (0.60), 1.235 (0.47), 1.370 (2.53), 1.605 ( 4.27), 1.670 (8.18), 1.793 (0.89), 1.811 (1.74), 1.834 (2.19), 1.857 (1.16), 2.045 (4.22) 16.00), 2.159 (1.61), 2.327 (0.92), 2.366 (0.92), 2.518 (4.78), 2.523 (4.22), 2.669 (1.05), 2.710 (0.87), 3.119 (8.34), 3.132 (10.53), 1.94), 3.674 (3.53), 5.754 (4.60), 7.257 (1.83), 7.275 (3.80), 7.291 (2.79), 7.295 (2.66), 7.356 (2.55), 7.373 (4.60), 7.391 (2.66), 7.444 (6.06), 7.461 (5.90), 7.464 (5.52), 7.479 (5.92), 7.482 (5.83), 7.498 (4.36), 7.622 (2.73), 7.643 (12.72), 7.651 (9.12), 7.69), 7.673 (1.72), 7.678 (1.77), 8.707 (2.17), 8.722 (4.09), 8.736 (1.92), 12.039 (6.06).

Example 23.

(-)-5-({[6-Bromo-3-methyl-2-(piperidin-1-yl)quinolin-4-yl]carbonyl}amino)-4-(2chlorophenyl)valeric acid (enantiomer 1).

To a solution of (-)-tert-butyl-5-({[6-bromo-3-methyl-2-(piperidin-1-yl)quinolin-4yl]carbonyl}amino)-4-(2-chlorophenyl)pentanoate (70 mg, 114 μmol, enantiomer 1, example 73A) in dichloromethane (2.0 ml) TFA (88 μl, 1.1 mmol) was added and the mixture was stirred overnight at RT. The mixture was then concentrated and mixed several times with dichloromethane and re-concentrated. The residue was dissolved in acetonitrile and purified by preparative HPLC (method 6). The combined target fractions were concentrated and the residue was lyophilized. 48 mg (98% pure, 99% ee, 73% thor.) of the title compound were obtained.

[a] _D20 = -17.0°, 589 nm, c = 0.27 g/100 ml ^, methanol;

LC-MS (method 1): Rt = 2.19 min; MS (ESIpos): m/z = 558/560 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: -0.060 (0.99), -0.008 (2.24), 0.008 (1.64), 0.084 (0.74), 1.607 (4.12), 1.672 (7.98), 1.782 (0.53), 1.793 (0.79), 1.812 (1.62), 1.835 (2.14), 1.858 (1.17), 2.014 (0.51), 2.035 (1.18), 2.046 (4.07), 2.073 (4.15) (5.01) 2.103 (2.60) (2.84) (5.77), 7.444 (5.50), 7.461 (5.08), 7.464 (4.86), 7.480 (5.49), 7.482 (5.54), 7.499 (4.21), 7.630 (2.09) (7.08), 7.680 (1.37), 7.685 (1.52), 8.712 (2.04), 8.726 (4.16), 8.740 (2.01).

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 12.02 (br. s, 1H), 8.73 (t, 1H), 7.71-7.62 (m, 2H), 7.54-7.42 (m, 3H), 7.37 (t, 1H), 7.31-7.24 (m, 1H), 3.95-3.45 (m, 3H, partially hidden), 3.19-3.08 (m, 4H), 2.20-2.01 (m, 6H), 1.95-1.73 ( m, 1H), 1.72-1.49 (m, 6H).

- 142 040220

Example 24.

(+)-5-({[6-Bromo-3-methyl-2-(piperidin-1-yl)quinolin-4-yl]carbonyl}amino)-4-(2chlorophenyl)valeric acid (enantiomer 2).

To a solution of (+)-tert-butyl-5-({[6-bromo-3-methyl-2-(piperidin-1-yl)quinolin-4yl]carbonyl}amino)-4-(2-chlorophenyl)pentanoate (70 mg, 114 μmol, enantiomer 2, example 74A) in dichloromethane (2.0 ml) TFA (88 μl, 1.1 mmol) was added and the mixture was stirred overnight at RT. The mixture was then concentrated and mixed several times with dichloromethane and re-concentrated. The residue was dissolved in acetonitrile and purified by preparative HPLC (method 6). The combined target fractions were concentrated and the residue was lyophilized. 43 mg (98% pure, 96% ee, 66% thor.) of the title compound were obtained.

^[ a] _D20 = +8. 1°, 589 nm, c = 0.26 g/100 ml, methanol;

LC-MS (method 1): R _t = 2.19 min; MS (ESIpos): m/z = 558/560 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: -0.149 (0.47), -0.008 (3.94), 0.008 (4.07), 0.146 (0.50), 1.606 (3.77), 1.671 (7.49), 1.793 (0.66), 1.810 (1.47), 1.834 (2.05), 1.857 (1.10), 2.024 (0.78), 2.044 (3.30), 2.077 (4.23) (1.53) (1.53) (4.94), 7.481 (5.29), 7.497 (3.95), 7.622 (2.32), 7.644 (12.05), 7.651 (8.27), 7.656 (7.28), 7.673 (1.50) (3.79), 8.740 (1.84).

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 12.05 (br. s, 1H), 8.73 (t, 1H), 7.69-7.61 (m, 2H), 7.53-7.42 (m, 3H), 7.37 (t, 1H), 7.31-7.23 (m, 1H), 3.76-3.62 (m, 2H), 3.62-3.53 (m, 1H), 3.20-3.06 (m, 4H), 2.20-1.98 (m, 6H ), 1.90-1.75 (m, 1H), 1.72-1.50 (m, 6H).

Example 25.

(+/-)-5-({[6-Bromo-3-methyl-2-(thiomorpholin-4-yl)quinolin-4-yl]carbonyl}amino)-4-(2chlorophenyl)valeric acid (racemate)

To a solution of (+/-)-tert-butyl-5-({[6-bromo-3-methyl-2-(thiomorpholin-4-yl)quinolin-4yl]carbonyl}amino)-4-(2-chlorophenyl )pentanoate (70 mg, 111 µmol, racemate, example 75A) in dichloromethane (810 µl) TFA (85 µl, 1.1 mmol) was added and the mixture was stirred overnight at RT. The mixture was then concentrated and mixed several times with dichloromethane and re-concentrated. The residue was dissolved in acetonitrile and purified by preparative HPLC (method 6). The combined target fractions were concentrated and the residue was lyophilized. 58 mg (98% pure, 89% thor.) of the title compound were obtained.

LC-MS (method 1): R _t = 2.11 min; MS (ESIpos): m/z = 576/578 [M+H]+.

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.022 (0.68), 1.004 (2.17), 1.234 (1.54), 1.394 (0.86), 1.809 (1.65), 1.831 (2.44), 1.854 (1.44 ), 2.037 (3.90), 2.064 (5.65), 2.072 (5.19), 2.085 (3.39), 2.095 (2.40), 2.134 (16.00), 2.196 (0.47), 2.327 (0.57), 2.670 (0.65), 2.710 (0.50 ), 2.787 (11.08), 2.798 (10.38), 2.864 (0.71), 3.045 (0.42), 3.414 (11.05), 3.425 (11.71), 3.584 (2.28), 3.676 (3.53), 7.255 (1.81), 7.273 (4.16 ), 7.293 (2.93), 7.353 (2.45), 7.372 (4.50), 7.391 (2.36), 7.442 (6.27), 7.462 (5.42), 7.478 (5.58), 7.495 (4.58), 7.655 (2.31), 7.677 (13.29 ), 7.681 (10.73), 7.686 (8.04), 7.704 (1.13), 7.708 (1.41), 8.732 (2.04), 8.745 (3.71), 8.759 (1.92).

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 12.01 (br. s, 1H), 8.75 (t, 1H), 7.73-7.64 (m, 2H), 7.58-7.42 (m, 3H) , 7.37 (t, 1H), 7.28 (t, 1H), 3.78-3.63 (m, 2H), 3.62-3.53 (m, 1H), 3.46-3.39 (m, 4H), 2.85-2.74 (m, 4H) , 2.22-1.98 (m, 6H), 1.92-1.74 (m, 1H).

Separation of enantiomers.

The title target compound (50 mg) was dissolved in methanol (50 ml) and separated into enantiomers by chiral phase preparative HPLC (see Examples 26 and 27) [column: Daicel Chiralpak ID, 5 μm, 250 mm x 20 mm; flow: 70 ml/min; sample injection: 0.40 ml; eluent: 30% methanol/70% carbon dioxide; duration of action 7 min, isocratic]. The combined target fractions were concentrated and the residue was lyophilized.

Example 26.

(+)-5-({[6-Bromo-3-methyl-2-(thiomorpholin-4-yl)quinolin-4-yl]carbonyl}amino)-4-(2chlorophenyl)valeric acid (enantiomer 1).

Separation of the enantiomers as described in Example 25 gave 8 mg (98% pure, 99% ee) of the title compound as the previously eluted enantiomer.

- 143 040220

[a] _D20 = +8.9°, 589 nm, c = 0.30 ^g /100 mL, methanol;

LC-MS (method 1): R _t = 2.08 min; MS (ESIpos): m/z = 576/578 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: -0.149 (1.02), 0.068 (1.62), 0.146 (1.00), 0.940 (0.50), 0.955 (0.52), 1.139 (0.50), 1.157 ( 0.52), 1.811 (1.54), 1.835 (2.04), 1.857 (1.14), 2.042 (3.63), 2.076 (4.73), 2.083 (5.00), 2.133 (16.00), 2.327 (1.22), 2.366 (1.12), 0.95), 2.669 (1.42), 2.710 (1.29), 2.788 (10.55), 3.425 (10.48), 3.587 (1.94), 3.677 (3.31), 7.256 (1.72), 7.275 (3.73), 7.294 (2.66), 2.26), 7.374 (4.08), 7.391 (2.24), 7.443 (5.60), 7.463 (4.80), 7.481 (5.08), 7.499 (4.23), 7.655 (1.74) 1.39), 8.720 (1.84), 8.735 (3.66), 8.749 (1.97), 12.054 (0.80).

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 12.05 (br. s, 1H), 8.74 (t, 1H), 7.74-7.62 (m, 2H), 7.58-7.42 (m, 3H) , 7.37 (t, 1H), 7.31-7.23 (m, 1H), 3.76-3.63 (m, 2H), 3.62-3.54 (m, 1H), 3.47-3.38 (m, 4H), 2.83-2.74 (m, 4H), 2.19-1.99 (m, 6H), 1.89-1.76 (m, 1H).

Example 27.

(-)-5-({[6-Bromo-3-methyl-2-(thiomorpholin-4-yl)quinolin-4-yl]carbonyl}amino)-4-(2chlorophenyl)valeric acid (enantiomer 2).

Separation of the enantiomers as described in Example 25 gave 8 mg (98% pure, 93% ee) of the title compound as the later eluted enantiomer.

[a] _D20 = -6.4°, 589 nm, c = 0.25 g/100 ml ^, methanol;

LC-MS (method 1): Rt = 2.08 min; MS (ESIpos): m/z = 576/578 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.149 (1.15), 0.008 (8.73), 0.069 (2.56), 0.146 (1.10), 1.812 (1.58), 1.834 (2.06), 1.859 (1.15 ), 2.043 (3.66), 2.083 (5.02), 2.133 (16.00), 2.328 (1.39), 2.366 (0.98), 2.523 (6.60), 2.670 (1.39), 2.709 (1.15), 2.786 (10.64), 3.425 (10.43 ), 3.588 (2.08), 3.677 (3.35), 7.256 (1.77), 7.274 (3.85), 7.292 (2.63), 7.354 (2.37), 7.374 (4.14), 7.391 (2.20), 7.441 (6.07), 7.461 (5.33 ), 7.481 (5.14), 7.498 (4.21), 7.655 (2.20), 7.677 (13.30), 7.686 (7.49), 7.709 (1.43), 8.734 (3.56), 12.050 (0.84).

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 12.05 (br. s, 1H), 8.73 (t, 1H), 7.73-7.63 (m, 2H), 7.59-7.41 (m, 3H), 7.37 (t, 1H), 7.31-7.22 (m, 1H), 3.76-3.63 (m, 2H), 3.62-3.53 (m, 1H), 3.47-3.38 (m, 4H), 2.83-2.73 (m, 4H ), 2.18-1.98 (m, 6H), 1.89-1.74 (m, 1H).

Example 28.

(+/-)-5-({[6-Bromo-2-(4,4-difluoropiperidin-1-yl)-3-methylquinolin-4-yl]carbonyl}amino)-4-(2chlorophenyl)valeric acid ( racemate)

To a solution of (+/-)-tert-butyl-5-({[6-bromo-2-(4,4-difluoropiperidin-1-yl)-3-methylquinolin-4yl]carbonyl}amino)-4-( 2-chlorophenyl)pentanoate (28 mg, 43.0 µmol, racemate, example 76A) in dichloromethane (320 µl) TFA (33 µl, 430 µmol) was added and the mixture was stirred overnight at RT. The mixture was then concentrated and mixed several times with dichloromethane and re-concentrated. The residue was dissolved in acetonitrile and purified by preparative HPLC (method 6). The combined target fractions were concentrated and the residue was lyophilized. 6 mg (98% pure, 23% thor.) of the title compound were obtained.

LC-MS (method 2): R _t = 1.13 min; MS (ESIpos): m/z = 594/596 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.149 (0.57), -0.008 (8.43), 0.008 (4.79), 0.146 (0.52), 1.234 (0.75), 1.810 (1.45), 1.831 ( 1.86), 1.854 (1.14), 2.034 (3.35), 2.062 (5.16), 2.093 (2.83), 2.118 (5.33), 2.170 (16.00) 0.98), 2.710 (0.58), 3.586 (1.93), 3.681 (3.12), 7.255 (1.54), 7.272 (3.22), 7.290 (2.24), 7.355 (2.13), 7.373 (3.61), 7.391 (1.95), 5.04), 7.459 (4.37), 7.481 (4.37), 7.499 (3.62), 7.658 (2.37), 7.680 (10.19), 7.688 (6.97), 7.693 (5.96) 2.79).

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 12.14 (br. s, 1H), 8.77 (t, 1H), 7.74-7.62 (m, 2H), 7.59-7.41 (m, 3H) , 7.37 (t, 1H), 7.31-7.23 (m, 1H), 3.76-3.62 (m, 2H), 3.62-3.53 (m, 1H), 2.24-1.97 (m, 11H), 1.89-1.75 (m, 1H).

Example 29.

(+/-)-5-({[6-Bromo-2-(3,6-dihydropyridin-1(2H)-yl)-3-methylquinolin-4-yl]carbonyl}amino)-4-(2chlorophenyl) valeric acid (racemate)

- 144 040220

To a solution of (+/-)-tert-butyl-5-({[6-bromo-2-(3,6-dihydropyridin-1(2H)-yl)-3-methylquinolin-4yl]carbonyl}amino)- 4-(2-chlorophenyl)pentanoate (80 mg, 131 µmol, racemate, example 77A) in dichloromethane (960 µl) TFA (100 µl, 1.3 mmol) was added and the mixture was stirred overnight at RT. The mixture was then concentrated and mixed several times with dichloromethane and re-concentrated. The residue was dissolved in acetonitrile and purified by preparative HPLC (method 6). The combined target fractions were concentrated and the residue was lyophilized. 65 mg (98% pure, 88% thor.) of the title compound were obtained.

LC-MS (method 1): R _t = 2.15 min; MS (ESIpos): m/z = 556/558 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.195 (1.62), 1.211 (1.64), 1.233 (0.51), 1.242 (0.74), 1.257 (0.81), 1.272 (0.44), 1.800 (0.79) , 1.819 (1.67), 1.842 (2.17), 1.865 (1.23), 2.052 (3.96), 2.086 (5.33) , 3680 (3.38), 3.796 (7.68), 5.818 (1.47), 5.844 (4.74), 5.863 (4.13), 5.889 (1.26), 7.256 (1.75), 7.274 (3.79), 7.293 (2.71), 7.357 (2.33) . , 7.675 (1.77), 7.680 (1.64), 8.721 (2.17), 8.735 (3.91), 8.748 (1.96), 12.047 (4.68).

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 12.05 (s, 1H), 8.73 (t, 1H), 7.70-7.60 (m, 2H), 7.57-7.41 (m, 3H), 7.37 (t, 1H), 7.28 (t, 1H), 5.93-5.79 (m, 2H), 3.80 (br. s, 2H), 3.73-3.63 (m, 2H), 3.63-3.54 (m, 1H), 3.27 (br. s, 2H, partially hidden), 2.30 (br. s, 2H), 2.19-1.99 (m, 6H), 1.91-1.72 (m, 1H).

Separation of enantiomers.

The title compound (60 mg) was dissolved in a mixture of isopropanol (3 ml), heptane (2 ml) and acetonitrile (1 ml), preferably in an ultrasonic bath, filtered and separated into enantiomers by preparative HPLC in a chiral phase (see Examples 30 and 31) [column: Daicel Chiralcel OX-H, 5 µm, 250 mm x 20 mm; flow: 15 ml/min; detection: 220 nm; temperature: 35°C; sample injection: 0.40 ml; eluent: 80% heptane/20% isopropanol; duration of action 16 min, isocratic]. The combined target fractions were concentrated and the corresponding residue was lyophilized in acetonitrile/water.

Example 30.

5-({[6-bromo-2-(3,6-dihydropyridin-1(2H)-yl)-3-methylquinolin-4-yl]carbonyl}amino)-4-(2chlorophenyl)valeric acid (enantiomer 1) .

Separation of the enantiomers as described in Example 29 gave the prepurified title compound as the previously eluted enantiomer (ee value 99%). Then further purified by preparative HPLC (method 7). The combined target fractions were concentrated and the residue was lyophilized in acetonitrile/water. 22 mg (98% pure, 37% thor.) of additionally purified title compound was obtained.

LC-MS (method 1): R _t = 2.15 min; MS (ESIpos): m/z = 556/558 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: -0.150 (1.15), 0.145 (1.01), 1.234 (0.91), 1.836 (2.69), 1.859 (1.58), 2.044 (4.28), 2.072 ( 6.37), 2.143 (16.00), 2.302 (4.72), 2.366 (1.79), 2.669 (1.95), 2.709 (1.62) 7.253 (2.12), 7.273 (4.35), 7.291 (3.03), 7.356 (2.86), 7.374 (4.65), 7.392 (2.49), 7.441 (6.91), 7.461 (6.23), 7.481 (6.16), 4.58), 7.617 (3.40), 7.639 (11.59), 7.652 (7.07), 7.657 (6.27), 7.674 (2.19), 8.750 (3.57).

Example 31.

5-({[6-bromo-2-(3,6-dihydropyridin-1(2H)-yl)-3-methylquinolin-4-yl]carbonyl}amino)-4-(2chlorophenyl)valeric acid (enantiomer 2) .

The separation of the enantiomers described in Example 29 gave the prepurified title compound as the later eluted enantiomer (ee value 99%). Then further purified by preparative HPLC (method 7). The combined target fractions were concentrated and the residue was lyophilized in acetonitrile/water. 11 mg (98% pure, 18% thor.) of additionally purified title compound was obtained.

LC-MS (method 1): Rt = 2.15 min; MS (ESIpos): m/z = 556/558 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.150 (2.35), 0.146 (2.13), 0.936 (2.03), 0.952 (2.03), 1.234 (6.29), 1.795 (2.13), 1.996 (4.48) ), 2.154 (16.00), 2.327 (8.96), 2.366 (4.59), 2.670 (6.72), 2.709 (5.01), 3.545 (3.09), 3.661 (4.16), 3.801 (10.77), 5.844 (6.61), 7.260 (4.05 ), 7.362 (4.27), 7.429 (6.08), 7.450 (6.93), 7.615 (3.84), 7.637 (14.83), 7.650 (10.03), 8.925 (1.71).

- 145 040220

Example 32.

(+/-)-5-({[6-Bromo-3-methyl-2-(1,2-oxazinan-2-yl)quinolin-4-yl]carbonyl}amino)-4-(2chlorophenyl)valeric acid (racemate)

Αν™

Ο^ΝΗ O ^{N 3}

To a solution of (+/-)-tert-butyl-5-({[6-bromo-3-methyl-2-(1,2-oxazinan-2-yl)quinolin-4yl]carbonyl}amino)-4- (2-Chlorophenyl)pentanoate (24 mg, 38.9 µmol, racemate, example 78A) in dichloromethane (1.0 ml) TFA (30 µl, 390 µmol) was added and the mixture was stirred overnight at RT. The mixture was then concentrated and mixed several times with dichloromethane and re-concentrated. The residue was dissolved in acetonitrile and purified by preparative HPLC (method 6). The combined target fractions were concentrated and the residue was lyophilized. 12 mg (98% pure, 56% thor.) of the title compound were obtained.

LC-MS (method 2): R _t = 1.11 min; MS (ESIpos): m/z = 560/562 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.008 (1.62), 1.172 (0.42), 1.189 (0.42), 1.696 (3.60), 1.708 (2.94), 1.784 (0.42), 1.795 (0.61) , 1.813 (1.31), 1.836 (1.81), 1.868 (3.31), 1.883 (3.96), 1.897 (2.58) 3.647 (0.92), 3.667 (1.81), 3.681 (2.72), 3.695 (1.97), 3.723 (1.12), 4.041 (3.52), 4.054 (5.58), 4.066 (3.45), 7.255 (1.27), 7.274 (2.96) , 7.293 (2.11) , 8.789 (1.61), 8.804 (3.12), 8.818 (1.54), 12.028 (0.59).

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 12.03 (br. s, 1H), 8.80 (t, 1H), 7.73 (s, 2H), 7.53 (br. s, 1H), 7.47 ( dd, 2H), 7.37 (t, 1H), 7.31-7.24 (m, 1H), 4.05 (t, 2H), 3.80-3.47 (m, 5H), 2.21-1.98 (m, 6H), 1.94-1.77 ( m, 3H), 1.75-1.64 (m, 2H).

Example 33.

(+/-)-5-({[6-Bromo-3-methyl-2-(pyrrolidin-1-yl)quinolin-4-yl]carbonyl}amino)-4-(2chlorophenyl)valeric acid (racemate)

To a solution of (+/-)-tert-butyl-5-({[6-bromo-3-methyl-2-(pyrrolidin-1-yl)quinolin-4yl]carbonyl}amino)-4-(2-chlorophenyl )pentanoate (380 mg, 632 μmol, racemate, example 79A) in dichloromethane (4.6 ml) TFA (490 μl, 6.3 mmol) was added and the mixture was stirred overnight at RT. The mixture was then concentrated and mixed several times with dichloromethane and re-concentrated. The residue was dissolved in acetonitrile and purified by preparative HPLC (method 6). The combined target fractions were concentrated and the residue was lyophilized. 256 mg (98% pure, 73% thor.) of the title compound were obtained.

LC-MS (method 1): R _t = 1.43 min; MS (ESIpos): m/z = 544/546 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: -0.008 (1.19), 0.008 (1.14), 1.241 (0.73), 1.256 (0.78), 1.271 (0.46), 1.785 (0.59), 1.796 ( 0.85), 1.814 (1.80), 1.838 (3.17), 1.871 (12.01), 2.026 (1.00), 2.047 (3.97), 2.080 (4.63), 2.090 (4.73), 2.111 (1.81), 2.119 (1.82), 2.138 3.86), 2.161 (9.89), 3.322 (16.00), 3.659 (2.60), 7.251 (1.67), 7.268 (3.84), 7.286 (2.77) 6.55) 1.99), 8.677 (3.85), 8.690 (1.92), 12.041 (3.75).

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 8.68 (t, 1H), 7.56 (dd, 1H), 7.52-7.40 (m, 4H), 7.37 (t, 1H), 7.317.23 ( m, 1H), 3.78-3.48 (m, 7H), 2.22-1.98 (m, 6H), 1.93-1.75 (m, 5H).

Separation of enantiomers.

The title target compound (220 mg) was adsorbed in methanol (15 ml), filtered and separated into enantiomers by chiral phase preparative HPLC (see Examples 34 and 35) [column: Daicel Chiralcel OX-H, 5 µm, 250 mm x 20 mm; flow: 80 ml/min; detection: 210 nm; temperature: 40°C; sample injection: 0.15 ml; eluent: 35% methanol/65% carbon dioxide; continue

- 146 040220 duration of action 5 min, isocratic]. The combined target fractions were concentrated and the residue was lyophilized.

Example 34.

(-)-5-({[6-Bromo-3-methyl-2-(pyrrolidin-1-yl)quinolin-4-yl]carbonyl}amino)-4-(2chlorophenyl)valeric acid (enantiomer 1).

Separation of the enantiomers as described in Example 33 gave the prepurified title compound as the previously eluted enantiomer (ee value 99%). Then further purified by preparative HPLC (method 6). The combined desired fractions were concentrated and the residue was dried in vacuo. 35 mg (98% pure) of further purified title compound was obtained.

[a] _D20 = -11.4°, 589 nm, c = 0.30 ^g /100 ml, methanol;

LC-MS (method 1): Rt = 1.49 min; MS (ESIpos): m/z = 544/546 [M+H]+.

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.811 (2.39), 1.835 (4.10), 1.871 (16.00), 2.043 (5.13), 2.076 (6.19), 2.086 (6.23), 2.134 (4.98) , 2.158 (13.15), 2.286 (0.46), 2.328 (1.03), 2.366 (0.61), 2.670 (1.10), 2.710 (0.68), 3.567 (13.61), 3.656 (3.65), 7.251 (2.39) 7.287 (3.69), 7.352 (3.53), 7.370 (6.08), 7.388 (3.80), 7.435 (8.06), 7.455 (6.95), 7.466 (9.27), 7.474 (6.88), 7.488 (14.78), 7.543 (7.22) , 7.548 (6.31), 7.565 (4.14), 7.570 (3.76), 8.661 (2.89), 8.676 (5.21), 8.690 (2.58), 12.038 (0.57).

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 12.04 (br. s, 1H), 8.68 (t, 1H), 7.55 (dd, 1H), 7.52-7.40 (m, 4H), 7.37 ( t, 1H), 7.31-7.23 (m, 1H), 3.77-3.48 (m, 7H), 2.24-1.97 (m, 6H), 1.95-1.75 (m, 5H).

Method B.

To a solution of (-)-tert-butyl-5-({[6-bromo-3-methyl-2-(pyrrolidin-1-yl)quinolin-4yl]carbonyl}amino)-4-(2-chlorophenyl)pentanoate (2.11 g, 3.51 mmol, enantiomer 2, example 293A) in dichloromethane (27 ml) was added TFA (6.0 ml, 77.24 mmol) and the mixture was left for 24 h at RT. The mixture was then concentrated and mixed several times with dichloromethane and re-concentrated. The residue was purified by preparative HPLC (method 6). The combined target fractions were concentrated and the residue was lyophilized. 1.44 g (100% pure, 75% th. y.) of the title compound was obtained.

[a] _D20 = -13.1°, 589 nm, c = 0.32 g ^/ 100 ml, methanol;

LC-MS (method 1): Rt = 1.44 min; MS (ESIpos): m/z = 544/546 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.795 (0.23), 1.814 (0.53), 1.837 (0.93), 1.871 (3.68), 2.026 (0.28), 2.046 (1.18), 2.079 (1.39) , 2.089 (1.41), 2.110 (0.55), 2.118 (0.54), 2.137 (1.15), 2.160 (3.09), 3.316 (16.00), 3.658 (0.81), 7.251 (0.50), 7.269 (1.13) , 7.352 (0.77), 7.371 (1.38), 7.389 (0.85), 7.437 (1.84), 7.457 (1.53), 7.469 (1.47), 7.477 (1.68), 7.491 (2.55), 7.545 (1.30), 7.549 (1.32) , 7.567 (0.78), 7.571 (0.80), 8.661 (0.60), 8.675 (1.17), 8.689 (0.60), 12.039 (1.84).

Example 35.

(+)-5-({[6-Bromo-3-methyl-2-(pyrrolidin-1-yl)quinolin-4-yl]arbonyl}amino)-4-(2chlorophenyl)valeric acid (enantiomer 2)

Method A.

The separation of the enantiomers described in Example 33 gave the prepurified title compound as the later eluted enantiomer (ee value 93%). Then further purified by preparative HPLC (method 6). The combined desired fractions were concentrated and the residue was dried in vacuo. 37 mg (98% pure) of further purified title compound was obtained.

[a] _D20 = +11.4°, 589 nm, c = 0.29 g/100 ml, methanol LC-MS (method 1): ^Rt = 1.49 min; MS (ESIpos): m/z = 544/546 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.794 (1.17), 1.811 (2.44), 1.836 (4.11), 1.872 (16.00), 2.045 (5.39), 2.078 (6.39), 2.088 (6.44) , 2.117 (2.50), 2.136 (5.11), 2.159 (13.11), 2.241 (0.50), 2.288 (0.50), 2.327 (0.83), 2.366 (0.67), 2.670 (0.83), 2.710 (0.67), 3.570 (13.00) . . , 12.040 (3.78).

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 12.04 (br. s, 1H), 8.68 (t, 1H), 7.59-7.53 (m, 1H), 7.53-7.40 (m, 4H), 7.37 (t, 1H), 7.30-7.23 (m, 1H), 3.79-3.48 (m, 7H), 2.21-2.00 (m, 6H), 1.92-1.77 (m, 5H).

Method B.

To a solution of tert-butyl-(4R)-5-({[6-bromo-3-methyl-2-(pyrrolidin-1-yl)quinolin-4yl]carbonyl}amino)-4-(2-chlorophenyl)pentanoate (2.16 g, 3.59 mmol, enantiomer 7, example 292A) in dichloromethane (28 ml) was added TFA (6.1 ml, 79.07 mmol) and the mixture was left for 24 h at RT. The mixture was then concentrated and mixed several times with dichloromethane and re-concentrated. The residue was purified by preparative HPLC (method 6). The combined target fractions were concentrated and the residue was lyophilized. 1.37 g (100% pure, 70% th. y.) of the title compound was obtained. For the parent compound, the R-configuration was determined using the VCD

- 147 040220 spectroscopy (see example 292A), so the title compound also has the R configuration.

[a] ^D20 = +11.3°, 589 nm, c = 0.30 g/100 mL, methanol;

LC-MS (method 1): R _t = 1.44 min; MS (ESIpos): m/z = 544/546 [M+H]+.

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.784 (0.16), 1.795 (0.23), 1.813 (0.53), 1.837 (0.95), 1.870 (3.74), 2.026 (0.28), 2.046 (1.18) , 2.079 (1.40), 2.089 (1.42), 2.110 (0.56), 2.118 (0.55), 2.137 (1.18), 2.159 (3.13), 3.315 (16.00), 3.658 (0.81), 7.249 (0.49), 7.268 (1.13) . , 7.548 (1.45), 7.565 (0.91), 7.570 (0.88), 8.660 (0.62), 8.674 (1.23), 8.688 (0.62), 12.038 (2.54).

Example 36.

5-[({6-Bromo-3-methyl-2-[3-methylpyrrolidin-1-yl]quinolin-4-yl}carbonyl)amino]-4-(2chlorophenyl)valeric acid (mixture of diastereoisomers)

To a solution of tert-butyl 5-[({6-bromo-3-methyl-2-[3-methylpyrrolidin-1-yl]quinolin-4yl}carbonyl)amino]-4-(2-chlorophenyl)pentanoate (25 mg, 40.6 µmol, mixture of diastereoisomers, example 80A) in dichloromethane (1.0 ml) TFA (31 µl, 410 µmol) was added and the mixture was stirred overnight at RT. TFA (31 μl, 410 μmol) was then added again and the mixture was stirred for an additional 24 h at RT. TFA (31 µl, 410 µmol) was then added again and the mixture was stirred for an additional 6 hours at 60°C. TFA (31 µl, 410 µmol) was then added again and the mixture was stirred for an additional 8 hours at 60°C. The mixture was then concentrated and mixed several times with dichloromethane and re-concentrated. The residue was dissolved in acetonitrile and purified by preparative HPLC (method 6). The combined target fractions were concentrated and the residue was lyophilized. 7 mg (98% pure, 31% thor.) of the title compound were obtained.

LC-MS (method 1): R _t = 1.59 min; MS (ESIpos): m/z = 560 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: -0.150 (0.99), -0.008 (14.17), 0.008 (8.09), 0.062 (1.26), 0.146 (1.04), 1.059 (16.00), 1.075 (15.93), 1.235 (1.80), 1.367 (2.66), 1.472 (1.69), 1.494 (2.37), 1.522 (1.83), 1.806 (2.03) (7.53) (6.63) (8.29), 7.482 (12.53), 7.539 (6.04), 7.561 (3.58), 7.951 (0.86), 8.699 (3.61).

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.74-8.65 (m, 1H), 7.59-7.51 (m, 1H), 7.51-7.40 (m, 4H), 7.407.33 (m, 1H), 7.31-7.22 (m, 1H), 3.76-3.52 (m, 6H), 3.28-3.17 (m, 1H, partially hidden), 2.29-1.97 (m, 8H), 1.90-1.76 (m, 1H) , 1.58-1.42 (m, 1H), 1.07 (d, 3H).

Example 37.

(+/-)-5-({[6-Bromo-2-(3,3-difluoropyrrolidin-1-yl)-3-methylquinolin-4-yl]carbonyl}amino)-4-(2chlorophenyl)valeric acid ( racemate)

To a solution of (+/-)-tert-butyl-5-({[6-bromo-2-(3,3-difluoropyrrolidin-1-yl)-3-methylquinolin-4yl]carbonyl}amino)-4-( 2-Chlorophenyl)pentanoate (30 mg, 47.1 µmol, racemate, example 81A) in dichloromethane (1.0 ml) TFA (36 µl, 470 µmol) was added and the mixture was stirred overnight at RT. TFA (31 μl, 410 μmol) was then added again and the mixture was stirred for an additional 24 h at RT. TFA (31 µl, 410 µmol) was then added again and the mixture was stirred for an additional 6 hours at 60°C. TFA (31 µl, 410 µmol) was then added again and the mixture was stirred for an additional 8 hours at 60°C. The mixture was then concentrated and mixed several times with dichloromethane and reconcentrated.

- 148 040220 roval. The residue was dissolved in acetonitrile and purified by preparative HPLC (method 6). The combined target fractions were concentrated and the residue was lyophilized. 12 mg (98% pure, 44% thor.) of the title compound were obtained.

LC-MS (method 1): R _t = 2.11 min; MS (ESIpos): m/z = 580/582 [M+H]+.

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: -0.149 (1.00), -0.008 (8.49), 0.008 (8.89), 0.049 (0.70), 0.063 (1.25), 0.146 (1.05), 0.943 (1.12), 0.960 (1.05), 1.235 (0.75), 1.813 (2.12), 1.836 (3.07), 1.860 (1.72), 2.041 (5.02), 2.071 (6.34) (4.19) 2.165 (12.61) 2.327 (1.40) 2.366 (0.92) (10.68) (3.59), 7.354 (3.10), 7.372 (5.57), 7.391 (3.17), 7.437 (8.89), 7.440 (8.96), 7.457 (7.54), 7.460 (7.51) (8.01), 7.590 (16.00), 7.628 (8.79), 7.633 (8.11), 7.650 (4.27), 7.655 (4.19), 7.952 (0.85), 8.699 (2.67), 8.712 (5.19), 8.726 (2.70).

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 12.04 (br. s, 1H), 8.71 (t, 1H), 7.64 (dd, 1H), 7.58 (d, 1H), 7.527.42 (m, 3H), 7.37 (t, 1H), 7.31-7.23 (m, 1H), 4.11-3.87 (m, 2H), 3.85-3.50 (m, 5H), 2.51-2.40 (m, 2H, hidden) , 2.23-1.96 (m, 6H), 1.90-1.74 (m, 1H).

Example 38.

(+/-)-5-({[6-Bromo-3-methyl-2-(1,2-oxazolidin-2-yl)quinolin-4-yl]carbonyl}amino)-4-(2chlorophenyl)valeric acid (racemate) jO

Ο^ΝΗ Ο ^Br ^ХХХ< ^CH3

To a solution of (+/-)-tert-butyl-5-({[6-bromo-3-methyl-2-(1,2-oxazolidin-2-yl)quinolin-4yl]carbonyl}amino)-4- (2-Chlorophenyl)pentanoate (110 mg, 182 µmol, racemate, example 82A) in dichloromethane (1.3 ml) TFA (140 µl, 1.8 mmol) was added and the mixture was stirred overnight at RT. The mixture was then concentrated and mixed several times with dichloromethane and re-concentrated. The residue was dissolved in acetonitrile and purified by preparative HPLC (method 6). The combined target fractions were concentrated and the residue was lyophilized. Received 80 mg (98% pure, 79% theoretical. output.) specified in the title compound.

LC-MS (method 1): R _t = 1.83 min; MS (ESIpos): m/z = 546/548 [M+H]+.

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (1.94), 0.008 (1.90), 1.782 (0.41), 1.793 (0.66), 1.814 (1.34), 1.835 (1.71), 1.858 (0.99 ), 2.033 (0.92), 2.045 (3.57), 2.073 (2.81), 2.081 (3.16), 2.093 (3.30), 2.121 (1.33), 2.129 (1.23), 2.141 (2.11), 2.164 (1.10), 2.210 (7.16 ), 2.240 (4.55), 2.257 (5.85), 2.276 (4.31), 2.294 (1.35), 3.604 (1.49), 3.651 (0.90), 3.670 (1.66), 3.684 (2.28), 3.698 (2.02), 3.714 (1.56 ), 3.771 (3.06), 3.822 (4.25), 3.840 (7.28), 3.859 (3.97), 7.257 (1.29), 7.275 (2.94), 7.293 (2.07), 7.356 (1.72), 7.375 (3.14), 7.393 (1.64 ), 7.445 (4.53), 7.447 (4.50), 7.465 (3.83), 7.467 (3.73), 7.486 (3.85), 7.502 (3.01), 7.707 (0.71), 7.729 (16.00), 7.756 (0.60), 8.767 (1.66 ), 8.782 (3.27), 8.796 (1.64), 12.043 (3.12).

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 12.04 (s, 1H), 8.78 (t, 1H), 7.78-7.69 (m, 2H), 7.53 (br. s, 1H), 7.51 -7.43 (m, 2H), 7.37 (t, 1H), 7.31-7.24 (m, 1H), 3.84 (t, 2H), 3.81-3.52 (m, 5H), 2.31-1.99 (m, 8H), 1.90 -1.74 (m, 1H).

Separation of enantiomers.

The title title compound (70 mg) was dissolved in a mixture of isopropanol (2 ml) and heptane (2 ml) and separated into enantiomers by preparative HPLC on a chiral phase (see Examples 39 and 40) [column: Daicel Chiralpak ID, 5 microns, 250 mmx20 mm; flow: 15 ml/min; sample injection: 0.4 ml; eluent: 50% isopropanol/50% (heptane + 0.2% TFA); duration of action 13 min, isocratic]. The combined target fractions were concentrated and the residue was lyophilized.

Example 39.

(-)-5-({[6-Bromo-3-methyl-2-(1,2-oxazolidin-2-yl)quinolin-4-yl]carbonyl}amino)-4-(2chlorophenyl)valeric acid (enantiomer 1).

Separation of the enantiomers as described in Example 38 gave the prepurified title compound as the previously eluted enantiomer (ee value 99%). Then further purified by preparative HPLC (method 7). The combined target fractions were concentrated and the residue was lyophilized in acetonitrile/water. 39 mg (98% pure) of further purified title compound was obtained.

[a] _D20 = -8.0°, 589 nm, c = 0.30 g/100 ml ^, methanol;

LC-MS (method 2): R _t = 0.94 min; MS (ESIpos): m/z = 546/548 [M+H]+.

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: -0.149 (0.87), -0.008 (7.75), 0.008 (6.54), 0.146 (0.84), 1.809

- 149 040220 (1.24), 1.832 (1.61), 1.856 (0.90), 2.039 (2.88), 2.073 (3.07), 2.084 (2.79), 2.133 (1.83), 2.209 (6.54), 2.240 (4.16), 2.257 (5.49) ), 2.276 (4.09), 2.294 (1.27), 2.327 (1.27), 2.366 (1.27), 2.523 (3.57), 2.669 (1.36), 2.710 (1.27), 3.600 (1.43), 3.667 (1.55), 3.682 (2.14 ), 3.697 (1.86), 3.771 (2.82), 3.822 (4.09), 3.840 (6.98), 3.859 (3.88), 7.256 (1.27), 7.274 (2.79), 7.292 (1.98), 7.355 (1.58), 7.374 (2.95 ), 7.392 (1.55), 7.444 (4.43), 7.464 (3.78), 7.484 (3.53), 7.501 (2.79), 7.707 (0.68), 7.729 (16.00), 8.777 (1.33), 8.791 (2.73), 8.805 (1.43 ).

Example 40.

(+)-5-({[6-Bromo-3-methyl-2-(1,2-oxazolidin-2-yl)quinolin-4-yl]carbonyl}amino)-4-(2chlorophenyl)valeric acid (enantiomer 2).

Separation of the enantiomers as described in Example 38 gave the prepurified title compound as the later eluted enantiomer (ee value 97%). Then further purified by preparative HPLC (method 7). The combined target fractions were concentrated and the residue was lyophilized in acetonitrile/water. 30 mg (98% pure) of further purified title compound was obtained.

[a] ^D20 = +14.0°, 589 nm, c = 0.25 g/100 mL, methanol;

LC-MS (method 2): Rt = 0.94 min; MS (ESIpos): m/z = 546/548 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: -0.149 (0.52), 0.146 (0.52), 1.790 (0.55), 1.808 (1.29), 1.831 (1.85), 1.854 (0.98), 2.014 ( 0.69), 2.036 (2.96), 2.067 (3.48), 2.078 (3.21), 2.088 (2.20), 2.102 (1.35), 2.128 (2.06), 2.152 (0.94), 2.211 (7.24), 2.240 (4.66), 6.01), 2.276 (4.41), 2.294 (1.36), 2.327 (0.74), 2.366 (0.66), 2.670 (0.77), 2.710 (0.69), 3.595 (1.54), 3.648 (0.94), 3.667 (1.68), 2.27) 2.04), 7.355 (1.74), 7.373 (3.20), 7.392 (1.67), 7.446 (4.48), 7.466 (3.78), 7.483 (3.92), 7.502 (3.00) 0.66), 8.784 (1.45), 8.799 (2.85), 8.812 (1.52).

Example 41.

5-[({6-Bromo-2-[3-methoxypyrrolidin-1-yl]-3-methylquinolin-4-yl}carbonyl)amino]-4-(2chlorophenyl)valeric acid (mixture of diastereoisomers)

To a solution of butyl 5-({[6-bromo-2-(3-methoxypyrrolidin-1-yl)-3-methylquinolin-4yl]carbonyl}amino)-4-(2-chlorophenyl)pentanoate (30 mg, 47.5 µmol, mixture of diastereoisomers, example 83A) in dichloromethane (1.0 ml) was added TFA (37 µl, 480 µmol) and the mixture was stirred overnight at RT. The mixture was then concentrated and mixed several times with dichloromethane and re-concentrated. The residue was dissolved in acetonitrile and purified by preparative HPLC (method 6). The combined target fractions were concentrated and the residue was lyophilized. 10 mg (98% pure, 37% thor.) of the title compound were obtained.

LC-MS (method 2): R _t = 0.80 min; MS (ESIpos): m/z = 574/576 [M+H]+.

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (1.41), 0.008 (1.36), 1.812 (0.64), 1.834 (0.89), 1.858 (0.55), 1.954 (0.60), 2.018 (1.00 ), 2.040 (1.85), 2.068 (2.03), 2.079 (1.86), 2.103 (0.85), 2.129 (1.23), 2.158 (3.82), 2.523 (0.81), 3.199 (0.60), 3.245 (16.00), 3.417 (0.42 ), 3.511 (1.14), 3.551 (0.87), 3.572 (0.89), 3.591 (0.88), 3.659 (0.88), 3.714 (0.98), 3.778 (0.79), 3.807 (0.63), 4.017 (1.34), 7.245 (0.44 ), 7.263 (0.96), 7.275 (0.93), 7.293 (0.63), 7.346 (0.69), 7.364 (1.23), 7.378 (1.10), 7.395 (0.66), 7.435 (2.45), 7.437 (2.36), 7.455 (2.05 ), 7.457 (1.93), 7.478 (2.83), 7.500 (3.63), 7.556 (1.97), 7.561 (1.29), 7.579 (1.19), 8.694 (1.08).

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 12.05 (br. s, 1H), 8.69 (br. s, 1H), 7.62-7.53 (m, 1H), 7.53-7.41 (m, 4H), 7.40-7.33 (m, 1H), 7.31-7.22 (m, 1H), 4.02 (br. s, 1H), 3.84-3.46 (m, 7H), 3.24 (s, 3H), 2.22-1.77 ( m, 9H).

Example 42.

(+/-)-5-({[6-Bromo-2-(3,3-dimethylpiperidin-1-yl)-3-methylquinolin-4-yl]carbonyl}amino)-4-(2chlorophenyl)valeric acid ( racemate)

- 150 040220

To a solution of (+/-)-tert-butyl-5-({[6-bromo-2-(3,3-dimethylpiperidin-1-yl)-3-methylquinolin-4yl]carbonyl}amino)-4-( 2-chlorophenyl)pentanoate (80 mg, 124 µmol, racemate, example 84A) in dichloromethane (910 µl) TFA (96 µl, 1.2 mmol) was added and the mixture was stirred overnight at RT. The mixture was then concentrated and mixed several times with dichloromethane and re-concentrated. The residue was dissolved in acetonitrile and purified by preparative HPLC (method 6). The combined target fractions were concentrated and the residue was lyophilized. 65 mg (98% pure, 87% thor.) of the title compound were obtained.

LC-MS (method 1): Rt = 2.43 min; MS (ESIpos): m/z = 586/588 [M+H] ⁺ .

1H-NMR (600 MHz, DMSO-d ₆ ) δ [ppm]: 1.007 (16.00), 1.377 (1.50), 1.386 (2.45), 1.392 (2.05), 1.723 (2.48), 1.731 (2.30), 1.740 (1.95 ), 1.753 (1.20), 1.762 (0.78), 1.818 (0.64), 1.829 (0.83), 1.839 (0.50), 1.919 (0.68), 1.929 (0.67), 2.182 (3.52), 2.386 (0.52), 2.614 (0.58 ), 2.868 (3.61), 3.043 (1.14), 3.476 (0.92), 3.635 (0.64), 7.232 (0.61), 7.244 (1.47), 7.256 (1.05), 7.339 (0.71), 7.351 (1.38), 7.364 (0.79 ), 7.420 (2.16), 7.433 (2.83), 7.442 (1.31), 7.632 (0.62), 7.646 (4.36), 7.668 (0.51), 9.138 (0.94).

1H-NMR (600 MHz, DMSO-d ₆ ) δ [ppm]: 9.14 (br. s, 1H), 7.69-7.60 (m, 2H), 7.48 (br. s, 1H), 7.45-7.40 (m, 2H), 7.35 (t, 1H), 7.27-7.21 (m, 1H), 3.64 (br. s, 2H), 3.52-3.44 (m, 1H), 3.04 (br. s, 2H), 2.87 (s, 2H), 2.18 (br. s, 3H), 1.98-1.88 (m, 1H), 1.87-1.78 (m, 1H), 1.78-1.68 (m, 4H), 1.41-1.34 (m, 2H), 1.01 ( s, 6H).

Separation of enantiomers.

The title target compound (50 mg) was dissolved in methanol (25 ml) and separated into enantiomers by chiral phase preparative HPLC (see Examples 43 and 44) [column: Daicel Chiralpak AD, 5 μm, 250 mm x 20 mm; flow: 80 ml/min; sample injection: 3 ml; eluent: 25% isopropanol/75% carbon dioxide; duration of action 9 min, isocratic]. The combined target fractions were concentrated and the residue was lyophilized.

Example 43.

(-)-5-({[6-Bromo-2-(3,3-dimethylpiperidin-1-yl)-3-methylquinolin-4-yl]carbonyl}amino)-4-(2chlorophenyl)valeric acid (enantiomer 1 ).

Separation of the enantiomers as described in Example 42 gave 10 mg (98% pure, 99% ee) of the title compound as the previously eluted enantiomer.

[a] _D20 = -12.0°, 589 nm, c = ^0.25 g/100 ml, methanol;

LC-MS (method 1): Rt = 2.45 min; MS (ESIpos): m/z = 586/588 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (2.83), 0.008 (3.24), 1.004 (16.00), 1.373 (1.13), 1.387 (1.81), 1.402 (1.39), 1.721 (1.36) ), 1.805 (0.50), 1.827 (0.66), 1.850 (0.42), 2.024 (1.09), 2.054 (1.93), 2.070 (1.15), 2.106 (0.65), 2.165 (5.23), 2.710 (0.41), 2.864 (4.18 ), 3.044 (1.53), 3.576 (0.67), 3.669 (0.97), 7.253 (0.55), 7.272 (1.28), 7.289 (0.91), 7.353 (0.75), 7.371 (1.38), 7.389 (0.74), 7.438 (1.91 ), 7.440 (1.92), 7.458 (1.75), 7.461 (1.78), 7.475 (1.85), 7.491 (1.37), 7.628 (0.41), 7.650 (5.99), 7.655 (2.96), 8.762 (0.98).

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 12.15 (br. s, 1H), 8.76 (t, 1H), 7.70-7.61 (m, 2H), 7.58-7.41 (m, 3H), 7.37 (t, 1H), 7.30-7.24 (m, 1H), 3.75-3.62 (m, 2H), 3.61-3.54 (m, 1H), 3.04 (br. s, 2H), 2.86 (s, 2H), 2.17 (s, 3H), 2.13-1.97 (m, 3H), 1.90-1.77 (m, 1H), 1.76-1.65 (m, 2H), 1.45-1.32 (m, 2H), 1.00 (s, 6H).

Example 44.

(+)-5-({[6-Bromo-2-(3,3-dimethylpiperidin-1-yl)-3-methylquinolin-4-yl]carbonyl}amino)-4-(2chlorophenyl)valeric acid (enantiomer 2 ).

The separation of the enantiomers described in Example 42 gave 10 mg (98% pure, 99% ee) of the title compound as the later eluted enantiomer.

[a] _D20 = +9.3°, 589 nm ^, c = 0.25 g/100 mL, methanol;

LC-MS (method 1): Rt = 2.45 min; MS (ESIpos): m/z = 586/588 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (3.58), 0.008 (3.59), 0.146 (0.41), 1.004 (16.00), 1.372 (1.15), 1.386 (1.87), 1.401 (1.40) ), 1.720 (1.37), 1.810 (0.50), 1.833 (0.71), 1.857 (0.42), 2.039 (1.14), 2.067 (1.73), 2.122 (0.84), 2.163 (5.31), 2.327 (0.42), 2.669 (0.46 ), 2.863 (4.18), 3.044 (1.59), 3.583 (0.66), 3.673 (1.01), 7.256 (0.55), 7.274 (1.29), 7.291 (0.94), 7.355 (0.79), 7.373 (1.42), 7.393 (0.73 ), 7.440 (2.01), 7.442 (2.03), 7.460 (1.83), 7.478 (1.90), 7.495 (1.41), 7.628 (0.41), 7.650 (6.13), 7.655 (3.12), 7.678 (0.41), 8.737 (1.17 ).

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 12.1 (br. s, 1H), 8.74 (t, 1H), 7.71-7.59 (m, 2H), 7.58-7.41 (m, 3H), 7.37 (t, 1H), 7.31-7.23 (m, 1H), 3.76-3.62 (m, 2H), 3.62-3.53 (m, 1H), 3.04 (br. s, 2H), 2.86 (s, 2H), 2.16 (s, 3H), 2.14-2.00 (m, 3H), 1.90-1.76 (m, 1H), 1.76-1.67 (m, 2H), 1.43-1.34 (m, 2H), 1.00 (s, 6H).

Example 45.

5-[({6-Bromo-3-methyl-2-[3-methylpiperidin-1-yl]quinolin-4-yl}carbonyl)amino]-4-(2chlorophenyl)valeric acid (mixture of diastereoisomers)

- 151 040220

To a solution of tert-butyl 5-[({6-bromo-3-methyl-2-[3-methylpiperidin-1-yl]quinolin-4yl}carbonyl)amino]-4-(2-chlorophenyl)pentanoate (100 mg, 159 µmol, mixture of diastereoisomers, example 85A) in dichloromethane (1.2 ml) was added TFA (120 µl, 1.6 mmol) and the mixture was stirred overnight at RT. The mixture was then concentrated and mixed several times with dichloromethane and re-concentrated. The residue was dissolved in acetonitrile and purified by preparative HPLC (method 6). The combined target fractions were concentrated and the residue was lyophilized. 82 mg (98% pure, 88% thor.) of the title compound were obtained.

LC-MS (method 1): R _t = 2.33 min; MS (ESIpos): m/z = 572/574 [M+H]+.

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 0.921 (4.93), 0.936 (4.95), 1.077 (0.56), 1.107 (0.57), 1.625 (0.46), 1.654 (0.54), 1.730 (1.03 ), 1.761 (1.00), 1.793 (1.35), 1.821 (1.21), 1.837 (1.07), 1.860 (0.44), 2.049 (1.51), 2.083 (1.79), 2.091 (1.94), 2.135 (6.39), 2.160 (0.58 ), 2.431 (0.42), 2.501 (16.00), 2.675 (0.41), 2.709 (0.64), 3.489 (3.11), 3.574 (1.10), 3.591 (1.05), 3.677 (1.20), 7.255 (0.62), 7.274 (1.47 ), 7.292 (1.12), 7.355 (0.86), 7.374 (1.53), 7.392 (0.80), 7.441 (2.18), 7.461 (1.95), 7.480 (2.10), 7.499 (1.51), 7.626 (0.50), 7.648 (5.52 ), 8.704 (0.73), 8.719 (1.40), 8.732 (0.68).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 12.05 (br. s, 1H), 8.72 (t, 1H), 7.70-7.61 (m, 2H), 7.58-7.41 (m, 3H ), 7.37 (t, 1H), 7.32-7.23 (m, 1H), 3.82-3.26 (m, 5H, partially hidden), 2.78-2.62 (m, 1H), 2.48-2.38 (m, 1H, partially hidden) , 2.20-1.98 (m, 6H), 1.90-1.54 (m, 5H), 1.17-1.01 (m, 1H), 0.93 (d, 3H).

Example 46.

(-)-5-[({6-Bromo-3-methyl-2-[3-methylpiperidin-1-yl]quinolin-4-yl}carbonyl)amino]-4-(2chlorophenyl)valeric acid (diastereoisomer 1) .

To a solution of (-)-tert-butyl-5-[({6-bromo-3-methyl-2-[3-methylpiperidin-1-yl]quinolin-4yl}carbonyl)amino]-4-(2-chlorophenyl )pentanoate (185 mg, 294 µmol, diastereoisomer 7, example 86A) in dichloromethane (2.2 ml) was added with TFA (230 µl, 2.9 mmol) and the mixture was left for 24 h at RT. The mixture was then concentrated and mixed several times with dichloromethane and re-concentrated. The residue was dissolved in acetonitrile and purified by preparative HPLC (method 7). The combined target fractions were concentrated and the residue was lyophilized in acetonitrile/water. 117 mg (98% pure, >99% ee, 68% thor.) of the title compound were obtained.

[a] _D20 = -20.6°, 589 nm, c = ^0.35 g/100 ml, methanol;

LC-MS (method 2): R _t = 1.20 min; MS (ESIpos): m/z = 572/574 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: -0.008 (1.52), 0.920 (13.64), 0.936 (13.90), 1.048 (0.47), 1.077 (1.44), 1.106 (1.50), 1.128 ( 0.61), 1.234 (0.50), 1.589 (0.44), 1.621 (1.24), 1.651 (1.47), 1.679 (0.69), 1.729 (2.53), 1.765 (2.53), 1.791 (3.56), 1.821 (3.15), 2.76) 1.30), 2.447 (2.04), 2.476 (1.42), 2.523 (0.75), 2.682 (1.18), 2.710 (2.27), 2.738 (1.14), 3.439 (2.24), 3.460 (3.55), 3.486 (1.99) 1.53), 3.593 (1.74), 3.680 (3.29), 7.256 (1.62), 7.274 (3.82), 7.291 (2.89), 7.355 (2.22), 7.374 (4.05) 5.48), 7.461 (4.98), 7.463 (4.84), 7.482 (5.43), 7.498 (4.02), 7.624 (1.48) 1.90), 8.715 (3.84), 8.729 (1.85), 12.043 (2.06).

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 12.04 (br. s, 1H), 8.71 (t, 1H), 7.70-7.60 (m, 2H), 7.53-7.42 (m, 3H), 7.37 (t, 1H), 7.31-7.23 (m, 1H), 3.78-3.63 (m, 2H), 3.63-3.52 (m, 1H), 3.51-3.38 (m, 2H), 2.71 (t, 1H), 2.45 (t, 1H), 2.21-1.98 (m, 6H), 1.91-1.55 (m, 5H), 1.17-1.02 (m, 1H), 0.93 (d, 3H).

Example 47.

(+)-5-[({6-Bromo-3-methyl-2-[3-methylpiperidin-1-yl]quinolin-4-yl}carbonyl)amino]-4-(2chlorophenyl)valeric acid (diastereoisomer 2) .

To a solution of (+)-tert-butyl-5-[({6-bromo-3-methyl-2-[3-methylpiperidin-1-yl]quinolin-4yl}carbonyl)amino]-4-(2-chlorophenyl )pentanoate (185 mg, 294 μmol, diastereoisomer 2, example 87A) in dichloromethane (1.6 ml) was added with TFA (170 μl, 2.2 mmol) and the mixture was left for 24 h at RT. The mixture was then concentrated and mixed several times with dichloromethane and re-concentrated. The residue was dissolved in acetonitrile and purified by preparative HPLC (method 7). The combined target fractions were concentrated and the residue was lyophilized in acetonitrile/water. 117 mg (98% pure, >99% ee, 68% thor.) of the title compound were obtained.

[a] _D20 = +24.9°, 589 nm, c = 0.34 ^g /100 ml, methanol;

LC-MS (method 2): Rt = 1.20 min; MS (ESIpos): m/z = 572/574 [M+H] ⁺ .

‘H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (2.59), 0.008 (2.07), 0.921 (13.42), 0.937 (13.48), 1.055

- 152 040220 (0.46), 1.081 (1.40), 1.105 (1.43), 1.134 (0.56), 1.623 (1.22), 1.653 (1.43), 1.682 (0.67), 1.732 (2.48), 1.766 (2.50), 1.793 (3.54) ), 1.814 (2.99), 1.823 (3.07), 1.837 (2.80), 1.861 (1.12), 2.048 (3.60), 2.083 (4.54), 2.091 (4.85), 2.136 (16.00), 2.160 (1.50), 2.432 (1.28 ), 2.461 (2.09), 2.524 (0.99), 2.670 (0.41), 2.695 (1.08), 2.724 (1.92), 2.752 (1.03), 3.448 (2.22), 3.471 (3.55), 3.497 (1.95), 3.577 (1.64 ), 3.593 (1.85), 3.681 (3.38), 3.973 (1.31), 7.257 (1.61), 7.275 (3.65), 7.292 (2.61), 7.295 (2.61), 7.357 (2.19), 7.375 (4.01), 7.394 (2.04 ), 7.441 (5.78), 7.444 (5.83), 7.461 (5.09), 7.464 (5.09), 7.483 (5.41), 7.499 (3.99), 7.634 (1.40), 7.657 (14.87), 7.663 (8.60), 7.680 (0.93 ), 7.685 (1.10), 8.706 (1.85), 8.720 (3.73), 8.734 (1.82).

Example 48.

(+)-5-[({6-Bromo-3-methyl-2-[3-methylpiperidin-1-yl]quinolin-4-yl}carbonyl)amino]-4-(2chlorophenyl)valeric acid (diastereoisomer 3) .

To a solution of (+)-tert-butyl-5-[({6-bromo-3-methyl-2-[3-methylpiperidin-1-yl]quinolin-4yl}carbonyl)amino]-4-(2-chlorophenyl )pentanoate (150 mg, 238 µmol, diastereoisomer 3, example 88A) in dichloromethane (1.8 ml) TFA (180 µl, 2.4 mmol) was added and the mixture was left for 24 h at RT. The mixture was then concentrated and mixed several times with dichloromethane and re-concentrated. The residue was dissolved in acetonitrile and purified by preparative HPLC (method 7). The combined target fractions were concentrated and the residue was lyophilized in acetonitrile/water. 102 mg (100% pure, >99% ee, 74% thor.) of the title compound were obtained.

[a] _D20 = +7.5°, 589 nm ^, c = 0.38 g/100 mL, methanol;

LC-MS (method 2): R _t = 1.20 min; MS (ESIpos): m/z = 572/574 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.921 (11.56), 0.937 (11.71), 1.050 (0.44), 1.077 (1.30), 1.106 (1.33), 1.128 (0.54), 1.234 (0.56) , 1.626 (1.13), 1.657 (1.35), 1.686 (0.66), 1.729 (2.37), 1.760 (2.30), 1.794 (2.97), 1.821 (2.75), 1.836 (2.48), 1.860 (1.04), 2.048 (3.26) , 2.083 (4.03), 2.090 (4.31), 2.104 (2.16), 2.135 (16.00), 2.159 (1.29), 2.429 (1.25), 2.458 (1.97), 2.669 (1.11), 2.697 (1.76), 2.726 (0.96) , 3.434 (2.04), 3.461 (3.58), 3.492 (1.67), 3.592 (1.60), 3.670 (2.24), 7.256 (1.35), 7.274 (3.19) , 7.392 (1.85), 7.441 (4.84), 7.461 (4.35), 7.480 (4.74), 7.499 (3.41), 7.625 (1.11), 7.648 (12.30), 7.654 (6.45), 7.672 (0.76), 7.676 (0.88) , 8.703 (1.72), 8.717 (3.36), 8.731 (1.65), 12.052 (0.67).

Example 49.

(-)-5-[({6-Bromo-3-methyl-2-[3-methylpiperidin-1-yl]quinolin-4-yl}carbonyl)amino]-4-(2chlorophenyl)valeric acid (diastereoisomer 4) .

To a solution of (-)-tert-butyl-5-[({6-bromo-3-methyl-2-[3-methylpiperidin-1-yl]quinolin-4yl}carbonyl)amino]-4-(2-chlorophenyl )pentanoate (140 mg, 223 μmol, diastereoisomer 4, example 89A) in dichloromethane (1.6 ml) was added with TFA (170 μl, 2.2 mmol) and the mixture was left for 30 h at RT. The mixture was then concentrated and mixed several times with dichloromethane and re-concentrated. The residue was dissolved in acetonitrile and purified by preparative HPLC (method 7). The combined target fractions were concentrated and the residue was lyophilized in acetonitrile/water. 78 mg (97% pure, >99% ee, 59% thor.) of the title compound were obtained.

[a] _D20 = -17.3°, 436 nm, c = 0.38 g ^/ 100 ml, methanol;

LC-MS (method 2): R _t = 1.20 min; MS (ESIpos): m/z = 572/574 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.921 (6.01), 0.936 (6.18), 1.077 (0.69), 1.106 (0.70), 1.626 (0.59), 1.657 (0.70), 1.729 (1.24) , 1.760 (1.21), 1.792 (1.61), 1.812 (1.34), 1.820 (1.42), 1.834 (1.41), 1.858 (0.57), 2.045 (1.68), 2.078 (2.14), 2.086 (2.32), 2.134 (8.43) . . , 7.480 (2.52), 7.498 (1.77), 7.624 (0.61), 7.647 (6.71), 7.675 (0.51), 8.705 (0.85), 8.719 (1.68), 8.733 (0.85).

Example 50.

(+/-)-5-({[6-Bromo-2-(3,3-difluoropiperidin-1-yl)-3-methylquinolin-4-yl]carbonyl}amino)-4-(2chlorophenyl)valeric acid ( racemate)

To a solution of (+/-)-tert-butyl-5-({[6-bromo-2-(3,3-difluoropiperidin-1-yl)-3-methylquinolin-4yl]carbonyl}amino)-4-( 2-chlorophenyl)pentanoate (100 mg, 154 µmol, racemate, example 90A) in dichloromethane (1.1 ml) was added with TFA (120 µl, 1.5 mmol) and the mixture was left for 16 h at RT. The mixture was then concentrated and mixed several times with dichloromethane and re-concentrated. The residue was dissolved in acetonitrile and purified by preparative HPLC (method 7). United target frocks

- 153 040220 the ions were concentrated and the residue was lyophilized. 70 mg (98% pure, 75% theoretical) of the title compound were obtained.

LC-MS (method 2): R _t = 1.13 min; MS (ESIpos): m/z = 594/596 [M+H]+.

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: -0.008 (2.73), 0.008 (2.65), 1.795 (0.82), 1.814 (1.76), 1.838 (2.35), 1.881 (4.53), 2.047 ( 5.28), 2.082 (7.13), 2.091 (7.78), 2.150 (16.00), 2.225 (0.40), 2.327 (0.75), 2.366 (0.66), 2.670 (0.74), 2.709 (0.63), 3.164 (5.24), 3.36) 2.29) 1.56), 8.720 (2.31), 8.734 (4.37), 8.748 (2.09), 12.047 (1.44).

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 12.05 (br. s, 1H), 8.73 (t, 1H), 7.76-7.64 (m, 2H), 7.59-7.42 (m, 3H) , 7.38 (t, 1H), 7.32-7.22 (m, 1H), 3.80-3.64 (m, 2H), 3.63-3.54 (m, 1H), 3.48 (t, 2H), 3.23-3.07 (m, 2H) , 2.20-2.00 (m, 8H), 1.94-1.74 (m, 3H).

Example 51.

(-)-5-({[6-Bromo-2-(3,3-difluoropiperidin-1-yl)-3-methylquinolin-4-yl]carbonyl}amino)-4-(2chlorophenyl)valeric acid (enantiomer 1 ).

To a solution of tert-butyl 5-({[6-bromo-2-(3,3-difluoropiperidin-1-yl)-3-methylquinolin-4yl]carbonyl}amino)-4-(2-chlorophenyl)pentanoate ( 660 mg, 1.01 mmol, enantiomer 1, example 91A) in dichloromethane (8.0 ml) was added with TFA (1.6 ml, 20 mmol) and the mixture was left for 18 h at RT. The mixture was then concentrated and mixed several times with dichloromethane and re-concentrated. The residue was purified by preparative HPLC (method 6). The combined target fractions were concentrated and the residue was lyophilized from acetonitrile/water. 479 mg (100% pure, >99% ee, 79% thor.) of the title compound were obtained.

[a]e ²⁰ = -17.6°, 589 nm, c = 0.39 g/100 ml, DMSO;

LC-MS (method 2): R _t = 1.13 min; MS (ESIpos): m/z = 594/596 [M+H]+.

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.149 (0.52), -0.008 (6.12), 0.008 (4.60), 0.146 (0.48), 1.797 (0.95), 1.815 (1.92), 1.838 ( 2.60), 1.881 (4.78), 2.048 (5.58), 2.083 (7.57), 2.092 (8.27), 2.150 (16.00), 2.327 (0.76), 2.366 (0.59), 2.669 (0.62), 2.710 (0.52), 5.51) 4.41) 10.23), 7.705 (8.55), 7.723 (1.42), 7.728 (1.67), 8.719 (2.31), 8.734 (4.43), 8.748 (2.10), 12.048 (3.00).

Example 52.

(+)-5-({[6-Bromo-2-(3,3-difluoropiperidin-1-yl)-3-methylquinolin-4-yl]carbonyl}amino)-4-(2chlorophenyl)valeric acid (enantiomer 2 ).

To a solution of tert-butyl 5-({[6-bromo-2-(3,3-difluoropiperidin-1-yl)-3-methylquinolin-4yl]carbonyl}amino)-4-(2-chlorophenyl)pentanoate ( 620 mg, 952 µmol, enantiomer 2, example 92A) in dichloromethane (8.0 ml) was added with TFA (1.5 ml, 19 mmol) and the mixture was left for 18 h at RT. The mixture was then concentrated and mixed several times with dichloromethane and re-concentrated. The residue was purified by preparative HPLC (method 6). The combined target fractions were concentrated and the residue was lyophilized from acetonitrile/water. 397 mg (100% pure, 98% ee, 70% thor.) of the title compound were obtained.

[a] _D20 = +12.1°, 589 nm ^, c = 0.37 g/100 ml, DMSO;

LC-MS (method 2): R _t = 1.13 min; MS (ESIpos): m/z = 594/596 [M+H]+.

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: -0.008 (3.83), 0.008 (3.53), 0.146 (0.41), 1.784 (0.53), 1.795 (0.82), 1.814 (1.73), 1.837 ( 2.38), 1.881 (4.61), 2.013 (0.53), 2.047 (5.23), 2.082 (7.24), 2.090 (7.79), 2.110 (4.09), 2.150 (16.00), 2.327 (0.51), 2.366 (0.50), 0.53), 2.709 (0.51), 3.163 (5.34), 3.447 (3.40), 3.476 (6.48), 3.504 (3.25), 3.594 (1.94), 3.685 (3.39), 7.258 (1.69), 7.275 (3.92), 2.77) 2.10), 7.695 (13.05), 7.700 (9.57), 7.705 (8.01), 7.723 (1.37), 7.728 (1.62), 8.720 (2.18), 8.734 (4.42), 8.748 (2.14)

Example 53.

5-[({6-Bromo-3-methyl-2-[3-(trifluoromethyl)piperidin-1-yl]quinolin-4-yl}carbonyl)amino]-4-(2chlorophenyl)valeric acid (mixture of diastereoisomers)

To a solution of tert-butyl-5-[({6-bromo-3-methyl-2-[3-(trifluoromethyl)piperidin-1-yl]quinoline-4

- 154 040220 yl}carbonyl)amino]-4-(2-chlorophenyl)pentanoate (156 mg, 228 µmol, mixture of diastereoisomers, example 93A) in dichloromethane (1.7 ml) TFA (180 µl, 2.3 mmol) was added and the mixture was stirred 16 h at CT. The mixture was then concentrated and mixed several times with dichloromethane and re-concentrated. The residue was purified by preparative HPLC (method 7). The combined target fractions were concentrated and the residue was lyophilized. Received 89 mg (98% pure, 61% theoretical. out.) specified in the title compound.

LC-MS (method 1): R _t = 2.33 min; MS (ESIpos): m/z = 626/628 [M+H]+.

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.367 (0.99), 1.466 (0.45), 1.487 (1.20), 1.496 (1.31), 1.517 (1.47), 1.525 (1.47), 1.547 (0.69) , 1.555 (0.65), 1.656 (1.14), 1.680 (1.14), 1.815 (3.30), 1.838 (2.92),2.004 (1.84), 2.034 (2.50), 2.048 (3.94), 2.083 (3.91), 2.092 (4.19) , 2.140 (13.11), 2.753 (1.91), 2.871 (1.12), 2.900 (1.56), 2.926 (0.80), 3.482 (1.80), 3.513 (1.67), 3.599 (1.70), 3.686 (2.90), 3.713 (3.39) . , 7.506 (3.81), 7.668 (0.50), 7.689 (16.00), 8.714 (1.66), 8.727 (3.04), 8.741 (1.61), 12.057 (0.83).

Example 54.

(+/-)-5-({[6-Bromo-3-methyl-2-(4-methylpiperazin-1-yl)quinolin-4-yl]carbonyl}amino)-4-(2chlorophenyl)valeric acid (racemate )

To a solution of (+/-)-tert-butyl-5-({[6-bromo-3-methyl-2-(4-methylpiperazin-1-yl)quinolin-4yl]carbonyl}amino)-4-(2 -chlorophenyl)pentanoate (135 mg, 214 μmol, racemate, example 94A) in dichloromethane (1.6 ml) was added with TFA (170 μl, 2.1 mmol) and the mixture was stirred for 16 h at RT. The mixture was then concentrated and mixed several times with dichloromethane and re-concentrated. The residue was purified by preparative HPLC (method 7). The combined target fractions were concentrated and the residue was lyophilized. 115 mg (98% pure, 92% thor.) of the title compound were obtained.

LC-MS (method 1): R _t = 1.23 min; MS (ESIpos): m/z = 573/575 [M+H]+.

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: -0.008 (2.30), 0.008 (2.32), 1.784 (0.56), 1.795 (0.95), 1.815 (1.86), 1.837 (2.38), 1.861 ( 1.34), 2.034 (1.33), 2.046 (5.04), 2.082 (4.92), 2.092 (5.43), 2.104 (2.68), 2.143 (16.00), 2.236 (0.40), 2.328 (0.48), 2.366 (0.50) 3.16), 2.670 (0.68), 2.710 (0.66), 2.923 (3.22), 3.599 (2.22), 3.650 (1.13), 3.670 (2.61), 3.684 (4.10), 3.699 (3.14) 4.49), 7.293 (3.29), 7.356 (2.73), 7.374 (4.99), 7.392 (2.56), 7.441 (7.40), 7.444 (6.82) 5.82), 7.503 (4.97), 7.664 (2.93), 7.686 (13.99), 7.694 (9.19), 7.699 (7.80), 7.717 (1.75) 2.36).

Example 55.

5-[({6-Bromo-2-[3-hydroxypiperidin-1-yl]-3-methylquinolin-4-yl}carbonyl)amino]-4-(2chlorophenyl)valeric acid (mixture of diastereoisomers)

To a solution of tert-butyl 5-[({6-bromo-2-[3-hydroxypiperidin-1-yl]-3-methylquinolin-4yl}carbonyl)amino]-4-(2-chlorophenyl)pentanoate (154 mg , 244 μmol, mixture of diastereoisomers, example 95A) in dichloromethane (1.8 ml) was added TFA (190 μl, 2.4 mmol) and the mixture was left for 16 h at RT. The mixture was then concentrated and mixed several times with dichloromethane and re-concentrated. The residue was purified by preparative HPLC (method 7). The combined target fractions were concentrated and the residue was lyophilized. 55 mg (98% pure, 38% thor.) of the title compound were obtained.

LC-MS (method 1): R _t = 1.71 min; MS (ESIpos): m/z = 574/576 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: -0.008 (3.27), 0.008 (3.32), 0.146 (0.42), 1.284 (0.43), 1.295 (0.55), 1.315 (1.31), 1.347 ( 1.48), 1.368 (0.70), 1.378 (0.62), 1.576 (1.16), 1.604 (1.23), 1.775 (1.85), 1.783

- 155 040220 (1.97), 1.795 (1.76), 1.810 (2.61), 1.835 (2.19), 1.857 (1.20), 1.882 (0.40), 1.913 (1.55), 1.922 (1.62), 1.944 (1.55), 2.044 (3.61) ), 2.078 (4.46), 2.086 (4.74), 2.133 (16.00), 2.156 (1.71), 2.327 (0.48), 2.366 (0.49), 2.523 (1.40), 2.631 (1.40), 2.664 (1.04), 2.710 (0.51 ), 2.745 (0.93), 2.775 (1.64), 2.804 (0.95), 3.357 (2.61), 3.388 (1.92), 3.512 (2.02), 3.543 (1.94), 3.593 (1.70), 3.682 (4.41), 4.864 (1.31 ), 7.256 (1.56), 7.274 (3.58), 7.294 (2.49), 7.355 (2.13), 7.374 (3.85), 7.393 (2.01), 7.441 (5.79), 7.444 (5.77), 7.461 (5.11), 7.464 (5.07 ), 7.481 (5.24), 7.501 (3.83), 7.619 (3.18), 7.642 (11.39), 7.654 (7.20), 7.659 (6.40), 7.676 (1.90), 7.682 (1.95), 8.721 (1.91), 8.735 (3.83 ), 8.749 (1.84).

Example 56.

5-[({2-[3-Aminopiperidin-1-yl]-6-bromo-3-methylquinolin-4-yl}carbonyl)amino]-4-(2chlorophenyl)valeric acid (mixture of diastereoisomers)

To a solution of tert-butyl-5-{[(6-bromo-2-{3-[(tert-butoxycarbonyl)amino]piperidin-1-yl}-3methylquinolin-4-yl)carbonyl]amino}-4-( 2-chlorophenyl)pentanoate (162 mg, 222 µmol, mixture of diastereoisomers, example 96A) in dichloromethane (1.6 ml) was added with TFA (170 µl, 2.2 mmol) and the mixture was left for 16 h at RT. The mixture was then concentrated and mixed several times with dichloromethane and re-concentrated. The residue was purified by preparative HPLC (method 7). The combined target fractions were concentrated and the residue was lyophilized. 38 mg (98% pure, 29% thor.) of the title compound were obtained.

LC-MS (method 1): Rt = 1.27 min; MS (ESIpos): m/z = 573/575 [M+H]+.

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: -0.149 (0.47), -0.008 (4.19), 0.008 (4.66), 0.146 (0.47), 1.442 (1.31), 1.469 (1.48), 1.676 (1.39), 1.836 (4.04), 1.859 (2.54), 1.961 (1.72), 1.985 (1.67), 2.043 (3.81) (0.88) (1.85) (4.15), 7.669 (12.29), 7.686 (7.15), 7.691 (6.32), 7.709 (2.23), 7.713 (2.15), 8.751 (1.26), 8.765 (2.72), 8.782 (2.10).

Example 57.

(+/-)-5-[({6-bromo-2-[3-ethylpiperidin-1-yl]-3-methylquinolin-4-yl}carbonyl)amino]-4-(2chlorophenyl)valeric acid (mixture of diastereoisomers )

x)

Ο^ΝΗ Oh

XII

To a solution of tert-butyl 5-[({6-bromo-2-[3-ethylpiperidin-1-yl]-3-methylquinolin-4yl}carbonyl)amino]-4-(2-chlorophenyl)pentanoate (157 mg , 244 μmol, mixture of diastereoisomers, example 97A) in dichloromethane (1.8 ml) was added TFA (190 μl, 2.4 mmol) and the mixture was left for 16 h at RT. The mixture was then concentrated and mixed several times with dichloromethane and re-concentrated. The residue was purified by preparative HPLC (method 7). The combined target fractions were concentrated and the residue was lyophilized. 93 mg (98% pure, 64% theoretical) of the title compound were obtained.

LC-MS (method 1): Rt = 2.43 min; MS (ESIpos): m/z = 586/588 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 0.890 (7.22), 0.909 (15.43), 0.927 (7.98), 1.033 (0.70), 1.062 (1.77), 1.085 (1.79), 1.114 (0.79 ), 1.239 (1.58), 1.256 (3.34), 1.274 (4.29), 1.291 (3.01), 1.563 (2.10), 1.598 (1.87), 1.631 (1.58), 1.745 (2.50), 1.780 (2.02), 1.814 (2.13 ), 1.837 (3.69), 1.876 (2.18), 2.049 (4.75), 2.080 (5.39), 2.093 (6.18), 2.124 (14.79), 2.163 (1.56), 2.367 (0.47), 2.426 (1.73), 2.710 (1.27 ), 2.738 (1.77), 3.493 (3.77), 3.516 (3.09), 3.596 (2.29), 3.678 (3.79), 7.252 (1.99), 7.271 (4.31), 7.290 (2.97), 7.354 (2.63), 7.373 (4.57 ), 7.392 (2.44), 7.437 (6.02), 7.457 (5.32), 7.483 (6.32), 7.502 (4.67), 7.624 (1.86), 7.647 (16.00), 7.676 (1.20), 8.699 (2.34), 8.713 (4.23 ), 8.727 (2.09).

- 156 040220

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 11.86 (br. s, 1H), 8.71 (t, 1H), 7.71-7.59 (m, 2H), 7.56-7.42 (m, 3H) , 7.37 (t, 1H), 7.27 (t, 1H), 3.78-3.43 (m, 5H), 2.82-2.61 (m, 1H), 2.48-2.34 (m, 1H), 2.21-1.97 (m, 6H) , 1.94-1.69 (m, 3H), 1.68-1.46 (m, 2H), 1.37-1.18 (m, 2H), 1.16-0.98 (m, 1H), 0.91 (t, 3H).

Example 58.

(+)-5-[({6-Bromo-2-[3-ethylpiperidin-1-yl]-3-methylquinolin-4-yl}carbonyl)amino]-4-(2chlorophenyl)valeric acid (diastereoisomer 1).

To a solution of (+)-tert-butyl-5-[({6-bromo-2-[3-ethylpiperidin-1-yl]-3-methylquinolin-4yl}carbonyl)amino]-4-(2-chlorophenyl) pentanoate (180 mg, 280 μmol, diastereoisomer 7, example 98A) in dichloromethane (2.4 ml) was added with TFA (470 μl, 6.2 mmol) and the mixture was left for 18 h at RT. The mixture was then concentrated and mixed several times with dichloromethane and re-concentrated. The residue was purified by preparative HPLC (method 7). The combined target fractions were concentrated and the residue was lyophilized from acetonitrile/water. 139 mg (100% pure, 85% thor.) of the title compound were obtained.

[a] _D20 = +4.8°, 589 nm, c = 0.42 ^g /100 ml, methanol;

LC-MS (method 1): Rt = 2.45 min; MS (ESIpos): m/z = 586/588 [M+H] ⁺ .

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.892 (6.73), 0.910 (16.00), 0.929 (8.30), 1.034 (0.54), 1.064 (1.47), 1.093 (1.52), 1.115 (0.67 ), 1.240 (1.18), 1.257 (2.88), 1.275 (3.82), 1.292 (2.63), 1.563 (1.82), 1.598 (1.77), 1.629 (1.43), 1.658 (0.62), 1.746 (2.07), 1.780 (1.69 ), 1.812 (1.62), 1.837 (2.98), 1.855 (2.28), 1.876 (1.78), 2.025 (0.94), 2.046 (3.88), 2.080 (4.53), 2.091 (5.07), 2.114 (11.74), 2.138 (3.29 ), 2.162 (1.21), 2.390 (0.94), 2.418 (1.59), 2.445 (0.97), 2.713 (1.14), 2.742 (2.05), 2.772 (1.11), 3.475 (2.07), 3.498 (3.51), 3.520 (2.33 ), 3.596 (1.74), 3.678 (3.39), 3.693 (2.66), 7.252 (1.52), 7.271 (3.65), 7.289 (2.67), 7.353 (2.16), 7.372 (3.99), 7.390 (2.07), 7.436 (5.20 ), 7.456 (4.37), 7.484 (5.31), 7.502 (4.33), 7.624 (1.33), 7.647 (13.21), 7.676 (1.03), 8.697 (1.87), 8.711 (3.78), 8.725 (1.91), 12.043 (4.25 ).

Example 59.

(-)-5-[({6-Bromo-2-[3-ethylpiperidin-1-yl]-3-methylquinolin-4-yl}carbonyl)amino]-4-(2chlorophenyl)valeric acid (diastereoisomer 2).

To a solution of (-)-tert-butyl-5-[({6-bromo-2-[3-ethylpiperidin-1-yl]-3-methylquinolin-4yl}carbonyl)amino]-4-(2-chlorophenyl) pentanoate (200 mg, 311 μmol, diastereoisomer 2, example 99A) in dichloromethane (2.6 ml) was added with TFA (530 μl, 6.8 mmol) and the mixture was left for 18 h at RT. The mixture was then concentrated and mixed several times with dichloromethane and re-concentrated. The residue was purified by preparative HPLC (method 7). The combined target fractions were concentrated and the residue was lyophilized from acetonitrile/water. 143 mg (100% pure, 78% th. y.) of the title compound were obtained.

[a] _D20 = -26.0°, 589 nm, c = 0.38 ^g /100 ml, methanol;

LC-MS (method 1): Rt = 2.45 min; MS (ESIpos): m/z = 586/588 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.889 (5.96), 0.908 (13.53), 0.926 (6.80), 1.034 (0.52), 1.062 (1.29), 1.085 (1.31), 1.114 (0.57) 1.240 (1.11), 1.256 (2.40), 1.274 (3.14), 1.283 (2.64), 1.291 (2.25), 1.301 (1.76), 1.558 (1.43), 1.604 (1.33), 1.635 (1.24), 1.665 (0.54) . . . . , 8.726 (1.55), 12.043 (3.31).

Example 60.

(-)-5-[({6-Bromo-2-[3-ethylpiperidin-1-yl]-3-methylquinolin-4-yl}carbonyl)amino]-4-(2chlorophenyl)valeric acid (diastereoisomer 3).

To a solution of (-)-tert-butyl-5-[({6-bromo-2-[3-ethylpiperidin-1-yl]-3-methylquinolin-4yl}carbonyl)amino]-4-(2-chlorophenyl) pentanoate (420 mg, 650 μmol, diastereoisomer 3, example 100A) in dichloromethane (5.5 ml) was added with TFA (1.1 ml, 14 mmol) and the mixture was left for 18 h at RT. The mixture was then concentrated and mixed several times with dichloromethane and re-concentrated. The residue was purified by preparative HPLC (method 7). The combined target fractions were concentrated and the residue was lyophilized from acetonitrile/water. 348 mg (100% pure, 91% thor.) of the title compound were obtained.

[a] _D20 = -5.1°, 589 nm, c ⁼ 0.48 g/100 ml, methanol;

LC-MS (method 1): Rt = 2.45 min; MS (ESIpos): m/z = 586/588 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.891 (6.76), 0.910 (16.00), 0.928 (8.20), 1.034 (0.55), 1.063 (1.49), 1.085 (1.52), 1.093 (1.51) , 1.114 (0.67), 1.239 (1.17), 1.257 (2.87), 1.274 (3.81), 1.292 (2.60), 1.563 (1.83), 1.597 (1.73), 1.629 (1.44), 1.660 (0.62), 1.745 (2.09) , 1.779 (1.67), 1.812 (1.63), 1.836 (3.03), 1.853 (2.24), 1.876 (1.77), 2.013 (0.54), 2.025 (0.97), 2.046 (3.88), 2.080 (4.59), 2.090 (5.07) , 2.114 (11.27), 2.138 (3.27), 2.162 (1.16), 2.390 (0.94), 2.418 (1.57), 2.713 (1.09), 2.742 (1.95), 2.771 (1.06), 3.474 (2.09) , 3.520 (2.33), 3.596 (1.71), 3.678 (3.31), 3.693 (2.57), 7.252 (1.56), 7.271 (3.74), 7.289 (2.72), 7.353

- 157 040220 (2.19) 7.372 (4.02) 7.390 (2.08) 7.436 (5.26) 7.456 (4.43) 7.484 (5.27) 7.502 (4.30) 7.624 (1.39) 7.647 (13.75) ), 8.697 (1.88), 8.712 (3.76), 8.726 (1.87), 12.047 (1.45).

Example 61.

(+)-5-[({6-Bromo-2-[3-ethylpiperidin-1-yl]-3-methylquinolin-4-yl}carbonyl)amino]-4-(2chlorophenyl)valeric acid (diastereoisomer 4).

To a solution of (+)-tert-butyl-5-[({6-bromo-2-[3-ethylpiperidin-1-yl]-3-methylquinolin-4yl}carbonyl)amino]-4-(2-chlorophenyl) pentanoate (463 mg, 720 μmol, diastereoisomer 4, example 101A) in dichloromethane (6.1 ml) was added with TFA (1.2 ml, 16 mmol) and the mixture was left for 18 h at RT. The mixture was then concentrated and mixed several times with dichloromethane and re-concentrated. The residue was purified by preparative HPLC (method 7). The pooled target fractions were concentrated and the residue was lyophilized from acetonitrile/water.

360 mg (100% pure, 85% thor.) of the title compound were obtained.

[a]D ²⁰ = +27.7°, 589 nm, c = 0.48 g/100 mL, methanol;

LC-MS (method 1): Rt = 2.45 min; MS (ESIpos): m/z = 586/588 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 0.888 (5.59), 0.907 (13.71), 0.925 (1.18), 1.084 (1.19), 1.092 (1.20), 1.113 (0.54), 1.123 (0.48 ), 1.238 (0.87), 1.256 (2.87), 1.282 (2.43), 1.290 (2.12), 1.300 (1.70), 1.317 (0.67), 1.557 (1.25), 1.565 (1.20), 1.635 (1.16), 1.665 (0.50 ), 1.744 (1.64), 1.778 (1.28), 1.793 (0.94), 1.814 (1.87), 1.876 (1.47), 2.033 (0.90), 2.049 (3.07), 2.078 (2.80), 2.085 (6.95), 1.033 (0.43 ), 1.062 (2.08), 1.265 (1.91), 1.273 (1.23), 1.573 (1.20), 1.603 (1.27), 1.836 (2.25), 1.854 (3.19), 2.094 (3.73), 2.125 (16.00), 2.139 (2.89 ), 2.163 (0.88), 2.402 (0.81), 2.430 (1.33), 2.458 (0.81), 2.701 (0.82), 2.731 (1.48), 2.759 (0.82), 3.485 (2.59), 3.515 (2.44), 3.599 (1.42 ), 3.624 (0.88), 3.642 (0.73), 3.662 (1.56), 3.676 (2.32), 7.253 (1.31), 7.272 (3.02), 7.292 (2.12), 7.355 (1.80), 7.374 (3.28), 7.392 (1.70 ), 7.440 (4.50), 7.460 (3.99), 7.483 (4.32), 7.501 (2.96), 7.624 (1.00), 7.647 (12.31), 7.652 (6.71), 7.670 (0.66), 7.675 (0.81), 8.699 (1.53 ), 8.713 (3.02), 8.727 (1.49), 12 .053 (0.70).

Example 62.

5-[({6-Bromo-2-[3-hydroxy-3-methylpiperidin-1-yl]-3-methylquinolin-4-yl}carbonyl)amino]-4-(2chlorophenyl)valeric acid (mixture of diastereoisomers)

To a solution of tert-butyl-5-[({6-bromo-2-[3-hydroxy-3-methylpiperidin-1-yl]-3-methylquinolin-4yl}carbonyl)amino]-4-(2-chlorophenyl) pentanoate (148 mg, 229 µmol, mixture of diastereoisomers, example 102A) in dichloromethane (1.7 ml) was added with TFA (180 µl, 2.3 mmol) and the mixture was left for 16 h at RT. The mixture was then concentrated and mixed several times with dichloromethane and re-concentrated. The residue was purified by preparative HPLC (method 7). The combined target fractions were concentrated and the residue was lyophilized. 106 mg (98% pure, 77% thor.) of the title compound were obtained.

LC-MS (method 1): Rt = 1.83 min; MS (ESIpos): m/z = 588/560 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (2.69), 1.190 (16.00), 1.557 (3.93), 1.570 (4.21), 1.613 (1.10), 1.627 (1.00), 1.796 (0.66 ), 1.814 (1.72), 1.836 (2.49), 1.859 (1.71), 2.045 (2.66), 2.061 (1.71), 2.079 (3.37), 2.086 (4.47), 2.134 (2.03), 2.165 (10.97), 2.855 (0.60 ), 3.021 (7.70), 3.075 (3.50), 3.592 (1.35), 3.676 (2.23), 4.614 (1.55), 7.254 (1.18), 7.274 (2.80), 7.292 (1.97), 7.356 (1.67), 7.374 (3.07 ), 7.392 (1.61), 7.441 (4.38), 7.461 (3.98), 7.481 (4.14), 7.499 (2.92), 7.614 (2.20), 7.636 (7.81), 7.649 (5.05), 7.654 (4.49), 7.671 (1.34 ), 7.676 (1.37), 8.712 (1.50), 8.727 (2.91), 8.741 (1.39).

Example 63.

5-[({6-Bromo-2-[3,5-dimethylpiperidin-1-yl]-3-methylquinolin-4-yl}carbonyl)amino]-4-(2chlorophenyl)valeric acid (mixture of diastereoisomers)

- 158 040220

To a solution of tert-butyl 5-[({6-bromo-2-[3,5-dimethylpiperidin-1-yl]-3-methylquinolin-4yl}carbonyl)amino]-4-(2-chlorophenyl)pentanoate ( 91 mg, 142 µmol, mixture of diastereoisomers, example 103A) in dichloromethane (4.8 ml) was added with TFA (110 µl, 1.4 mmol) and the mixture was stirred for 42 h at RT. TFA (105 µl, 0.7 mmol) was then added again and the mixture was stirred for an additional 66 h at RT. The mixture was then concentrated and mixed several times with dichloromethane and re-concentrated. The residue was first prepurified by preparative HPLC (method 6) and then further purified by preparative HPLC (method 7). The combined target fractions were concentrated and the residue was lyophilized. 47 mg (100% pure, 57% thor.) of the title compound were obtained.

LC-MS (method 1): Rt = 2.42 & 2.44 min; MS (ESIpos): m/z = 586/586 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.718 (1.40), 0.748 (1.54), 0.778 (0.50), 0.898 (15.75), 0.913 (16.00), 1.005 (3.11), 1.021 (3.17) , 1.234 (0.86), 1.424 (0.56), 1.437 (1.00), 1.451 (0.61), 1.808 (3.64), 1.839 (3.30), 1.861 (1.10), 2.049 (3.42), 2.083 (3.96), 2.090 (4.17) 2.134 (11.83), 2.164 (3.04), 2.266 (1.30), 2.294 (2.05), 2.323 (1.27), 2.848 (0.48), 3.116 (0.65), 3.146 (0.56), 3.488 (2.66), 3.517 (2.54) , 3.592 (1.54), 3.674 (2.27), 7.256 (1.27), 7.274 (2.92), 7.292 (2.07), 7.356 (1.74), 7.375 (3.20), 7.393 (1.71), 7.440 (4.43), 7.460 (4.05) , 7.480 (4.37), 7.499 (3.07), 7.625 (0.76), 7.647 (13.38), 7.673 (0.59), 8.692 (1.42), 8.705 (2.74), 12.049 (1.42).

Example 64.

5-[({6-Bromo-2-[3-(difluoromethyl)piperidin-1-yl]-3-methylquinolin-4-yl}carbonyl)amino]-4-(2chlorophenyl)valeric acid (mixture of diastereoisomers)

To a solution of tert-butyl 5-[({6-bromo-2-[3-(difluoromethyl)piperidin-1-yl]-3-methylquinolin-4yl}carbonyl)amino]-4-(2-chlorophenyl)pentanoate (116 mg, 48% pure, 83.0 µmol, mixture of diastereoisomers, example 104A) in dichloromethane (2.9 ml) TFA (64 µl, 830 µmol) was added and the mixture was stirred for 18 h at RT. TFA (64 μl, 830 μmol) was then added again and the mixture was stirred for an additional 24 h at RT. TFA (64 μl, 830 μmol) was then added again and the mixture was stirred for an additional 24 h at RT. The mixture was then concentrated and mixed several times with dichloromethane and re-concentrated. The residue was purified by preparative HPLC (method 7). The combined target fractions were concentrated and the residue was lyophilized. 34 mg (93% pure, 63% thor.) of the title compound were obtained.

LC-MS (method 1): Rt = 2.19 min; MS (ESIpos): m/z = 608/610 [M+H]+.

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: -0.149 (1.13), -0.008 (16.00), 0.008 (9.90), 0.146 (1.18), 1.235 (0.65), 1.397 (0.96), 1.427 (1.09), 1.664 (0.92), 1.812 (2.31), 1.853 (2.49), 2.044 (2.96) (2.40) (2.57), 7.293 (1.87), 7.356 (1.61), 7.375 (2.92), 7.392 (1.66), 7.439 (4.40) (3.79), 7.502 (3.10), 7.677 (13.34), 8.734 (2.31), 12.043 (1.13).

Example 65.

5-[({6-Bromo-2-[(3S)-3-fluoropyrrolidin-1-yl]-3-methylquinolin-4-yl}carbonyl)amino]-4-(2chlorophenyl)valeric acid (mixture of epimers)

- 159 040220

To a solution of tert-butyl-5-[({6-bromo-2-[(3S)-3-fluoropyrrolidin-1-yl]-3-methylquinolin-4yl}carbonyl)amino]-4-(2-chlorophenyl) pentanoate (141 mg, 89% pure, 203 µmol, epimer mixture, example 105A) in dichloromethane (2.2 ml) TFA (160 µl, 2.0 mmol) was added and the mixture was stirred 42 h at RT. TFA (80 μl, 1.0 mmol) was then added again and the mixture was stirred for an additional 24 h at RT. The mixture was then concentrated and mixed several times with dichloromethane and re-concentrated. The residue was purified by preparative HPLC (method 7). The combined target fractions were concentrated and the residue was lyophilized. 44 mg (94% pure, 36% thor.) of the title compound were obtained.

LC-MS (method 1): R _t = 1.75 min; MS (ESIpos): m/z = 562/564 [M+H]+.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: -0.149 (0.50), -0.008 (4.85), 0.008 (4.45), 0.146 (0.45), 1.235 (0.77), 1.797 (1.23), 1.818 (2.56), 1.838 (3.44), 1.862 (1.98), 1.988 (0.79), 2.047 (7.30), 2.076 (7.77), 2.088 (7.95) 2.366 (0.79), 2.669 (0.79), 2.709 (0.74), 3.600 (6.02), 3.866 (2.36), 3.884 (2.32), 3.911 (2.23), 3.944 (1.37), 4.013 (1.48), 4.046 (1.24), 5.330 (3.51), 5.464 (3.44) 7.401 (2.31) 7.437 (10.14) 7.440 (9.69) 7.457 (8.61) 7.459 (8.00) 7.473 (5.24) 7.476 (5.21) 7.491 (5.14) 7.526 (10.05), 7.530 (9.68), 7.574 (5.17), 7.579 (8.88), 7.585 (4.72), 7.596 (2.97), 7.602 (5.05), 7.607 (2.72), 7.893 (1.57), 8.694 (4.86), 12.050 (1.46).

Example 66.

5-[({6-Bromo-2-[(3R)-3-fluoropyrrolidin-1-yl]-3-methylquinolin-4-yl}carbonyl)amino]-4-(2chlorophenyl)valeric acid (mixture of epimers)

A

Λ/\/ΟΗ

Ο^ΝΗ Oh

Br ^ ^ ^ X ^ C From XIX N NX ..... _F

To a solution of tert-butyl-5-[({6-bromo-2-[(3R)-3-fluoropyrrolidin-1-yl]-3-methylquinolin-4yl}carbonyl)amino]-4-(2-chlorophenyl) pentanoate (120 mg, 96% pure, 187 µmol, epimer mixture, example 106A) in dichloromethane (2.4 ml) TFA (140 µl, 1.9 mmol) was added and the mixture was stirred 42 h at RT. TFA (80 μl, 1.0 mmol) was then added again and the mixture was stirred for an additional 24 h at RT. TFA (80 μl, 1.0 mmol) was then added again and the mixture was stirred for an additional 24 h at RT. The mixture was then concentrated and mixed several times with dichloromethane and re-concentrated. The residue was purified by preparative HPLC (method 11). The combined target fractions were concentrated and the residue was lyophilized. Received 86 mg (97% pure, 79% theoretical. yield.) specified in the title compound.

LC-MS (method 1): R _t = 1.76 min; MS (ESIpos): m/z = 562/564 [M+H]+.

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.149 (0.49), 0.146 (0.51), 1.798 (1.12), 1.817 (2.38), 1.839 (3.22), 1.862 (1.84), 2.049 (7.23 ), 2.078 (7.50), 2.089 (7.59), 2.121 (3.46), 2.139 (4.86), 2.176 (16.00), 2.327 (0.85), 2.366 (0.67), 2.670 (0.79), 2.710 (0.70), 3.600 (5.99 ), 3.626 (4.79), 3.657 (4.00), 3.867 (2.42), 3.883 (2.41), 3.912 (2.32), 3.945 (1.44), 4.012 (1.54), 4.046 (1.33), 5.331 (3.59), 5.465 (3.56 ), 5.754 (6.66), 7.245 (1.53), 7.263 (4.27), 7.280 (4.74), 7.297 (2.23), 7.326 (0.79), 7.346 (2.69), 7.364 (5.42), 7.383 (4.83), 7.400 (2.08 ), 7.437 (9.28), 7.440 (9.14), 7.457 (7.78), 7.477 (5.10), 7.492 (4.88), 7.504 (7.74), 7.508 (7.57), 7.526 (9.34), 7.530 (9.61), 7.574 (4.77 ), 7.580 (8.37), 7.585 (4.71), 7.596 (2.81), 7.602 (4.80), 7.607 (2.77), 8.693 (4.97), 12.045 (3.38).

Separation of a mixture of epimers:

The title title compound (72 mg) was dissolved in methanol (12 ml) and separated into enantiomers/epimers by preparative SLC on chiral phase (see Examples 67 and 68) [column: Daicel Chiralcel OX-H, 5 µm, 250 mm x 30 mm; flow: 100 ml/min; sample injection: 1.0 ml; eluent: 20% methanol/80% carbon dioxide; duration of action 21 min, isocratic, UV detection 210 nm, temperature 40°C]. The combined target fractions were concentrated and the corresponding residue was lyophilized.

- 160 040220

Example 67.

(+)-5-[({6-Bromo-2-[(3R)-3-fluoropyrrolidin-1-yl]-3-methylquinolin-4-yl}carbonyl)amino]-4-(2chlorophenyl)valeric acid ( epimer 1).

Separation of enantiomers as described in Example 66 gave 16 mg (100% pure, >99% ee) of the title compound as the previously eluted epimer/enantiomer.

[a] _D20 = +22.1°, 589 nm, c = 0.29 ^g /100 ml, methanol;

LC-MS (method 1): R _t = 1.79 min; MS (ESIpos): m/z = 562/564 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.149 (0.64), -0.008 (5.27), 0.008 (5.32), 0.070 (0.55), 0.146 (0.62), 1.236 (0.44), 1.359 ( 1.61), 1.754 (0.54), 1.819 (2.40), 1.840 (3.08), 1.865 (1.93), 2.025 (2.41), 2.051 (6.86), 2.078 (7.50), 2.092 (6.21), 2.100 (4.56), 3.52), 2.141 (5.17), 2.177 (16.00), 2.295 (0.60), 2.327 (0.93), 2.670 (0.75), 2.994 (0.93), 3.207 (0.79), 3.601 (5.46), 3.672 (4.92), 1.34) 2.55), 7.264 (5.98), 7.283 (4.16), 7.347 (3.88), 7.366 (6.57), 7.384 (3.70), 7.437 (8.61), 7.440 (9.05) 7.69), 7.493 (5.77), 7.496 (5.99), 7.508 (8.92), 7.530 (14.54), 7.580 (8.24) 2.80), 8.695 (5.16), 8.708 (2.51), 12.041 (3.60).

Example 68.

(+)-5-[({6-Bromo-2-[(3R)-3-fluoropyrrolidin-1-yl]-3-methylquinolin-4-yl}carbonyl)amino]-4-(2chlorophenyl)valeric acid ( epimer 2).

The separation of enantiomers described in Example 66 gave 14 mg (100% pure, 82% ee) of the title compound as a later eluted epimer/enantiomer.

[a] _D20 = +40.7°, 589 nm ^, c = 0.30 g/100 mL, methanol;

LC-MS (method 1): Rt = 1.79 min; MS (ESIpos): m/z = 562/564 [M+H]+.

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: -0.149 (1.09), -0.008 (9.27), 0.008 (8.56), 0.069 (2.49), 0.146 (1.09), 1.235 (0.52), 1.359 (1.59), 1.754 (0.45), 1.798 (1.61), 1.819 (2.89), 1.839 (3.82), 1.861 (2.49), 2.048 (7.89), 2.089 (9.53) (1.47) (2.56) (1.02), 6.316 (0.69), 7.260 (4.27), 7.280 (5.78), 7.298 (3.93), 7.365 (4.76), 7.383 (6.42), 7.400 (3.96) (10.05), 7.457 (8.53), 7.460 (8.18), 7.486 (6.83), 7.504 (13.27), 7.525 (16.00), 7.574 (8.23), 7.579 (8.63), 7.596 (4.62), 7.601 (5.03), 7.879 (1.37), 8.675 (3.25), 8.689 (5.67), 8.703 (3.18), 9.688 (0.50), 12.040 (7.44).

Example 69.

5-[({6-Bromo-2-[trans-3,4-difluoropyrrolidin-1-yl]-3-methylquinolin-4-yl}carbonyl)amino]-4-(2chlorophenyl)valeric acid (mixture of diastereoisomers)

To a solution of tert-butyl-5-[({6-bromo-2-[trans-3,4-difluoropyrrolidin-1-yl]-3-methylquinolin-4yl}carbonyl)amino]-4-(2-chlorophenyl) pentanoate (169 mg, 77% pure, 204 µmol, mixture of diastereoisomers, example 107A) in dichloromethane (2.3 ml) TFA (160 µl, 2.0 mmol) was added and the mixture was stirred 42 h at RT. The mixture was then concentrated and mixed several times with dichloromethane and re-concentrated. The residue was purified by preparative HPLC (method 6). The combined target fractions were respectively concentrated and the corresponding residue was lyophilized. 8 mg (100% pure, 7% theoretical) of the first batch of the title compound and 57 mg (98% pure, 47% of theor.) of the second batch of the title compound were obtained.

Analysis of the first batch:

LC-MS (method 1): R _t = 1.96 min; MS (ESIpos): m/z = 580/582 [M+H] ⁺ .

1H-NMR (600 MHz, DMSO-d6) δ [ppm]: 1.235 (1.28), 1.258 (0.52), 1.372 (6.58), 1.822 (1.87), 1.836 (3.94), 1.851 (4.34), 1.866 (2.51) , 1.986 (0.72), 2.065 (8.57), 2.083 (9.10), 2.108 (4.07), 2.130 (4.83),2.141 (4.69), 2.162 (3.43), 2.198 (16.00), 2.308 (0.51), 3.613 (3.36) 3.645 (3.02), 3.758 (4.47), 4.101 (3.01), 4.175 (3.15), 5.378 (6.46), 5.468 (6.57), 5.743 (0.97), 7.252 (2.23), 7.264 (4.72), 7.278 (4.83) , 7.352 (2.93) , 7.616 (6.75), 7.630 (4.65), 7.888 (1.25), 8.680 (7.05), 12.012 (1.02).

Analysis of the second batch:

LC-MS (method 1): R _t = 1.96 min; MS (ESIpos): m/z = 580/582 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: -0.149 (0.66), -0.008 (6.04), 0.008 (5.65), 0.146 (0.64), 1.157

- 161 040220 (0.68), 1.175 (1.34), 1.192 (0.75), 1.234 (0.57), 1.367 (1.36), 1.801 (1.23), 1.819 (2.68), 1.842 (3.65), 1.865 (2.07), 1.988 (2.50) ), 2.049 (6.83), 2.077 (7.97), 2.089 (8.19), 2.114 (3.09), 2.139 (3.90), 2.192 (16.00), 2.304 (0.43), 2.327 (1.16), 2.366 (0.91), 2.523 (3.13 ), 2.670 (1.02), 2.710 (1.00), 3.600 (3.25), 3.647 (2.77), 3.741 (3.54), 4.020 (0.79), 4.038 (0.93), 4.074 (2.36), 4.100 (2.22), 4.183 (2.45 ), 5.354 (5.11), 5.360 (5.45), 5.494 (5.49), 5.500 (5.36), 5.754 (2.75), 7.246 (1.66), 7.264 (4.63), 7.282 (5.06), 7.301 (2.25), 7.348 (2.63 ), 7.366 (5.81), 7.385 (5.15), 7.403 (2.16), 7.439 (10.44), 7.458 (8.76), 7.476 (5.56), 7.479 (5.83), 7.494 (6.33), 7.509 (3.43), 7.544 (5.83 ), 7.548 (6.45), 7.566 (10.80), 7.571 (11.57), 7.609 (5.56), 7.615 (9.74), 7.621 (5.65), 7.631 (3.13), 7.637 (5.38), 7.643 (3.27), 7.893 (0.68 ), 8.688 (3.29), 8.702 (6.42), 8.716 (3.43), 12.035 (0.98).

Example 70.

(+/-)-5-[({6-bromo-2-[cis-3,4-difluoropyrrolidin-1-yl]-3-methylquinolin-4-yl}carbonyl)amino]-4-(2chlorophenyl)valeric acid (racemate)

To a solution of (+/-)-tert-butyl-5-[({6-bromo-2-[cis-3,4-difluoropyrrolidin-1-yl]-3-methylquinolin-4yl}carbonyl)amino]-4 -(2-chlorophenyl)pentanoate (160 mg, 93% pure, 233 µmol, racemate, example 108A) in dichloromethane (2.3 ml) TFA (180 µl, 2.3 mmol) was added and the mixture was stirred 66 h at RT. The mixture was then concentrated and mixed several times with dichloromethane and re-concentrated. The residue was purified by preparative HPLC (method 11). The combined target fractions were concentrated and the residue was lyophilized. 68 mg (93% pure, 47% thor.) of the title compound were obtained.

LC-MS (method 1): Rt = 1.93 min; MS (ESIpos): m/z = 580/582 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: -0.149 (1.26), -0.008 (12.03), 0.008 (11.85), 0.146 (1.32), 1.157 (0.60), 1.174 (1.32), 1.192 (0.60), 1.236 (0.54), 1.368 (0.42), 1.797 (1.08), 1.816 (2.41), 1.839 (3.25) (7.22), 2.137 (6.02), 2.160 (14.20), 2.297 (0.42), 2.327 (1.80), 2.366 (1.86), 2.523 (6.44), 2.669 (2.11) (3.07) (2.05) 3.586 (2.89) 3.671 (3.55) 3.782 (3.19) (3.25) (4.69), 8.678 (3.13), 8.693 (6.38), 8.707 (3.13), 12.043 (7.52).

Example 71.

5-[({6-Bromo-2-[3-fluoro-3-methylpyrrolidin-1-yl]-3-methylquinolin-4-yl}carbonyl)amino]-4-(2chlorophenyl)valeric acid (mixture of diastereoisomers)

To a solution of tert-butyl-5-[({6-bromo-2-[3-fluoro-3-methylpyrrolidin-1-yl]-3-methylquinolin-4yl}carbonyl)amino]-4-(2-chlorophenyl) pentanoate (120 mg, 96% pure, 181 µmol, mixture of diastereoisomers, example 109A) in dichloromethane (2.4 ml) TFA (140 µl, 1.8 mmol) was added and the mixture was stirred 42 h at RT. TFA (70 µl, 0.9 mmol) was then added again and the mixture was stirred for an additional 24 h at RT. The mixture was then concentrated and mixed several times with dichloromethane and re-concentrated. The residue was purified by preparative HPLC (method 11). The combined target fractions were concentrated and the residue was lyophilized. 83 mg (100% pure, 79% thor.) of the title compound were obtained.

LC-MS (method 1): Rt = 1.89 min; MS (ESIpos): m/z = 576/578 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.008 (2.03), 1.157 (4.22), 1.175 (8.34), 1.192 (4.18), 1.541 (8.21), 1.593 (8.22), 1.817 (0.84) , 1.839 (1.06), 1.862 (0.58), 1.988 (16.00), 2.018 (0.92), 2.048 (2.34),2.078 (2.77), 2.088 (2.72), 2.114 (1.68), 2.134 (2.41), 2.170 (5.51) , 2.327 (0.45), 2.523 (1.92), 2.670 (0.43),3.616 (1.97), 3.798 (0.72), 3.829 (0.51), 3.890 (0.85), 3.921 (1.25), 3.947 (0.84), 4.003 (1.38) , 4.021 (3.82),4.038 (3.71), 4.056 (1.22), 7.246 (0.61), 7.262 (1.49), 7.281 (1.62), 7.298 (0.74), 7.346 (1.01), 7.365 (1.86),7.382

- 162 040220 (1.59), 7.401 (0.70), 7.437 (3.28), 7.457 (2.76), 7.474 (1.73), 7.494 (3.00), 7.499 (2.45), 7.516 (3.28), 7.521 (3.10), 7.566 (1.68) ), 7.572 (2.81), 7.578 (1.55), 7.589 (0.99), 7.594 (1.61), 7.600 (0.88), 8.692 (1.46), 12.038 (3.86).

Example 72.

(+/-)-5-({[6-Bromo-3-methyl-2-(3,3,4,4-tetrafluoropyrrolidin-1-yl)quinolin-4-yl]carbonyl}amino)-4(2 -chlorophenyl)valeric acid (racemate)

To a solution of (+/-)-tert-butyl-5-({[6-bromo-3-methyl-2-(3,3,4,4-tetrafluoropyrrolidin-1-yl)quinolin4-yl]carbonyl}amino )-4-(2-Chlorophenyl)pentanoate (69 mg, 9% pure, 9.49 µmol, racemate, example 110A) in dichloromethane (910 µl) was added with TFA (7.3 µl, 95 µmol) and the mixture was stirred for 18 h at RT. TFA (7.3 µl, 95 µmol) was then added again and the mixture was stirred for an additional 48 h at RT. The mixture was then concentrated and mixed several times with dichloromethane and re-concentrated. The residue was purified by preparative HPLC (method 11). The combined target fractions were concentrated and the residue was lyophilized. 4 mg (100% pure, 68% thor.) of the title compound were obtained.

LC-MS (method 1): Rt = 2.21 min; MS (ESIpos): m/z = 616/618 [M+H] ⁺ .

1H-NMR (600 MHz, DMSO-d ₆ ) δ [ppm]: -0.052 (0.83), 0.854 (0.54), 0.901 (1.54), 0.911 (1.52), 1.236 (2.63), 1.262 (1.41), 1.300 ( 0.66), 1.338 (0.74), 1.369 (1.41), 1.820 (1.99), 1.834 (4.21), 1.848 (4.54), 1.864 (2.58), 2.047 (3.16), 2.060 (9.95), 2.078 (9.12), 7.22), 2.092 (4.10), 2.099 (3.52), 2.107 (3.71), 2.125 (4.63), 2.132 (5.17), 2.139 (6.68), 2.156 (4.33), 2.184 (16.00), 2.256 (0.78), 0.61) 4.30), 7.373 (7.46), 7.385 (4.17), 7.443 (11.50), 7.457 (10.28), 7.482 (9.64), 7.495 (8.17) 5.70), 7.888 (0.93), 8.680 (4.82), 8.689 (8.49), 8.698 (4.46), 12.010 (4.14).

Example 73.

(+/-)-5 -[({2-[3-azabicyclo[3.1.1 ]hept-3-yl]-6-bromo-3-methylquinolin-4-yl}carbonyl)amino]-4-(2chlorophenyl )valeric acid (racemate)

To a solution of (+/-)-tert-butyl-5-[({2-[3-azabicyclo[3.1.1]hept-3-yl]-6-bromo-3-methylquinolin-4yl}carbonyl)amino] -4-(2-Chlorophenyl)pentanoate (63 mg, 100 µmol, racemate, example 111A) in dichloromethane (2.5 ml) TFA (120 µl, 1.5 mmol) was added and the mixture was stirred for 24 h at RT. TFA (7.3 µl, 95 µmol) was then added again and the mixture was stirred for an additional 48 h at RT. The mixture was then concentrated and mixed several times with dichloromethane and re-concentrated. The residue was purified by preparative HPLC (method 11). The combined target fractions were concentrated and the residue was lyophilized. 38 mg (100% pure, 66% theoretical) of the title compound were obtained.

LC-MS (method 1): Rt = 2.07 min; MS (ESIpos): m/z = 570/572 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: -0.149 (1.04), -0.008 (9.81), 0.008 (9.81), 0.146 (1.07), 1.235 (0.70), 1.369 (1.83), 1.426 (1.48), 1.439 (9.09), 1.445 (8.32), 1.455 (8.53), 1.461 (9.55), 1.474 (1.76) (0.56), 2.046 (5.15), 2.076 (9.00), 2.087 (12.29), 2.102 (8.74), 2.108 (8.81), 2.124 (4.50) (0.46), 2.300 (0.56), 2.327 (0.86), 2.366 (0.93), 2.670 (0.83), 2.710 (0.93), 3.591 (2.83), 3.666 (3.99) (5.24), 7.291 (3.69), 7.354 (3.39), 7.373 (6.14), 7.391 (3.73), 7.438 (8.74), 7.441 (8.70), 7.458 (7.05) (4.78), 7.524 (7.63), 7.546 (15.61), 7.581 (8.77), 7.587 (8.16), 7.603 (4.20) (0.42).

Example 74 (+/-)-5 -[({2-[3-azabicyclo[3.2.1]oct-3-yl]-6-bromo-3-methylquinolin-4-yl}carbonyl)amino]-4- (2chlorophenyl)valeric acid (racemate)

- 163 040220

To a solution of (+/-)-tert-butyl-5-[({2-[3-azabicyclo[3.2.1]oct-3-yl]-6-bromo-3-methylquinolin-4yl}carbonyl)amino] -4-(2-Chlorophenyl)pentanoate (77 mg, 120 µmol, racemate, example 112A) in dichloromethane (2.0 ml) TFA (140 µl, 1.8 mmol) was added and the mixture was stirred 48 h at RT. TFA (140 μl, 1.8 mmol) was then added again and the mixture was stirred for an additional 18 h at RT. The mixture was then concentrated and mixed several times with dichloromethane and re-concentrated. The residue was purified by preparative HPLC (method 11). The combined target fractions were concentrated and the residue was lyophilized. 38 mg (100% pure, 54% thor.) of the title compound were obtained.

LC-MS (method 1): Rt = 2.40 min; MS (ESIpos): m/z = 584/586 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.149 (0.42), -0.008 (3.49), 0.008 (3.22), 0.147 (0.42), 1.236 (0.97), 1.325 (1.08), 1.349 ( 1.552 (10.36), 1.652 (4.29), 1.664 (4.68), 1.702 (1.24), 1.749 (5.47), 1.768 (5.29), 1.808 (2.02), 1.830 (2.75), 1.853 (1.69), 4.17) 0.81) 4.53), 7.292 (3.24), 7.354 (2.83), 7.373 (5.00), 7.391 (2.71), 7.443 (7.29), 7.445 (7.37), 7.466 (7.25) 4.66), 7.627 (14.17), 7.643 (8.36), 7.648 (7.56), 7.666 (2.56), 7.671 (2.59), 8.734 (2.17), 8.748 (4.20), 8.762 (2.05).

Example 75.

(+/-)-5-({[6-Bromo-2-(3,3-difluoroazetidin-1-yl)-3-methylquinolin-4-yl]carbonyl}amino)-4-(2chlorophenyl)valeric acid ( racemate)

To a solution of (+/-)-tert-butyl-5-({[6-bromo-2-(3,3-difluoroazetidin-1-yl)-3-methylquinolin-4yl]carbonyl}amino)-4-( 2-Chlorophenyl)pentanoate (30 mg, 96% pure, 46.2 µmol, racemate, Example 113A) in dichloromethane (1.9 mL) TFA (36 µL, 460 µmol) was added and the mixture was stirred 18 h at RT. TFA (36 μl, 460 μmol) was then added again and the mixture was stirred for an additional 24 h at RT. TFA (18 μl, 230 μmol) was then added again and the mixture was stirred for an additional 24 h at RT. The mixture was then concentrated and mixed several times with dichloromethane and re-concentrated. The residue was purified by preparative HPLC (method 11). The combined target fractions were concentrated and the residue was lyophilized. 18 mg (100% pure, 69% thor.) of the title compound were obtained.

LC-MS (method 1): Rt = 2.00 min; MS (ESIpos): m/z = 566/568 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: -0.149 (1.80), 0.008 (14.73), 0.146 (1.67), 1.236 (1.47), 1.367 (1.27), 1.793 (1.20), 1.813 ( 2.47), 1.835 (3.20), 1.858 (1.80), 2.041 (9.47), 2.066 (14.00), 2.085 (9.27), 2.113 (3.20), 2.133 (3.93) 2.07) 2.20) 7.87), 7.610 (16.00), 7.647 (8.87), 7.652 (7.80), 7.669 (4.27), 7.674 (4.07), 8.693 (3.07), 8.707 (5.87), 8.722 (2.93)

Example 76.

5-[({6-Bromo-2-[3-cyanopiperidin-1-yl]-3-methylquinolin-4-yl}carbonyl)amino]-4-(2chlorophenyl)valeric acid (mixture of diastereoisomers)

- 164 040220

To a solution of tert-butyl 5-[({6-bromo-2-[3-cyanopiperidin-1-yl]-3-methylquinolin-4yl}carbonyl)amino]-4-(2-chlorophenyl)pentanoate (197 mg , 308 μmol, mixture of diastereoisomers, example 114A) in dichloromethane (4.0 ml) was added TFA (360 μl, 4.6 mmol) and the mixture was stirred overnight at RT. The mixture was then concentrated and mixed several times with dichloromethane and re-concentrated. The residue was purified by preparative HPLC (method 8), first prepurified and then further purified twice more by the same method. The combined target fractions were concentrated and the residue was lyophilized. 55 mg (95% pure, 29% thor.) of the title compound were obtained.

LC-MS (method 1): R _t = 1.97 min; MS (ESIpos): m/z = 583/585 [M+H]+.

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: -0.008 (3.11), 0.008 (3.20), 0.938 (0.76), 0.955 (0.75), 1.488 (9.73), 1.656 (0.56), 1.667 ( 0.80), 1.719 (1.80), 1.802 (2.69), 1.825 (3.97), 1.846 (2.65), 1.876 (4.02), 1.888 (5.87), 1.901 (4.88), 2.003 (1.54), 2.015 (3.69), 2.041 ( 6.06) 0.46), 2.670 (0.55), 2.710 (0.66), 2.756 (4.54), 3.020 (2.08), 3.212 (2.91), 3.268 (4.82), 3.276 (4.72), 3.295 (4.84), 3.328 (5.24) 3.75), 3.456 (3.51), 3.473 (2.89), 3.487 (2.47), 3.580 (2.53), 3.681 (3.48), 7.252 (1.84), 7.270 (4.21),7.287 (2.95), 7.352 (2.53), 4.60), 7.389 (2.37), 7.436 (6.16), 7.440 (5.96), 7.456 (5.23), 7.459 (4.98) 12.09), 7.699 (8.72), 7.717 (1.14), 7.721 (1.37), 7.891 (0.91), 8.753 (2.20), 8.767 (4.21), 8.781 (2.02).

Example 77.

(+/-)-5-({[6-Bromo-2-(3,6-dihydro-2H-1,2-oxazin-2-yl)-3-methylquinolin-4-yl]carbonyl}amino)- 4-(2chlorophenyl)valeric acid (racemate)

To a solution of (+/-)-tert-butyl-5 -({[6-bromo-2-(3,6-dihydro-2H-1,2-oxazin-2-yl)-3-methylquinolin-4yl] carbonyl}amino)-4-(2-chlorophenyl)pentanoate (65 mg, 106 µmol, racemate, example 115A) in dichloromethane (2.0 ml) TFA (160 µl, 2.1 mmol) was added and the mixture was stirred for 18 h at RT. The mixture was then concentrated and mixed several times with dichloromethane and re-concentrated. The residue was purified by preparative HPLC (method 6). The combined target fractions were concentrated and the residue was lyophilized. 51 mg (97% pure, 83% thor.) of the title compound were obtained.

(8.69), (8.46), (6.50), (2.18),

LC-MS (method 1): R _t = 2.09 min; MS (ESIpos): m/z = 558/560 [M+H]+. 1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.935 (1.33), 0.952 (1.27),

1.809

2.327

4.505

7.346 (1.67), 1.830 (1.32), (0.72), 2.365 (0.70), (4.29), 5.990 (1.44), (1.76), 7.365 (3.36),

1.945

2.669

6.015

7.384 (1.75), 1.972 (2.68), 1.992 (3.01), (0.84), 2.730 (4.10), 3.334 (2.23), (3.42), 6.049 (2.99), 6.074 (1.24), (1.70), 7.436 (4.65) ), 7.459 (5.68),

1.066

2.006

3.556

7.246

7.481 (15.75), 7.745 (16.00), 8.955 (2.23).

Example 78.

5-[({6-Bromo-2-[3-fluoropiperidin-1-yl]-3-methylquinolin-4-yl}carbonyl)amino]-4-(2chlorophenyl)valeric acid (mixture of diastereoisomers) (1.35), 1.082 (1.38), 1.531 (3.92), 2.033 (2.92), 2.187 (1.91), 3.673 (2.35), 4.069 (1.38), 7.264 (3.21), 7.282 (2.65), 7.548 (0.84), 7.743

- 165 040220

To a solution of tert-butyl 5-[({6-bromo-2-[3-fluoropiperidin-1-yl]-3-methylquinolin-4yl}carbonyl)amino]-4-(2-chlorophenyl)pentanoate (75 mg , 118 μmol, mixture of diastereoisomers, example 116A) in dichloromethane (870 μl) was added with TFA (91 μl, 1.2 mmol) and the mixture was left for 16 h at RT. The mixture was then concentrated and mixed several times with dichloromethane and re-concentrated. The residue was purified by preparative HPLC (method 7). The combined target fractions were concentrated and the residue was lyophilized. 56 mg (98% pure, 80% thor.) of the title compound were obtained.

LC-MS (method 2): Rt = 1.09 min; MS (ESIpos): m/z = 576/578 [M+H]+.

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: -0.008 (2.24), 0.008 (2.48), 1.642 (1.63), 1.765 (0.52), 1.793 (1.91), 1.810 (3.01), 1.819 ( 2.66), 1.834 (3.26), 1.858 (1.97), 1.900 (2.78), 1.920 (2.26), 1.950 (1.57), 1.982 (0.97), 2.011 (0.73) 5.00), 2.088 (5.22), 2.143 (16.00), 2.217 (0.40), 2.327 (0.45), 2.366 (0.51), 2.523 (1.47), 2.669 (0.48), 2.710 (0.56), 3.094 (1.88), 2.00), 3.377 (2.00), 3.410 (1.07), 3.434 (1.75), 3.465 (1.09), 3.593 (1.93), 3.679 (3.48), 4.816 (1.35), 4.936 (1.31), 7.256 (1.72) 4.01), 7.294 (2.80), 7.356 (2.44), 7.374 (4.45), 7.393 (2.29), 7.441 (6.25), 7.444 (6.25), 7.461 (5.34) 4.68), 7.647 (2.48), 7.669 (13.43), 7.675 (9.66), 7.680 (8.33), 7.697 (1.60) 0.87).

Example 79.

5-[({6-Bromo-3-methyl-2-[2-methylpyrrolidin-1-yl]quinolin-4-yl}carbonyl)amino]-4-(2chlorophenyl)valeric acid (mixture of diastereoisomers)

(+/-)-2-methylpyrrolidine (9 mg, 100 µmol) was provided in a well of a 96-well MTP and mixed with a solution of (+/-)-tert-butyl-5-{[(6-bromo-2-chloro -3-methylquinolin-4-yl)carbonyl]amino}-4-(2chlorophenyl)pentanoate (57 mg, 100 µmol, racemate, Example 37A) in NMP (800 µl), followed by DIPEA (50 µl, 287 µmol ). The MTR was covered with cling film and shaken overnight at 120°C. Then the solvent was removed in a spin dryer, and the residue was mixed with TFA (800 μl, 10.4 mmol). The MTP was re-capped with cling film and shaken overnight at CT. Then das TFA was removed in a spin dryer and the residue was dissolved in DMF (600 μl). The solution was filtered with a filter plate and the filtrate was purified by preparative HPLC-MS (method 17). After removal of the solvent and drying in vacuo, 6 mg (100% pure, 11% theoretical) of the title compound was obtained.

LC-MS (method 16): Rt = 0.95 min; MS (ESIpos): m/z = 558/560 [M+H] ⁺ .

Example 80.

(-)-5-[({6-Bromo-3-methyl-2-[(2S)-2-methylpyrrolidin-1-yl]quinolin-4-yl}carbonyl)amino]-4-(2chlorophenyl)valeric acid (epimer 1) η

ΝΗ Oh

Br.^X^CH ₃ ΤΙ x n ₃ s

To a solution of (-)-tert-butyl-5-[({6-bromo-3-methyl-2-[(2S)-2-methylpyrrolidin-1-yl]quinolin-4yl}carbonyl)amino]-4- (2-chlorophenyl)pentanoate (135 mg, 220 µmol, epimer 1, example 118A) in dichloromethane (1.7 ml) TFA (370 µl, 4.8 mmol) was added and the mixture was left for 24 h at RT. The mixture was then concentrated and mixed several times with dichloromethane and re-concentrated. The residue was purified by preparative HPLC (method 7). The combined target fractions were concentrated and the residue was lyophilized. 56 mg (100% pure, 46% thor.) of the title compound were obtained.

[a] _D20 = -33.3°, 589 nm, c = 0.40 ^g /100 ml, methanol;

LC-MS (method 1): Rt = 1.88 min; MS (ESIpos): m/z = 558/560 [M+H] ⁺ .

'H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.141 (15.77), 1.156 (16.00), 1.370 (0.82), 1.512 (0.44), 1.539

- 166 040220 (1.29), 1.557 (1.57), 1.579 (1.54), 1.606 (0.94), 1.663 (1.38), 1.689 (1.45), 1.709 (0.94), 1.792 (0.79), 1.810 (1.53), 1.832 (1.99) ), 1.854 (1.21), 1.896 (1.94), 2.041 (4.08), 2.097 (10.55), 2.127 (4.78), 2.327 (0.46), 2.669 (0.44), 3.587 (2.86), 3.610 (1.84), 3.623 (2.08 ), 3.691 (1.33), 3.716 (2.88), 3.732 (3.30), 3.756 (2.27), 4.360 (1.38), 4.375 (2.28), 4.397 (2.15), 4.413 (1.32), 7.260 (1.69), 7.278 (3.73 ), 7.297 (2.73), 7.362 (2.89), 7.381 (4.34), 7.398 (2.39), 7.436 (6.24), 7.455 (5.02), 7.481 (4.21), 7.498 (8.03), 7.520 (9.92), 7.566 (5.37 ), 7.571 (4.99), 7.588 (2.85), 7.594 (2.78), 8.688 (2.06), 8.702 (3.28).

Example 81.

(-)-5-[({6-Bromo-3-methyl-2-[(2S)-2-methylpyrrolidin-1-yl]quinolin-4-yl}carbonyl)amino]-4-(2chlorophenyl)valeric acid (epimer 2).

To a solution of (-)-tert-butyl-5-[({6-bromo-3-methyl-2-[(2S)-2-methylpyrrolidin-1-yl]quinolin-4yl}carbonyl)amino]-4- (2-Chlorophenyl)pentanoate (130 mg, 211 µmol, epimer 2, example 119A) in dichloromethane (1.6 ml) TFA (360 µl, 4.7 mmol) was added and the mixture was left for 24 h at RT. The mixture was then concentrated and mixed several times with dichloromethane and re-concentrated. The residue was purified by preparative HPLC (method 7). The combined target fractions were concentrated and the residue was lyophilized. 71 mg (100% pure, 60% thor.) of the title compound were obtained.

[a]D ²⁰ = -9.2°, 589 nm, c = 0.47 g/100 ml, methanol;

LC-MS (method 1): Rt = 1.87 min; MS (ESIpos): m/z = 558/560 [M+H]+.

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 1.142 (15.85), 1.157 (16.00), 1.346 (0.61), 1.511 (0.44), 1.540 (1.31), 1.556 (1.56), 1.563 (1.55) ), 1.579 (1.52), 1.607 (0.99), 1.660 (1.32), 1.684 (1.35), 1.705 (0.86), 1.793 (0.68), 1.813 (1.62), 1.835 (2.04), 1.859 (1.20), 1.897 (1.92 ), 1.912 (1.82), 2.021 (0.92), 2.047 (4.11), 2.075 (5.50), 2.104 (14.49), 2.142 (4.74), 2.164 (2.34), 2.201 (0.49), 3.611 (2.35), 3.661 (2.85 ), 3.678 (2.70), 3.695 (2.70), 3.712 (2.42), 3.720 (2.96), 3.737 (2.63), 3.761 (1.12), 4.362 (1.27), 4.377 (2.15), 4.392 (1.83), 4.399 (2.04 ), 4.414 (1.23), 7.242 (1.76), 7.260 (4.06), 7.279 (2.87), 7.343 (2.51), 7.362 (4.68), 7.380 (2.49), 7.438 (6.32), 7.458 (5.90), 7.472 (5.71 ), 7.491 (4.08), 7.503 (5.93), 7.525 (9.65), 7.573 (5.51), 7.579 (5.04), 7.596 (2.97), 7.601 (2.83), 8.689 (2.01), 8.703 (3.73), 11.998 (0.66 ).

Example 82.

(+)-5-[({6-Bromo-3-methyl-2-[(2R)-2-methylpyrrolidin-1-yl]quinolin-4-yl}carbonyl)amino]-4-(2chlorophenyl)valeric acid (epimer 1)

To a solution of (+)-tert-butyl-5-[({6-bromo-3-methyl-2-[(2R)-2-methylpyrrolidin-1-yl]quinolin-4yl}carbonyl)amino]-4- (2-chlorophenyl)pentanoate (135 mg, 220 µmol, epimer 1, example 121A) in dichloromethane (1.6 ml) TFA (360 µl, 4.7 mmol) was added and the mixture was left for 24 h at RT. The mixture was then concentrated and mixed several times with dichloromethane and re-concentrated. The residue was purified by preparative HPLC (method 7). The combined target fractions were concentrated and the residue was lyophilized. 66 mg (100% pure, 56% thor.) of the title compound were obtained.

[a] _D20 = +10.3°, 589 nm ^, c = 0.27 g/100 mL, methanol;

LC-MS (method 1): R _t = 1.83 min; MS (ESIpos): m/z = 558/560 [M+H]+.

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (1.99), 0.008 (1.83), 0.069 (0.74), 1.142 (15.94), 1.157 (16.00), 1.512 (0.42), 1.540 (1.20) ), 1.556 (1.41), 1.563 (1.38), 1.579 (1.40), 1.591 (1.01), 1.607 (0.94), 1.659 (1.18), 1.684 (1.19), 1.703 (0.76), 1.813 (1.41), 1.832 (1.75 ), 1.857 (1.04), 1.897 (1.67), 1.911 (1.60), 2.014 (0.79), 2.041 (3.65), 2.068 (4.96), 2.103 (12.77), 2.135 (4.21), 2.158 (2.42), 2.200 (0.41 ), 2.327 (0.42), 2.669 (0.40), 3.616 (1.97), 3.661 (2.55), 3.676 (2.39), 3.695 (2.33), 3.712 (2.11), 3.720 (2.73), 3.736 (2.47), 3.745 (1.54 ), 3.761 (1.03), 4.361 (1.20), 4.377 (2.01), 4.392 (1.64), 4.399 (1.83), 4.414 (1.14), 7.242 (1.70), 7.260 (3.70), 7.277 (2.72), 7.280 (2.68 ), 7.342 (2.47), 7.361 (4.37), 7.377 (2.29), 7.435 (5.99), 7.438 (5.94), 7.455 (5.61), 7.458 (5.42), 7.469 (5.23), 7.473 (5.18), 7.489 (3.79 ), 7.502 (6.11), 7.524 (10.25), 7.573 (6.05), 7.578 (5.39), 7.595 (3.25), 7.601 (3.05), 8.693 (1.77), 8.708 (3.30).

Example 83.

(+)-5-[({6-Bromo-3-methyl-2-[(2R)-2-methylpyrrolidin-1-yl]quinolin-4-yl}carbonyl)amino]-4-(2chlorophenyl)valeric acid (epimer 2).

To a solution of (+)-tert-butyl-5-[({6-bromo-3-methyl-2-[(2R)-2-methylpyrrolidin-1-yl]quinolin-4yl}carbonyl)amino]-4- (2-chlorophenyl)pentanoate (130 mg, 211 µmol, epimer 2, example 122A) in dichloromethane (1.6 ml) TFA (360 µl, 4.7 mmol) was added and the mixture was left for 24 h at RT. Then a mixture of scon

- 167 040220 was centered and mixed several times with dichloromethane and re-concentrated. The residue was purified by preparative HPLC (method 7). The combined target fractions were concentrated and the residue was lyophilized. 67 mg (100% pure, 57% theoretical) of the title compound were obtained.

[a] _D20 = +32.3°, 589 nm, c = 0.29 ^g /100 mL, methanol;

LC-MS (method 1): R _t = 1.82 min; MS (ESIpos): m/z = 558/560 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: -0.008 (1.45), 0.008 (1.37), 0.070 (1.15), 1.141 (15.90), 1.156 (16.00), 1.234 (0.48), 1.511 ( 1.540 (1.33), 1.556 (1.56), 1.563 (1.54), 1.578 (1.53), 1.591 (1.12), 1.607 (1.00), 1.618 (0.48), 1.646 (0.89), 1.663 (1.38), 1.688 ( 1.40), 1.708 (0.86), 1.792 (0.76), 1.810 (1.48), 1.832 (1.92), 1.854 (1.17), 1.879 (1.22), 1.895 (1.83), 1.910 (1.71), 1.924 (1.44), 3.92) 1.34), 3.708 (1.88), 3.715 (2.78), 3.732 (3.09), 3.740 (2.44), 3.756 (2.09), 4.360 (1.33), 4.375 (2.20) 2.08), 4.413 (1.27), 7.260 (1.62), 7.278 (3.41), 7.297 (2.41), 7.362 (2.67),7.381 (3.92), 7.399 (2.14), 7.435 (5.68), 7.438 (5.69), 7.458 (4.55), 7.481 (3.87), 7.498 (7.60), 7.520 (9.64), 7.566 (5.08), 7.572 (4.98), 7.588 (2.76), 7.594 (2.84), 8.688 (1.91), 3.11), 8.715 (1.87).

Example 84.

(+/-)-5 -({[6-Bromo-2-(3,4-dihydroisoquinolin-2( 1 H)-yl)-3-methylquinolin-4-yl]carbonyl}amino)-4-(2chlorophenyl )valeric acid (racemate)

Provided 1,2,3,4-tetrahydroisoquinoline (13 mg, 100 µmol) in a well of a 96-well MTP and mixed with a solution of (+/-)-tert-butyl-5-{[(6-bromo-2-chloro -3-methylquinolin-4-yl)carbonyl]amino}-4-(2chlorophenyl)pentanoate (57 mg, 100 µmol, racemate, Example 37A) in NMP (800 µl), followed by DIPEA (50 µl, 287 µmol ). The MTP was covered with cling film and shaken overnight at 120°C. Then the solvent was removed in a spin dryer, and the residue was mixed with TFA (800 μl, 10.4 mmol). The MTP was re-capped with cling film and shaken overnight at CT. Then TFA was removed in a spin dryer and the residue was dissolved in DMF (600 μl). The solution was filtered with a filter plate and the filtrate was purified by preparative HPLC-MS (method 17). After removal of the solvent and drying in vacuo, 12 mg (96% pure, 19% theoretical) of the title compound was obtained.

LC-MS (method 16): Rt = 1.26 min; MS (ESIpos): m/z = 606/608 [M+H] ⁺ .

Example 85.

5-[({6-Bromo-2-[3-carbamoylpiperidin-1-yl]-3-methylquinolin-4-yl}carbonyl)amino]-4-(2chlorophenyl)valeric acid (mixture of diastereoisomers)

Based on (+/-)-piperidine-3-carboxamide (13 mg, 100 µmol) and (+/-)-tert-butyl-5-{[(6-bromo-2chloro-3-methylquinolin-4-yl) carbonyl]amino}-4-(2-chlorophenyl)pentanoate (57 mg, 100 µmol, racemate, example 37A) by analogy with the preparation of (+/-)-5-({[6-bromo-2-(3.4 -dihydroisoquinolin-2(1H)-yl)-3methylquinolin-4-yl]carbonyl}amino)-4-(2-chlorophenyl)valeric acid (Example 84) gave 11 mg (95% pure, 18% tho.) specified in the connection header.

LC-MS (method 16): Rt = 1.00 min; MS (ESIpos): m/z = 601/603 [M+H]+.

Example 86.

(+/-)-5-({[6-Bromo-3-methyl-2-(octahydro-2H-isoindol-2-yl)quinolin-4-yl]carbonyl}amino)-4-(2chlorophenyl)valeric acid (racemate or mixture of diastereoisomers)

- 168 040220

Starting from octahydro-III-isoindole hydrochloride (13 mg, couple per free amine, stereochemistry unknown)

100 µmol, amount of substance from rasi (+/-)-tert-butyl-5-{[(6-bromo-2-chloro-3methylquinolin-4-yl)carbonyl]amino}-4-(2-chlorophenyl)pentanoate ( 57 mg, 100 µmol, racemate, example 37A) by analogy with the preparation of (+/-)-5-({[6-bromo-2-(3,4-dihydroisoquinolin-2(III)-yl)-3methylquinolin-4 -yl]carbonyl}amino)-4-(2-chlorophenyl)valeric acid (Example 84) gave 8 mg (100% pure, 13% theoretical) of the title compound.

LC-MS (method 16): Rt = 0.95 min; MS (ESIpos): m/z = 598/600 [M+H] ⁺ .

Example 87.

(+/-)-5-({[6-Bromo-2-(1,1-dioxidothiomorpholin-4-yl)-3-methylquinolin-4-yl]carbonyl}amino)-4-(2chlorophenyl)valeric acid ( racemate)

Coming from thiomorpholine-1,1-dioxid (14mg, 100µmol) and (+/-)-tert-butyl-5-{[(6-bromo-2-chloro-3methylquinolin-4-yl)carbonyl]amino} -4-(2-chlorophenyl)pentanoates (57 mg, 100 µmol, racemate, example 37A) by analogy with the preparation of (+/-)-5-({[6-bromo-2-(3,4-dihydroisoquinoline-2 (III)-yl)-3-methylquinolin-4-yl]carbonyl}amino)-4-(2-chlorophenyl)valeric acid (Example 84) gave 1 mg (100% pure, 2% theoretical) of the title compound .

LC-MS (method 16): Rt = 1.08 min; MS (ESIpos): m/z = 608/610 [M+H] ⁺ .

Example 88.

(+/-)-5-({[6-Bromo-3-methyl-2-(4-oxoimidazolidin-1-yl)quinolin-4-yl]carbonyl}amino)-4-(2chlorophenyl)valeric acid (racemate )

Starting from imidazolidin-4-one-hydrochloride (9 mg, 100 µmol, amount of substance based on free amine) and (+/-)-tert-butyl-5-{ [(6-bromo-2-chloro-3- methylquinolin-4-yl)carbonyl]amino}-4-(2chlorophenyl)pentanoate (57 mg, 100 µmol, racemate, Example 37A) by analogy with the preparation of (+/-)-5({[6-bromo-2-( 3,4-dihydroisoquinolin-2(1H)-yl)-3-methylquinolin-4-yl]carbonyl}amino)-4-(2chlorophenyl)valeric acid (Example 84) gave 1.7 mg (100% pure, 3% theory. out) specified in the connection header.

LC-MS (method 16): Rt = 1.00 min; MS (ESIpos): m/z = 559/561 [M+H] ⁺ .

Example 89.

5-[({6-Bromo-3-methyl-2-[2-methylmorpholin-4-yl]quinolin-4-yl}carbonyl)amino]-4-(2chlorophenyl)valeric acid (mixture of diastereoisomers)

- 169 040220

Based on (+/-)-2-methylmorpholine (10mg, 100µmol) and (+/-)-tert-butyl-5-{[(6-bromo-2-chloro-3methylquinolin-4-yl)carbonyl] amino}-4-(2-chlorophenyl)pentanoate (57 mg, 100 µmol, racemate, Example 37A) by analogy with the preparation of (+/-)-5-({[6-bromo-2-(3,4-dihydroisoquinoline -2(III)-yl)-3methylquinolin-4-yl]carbonyl}amino)-4-(2-chlorophenyl)valeric acid (Example 84) gave 1.7 mg (100% pure, 3% th. y.) connection header.

LC-MS (method 16): Rt = 1.14 min; MS (ESIpos): m/z = 574/576 [M+H] ⁺ .

Example 90.

(+/-)-5-({[6-Bromo-3-methyl-2-(1,4-oxazepan-4-yl)quinolin-4-yl]carbonyl}amino)-4-(2chlorophenyl)valeric acid (racemate)

Based on 1,4-oxazepane hydrochloride (10 mg, 100 µmol, amount of substance based on free amine) and (+/-)-tert-butyl-5-{[(6-bromo-2-chloro-3- methylquinolin-4-yl)carbonyl]amino}-4-(2chlorophenyl)pentanoate (57 mg, 100 µmol, racemate, Example 37A) by analogy with the preparation of (+/-)-5({[6-bromo-2-( 3,4-dihydroisoquinolin-2( 1 H)-yl)-3-methylquinolin-4-yl]carbonyl}amino)-4-(2chlorophenyl)valeric acid (Example 84) gave 3.4 mg (100% pure, 6% theory .out) specified in the connection header.

LC-MS (method 16): Rt = 1.10 min; MS (ESIpos): m/z = 574/576 [M+H] ⁺ .

Example 91.

5-[({6-Bromo-2-[3-isopropylpiperidin-1-yl]-3-methylquinolin-4-yl}carbonyl)amino]-4-(2chlorophenyl)valeric acid (mixture of diastereoisomers)

Based on (+/-)-3-isopropylpiperidine (13 mg, 100 µmol) and (+/-)-tert-butyl-5-{[(6-bromo-2-chloro3-methylquinolin-4-yl)carbonyl] amino}-4-(2-chlorophenyl)pentanoate (57 mg, 100 µmol, racemate, Example 37A) by analogy with the preparation of (+/-)-5-({[6-bromo-2-(3,4-dihydroisoquinoline -2(III)-yl)-3-methylquinolin-4-yl]carbonyl}amino)-4-(2-chlorophenyl)valeric acid (Example 84) gave 10 mg (99% pure, 16% theoretical yield) of the indicated connection header.

LC-MS (method 16): R _t = 1.28 min; MS (ESIpos): m/z = 600/602 [M+H] ⁺ .

Example 92.

(+/-)-5-({[6-Bromo-2-(3-methoxyazetidin-1-yl)-3-methylquinolin-4-yl]carbonyl}amino)-4-(2chlorophenyl)valeric acid (racemate)

- 170 040220

Based on 3-methoxyazetidine hydrochloride (9 mg, 100 µmol, amount of substance based on free amine) and (+/-)-tert-butyl-5-{[(6-bromo-2-chloro-3-methylquinoline- 4-yl)carbonyl]amino}-4-(2-chlorophenyl)pentanoate (57 mg, 100 µmol, racemate, Example 37A) by analogy with the preparation of (+/-)-5({[6-bromo-2-(3 ,4-dihydroisoquinolin-2( 1 H)-yl)-3-methylquinolin-4-yl]carbonyl} amino)-4-(2chlorophenyl)valeric acid (Example 84) received 3.2 mg (100% purity, 7% theory. out) specified in the connection header.

LC-MS (method 16): Rt = 0.88 min; MS (ESIpos): m/z = 560/562 [M+H] ⁺ .

Example 93.

5-[({6-Bromo-2-[3-(methoxymethyl)piperidin-1-yl]-3-methylquinolin-4-yl}carbonyl)amino]-4-(2chlorophenyl)valeric acid (mixture of diastereoisomers) jO ci ^X^ he ο^,νη o

H ^ ^cH ₃ γ Ό ³

Based on (+/-)-3-(methoxymethyl)piperidine (13mg, 100µmol) and (+/-)-tert-butyl-5-{[(6-bromo-2chloro-3-methylquinolin-4-yl )carbonyl]amino}-4-(2-chlorophenyl)pentanoate (57 mg, 100 µmol, racemate, example 37A) by analogy with the preparation of (+/-)-5-({[6-bromo-2-(3, 4-dihydroisoquinolin-2(III)-yl)-3methylquinolin-4-yl]carbonyl}amino)-4-(2-chlorophenyl)valeric acid (Example 84) gave 10 mg (100% pure, 16% of theoretical yield). ) specified in the connection header.

LC-MS (method 16): R _t = 1.18 min; MS (ESIpos): m/z = 602/604 [M+H] ⁺ .

Example 94.

(+/-)-5-[({6-bromo-3-methyl-2-[(2-phenylethyl)amino]quinolin-4-yl}carbonyl)amino]-4-(2chlorophenyl)valeric acid (racemate)

Starting from 2-phenylethanamine (12 mg, 100 µmol) and (+/-)-tert-butyl-5-{[(6-bromo-2-chloro-3methylquinolin-4-yl)carbonyl]amino}-4-( 2-chlorophenyl)pentanoate (57 mg, 100 µmol, racemate, example 37A) in analogy with the preparation of (+/-)-5-({[6-bromo-2-(3,4-dihydroisoquinoline-2(III)- yl)-3methylquinolin-4-yl]carbonyl}amino)-4-(2-chlorophenyl)valeric acid (Example 84) gave 8.5 mg (97% pure, 14% theoretical) of the title compound.

LC-MS (method 16): R _t = 0.97 min; MS (ESIpos): m/z = 594/596 [M+H] ⁺ .

Example 95.

(+/-)-5-[({6-bromo-3-methyl-2-[methyl(2-phenylethyl)amino]quinolin-4-yl}carbonyl)amino]-4-(2chlorophenyl)valeric acid (racemate )

- 171 040220

Starting from N-methyl-2-phenylethanamine (14mg, 100µmol) and (+/-)-tert-butyl-5-{[(6-bromo-2-chloro-3methylquinolin-4-yl)carbonyl]amino} -4-(2-chlorophenyl)pentanoate (57 mg, 100 µmol, racemate, example 37A) by analogy with the preparation of (+/-)-5-({[6-bromo-2-(3,4-dihydroisoquinoline-2 (III)-yl)-3-methylquinolin-4-yl]carbonyl}amino)-4-(2-chlorophenyl)valeric acid (Example 84) gave 8 mg (98% pure, 12% theoretical) of the title compound .

LC-MS (method 16): R _t = 1.23 min; MS (ESIpos): m/z = 608/610 [M+H] ⁺ .

Example 96.

(+/-)-5-({[2-(benzylamino)-6-bromo-3-methylquinolin-4-yl]carbonyl}amino)-4-(2chlorophenyl)valeric acid (racemate)

Starting from 1-phenylmethanamine (11 mg, 100 µmol) and (+/-)-tert-butyl-5-{[(6-bromo-2-chloro-3methylquinolin-4-yl)carbonyl]amino}-4-( 2-chlorophenyl)pentanoate (57 mg, 100 µmol, racemate, example 37A) in analogy with the preparation of (+/-)-5-({[6-bromo-2-(3,4-dihydroisoquinoline-2(III)- yl)-3methylquinolin-4-yl]carbonyl}amino)-4-(2-chlorophenyl)valeric acid (Example 84) gave 4 mg (94% pure, 6% theoretical) of the title compound.

LC-MS (method 16): R _t = 1.04 min; MS (ESIpos): m/z = 580/582 [M+H] ⁺ .

Example 97.

(+/-)-5-({[6-Bromo-2-(cyclobutylamino)-3-methylquinolin-4-yl]carbonyl}amino)-4-(2chlorophenyl)valeric acid (racemate)

Based on cyclobutanamine hydrochloride (7 mg, 100 µmol, amount of substance based on free amine) and (+/-)-tert-butyl-5-{[(6-bromo-2-chloro-3-methylquinoline-4- yl)carbonyl]amino}-4-(2chlorophenyl)pentanoate (57 mg, 100 µmol, racemate, Example 37A) by analogy with the preparation of (+/-)-5({[6-bromo-2-(3,4- dihydroisoquinolin-2(III)-yl)-3-methylquinolin-4-yl]carbonyl}amino)-4-(2chlorophenyl)valeric acid (Example 84) gave 2 mg (100% pure, 4% theoretical yield) of the indicated in the connection header.

LC-MS (method 16): R _t = 0.87 min; MS (ESIpos): m/z = 544/546 [M+H] ⁺ .

Example 98.

(+/-)-5-[({6-bromo-3-methyl-2-[(3,3,3-trifluoropropyl)amino]quinolin-4-yl}carbonyl)amino]-4-(2chlorophenyl)valeric acid (racemate)

- 172 040220

Starting from 3,3,3-trifluoropropan-1-amine (11 mg, 100 µmol) and (+/-)-tert-butyl-5-{[(6-bromo-2-chloro3-methylquinolin-4-yl) carbonyl]amino}-4-(2-chlorophenyl)pentanoate (57 mg, 100 µmol, racemate, example 37A) by analogy with the preparation of (+/-)-5-({[6-bromo-2-(3.4 -dihydroisoquinolin-2(III)-yl)-3methylquinolin-4-yl]carbonyl}amino)-4-(2-chlorophenyl)valeric acid (Example 84) gave 1.5 mg (98% pure, 2% th. y.) specified in the connection header.

LC-MS (method 16): Rt = 1.09 min; MS (ESIpos): m/z = 586/588 [M+H] ⁺ .

Example 99.

(+/-)-5-[({6-bromo-2-[(cyclohexylmethyl)amino]-3-methylquinolin-4-yl}carbonyl)amino]-4-(2chlorophenyl)valeric acid (racemate) jO

J^^OH

Ο^ΝΗ Oh

Η ₃ u ^H LJ

Starting from 1-cyclohexylmethanamine (11 mg, 100 µmol) and (+/-)-tert-butyl-5-{[(6-bromo-2-chloro-3methylquinolin-4-yl)carbonyl]amino}-4-( 2-chlorophenyl)pentanoate (57 mg, 100 µmol, racemate, example 37A) in analogy with the preparation of (+/-)-5-({[6-bromo-2-(3,4-dihydroisoquinoline-2(III)- yl)-3methylquinolin-4-yl]carbonyl}amino)-4-(2-chlorophenyl)valeric acid (Example 84) gave 5 mg (98% pure, 9% theoretical) of the title compound.

LC-MS (method 16): Rt = 0.96 min; MS (ESIpos): m/z = 586/588 [M+H] ⁺ .

Example 100.

(+/-)-5-[({6-bromo-2-[(cyclopropylmethyl)amino]-3-methylquinolin-4-yl}carbonyl)amino]-4-(2chlorophenyl)valeric acid (racemate) jO

Ο^ΝΗ O ^Br ^^V ^CH 3 η V

Based on 1-cyclopropylmethanamine hydrochloride (7 mg, 100 µmol, amount of substance based on free amine) and (+/-)-tert-butyl-5-{[(6-bromo-2-chloro-3-methylquinoline- 4-yl)carbonyl]amino}4-(2-chlorophenyl)pentanoate (57 mg, 100 µmol, racemate, example 37A) by analogy with the preparation of (+/-)-5-({[6-bromo-2-( 3,4-dihydroisoquinolin-2(III)-yl)-3-methylquinolin-4-yl]carbonyl}amino)-4-(2chlorophenyl)valeric acid (Example 84) received 1.7 mg (100% pure, 3% theory. out) specified in the connection header.

LC-MS (method 16): Rt = 0.86 min; MS (ESIpos): m/z = 544/546 [M+H] ⁺ .

Example 101.

(+/-)-5-({[6-Bromo-2-(butylamino)-3-methylquinolin-4-yl]carbonyl}amino)-4-(2chlorophenyl)valeric acid (racemate)

- 173 040220

Starting from butan-1-amine (7.31 mg, 100 µmol) and (+/-)-tert-butyl-5-{[(6-bromo-2-chloro-3methylquinolin-4-yl)carbonyl]amino}-4 -(2-chlorophenyl)pentanoate (57 mg, 100 µmol, racemate, example 37A) by analogy with the preparation of (+/-)-5-({[6-bromo-2-(3,4-dihydroisoquinoline-2(III )-yl)-3methylquinolin-4-yl]carbonyl}amino)-4-(2-chlorophenyl)valeric acid (Example 84) gave 1.7 mg (100% pure, 3% theoretical) of the title compound.

LC-MS (method 16): R _t = 0.88 min; MS (ESIpos): m/z = 546/548 [M+H]+.

Example 102.

(+/-)-5-({[6-Bromo-2-(isobutylamino)-3-methylquinolin-4-yl]carbonyl}amino)-4-(2chlorophenyl)valeric acid (racemate)

Based on 2-methylpropan-1-amine (7 mg, 100 µmol) and (+/-)-tert-butyl-5-{[(6-bromo-2-chloro-3-methylquinolin-4-yl)carbonyl]amino }-4-(2-chlorophenyl)pentanoate (57 mg, 100 µmol, racemate, example 37A) by analogy with the preparation of (+/-)-5-({[6-bromo-2-(3,4-dihydroisoquinoline- 2(III)-yl)-3methylquinolin-4-yl]carbonyl}amino)-4-(2-chlorophenyl)valeric acid (Example 84) gave 1.6 mg (100% pure, 3% thor.) of the title connections.

LC-MS (method 16): Rt = 0.88 min; MS (ESIpos): m/z = 546/548 [M+H]+.

Example 103.

(+/-)-5-({[6-Bromo-2-(cyclopentylamino)-3-methylquinolin-4-yl]carbonyl}amino)-4-(2chlorophenyl)valeric acid (racemate)

Starting from cyclopentanamine (8.5 mg, 100 µmol) and (+/-)-tert-butyl-5-{[(6-bromo-2-chloro-3-methylquinolin-4-yl)carbonyl]amino}-4-(2 -chlorophenyl)pentanoate (57 mg, 100 µmol, racemate, example 37A) by analogy with the preparation of (+/-)-5-({[6-bromo-2-(3,4-dihydroisoquinolin-2(III)-yl )-3methylquinolin-4-yl]carbonyl}amino)-4-(2-chlorophenyl)valeric acid (Example 84) gave 6 mg (98% pure, 10% theoretical) of the title compound.

LC-MS (method 16): R _t = 0.89 min; MS (ESIpos): m/z = 558/560 [M+H]+.

Example 104.

(+/-)-5-[({6-bromo-2-[(2-methoxyethyl)amino]-3-methylquinolin-4-yl}carbonyl)amino]-4-(2chlorophenyl)valeric acid (racemate)

Starting from 2-methoxyethanamine (7.5 mg, 100 µmol) and (+/-)-tert-butyl-5-{[(6-bromo-2-chloro-3-methylquinolin-4-yl)carbonyl]amino}-4- (2-chlorophenyl)pentanoate (57 mg, 100 µmol, racemate, example 37A) by analogy with the preparation of (+/-)-5-({[6-bromo-2-(3,4-dihydroisoquinoline-2(III) -yl)-3methylquinolin-4-yl]carbonyl}amino)-4-(2-chlorophenyl)valeric acid (Example 84) gave 5 mg (100% pure, 10% theoretical) of the title compound.

LC-MS (method 16): R _t = 0.83 min; MS (ESIpos): m/z = 548/550 [M+H]+.

Example 105.

(+/-)-5-({[2-(Azepan-1-yl)-6-bromo-3-methylquinolin-4-yl]carbonyl}amino)-4-(2- 174 040220 chlorophenyl)valeric acid ( racemate)

Based on azepan (10 mg, 100 µmol) and (+/-)-tert-butyl-5-{[(6-bromo-2-chloro-3-methylquinolin-4yl)carbonyl]amino}-4-(2- chlorophenyl)pentanoate (57 mg, 100 µmol, racemate, example 37A) by analogy with the preparation of (+/-)-5-({[6-bromo-2-(3,4-dihydroisoquinolin-2(1H)-yl) -3-methylquinolin-4yl]carbonyl}amino)-4-(2-chlorophenyl)valeric acid (Example 84) gave 9 mg (100% pure, 15% theoretical) of the title compound.

LC-MS (method 16): R _t = 1.14 min; MS (ESIpos): m/z = 572/574 [M+H] ⁺ .

Example 106.

(-)-5-({[2-(Azepan-1-yl)-6-bromo-3-methylquinolin-4-yl]carbonyl}amino)-4-(2chlorophenyl)valeric acid (enantiomer 1).

To a solution of (-)-tert-butyl-5-({[2-(azepan-1-yl)-6-bromo-3-methylquinolin-4-yl]carbonyl}amino)-4(2-chlorophenyl)pentanoate (460 mg, 731 μmol, enantiomer 7, example 124A) in dichloromethane (5.6 ml) was added TFA (1.2 ml, 16 mmol) and the mixture was left for 22 h at RT. The mixture was then concentrated and mixed several times with dichloromethane and re-concentrated. The residue was purified by preparative HPLC (method 6). The combined target fractions were concentrated and the residue was lyophilized. 353 mg (100% pure, 84% thor.) of the title compound were obtained.

[a] _D20 = -11.0°, 589 nm, c = ^0.45 g/100 ml, methanol;

LC-MS (method 1): Rt = 2.24 min; MS (ESIpos): m/z = 572/574 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.234 (0.92), 1.602 (13.71), 1.781 (9.13), 1.838 (2.48), 1.861 (1.35), 1.885 (0.41), 2.015 (0.52) , 2.027 (0.93), 2.047 (3.94), 2.080 (5.20), 2.088 (5.61), 2.097 (3.42), 2.126 (16.00), 2.158 (1.47), 2.188 (0.52), 3.488 (10.68) , 3.517 (10.53) . , 8.684 (2.11), 8.698 (4.20), 8.712 (2.10), 12.061 (0.74).

Example 107.

(+)-5-({[2-(azepan-1-yl)-6-bromo-3-methylquinolin-4-yl]carbonyl}amino)-4-(2chlorophenyl)valeric acid (enantiomer 2).

To a solution of (+)-tert-butyl-5-({[2-(azepan-1-yl)-6-bromo-3-methylquinolin-4-yl]carbonyl}amino)-4(2-chlorophenyl)pentanoate (460 mg, 731 μmol, enantiomer 2, example 125A) in dichloromethane (5.6 ml) was added TFA (1.2 ml, 16 mmol) and the mixture was left for 22 h at RT. The mixture was then concentrated and mixed several times with dichloromethane and re-concentrated. The residue was purified by preparative HPLC (method 6). The combined target fractions were concentrated and the residue was lyophilized. 312 mg (100% pure, 74% thor.) of the title compound were obtained.

[a] _D20 = +12.5°, 589 nm ^, c = 0.50 g/100 mL, methanol;

LC-MS (method 1): Rt = 2.25 min; MS (ESIpos): m/z = 572/574 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 1.602 (13.76), 1.780 (9.07), 1.839 (2.47), 1.861 (1.35), 1.884 (0.43), 2.048 (3.93), 2.082 (5.18) ), 2.089 (5.61), 2.126 (16.00), 2.159 (1.44), 2.188 (0.56), 3.488 (10.85), 3.503 (15.65), 3.517 (10.64), 3.592 (2.07), 3.666 (2.71), 7.255 (1.73 ), 7.273 (4.04), 7.293 (2.84), 7.355 (2.51), 7.374 (4.61), 7.392 (2.69), 7.438 (6.62), 7.441 (6.85), 7.458 (5.22), 7.461 (5.35), 7.482 (5.16 ), 7.499 (3.67), 7.525 (5.79), 7.547 (10.73), 7.591 (5.94), 7.596 (5.65), 7.613 (3.13), 7.618 (3.13), 8.684 (2.16), 8.698 (4.31), 8.712 (2.14 ), 12.058 (0.92).

Example 108.

5-[({6-Bromo-3-methyl-2-[2-methylpiperidin-1-yl]quinolin-4-yl}carbonyl)amino]-4-(2chlorophenyl)valeric acid (mixture of diastereoisomers)

- 175 040220 i J (ΊΝΗ o

H 3

XXX n ₃ s^X

Based on (+/-)-2-methylpiperidine (10mg, 100µmol) and (+/-)-tert-butyl-5-{[(6-bromo-2-chloro-3methylquinolin-4-yl)carbonyl] amino}-4-(2-chlorophenyl)pentanoate (57 mg, 100 µmol, racemate, Example 37A) by analogy with the preparation of (+/-)-5-({[6-bromo-2-(3,4-dihydroisoquinoline -2(1H)-yl)-3methylquinolin-4-yl]carbonyl}amino)-4-(2-chlorophenyl)valeric acid (Example 84) gave 2 mg (94% pure, 3% theoretical) of the indicated connection header.

LC-MS (method 16): Rt = 1.13 min; MS (ESIpos): m/z = 572/574 [M+H] ⁺ .

Example 109.

(+/-)-5-({[6-Bromo-2-(ethylamino)-3-methylquinolin-4-yl]carbonyl}amino)-4-(2chlorophenyl)valeric acid (racemate)

XI

Ο^,ΝΗ O

Br H

XXX_

H ³

Based on ethanamine hydrochloride (5 mg, 100 µmol, amount of substance based on free amine) and (+/-)-tert-butyl-5 - {[(6-bromo-2-chloro-3-methylquinoline-4- yl)carbonyl]amino}-4-(2chlorophenyl)pentanoate (57 mg, 100 µmol, racemate, Example 37A) by analogy with the preparation of (+/-)-5({[6-bromo-2-(3,4- dihydroisoquinolin-2(1H)-yl)-3-methylquinolin-4-yl]carbonyl}amino)-4-(2chlorophenyl)valeric acid (Example 84) gave 1.8 mg (100% pure, 3% th. y.) specified in the connection header.

LC-MS (method 16): Rt = 0.8 min; MS (ESIpos): m/z = 518/520 [M+H] ⁺ .

Example 110.

(+/-)-5 -({[2-(5-azaspiro[2.5] oct-5-yl)-6-bromo-3-methylquinolin-4-yl]carbonyl}amino)-4-(2chlorophenyl)valeric acid (racemate)

Based on 5-azaspiro[2.5]octane hydrochloride (11 mg, 100 µmol, amount of substance based on free amine) and (+/-)-tert-butyl-5-{[(6-bromo-2-chloro- 3-methylquinolin-4-yl)carbonyl]amino}-4-(2chlorophenyl)pentanoate (57 mg, 100 µmol, racemate, Example 37A) by analogy with the preparation of (+/-)-5({[6-bromo-2 -(3,4-dihydroisoquinolin-2(1H)-yl)-3-methylquinolin-4-yl]carbonyl}amino)-4-(2chlorophenyl)valeric acid (Example 84) gave 2.6 mg (100% pure, 4 % theor. out.) of the compound specified in the header.

LC-MS (method 16): R _t = 1.23 min; MS (ESIpos): m/z = 584/586 [M+H] ⁺ .

Example 111.

(+/-)-5-({[6-Bromo-3-methyl-2-(piperidin-1-yl)quinolin-4-yl]carbonyl}amino)-4-[2(trifluoromethyl)phenyl]valeric acid (racemate)

- 176 040220

to a solution of

(+/-)-tert-butyl-5-({[6-bromo-3-methyl-2-(piperidin-1-yl)quinolin-4 yl]carbonyl}amino)-4-[2-(trifluoromethyl) phenyl]pentanoate (85 mg, 131 μmol, racemate, example 126A) in dichloromethane (1.5 ml) was added with TFA (200 μl, 2.6 mmol) and the mixture was stirred for 18 h at RT. The mixture was then concentrated and mixed several times with dichloromethane and re-concentrated. The residue was purified by preparative HPLC (method 7). The combined target fractions were concentrated and the residue was lyophilized. Received 52 mg (100% pure, 67% theoretical. yield.) indicated in the title compound.

LC-MS (method 1): Rt = 2.23 min; MS (ESIpos): m/z = 592/594 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 1.611 (5.32), 1.679 (10.54), 1.897 (1.82), 1.907 (1.73), 1.928 (2.08), 1.942 (1.97), 1.962 (1.64) ), 1.979 (2.69), 1.992 (1.70), 2.003 (3.05), 2.023 (0.92), 2.040 (1.68), 2.055 (3.02), 2.078 (3.08), 2.096 (1.81), 2.114 (3.33), 2.165 (16.00 ), 3.150 (13.69), 3.606 (1.32), 3.623 (2.06), 3.639 (2.27), 3.684 (1.45), 3.700 (2.32), 3.716 (1.96), 3.733 (1.31), 7.435 (1.23), 7.463 (2.79 ), 7.482 (4.90), 7.501 (3.01), 7.634 (2.00), 7.656 (15.77), 7.664 (9.55), 7.687 (3.06), 7.707 (5.08), 7.724 (11.45), 7.733 (8.28), 7.742 (6.88 ), 8.767 (2.49), 8.782 (4.97), 8.796 (2.45), 12.044 (0.78).

Example 112.

(-)-5-({[6-Bromo-3-methyl-2-(piperidin-1-yl)quinolin-4-yl]carbonyl}amino)-4-[2(trifluoromethyl)phenyl]valeric acid (enantiomer 1).

To a solution of (-)-tert-butyl-5-({[6-bromo-3-methyl-2-(piperidin-1-yl)quinolin-4yl]carbonyl}amino)-4-[2-(trifluoromethyl) phenyl]pentanoate (225 mg, 347 µmol, enantiomer 1, example 127A) in dichloromethane (2.6 ml) was added with TFA (590 µl, 7.6 mmol) and the mixture was left for 24 h at RT. The mixture was then concentrated and mixed several times with dichloromethane and re-concentrated. The residue was purified by preparative HPLC (method 7). The combined target fractions were concentrated and the residue was lyophilized. 142 mg (100% pure, 69% th. y.) of the title compound were obtained.

[a] _D20 = -20.5°, 589 nm, c = 0.37 ^g /100 ml, methanol;

LC-MS (method 1): R _t = 2.25 min; MS (ESIpos): m/z = 592/594 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 1.163 (1.22), 1.181 (2.62), 1.199 (1.29), 1.614 (4.47), 1.681 (8.91), 1.897 (1.55), 1.907 (1.43 ), 1.928 (1.72), 1.942 (1.72), 1.964 (1.35), 1.981 (2.37), 1.993 (1.47), 2.005 (2.77), 2.024 (0.81), 2.041 (1.51), 2.055 (2.72), 2.078 (2.75 ), 2.096 (1.57), 2.114 (2.87), 2.166 (13.61), 2.328 (0.45), 3.077 (0.70), 3.089 (0.80), 3.095 (0.79), 3.107 (0.82), 3.160 (11.47), 3.324 (2.20 ), 3.345 (2.07), 3.589 (2.39), 3.605 (2.50), 3.622 (2.85), 3.638 (2.83), 3.685 (1.74), 3.700 (2.38), 3.716 (2.02), 3.733 (1.42), 7.432 (0.97 ), 7.464 (2.39), 7.483 (4.25), 7.501 (2.59), 7.643 (1.56), 7.665 (16.00), 7.672 (8.78), 7.689 (2.46), 7.708 (4.46), 7.724 (9.86), 7.734 (6.97 ), 7.742 (5.94), 8.769 (2.26), 8.784 (4.59), 8.799 (2.17).

Example 113.

(+)-5-({[6-Bromo-3-methyl-2-(piperidin-1-yl)quinolin-4-yl]carbonyl}amino)-4-[2(trifluoromethyl)phenyl]valeric acid (enantiomer 2).

To a solution of (+)-tert-butyl-5-({[6-bromo-3-methyl-2-(piperidin-1-yl)quinolin-4yl]carbonyl}amino)-4-[2-(trifluoromethyl) phenyl]pentanoate (230 mg, 355 µmol, enantiomer 2, example 128A) in dichloromethane (2.7 ml) was added with TFA (600 µl, 7.8 mmol) and the mixture was left for 24 h at RT. The mixture was then concentrated and mixed several times with dichloromethane and re-concentrated. The residue was purified by preparative HPLC (method 7). The combined target fractions were concentrated and the residue was lyophilized. 158 mg (100% pure, 75% thor.) of the title compound were obtained.

[a] _D20 = +22.7°, 589 nm, c = 0.49 ^g /100 ml, methanol;

LC-MS (method 1): R _t = 2.25 min; MS (ESIpos): m/z = 592/594 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.614 (4.61), 1.681 (9.03), 1.896 (1.62), 1.907 (1.52), 1.928 (1.80), 1.942 (1.79), 1.963 (1.45) , 1.980 (2.43), 1.993 (1.57), 2.004 (2.84), 2.025 (0.92), 2.040 (1.60) , 2.328 (0.42), 3.160 (11.56), 3.324 (2.39), 3.492 (2.62), 3.589 (1.71), 3.606 (1.97), 3.622 (2.44), 3.639 (2.48), 3.684 (1.64), 3.699 (2.30) . , 7.708 (4.85), 7.724 (10.06), 7.734 (7.01), 7.742 (5.89), 8.769 (2.40), 8.784 (4.53), 8.799 (2.10).

Example 114.

(+/-)-5-({[6-Bromo-3-methyl-2-(pyrrolidin-1-yl)quinolin-4-yl]carbonyl}amino)-4-[2- 177 040220 (trifluoromethyl)phenyl ]valeric acid (racemate)

To a solution of (+/-)-tert-butyl-5-({[6-bromo-3-methyl-2-(pyrrolidin-1-yl)quinolin-4yl]carbonyl}amino)-4-[2-( trifluoromethyl)phenyl]pentanoate (85 mg, 134 µmol, racemate, example 129A) in dichloromethane (1.5 ml) was added with TFA (210 µl, 2.7 mmol) and the mixture was stirred for 18 h at RT. The mixture was then concentrated and mixed several times with dichloromethane and re-concentrated. The residue was purified by preparative HPLC (method 7). The combined target fractions were concentrated and the residue was lyophilized. 40 mg (100% pure, 52% thor.) of the title compound were obtained.

LC-MS (method 1): R _t = 1.54 min; MS (ESIpos): m/z = 578/580 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 1.879 (16.00), 1.924 (3.02), 1.951 (2.34), 1.968 (2.79), 1.980 (1.68), 1.992 (2.98), 2.011 (1.08) ), 2.037 (1.55), 2.053 (3.01), 2.076 (3.20), 2.093 (2.11), 2.113 (3.51), 2.181 (6.81), 2.281 (0.57), 2.327 (0.41), 3.318 (6.26), 3.709 (2.16 ), 3.725 (1.96), 3.741 (1.48), 7.341 (0.65), 7.434 (0.44), 7.457 (2.26), 7.477 (11.20), 7.500 (13.68), 7.550 (6.77), 7.555 (6.41), 7.572 (3.79 ), 7.578 (3.74), 7.685 (1.86), 7.705 (5.30), 7.716 (8.48), 7.733 (10.38), 7.747 (2.43), 8.715 (2.47), 8.729 (4.76), 8.744 (2.37).

Example 115.

(+)-5-({[6-Bromo-3-methyl-2-(pyrrolidin-1-yl)quinolin-4-yl]carbonyl}amino)-4-[2(trifluoromethyl)phenyl]valeric acid (enantiomer 1).

To a solution of (+)-tert-butyl-5-({[6-bromo-3-methyl-2-(pyrrolidin-1-yl)quinolin-4yl]carbonyl}amino)-4-[2-(trifluoromethyl) phenyl]pentanoate (160 mg, 252 µmol, enantiomer 7, example 130A) in dichloromethane (1.9 ml) was added with TFA (430 µl, 5.5 mmol) and the mixture was left for 22 h at RT. The mixture was then concentrated and mixed several times with dichloromethane and re-concentrated. The residue was purified by preparative HPLC (method 7). The combined target fractions were concentrated and the residue was lyophilized. 73 mg (100% pure, 50% thor.) of the title compound were obtained.

[a] _D20 = +18.9°, 589 nm, c = 0.47 g/100 mL ^, methanol;

LC-MS (method 1): R _t = 1.52 min; MS (ESIpos): m/z = 578/580 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.879 (16.00), 1.925 (2.74), 1.954 (2.21), 1.971 (2.77), 1.984 (1.69), 1.996 (3.01), 2.014 (1.13) , 2.041 (1.58), 2.055 (3.04), 2.079 (3.17), 2.096 (2.13), 2.115 (3.52), 2.138 (2.71), 2.181 (6.83), 2.281 (0.59), 2.328 (0.43) 3.693 (1.38), 3.709 (2.16), 3.725 (1.92), 3.742 (1.48), 7.335 (0.61), 7.459 (2.16), 7.477 (10.75), 7.500 (13.45), 7.551 (6.29), 7.556 (6.19) , 7.573 (3.60), 7.578 (3.64), 7.686 (1.82), 7.706 (5.20), 7.717 (8.11), 7.734 (10.70), 7.749 (2.41), 8.711 (2.44), 8.726 (4.79), 8.741 (2.38) , 12.044 (0.69).

Example 116.

(-)-5-({[6-Bromo-3-methyl-2-(pyrrolidin-1-yl)quinolin-4-yl]carbonyl}amino)-4-[2(trifluoromethyl)phenyl]valeric acid (enantiomer 2).

To a solution of (-)-tert-butyl-5-({[6-bromo-3-methyl-2-(pyrrolidin-1-yl)quinolin-4yl]carbonyl}amino)-4-[2-(trifluoromethyl) phenyl]pentanoate (170 mg, 268 µmol, enantiomer 2, example 131A) in dichloromethane (2.1 ml) was added with TFA (450 µl, 5.9 mmol) and the mixture was left for 22 h at RT. The mixture was then concentrated and mixed several times with dichloromethane and re-concentrated. The residue was purified by preparative HPLC (method 7). The combined target fractions were concentrated and the residue was lyophilized. Received 81 mg (100% pure, 52% theoretical. yield.) specified in the title compound.

[a] _D20 = -17.5°, 589 nm, c = 0.41 g ^/ 100 ml, methanol;

LC-MS (method 1): Rt = 1.52 min; MS (ESIpos): m/z = 578/580 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 1.236 (0.42), 1.885 (16.00), 1.935 (2.55), 1.957 (2.22), 1.974 (2.98), 1.986 (1.84), 1.998 (3.37) ), 2.016 (1.29), 2.041 (1.73), 2.056 (3.35), 2.080 (3.42), 2.097 (2.31), 2.115 (3.73), 2.137 (2.74), 2.186 (6.71), 2.328 (0.54), 2.670 (0.46 ), 3.597 (11.63), 3.711 (2.35), 3.727 (2.10), 3.744 (1.60), 7.246 (0.44), 7.334 (0.66), 7.459 (2.46), 7.478 (5.04), 7.497 (4.57), 7.519 (2.99 ), 7.567 (3.96), 7.588 (2.35), 7.687 (1.96), 7.706 (5.62), 7.717 (8.55), 7.734 (12.13), 7.750 (2.51), 8.719 (2.21), 8.734 (4.05), 8.748 (2.14 ), 12.028 (1.34).

Example 117.

(+/-)-5-({[6-Bromo-2-(3,3-difluoropiperidin-1-yl)-3-methylquinolin-4-yl]carbonyl}amino)-4-[2(trifluoromethyl)phenyl ]valeric acid (racemate)

- 178 040220

To a solution of (+/-)-tert-butyl-5-({[6-bromo-2-(3,3-difluoropiperidin-1-yl)-3-methylquinolin-4yl]carbonyl}amino)-4-[ 2-(trifluoromethyl)phenyl]pentanoate (85 mg, 124 µmol, racemate, example 132A) in dichloromethane (1.5 ml) TFA (190 µl, 2.5 mmol) was added and the mixture was stirred for 18 h at RT. The mixture was then concentrated and mixed several times with dichloromethane and re-concentrated. The residue was purified by preparative HPLC (method 7). The combined target fractions were concentrated and the residue was lyophilized. 46 mg (100% pure, 59% thor.) of the title compound were obtained.

LC-MS (method 1): Rt = 2.17 min; MS (ESIpos): m/z = 628/630 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 1.896 (6.19), 1.980 (2.25), 2.004 (2.45), 2.055 (3.73), 2.078 (4.51), 2.114 (5.44), 2.136 (4.06 ), 2.185 (12.02), 2.670 (0.22), 3.180 (6.09), 3.463 (3.22), 3.492 (5.91), 3.520 (3.16), 3.648 (1.96), 3.710 (1.91), 7.465 (2.61), 7.483 (4.20 ), 7.501 (2.79), 7.707 (16.00), 7.725 (9.34), 7.738 (8.33), 8.793 (3.72), 12.049 (0.53).

Example 118.

(-)-5-({[6-Bromo-2-(3,3-difluoropiperidin-1-yl)-3-methylquinolin-4-yl]carbonyl}amino)-4-[2(trifluoromethyl)phenyl]valeric acid (enantiomer 1).

To a solution of (-)-tert-butyl-5-({[6-bromo-2-(3,3-difluoropiperidin-1-yl)-3-methylquinolin-4yl]carbonyl}amino)-4-[2- (trifluoromethyl)phenyl]pentanoate (85 mg, 124 µmol, enantiomer 7, example 133A) in dichloromethane (960 µl) TFA (210 µl, 2.7 mmol) was added and the mixture was left for 22 h at RT. The mixture was then concentrated and mixed several times with dichloromethane and re-concentrated. The residue was purified by preparative HPLC (method 7). The combined target fractions were concentrated and the residue was lyophilized. 65 mg (100% pure, 83% thor.) of the title compound were obtained.

[a] _D20 = -18.2°, 589 nm, c = 0.49 g ^/ 100 ml, methanol;

LC-MS (method 1): Rt = 2.19 min; MS (ESIpos): m/z = 628/630 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.899 (4.56), 1.946 (1.50), 1.953 (1.22), 1.967 (1.16), 1.984 (1.98), 1.997 (1.22), 2.008 (2.30) , 2.028 (0.88), 2.043 (1.59), 2.057 (3.11), 2.065 (2.55), 2.081 (3.82) . , 7.467 (2.12) , 8.777 (1.83), 8.792 (3.78), 8.807 (1.84), 12.035 (1.20).

Example 119.

(+)-5-({[6-Bromo-2-(3,3-difluoropiperidin-1-yl)-3-methylquinolin-4-yl]carbonyl}amino)-4-[2(trifluoromethyl)phenyl]valeric acid (enantiomer 2).

To a solution of (+)-tert-butyl-5-({[6-bromo-2-(3,3-difluoropiperidin-1-yl)-3-methylquinolin-4yl]carbonyl}amino)-4-[2- (trifluoromethyl)phenyl]pentanoate (60 mg, 87.6 µmol, enantiomer 2, example 134A) in dichloromethane (670 µl) TFA (150 µl, 1.9 mmol) was added and the mixture was left for 22 h at RT. The mixture was then concentrated and mixed several times with dichloromethane and re-concentrated. The residue was purified by preparative HPLC (method 7). The combined target fractions were concentrated and the residue was lyophilized. 38 mg (100% pure, 69% thor.) of the title compound were obtained.

[a] _D20 = +18.9°, 589 nm, c = 0.39 g/100 mL ^, methanol;

LC-MS (method 1): R _t = 2.19 min; MS (ESIpos): m/z = 628/630 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 1.898 (4.75), 1.944 (1.51), 1.965 (1.18), 1.982 (1.96), 1.995 (1.22), 2.006 (2.25), 2.026 (0.88 ), 2.041 (1.53), 2.055 (3.13), 2.063 (2.55), 2.079 (3.69), 2.097 (3.46), 2.116 (4.22), 2.136 (2.97), 2.150 (2.39), 2.185 (10.76), 2.225 (0.69 ), 3.180 (4.82), 3.463 (2.94), 3.492 (5.61), 3.520 (2.84), 3.632 (1.38), 3.648 (1.51), 3.710 (1.47), 3.726 (1.28), 7.466 (2.20), 7.485 (3.79 ), 7.503 (2.39), 7.684 (1.67), 7.691 (1.73), 7.707 (16.00), 7.726 (7.79), 7.742 (6.86), 7.757 (1.83), 8.777 (1.83), 8.791 (3.69), 8.806 (1.78 ), 12.037 (0.82).

Example 120.

(+/-)-5-({[2-(Azepan-1-yl)-6-bromo-3-methylquinolin-4-yl]carbonyl}amino)-4-[2(trifluoromethyl)phenyl]valeric acid ( racemate)

- 179 040220

To a solution of (+/-)-tert-butyl-5-({[2-(azepan-1-yl)-6-bromo-3-methylquinolin-4-yl]carbonyl}amino)-4-[2- (trifluoromethyl)phenyl]pentanoate (85 mg, 128 µmol, racemate, example 135A) in dichloromethane (1.5 ml) TFA (200 µl, 2.6 mmol) was added and the mixture was stirred for 18 h at RT. The mixture was then concentrated and mixed several times with dichloromethane and re-concentrated. The residue was purified by preparative HPLC (method 7). The combined target fractions were concentrated and the residue was lyophilized. 60 mg (100% pure, 77% thor.) of the title compound were obtained.

LC-MS (method 1): R _t = 2.28 min; MS (ESIpos): m/z = 606/608 [M+H]+.

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 1.610 (14.32), 1.791 (9.69), 1.899 (1.71), 1.908 (1.60), 1.930 (2.04), 1.945 (1.85), 1.961 (1.78) ), 1.978 (2.56), 1.990 (1.59), 2.002 (2.80), 2.011 (1.67), 2.041 (1.48), 2.056 (2.80), 2.079 (3.00), 2.097 (1.87), 2.116 (3.51), 2.152 (11.34 ), 3.505 (10.82), 3.519 (16.00), 3.533 (10.80), 3.609 (1.63), 3.624 (1.73), 3.705 (1.75), 3.720 (1.56), 7.371 (0.83), 7.463 (2.07), 7.482 (4.24 ), 7.501 (2.63), 7.537 (5.32), 7.559 (10.25), 7.599 (5.62), 7.604 (5.69), 7.622 (2.80), 7.626 (2.98), 7.689 (1.75), 7.709 (4.73), 7.722 (8.25 ), 7.739 (9.99), 7.754 (2.31), 8.739 (2.25), 8.754 (4.52), 8.769 (2.24), 12.037 (1.01).

Example 121.

(-)-5-({[2-(Azepan-1-yl)-6-bromo-3-methylquinolin-4-yl]carbonyl}amino)-4-[2(trifluoromethyl)phenyl]valeric acid (enantiomer 1 ).

To a solution of (-)-tert-butyl-5-({[2-(azepan-1-yl)-6-bromo-3-methylquinolin-4-yl]carbonyl}amino)-4[2-(trifluoromethyl) phenyl]pentanoate (70 mg, 106 µmol, enantiomer 7, example 136A) in dichloromethane (810 µl) TFA (180 µl, 2.3 mmol) was added and the mixture was left for 24 h at RT. The mixture was then concentrated and mixed several times with dichloromethane and re-concentrated. The residue was purified by preparative HPLC (method 7). The combined target fractions were concentrated and the residue was lyophilized. 44 mg (100% pure, 69% thor.) of the title compound were obtained.

[a] _D20 = -17.2°, 589 nm, c = 0.43 g ^/ 100 ml, methanol;

LC-MS (method 1): Rt = 2.30 min; MS (ESIpos): m/z = 606/608 [M+H]+.

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 1.609 (14.30), 1.790 (9.46), 1.896 (1.66), 1.905 (1.58), 1.927 (2.05), 1.942 (1.89), 1.957 (1.86 ), 1.973 (2.51), 1.986 (1.54), 1.997 (2.79), 2.007 (1.65), 2.037 (1.43), 2.052 (2.75), 2.075 (2.90), 2.093 (1.79), 2.112 (3.33), 2.150 (11.02 ), 2.328 (0.44), 2.670 (0.42), 3.504 (11.33), 3.518 (16.00), 3.533 (11.13), 3.607 (1.63), 3.621 (1.70), 3.704 (1.72), 7.369 (0.84), 7.462 (2.12 ), 7.481 (4.20), 7.500 (2.62), 7.536 (5.72), 7.558 (10.90), 7.599 (6.17), 7.604 (5.82), 7.621 (3.10), 7.626 (3.06), 7.688 (1.73), 7.707 (4.75 ), 7.721 (8.19), 7.737 (9.36), 7.752 (2.20), 8.740 (2.23), 8.755 (4.40), 8.770 (2.18), 12.042 (0.47).

Example 122.

(+)-5-({[2-(Azepan-1-yl)-6-bromo-3-methylquinolin-4-yl]carbonyl}amino)-4-[2(trifluoromethyl)phenyl]valeric acid (enantiomer 2 ).

To a solution of (+)-tert-butyl-5-({[2-(azepan-1-yl)-6-bromo-3-methylquinolin-4-yl]carbonyl}amino)-4[2-(trifluoromethyl) phenyl]pentanoate (65 mg, 98.1 µmol, enantiomer 2, example 137A) in dichloromethane (750 µl) TFA (170 µl, 2.2 mmol) was added and the mixture was left for 24 h at RT. The mixture was then concentrated and mixed several times with dichloromethane and re-concentrated. The residue was purified by preparative HPLC (method 7). The combined target fractions were concentrated and the residue was lyophilized. 44 mg (100% pure, 74% thor.) of the title compound were obtained.

[a] _D20 = +16.9°, 589 nm, c = 0.38 g/100 mL ^, methanol;

LC-MS (method 1): Rt = 2.30 min; MS (ESIpos): m/z = 606/608 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.234 (0.46), 1.341 (0.42), 1.353 (0.63), 1.371 (2.44), 1.609 (14.42), 1.790 (9.61), 1.896 (1.69) , 1.906 (1.59), 1.927 (2.08), 1.942 (1.89), 1.957 (1.81), 1.974 (2.47), 1.987 (1.58), 1.998 (2.65), 2.038 (1.46), 2.053 (2.67), 2.076 (2.81) , 2.094 (1.80), 2.114 (3.37), 2.151 (11.17), 3.504 (11.21), 3.518 (16.00), 3.533 (11.08), 3.608 (1.66), 3.622 (1.72), 3.704 (1.75), 3.720 (1.56) , 7.367 (0.82), 7.462 (2.06), 7.481 (4.17), 7.499 (2.61), 7.536 (5.40), 7.558 (10.42), 7.599 (5.89) , 7.688 (1.66), 7.707 (4.67), 7.721 (8.20), 7.737 (9.48), 7.752 (2.35), 8.740 (2.22), 8.755 (4.42), 8.770 (2.21).

- 180 040220

Example 123.

5-[({6-Bromo-2-[3-fluoropiperidin-1-yl]-3-methylquinolin-4-yl}carbonyl)amino]-4-[2(trifluoromethyl)phenyl]valeric acid (mixture of diastereoisomers)

To a solution of tert-butyl 5-[({6-bromo-2-[3-fluoropiperidin-1-yl]-3-methylquinolin-4yl}carbonyl)amino]-4-[2-(trifluoromethyl)phenyl]pentanoate (85 mg, 128 µmol, mixture of diastereoisomers, example 138A) in dichloromethane (1.5 ml) was added TFA (200 µl, 2.6 mmol) and the mixture was stirred for 18 h at RT. The mixture was then concentrated and mixed several times with dichloromethane and re-concentrated. The residue was purified by preparative HPLC (method 7). The combined target fractions were concentrated and the residue was lyophilized. 55 mg (100% pure, 71% thor.) of the title compound were obtained.

LC-MS (method 1): R _t = 2.12 min; MS (ESIpos): m/z = 610/612 [M+H]+.

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 1.652 (1.93), 1.773 (0.54), 1.812 (1.78), 1.829 (1.51), 1.908 (4.68), 1.928 (4.50), 1.943 (3.34 ), 1.952 (3.13), 1.982 (3.45), 1.994 (2.44), 2.006 (3.39), 2.041 (1.73), 2.057 (2.96), 2.080 (3.00), 2.097 (1.82), 2.116 (3.20), 2.140 (2.39 ), 2.178 (14.18), 3.084 (1.27), 3.114 (2.24), 3.170 (2.37), 3.186 (2.31), 3.214 (1.29), 3.317 (12.17), 3.395 (2.33), 3.428 (1.26), 3.452 (2.01 ), 3.480 (1.30), 3.613 (1.25), 3.628 (1.89), 3.644 (2.09), 3.707 (1.99), 4.824 (1.57), 4.945 (1.58), 7.465 (2.95), 7.484 (4.87), 7.502 (3.00 ), 7.658 (2.05), 7.681 (16.00), 7.688 (10.91), 7.710 (6.16), 7.725 (10.19), 7.741 (8.20), 7.755 (2.49), 8.772 (2.36), 8.787 (4.50), 8.801 (2.20 ), 12.043 (0.89).

Example 124.

5-[({6-Bromo-2-[3-ethylpiperidin-1-yl]-3-methylquinolin-4-yl}carbonyl)amino]-4-[2(trifluoromethyl)phenyl]valeric acid (mixture of diastereoisomers)

To a solution of tert-butyl 5-[({6-bromo-2-[3-ethylpiperidin-1-yl]-3-methylquinolin-4yl}carbonyl)amino]-4-[2-(trifluoromethyl)phenyl]pentanoate (85 mg, 126 μmol, mixture of diastereoisomers, example 139A) in dichloromethane (1.5 ml) was added TFA (190 μl, 2.5 mmol) and the mixture was stirred for 18 h at RT. The mixture was then concentrated and mixed several times with dichloromethane and re-concentrated. The residue was purified by preparative HPLC (method 7). The combined target fractions were concentrated and the residue was lyophilized. 45 mg (100% pure, 58% thor.) of the title compound were obtained.

LC-MS (method 1): R _t = 2.48 min; MS (ESIpos): m/z = 620/622 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.895 (6.54), 0.913 (16.00), 0.932 (8.08), 1.042 (0.48), 1.070 (1.30), 1.092 (1.32), 1.099 (1.35) , 1.121 (0.59), 1.131 (0.54), 1.245 (1.03), 1.262 (2.36), 1.279 (3.38), 1.296 (2.77), 1.310 (1.63), 1.570 (1.54), 1.578 (1.49), 1.596 (1.25) , 1.611 (1.37), 1.642 (1.23), 1.752 (1.86), 1.785 (1.25), 1.853 (1.69), 1.892 (2.33), 1.926 (1.42), 1.939 (1.34), 1.948 (1.17), 1.961 (1.05) , 1.978 (1.80),1.991 (1.10), 2.002 (2.03), 2.019 (0.80), 2.041 (1.16), 2.056 (2.01), 2.079 (2.14), 2.097 (1.54), 2.115 (3.36),2.133 (4.50) , 2.159 (7.40), 2.417 (0.90), 2.443 (1.33), 2.474 (0.85), 2.721 (1.01), 2.749 (1.83), 2.778 (1.01), 3.513 (2.86), 3.534 (2.38), 3.614 (1.11) , 3.628 (1.30), 3.701 (0.98), 3.717 (1.62), 3.734 (1.43), 3.751 (0.99) , 7.657 (15.46), 7.686 (1.56), 7.707 (3.81), 7.723 (5.27), 7.738 (7.56), 7.756 (1.73), 8.753 (1.67), 8.768 (3.28), 8.782 (1.65), 12.055 (0.48) .

Example 125.

5-[({6-Bromo-3-methyl-2-[3-methylpiperidin-1-yl]quinolin-4-yl}carbonyl)amino]-4-[2(trifluoromethyl)phenyl]valeric acid (mixture of diastereoisomers)

- 181 040220

To a solution of tert-butyl-5-[({6-bromo-3-methyl-2-[3-methylpiperidin-1-yl]quinolin-4yl}carbonyl)amino]-4-[2-(trifluoromethyl)phenyl] pentanoate (85 mg, 128 µmol, mixture of diastereoisomers, example 140A) in dichloromethane (1.5 ml) TFA (200 µl, 2.6 mmol) was added and the mixture was stirred for 18 h at RT. The mixture was then concentrated and mixed several times with dichloromethane and re-concentrated. The residue was purified by preparative HPLC (method 7). The combined target fractions were concentrated and the residue was lyophilized. 66 mg (100% pure, 85% thor.) of the title compound were obtained.

LC-MS (method 1): R _t = 2.36 min; MS (ESIpos): m/z = 606/608 [M+H]+.

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 0.961 (11.43), 0.977 (11.69), 1.119 (1.33), 1.142 (1.37), 1.170 (0.55), 1.668 (1.15), 1.698 (1.36) ), 1.772 (2.38), 1.805 (2.36), 1.831 (3.01), 1.861 (1.82), 1.931 (1.31), 1.942 (1.22), 1.963 (1.52), 1.977 (1.40), 1.995 (1.27), 2.012 (1.97 ), 2.025 (1.20), 2.036 (2.22), 2.045 (1.32), 2.073 (1.16), 2.088 (2.19), 2.112 (2.28), 2.129 (1.30), 2.148 (2.41), 2.202 (9.83), 2.362 (0.23 ), 2.401 (0.17), 2.472 (1.26), 2.724 (1.08), 2.753 (1.97), 2.781 (1.07), 3.488 (2.15), 3.514 (3.81), 3.543 (1.91), 3.647 (1.13), 3.663 (1.43 ), 3.678 (1.25), 3.745 (1.32), 7.468 (0.77), 7.498 (1.91), 7.517 (3.49), 7.535 (2.12), 7.670 (0.83), 7.692 (16.00), 7.721 (1.57), 7.742 (3.68 ), 7.758 (7.71), 7.770 (5.90), 8.795 (1.69), 8.809 (3.31), 8.824 (1.65), 12.057 (0.39).

Example 126.

(+/-)-5-({[6-Bromo-3-methyl-2-(piperidin-1-yl)quinolin-4-yl]carbonyl}amino)-4-[2(trifluoromethoxy)phenyl]valeric acid (racemate)

To a solution of (+/-)-tert-butyl-5-({[6-bromo-3-methyl-2-(piperidin-1-yl)quinolin-4yl]carbonyl}amino)-4-[2-( trifluoromethoxy)phenyl]pentanoate (85 mg, 128 µmol, racemate, example 141A) in dichloromethane (1.5 ml) was added with TFA (200 µl, 2.6 mmol) and the mixture was stirred for 18 h at RT. The mixture was then concentrated and mixed several times with dichloromethane and re-concentrated. The residue was purified by preparative HPLC (method 7). The combined target fractions were concentrated and the residue was lyophilized. 58 mg (100% pure, 75% thor.) of the title compound were obtained.

LC-MS (method 1): R _t = 2.28 min; MS (ESIpos): m/z = 608/610 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 1.609 (5.45), 1.674 (10.79), 1.802 (1.40), 1.816 (1.97), 1.826 (1.94), 1.836 (2.70), 1.860 (2.03) ), 1.888 (0.49), 2.034 (0.85), 2.048 (3.13), 2.062 (3.86), 2.074 (15.09), 2.105 (2.80), 2.141 (13.35), 2.223 (0.46), 3.142 (14.21), 3.358 (1.72 ), 3.378 (2.31), 3.389 (2.71), 3.405 (2.55), 3.585 (0.80), 3.600 (1.32), 3.618 (2.89), 3.634 (3.97), 3.644 (3.21), 3.659 (3.20), 3.677 (2.34 ), 3.693 (1.16), 3.711 (0.65), 7.362 (4.71), 7.366 (4.18), 7.380 (1.52), 7.386 (2.11), 7.401 (8.29), 7.411 (6.88), 7.418 (6.54), 7.423 (7.52 ), 7.436 (2.09), 7.462 (1.58), 7.548 (5.03), 7.554 (3.43), 7.561 (4.22), 7.572 (3.66), 7.630 (2.79), 7.652 (16.00), 7.658 (11.38), 7.663 (9.59 ), 7.680 (1.69), 7.685 (1.88), 8.732 (2.66), 8.746 (5.24), 8.761 (2.61), 12.069 (0.60).

Example 127.

(-)-5-({[6-Bromo-3-methyl-2-(piperidin-1-yl)quinolin-4-yl]carbonyl}amino)-4-[2(trifluoromethoxy)phenyl]valeric acid (enantiomer 1).

To a solution of (-)-tert-butyl-5-({[6-bromo-3-methyl-2-(piperidin-1-yl)quinolin-4yl]carbonyl}amino)-4-[2-(trifluoromethoxy) phenyl]pentanoate (90 mg, 135 µmol, enantiomer 1, example 142A) in dichloromethane (1.0 ml) TFA (230 µl, 3.0 mmol) was added and the mixture was left for 22 h at RT. The mixture was then concentrated and mixed several times with dichloromethane and re-concentrated. The residue was purified by preparative HPLC (method 7). Combined target scon fractions

- 182 040220 was centered and the residue was lyophilized. Received 50 mg (100% pure, 61% theoretical. yield.) specified in the title compound.

[a] _D20 = -18.0°, 589 nm, c = 0.49 g/100 ml ^, methanol;

LC-MS (method 1): R _t = 2.29 min; MS (ESIpos): m/z = 608/610 [M+H]+.

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.609 (5.83), 1.674 (11.45), 1.803 (1.47), 1.817 (2.13), 1.826 (2.21), 1.837 (2.80), 1.861 (2.09) , 1.888 (0.51), 2.051 (3.70), 2.077 (16.00), 2.107 (3.39), 2.140 (13.75), 2.222 (0.47), 3.142 (14.84), 3.390 (2.52), 3.405 (2.42) . , 7.366 (4.34) , 7.549 (5.35), 7.554 (3.69), 7.561 (4.42), 7.572 (3.74), 7.630 (3.18), 7.651 (15.85), 7.658 (11.08) , 8.729 (2.97), 8.744 (5.43), 8.758 (2.65), 12.048 (9.94).

Example 128.

(+)-5-({[6-Bromo-3-methyl-2-(piperidin-1-yl)quinolin-4-yl]carbonyl}amino)-4-[2(trifluoromethoxy)phenyl]valeric acid (enantiomer 2).

To a solution of (+)-tert-butyl-5-({[6-bromo-3-methyl-2-(piperidin-1-yl)quinolin-4yl]carbonyl}amino)-4-[2-(trifluoromethoxy) phenyl]pentanoate (80 mg, 120 μmol, enantiomer 2, example 143A) in dichloromethane (930 μl) TFA (200 μl, 2.6 mmol) was added and the mixture was left for 22 h at RT. The mixture was then concentrated and mixed several times with dichloromethane and re-concentrated. The residue was purified by preparative HPLC (method 7). The combined target fractions were concentrated and the residue was lyophilized. 45 mg (100% pure, 62% thor.) of the title compound were obtained.

[a] _D20 = +18.6°, 589 nm, c = 0.42 ^g /100 mL, methanol;

LC-MS (method 1): Rt = 2.29 min; MS (ESIpos): m/z = 608/610 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 1.609 (5.47), 1.674 (10.78), 1.802 (1.28), 1.815 (1.94), 1.825 (1.99), 1.836 (2.69), 1.860 (2.04) ), 1.887 (0.50), 2.049 (3.08), 2.075 (15.31), 2.105 (2.79), 2.140 (13.35), 2.222 (0.46), 2.327 (0.57), 2.670 (0.58), 3.142 (14.18), 3.390 (2.48 ), 3.403 (2.39), 3.585 (0.80), 3.599 (1.32), 3.617 (2.90), 3.633 (3.99), 3.659 (3.26), 3.676 (2.36), 3.693 (1.16), 3.709 (0.65), 7.362 (4.65 ), 7.380 (1.46), 7.387 (2.06), 7.401 (8.36), 7.412 (6.83), 7.418 (6.44), 7.424 (7.64), 7.436 (2.15), 7.460 (1.59), 7.548 (5.00), 7.561 (4.22 ), 7.572 (3.68), 7.629 (2.93), 7.651 (16.00), 7.658 (10.68), 7.662 (9.54), 7.680 (1.74), 7.685 (1.95), 8.729 (2.66), 8.744 (5.30), 8.758 (2.62 ), 12.050 (3.04).

Example 129.

(+/-)-5-({[6-Bromo-3-methyl-2-(pyrrolidin-1-yl)quinolin-4-yl]carbonyl}amino)-4-[2(trifluoromethoxy)phenyl]valeric acid (racemate)

To a solution of (+/-)-tert-butyl-5-({[6-bromo-3-methyl-2-(pyrrolidin-1-yl)quinolin-4yl]carbonyl}amino)-4-[2-( trifluoromethoxy)phenyl]pentanoate (85 mg, 131 μmol, racemate, example 144A) in dichloromethane (1.5 ml) was added with TFA (200 μl, 2.6 mmol) and the mixture was stirred for 18 h at RT. The mixture was then concentrated and mixed several times with dichloromethane and re-concentrated. The residue was purified by preparative HPLC (method 7). The combined target fractions were concentrated and the residue was lyophilized. Received 53 mg (100% pure, 68% theoretical. yield.) specified in the title compound.

LC-MS (method 1): Rt = 1.60 min; MS (ESIpos): m/z = 594/596 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: -0.008 (1.22), 0.008 (1.27), 1.803 (0.93), 1.816 (1.30), 1.825 (1.46), 1.837 (2.26), 1.875 ( 10.81), 2.032 (0.74), 2.046 (2.32), 2.056 (1.86), 2.073 (10.27), 2.081 (6.67), 2.103 (1.93), 2.115 (1.46), 2.125 (1.55) 16.00), 3.356 (0.63), 3.386 (1.60), 3.401 (1.57), 3.613 (2.82), 3.628 (1.60), 3.643 (1.41), 3.660 (1.95), 3.677 (1.62), 3.694 (0.98), 0.55) 4.63), 7.415 (4.68), 7.432 (1.15), 7.473 (5.13), 7.495 (8.79), 7.549 (6.82), 7.555 (6.12), 7.571 (4.26) 3.33), 8.709 (1.70), 12.049 (1.68).

Example 130.

(-)-5-({[6-Bromo-3-methyl-2-(pyrrolidin-1-yl)quinolin-4-yl]carbonyl}amino)-4-[2(trifluoromethoxy)phenyl]valeric acid (enantiomer 1).

To a solution of (-)-tert-butyl-5-({[6-bromo-3-methyl-2-(pyrrolidin-1-yl)quinolin-4yl]carbonyl}amino)-4-[2-(trifluoromethoxy) phenyl]pentanoate (140 mg, 215 µmol, enantiomer 7, example

- 183 040220

145A) in dichloromethane (1.7 mL) TFA (360 μL, 4.7 mmol) was added and the mixture was left for 22 h at RT. The mixture was then concentrated and mixed several times with dichloromethane and re-concentrated. The residue was purified by preparative HPLC (method 6). The combined target fractions were concentrated and the residue was lyophilized. 97 mg (100% pure, 76% thor.) of the title compound were obtained.

[a] _D20 = -16.7°, 589 nm, c = 0.41 g ^/ 100 ml, methanol;

LC-MS (method 1): R _t = 1.58 min; MS (ESIpos): m/z = 594/596 [M+H]+.

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.825 (0.44), 1.836 (0.68), 1.875 (3.31), 2.046 (0.70), 2.074 (2.84), 2.103 (0.59), 2.116 (0.44) , 2.125 (0.47), 2.162 (1.28), 3.313 (16.00), 3.386 (0.48), 3.401 (0.47) . , 7.549 (2.09), 7.555 (1.90), 7.571 (1.31), 7.577 (0.92), 8.679 (0.54), 8.694 (1.03), 8.709 (0.52), 12.043 (2.77).

Example 131.

(+)-5-({[6-Bromo-3-methyl-2-(pyrrolidin-1-yl)quinolin-4-yl]carbonyl}amino)-4-[2(trifluoromethoxy)phenyl]valeric acid (enantiomer 2).

To a solution of (+)-tert-butyl-5-({[6-bromo-3-methyl-2-(pyrrolidin-1-yl)quinolin-4yl]carbonyl}amino)-4-[2-(trifluoromethoxy) phenyl]pentanoate (130 mg, 200 µmol, enantiomer 2, example 146A) in dichloromethane (1.5 ml) TFA (340 µl, 4.4 mmol) was added and the mixture was left for 22 h at RT. The mixture was then concentrated and mixed several times with dichloromethane and re-concentrated. The residue was purified by preparative HPLC (method 6). The combined target fractions were concentrated and the residue was lyophilized. 94 mg (100% pure, 79% thor.) of the title compound were obtained.

[a] _D20 = +48.5°, 589 nm, c = 0.41 ^g /100 mL, methanol;

LC-MS (method 1): R _t = 1.58 min; MS (ESIpos): m/z = 594/596 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (3.65), 1.815 (2.03), 1.825 (2.29), 1.836 (3.45), 1.879 (16.00), 2.007 (0.46), 2.032 (1.10) ), 2.046 (3.63), 2.055 (2.83), 2.074 (14.77), 2.102 (2.92), 2.124 (2.33), 2.163 (6.20), 2.327 (0.57), 2.669 (0.50), 3.385 (2.83), 3.401 (2.67 ), 3.581 (11.94), 3.612 (5.50), 3.628 (2.90), 3.644 (2.39), 3.661 (3.14), 3.678 (2.59), 3.694 (1.61), 3.712 (0.91), 7.346 (3.62), 7.356 (5.66 ), 7.375 (2.23), 7.381 (2.65), 7.398 (9.07), 7.407 (7.10), 7.416 (7.30), 7.433 (1.86), 7.482 (2.36), 7.504 (3.73), 7.546 (6.03), 7.559 (7.96 ), 7.569 (5.48), 7.578 (3.09), 8.685 (2.29), 8.699 (4.21), 8.713 (2.32), 12.044 (3.05).

Example 132.

(+/-)-5-({[6-Bromo-2-(3,3-difluoropiperidin-1-yl)-3-methylquinolin-4-yl]carbonyl}amino)-4-[2(trifluoromethoxy)phenyl ]valeric acid (racemate)

To a solution of (+/-)-tert-butyl-5-({[6-bromo-2-(3,3-difluoropiperidin-1-yl)-3-methylquinolin-4yl]carbonyl}amino)-4-[ 2-(trifluoromethoxy)phenyl]pentanoate (85 mg, 121 μmol, racemate, example 147A) in dichloromethane (1.5 ml) TFA (190 μl, 2.4 mmol) was added and the mixture was stirred 18 h at RT. The mixture was then concentrated and mixed several times with dichloromethane and re-concentrated. The residue was purified by preparative HPLC (method 7). The combined target fractions were concentrated and the residue was lyophilized. 56 mg (100% pure, 72% thor.) of the title compound were obtained.

LC-MS (method 1): R _t = 2.21 min; MS (ESIpos): m/z = 644/646 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.805 (1.11), 1.818 (1.77), 1.828 (1.91), 1.839 (2.54), 1.887 (5.28), 2.050 (4.05), 2.077 (16.00) , 2.115 (4.22), 2.159 (11.45), 2.245 (0.46), 3.174 (6.42), 3.360 (1.50), 3.391 (2.46), 3.406 (2.34), 3.456 (3.91), 3.485 (7.30) , 3.595 (0.77), 3.610 (1.24), 3.628 (2.53),3.644 (3.42), 3.657 (3.10), 3.672 (2.69), 3.689 (1.99), 3.705 (1.05), 3.722 (0.56), 7.363 (4.21) , 7.382 (1.32) , 7.576 (3.35), 7.680 (2.13), 7.702 (14.18), 7.707 (10.77), 7.712 (8.50), 7.729 (1.33), 7.734 (1.48), 8.743 (2.48), 8.758 (4.81) , 12.069 (0.56).

Example 133.

(-)-5-({[6-Bromo-2-(3,3-difluoropiperidin-1-yl)-3-methylquinolin-4-yl]carbonyl}amino)-4-[2(trifluoromethoxy)phenyl]valeric acid (enantiomer 1).

To a solution of (-)-tert-butyl-5-({[6-bromo-2-(3,3-difluoropiperidin-1-yl)-3-methylquinolin-4yl]carbonyl}amino)-4-[2- (trifluoromethoxy)phenyl]pentanoate (115 mg, 164 µmol, enantiomer 1, example

- 184 040220

148A) in dichloromethane (1.3 mL) TFA (280 μL, 3.6 mmol) was added and the mixture was left for 22 h at RT. The mixture was then concentrated and mixed several times with dichloromethane and re-concentrated. The residue was purified by preparative HPLC (method 7). The combined target fractions were concentrated and the residue was lyophilized. 92 mg (100% pure, 86% thor.) of the title compound were obtained.

[a] ^D20 = -15.9°, 589 nm, c = 0.39 g/100 ml, methanol;

LC-MS (method 2): Rt = 1.17 min; MS (ESIpos): m/z = 644/646 [M+H]+.

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 1.806 (0.97), 1.818 (1.67), 1.829 (1.78), 1.840 (2.38), 1.887 (4.81), 2.054 (3.60), 2.080 (16.00 ), 2.093 (6.95), 2.115 (3.93), 2.159 (10.72), 2.245 (0.45), 3.174 (5.85), 3.362 (0.96), 3.392 (2.07), 3.407 (2.04), 3.456 (3.60), 3.485 (6.81 ), 3.513 (3.40), 3.595 (0.68), 3.611 (1.12), 3.628 (2.37), 3.644 (3.21), 3.658 (2.83), 3.671 (2.52), 3.689 (1.85), 3.704 (0.96), 3.722 (0.52 ), 7.364 (4.04), 7.368 (3.55), 7.383 (1.21), 7.389 (1.74), 7.404 (6.92), 7.414 (5.86), 7.421 (5.49), 7.426 (6.17), 7.439 (1.40), 7.494 (1.13 ), 7.554 (4.44), 7.559 (3.07), 7.566 (3.66), 7.577 (3.23), 7.680 (2.15), 7.702 (14.00), 7.707 (10.50), 7.712 (8.41), 7.730 (1.33), 7.734 (1.49 ), 8.741 (2.35), 8.755 (4.60), 8.770 (2.27), 12.052 (2.47).

Example 134.

(+)-5-({[6-Bromo-2-(3,3-difluoropiperidin-1-yl)-3-methylquinolin-4-yl]carbonyl}amino)-4-[2(trifluoromethoxy)phenyl]valeric acid (enantiomer 2).

To a solution of (+)-tert-butyl-5-({[6-bromo-2-(3,3-difluoropiperidin-1-yl)-3-methylquinolin-4yl]carbonyl}amino)-4-[2- (trifluoromethoxy)phenyl]pentanoate (105 mg, 150 µmol, enantiomer 2, example 149A) in dichloromethane (1.2 ml) TFA (250 µl, 3.3 mmol) was added and the mixture was left for 22 h at RT. The mixture was then concentrated and mixed several times with dichloromethane and re-concentrated. The residue was purified by preparative HPLC (method 7). The combined target fractions were concentrated and the residue was lyophilized. Received 81 mg (99% pure, 83% theoretical. yield.) specified in the title compound.

[a] _D20 = +17.2°, 589 nm, c = 0.42 g/100 mL ^, methanol;

LC-MS (method 2): R _t = 1.17 min; MS (ESIpos): m/z = 644/646 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (1.53), 0.008 (1.48), 1.806 (1.02), 1.819 (1.71), 1.829 (1.81), 1.840 (2.41), 1.887 (4.81 ), 2.053 (3.70), 2.079 (16.00), 2.093 (6.81), 2.116 (3.90), 2.159 (10.73), 2.245 (0.44), 3.174 (5.91), 3.392 (2.02), 3.406 (1.98), 3.456 (3.65 ), (1.11), 3.628 (2.38), 3.644 (3.22), 3.658 (2.82), 3.672 (2.49), (2.52), 7.359 (3.13), 7.364 (4.16), 7.368 (3.61), 7.382 (1.24), (5.65), 7.426 (6.34), 7.439 (1.47), 7.496 (1.14), 7.554 (4.57),

3.485 (6.90), 3.513 (3.41), 3.595 (0.67), 3.610

3.689 (1.85), 3.704 (0.95), 3.722 (0.52), 7.354

7.389 (1.78), 7.404 (7.08), 7.414 (6.10), 7.421

7.559 (3.07), 7.566 (3.74), 7.577 (3.32), 7.680 (2.29), 7.702 (14.75), 7.707 (10.95), 7.712 (8.88), 8.756 (4.69), 8.770 (2.33), 12.055 (2.70).

Example 135.

(+/-)-5-({[2-(Azepan-1-yl)-6-bromo-3-methylquinolin-4-yl]carbonyl}amino)-4-[2(trifluoromethoxy)phenyl]valeric acid ( racemate)

To a solution of (+/-)-tert-butyl-5-({[2-(azepan-1-yl)-6-bromo-3-methylquinolin-4-yl]carbonyl}amino)-4-[2- (trifluoromethoxy)phenyl]pentanoate (85 mg, 125 µmol, racemate, example 150A) in dichloromethane (1.1 ml) TFA (210 µl, 2.8 mmol) was added and the mixture was left for 18 h at RT. The mixture was then concentrated and mixed several times with dichloromethane and re-concentrated. The residue was purified by preparative HPLC (method 7). The combined target fractions were concentrated and the residue was lyophilized. 52 mg (100% pure, 67% theoretical) of the title compound were obtained.

LC-MS (method 1): R _t = 2.34 min; MS (ESIpos): m/z = 622/624 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.234 (0.73), 1.605 (14.46), 1.784 (9.83), 1.835 (2.54), 1.859 (1.84), 1.886 (0.52), 2.032 (0.83) , 2.046 (2.81), 2.073 (13.10), 2.124 (8.68), 2.215 (0.46), 2.327 (0.46) , 3.509 (16.00), 3.523 (10.92), 3.571 (0.90), 3.586 (1.30), 3.604 (2.18), 3.618 (2.63), 3.635 (1.81), 3.662 (2.15), 3.679 (1.80) . , 7.597 (6.11), 7.602 (5.59), 7.619 (3.18), 7.625 (3.00), 8.702 (2.26), 8.717 (4.27), 8.731 (2.14), 12.058 (0.97).

- 185 040220

Example 136.

(-)-5-({[2-(Azepan-1-yl)-6-bromo-3-methylquinolin-4-yl]carbonyl}amino)-4-[2(trifluoromethoxy)phenyl]valeric acid (enantiomer 1 ).

To a solution of (-)-tert-butyl-5-({[2-(azepan-1-yl)-6-bromo-3-methylquinolin-4-yl]carbonyl}amino)-4[2-(trifluoromethoxy) phenyl]pentanoate (145 mg, 214 µmol, enantiomer 7, example 151A) in dichloromethane (1.6 ml) was added with TFA (360 µl, 4.7 mmol) and the mixture was left for 24 h at RT. The mixture was then concentrated and mixed several times with dichloromethane and re-concentrated. The residue was purified by preparative HPLC (method 7). The combined target fractions were concentrated and the residue was lyophilized. 75 mg (100% pure, 56% thor.) of the title compound were obtained.

[a] ^D20 = -16.5°, 589 nm, c = 0.35 g/100 ml, methanol;

LC-MS (method 1): Rt = 2.34 min; MS (ESIpos): m/z = 622/624 [M+H]+.

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (1.64), 0.008 (2.00), 1.371 (0.52), 1.605 (14.32), 1.613 (12.24), 1.784 (9.58), 1.824 (2.16) ), 1.836 (2.49), 1.860 (1.82), 1.887 (0.48), 2.032 (0.82), 2.046 (2.82), 2.061 (3.46), 2.073 (12.90), 2.079 (9.89), 2.124 (8.41), 2.215 (0.43 ), 3.388 (2.27), 3.404 (2.15), 3.495 (11.59), 3.509 (16.00), 3.524 (11.30), 3.571 (0.87), 3.586 (1.27), 3.604 (2.17), 3.619 (2.60), 3.635 (1.74 ), 3.645 (1.58), 3.663 (2.15), 3.679 (1.76), 3.694 (1.07), 3.714 (0.57), 7.353 (3.36), 7.358 (4.32), 7.362 (3.85), 7.378 (1.75), 7.385 (2.43 ), 7.399 (7.64), 7.410 (6.64), 7.417 (6.07), 7.421 (6.62), 7.435 (1.61), 7.532 (6.31), 7.554 (14.24), 7.562 (4.07), 7.573 (3.33), 7.597 (6.38 ), 7.603 (5.95), 7.620 (3.35), 7.625 (3.23), 8.704 (2.31), 8.718 (4.42), 8.732 (2.22), 12.060 (0.53).

Example 137.

(+)-5-({[2-(Azepan-1-yl)-6-bromo-3-methylquinolin-4-yl]carbonyl}amino)-4-[2(trifluoromethoxy)phenyl]valeric acid (enantiomer 2 ).

To a solution of (+)-tert-butyl-5-({[2-(azepan-1-yl)-6-bromo-3-methylquinolin-4-yl]carbonyl}amino)-4[2-(trifluoromethoxy) phenyl]pentanoate (140 mg, 206 µmol, enantiomer 2, example 152A) in dichloromethane (1.6 ml) TFA (350 µl, 4.5 mmol) was added and the mixture was left for 24 h at RT. The mixture was then concentrated and mixed several times with dichloromethane and re-concentrated. The residue was purified by preparative HPLC (method 7). The combined target fractions were concentrated and the residue was lyophilized. 88 mg (100% pure, 68% thor.) of the title compound were obtained.

[a] _D20 = +16.9°, 589 nm, c = 0.44 ^g /100 mL, methanol;

LC-MS (method 1): Rt = 2.34 min; MS (ESIpos): m/z = 622/624 [M+H]+.

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.606 (14.31), 1.784 (9.86), 1.837 (2.55), 1.861 (1.79), 1.888 (0.53), 2.049 (2.72), 2.076 (13.15) , 2.125 (8.84), 2.215 (0.47), 2.328 (0.42), 2.670 (0.44), 3.390 (2.07) 3.587 (1.31), 3.605 (2.21), 3.620 (2.66), 3.637 (1.81), 3.664 (2.19), 3.680 (1.85), 7.359 (4.31), 7.385 (2.45), 7.400 (7.84), 7.410 (6.35) , 7.422 (6.61) , 8.701 (2.25), 8.716 (4.35), 8.730 (2.19), 12.046 (2.47).

Example 138.

5-[({6-Bromo-2-[3-fluoropiperidin-1-yl]-3-methylquinolin-4-yl}carbonyl)amino]-4-[2(trifluoromethoxy)phenyl]valeric acid (mixture of diastereoisomers)

To a solution of tert-butyl 5-[({6-bromo-2-[3-fluoropiperidin-1-yl]-3-methylquinolin-4yl}carbonyl)amino]-4-[2-(trifluoromethoxy)phenyl]pentanoate (85 mg, 125 µmol, mixture of diastereoisomers, example 153A) in dichloromethane (1.1 ml) TFA (210 µl, 2.7 mmol) was added and the mixture was left for 18 h at RT. The mixture was then concentrated and mixed several times with dichloromethane and re-concentrated. The residue was purified by preparative HPLC (method 7). The combined target fractions were concentrated and the residue was lyophilized. 55 mg (100% pure, 71% thor.) of the title compound were obtained.

LC-MS (method 1): Rt = 2.18 min; MS (ESIpos): m/z = 626/628 [M+H]+.

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (2.06), 0.008 (2.52), 1.236 (0.83), 1.646 (1.98), 1.768 (0.68), 1.815 (3.36), 1.826 (3.43) ), 1.837 (3.81), 1.861 (2.67), 1.902 (3.30), 1.922 (2.78), 1.953 (1.96), 1.987 (1.15), 2.010 (0.72), 2.050 (2.99), 2.077 (14.97), 2.104 (2.52 ), 2.153 (12.67), 2.328 (0.48), 2.670 (0.45), 3.074 (1.28), 3.104 (2.25), 3.163 (2.42), 3.176 (2.36), 3.208 (1.25), 3.350 (2.24), 3.387 (4.28 ), 3.411 (3.01), 3.438

- 186 040220 (2.24), 3.472 (1.37), 3.590 (0.69), 3.605 (1.17), 3.622 (2.52), 3.639 (3.61), 3.652 (3.10), 3.680 (1.90), 4.820 (1.66), 4.939 (1.69) ), 7.362 (4.58), 7.366 (4.02), 7.381 (1.37), 7.387 (1.93), 7.402 (7.98), 7.412 (6.54), 7.419 (6.20), 7.424 (7.11), 7.437 (1.74), 7.474 (1.39 ), 7.551 (4.96), 7.563 (4.09), 7.574 (3.61), 7.654 (2.68), 7.675 (16.00), 7.681 (11.09), 7.686 (9.41), 7.704 (1.75), 7.708 (1.85), 8.736 (2.62 ), 8.750 (5.19), 8.765 (2.57), 12.057 (1.66).

Example 139.

5-[({6-Bromo-2-[3-ethylpiperidin-1-yl]-3-methylquinolin-4-yl}carbonyl)amino]-4-[2(trifluoromethoxy)phenyl]valeric acid (mixture of diastereoisomers)

To a solution of tert-butyl 5-[({6-bromo-2-[3-ethylpiperidin-1-yl]-3-methylquinolin-4yl}carbonyl)amino]-4-[2-(trifluoromethoxy)phenyl]pentanoate (85 mg, 123 μmol, mixture of diastereoisomers, example 154A) in dichloromethane (1.5 ml) was added TFA (190 μl, 2.5 mmol) and the mixture was stirred for 18 h at RT. The mixture was then concentrated and mixed several times with dichloromethane and re-concentrated. The residue was purified by preparative HPLC (method 7). The combined target fractions were concentrated and the residue was lyophilized. 60 mg (100% pure, 77% thor.) of the title compound were obtained.

LC-MS (method 1): Rt = 2.52 min; MS (ESIpos): m/z = 636/638 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.892 (6.52), 0.911 (16.00), 0.930 (8.01), 1.039 (0.62), 1.059 (1.34), 1.067 (1.35), 1.090 (1.31) , 1.097 (1.32), 1.119 (0.60), 1.128 (0.53), 1.242 (1.02), 1.260 (2.47), 1.277 (3.35), 1.295 (2.40), 1.564 (1.51), 1.573 (1.45), 1.590 (1.24) , 1.601 (1.32), 1.635 (1.16), 1.749 (1.81), 1.782 (1.45), 1.801 (0.96), 1.814 (1.34), 1.825 (1.40), 1.837 (2.34), 1.858 (2.39), 1.884 (1.66) . , 3.363 (0.67), 3.393 (1.53), 3.406 (1.51), 3.495 (2.71), 3.525 (2.53), 3.585 (0.64) . , 7.554 (2.88), 7.566 (2.50), 7.576 (2.07), 7.631 (1.14), 7.654 (12.66), 7.682 (0.77), 8.718 (1.71), 8.733 (3.25), 8.747 (1.66), 12.046 (0.84) .

Example 140.

5-[({6-Bromo-3-methyl-2-[3-methylpiperidin-1-yl]quinolin-4-yl}carbonyl)amino]-4-[2(trifluoromethoxy)phenyl]valeric acid (mixture of diastereoisomers)

To a solution of tert-butyl-5-[({6-bromo-3-methyl-2-[3-methylpiperidin-1-yl]quinolin-4yl}carbonyl)amino]-4-[2-(trifluoromethoxy)phenyl] pentanoate (85 mg, 125 µmol, mixture of diastereoisomers, example 155A) in dichloromethane (1.1 ml) TFA (210 µl, 2.8 mmol) was added and the mixture was left for 18 h at RT. The mixture was then concentrated and mixed several times with dichloromethane and re-concentrated. The residue was purified by preparative HPLC (method 7). The combined target fractions were concentrated and the residue was lyophilized. 56 mg (100% pure, 71% thor.) of the title compound were obtained.

LC-MS (method 1): Rt = 2.42 min; MS (ESIpos): m/z = 622/624 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.923 (14.04), 0.939 (14.42), 1.054 (0.58), 1.080 (1.68), 1.109 (1.75), 1.132 (0.71), 1.235 (0.89) , 1.628 (1.42), 1.658 (1.67), 1.685 (0.79), 1.733 (3.00), 1.766 (3.19), 1.800 (3.96), 1.816 (3.37), 1.825 (3.80), 1.835 (3.76), 1.860 (1.79) . . . , 7.550 (4.02), 7.563 (3.50), 7.573 (2.95), 7.631 (1.47), 7.654 (16.00), 7.682 (1.06), 8.720 (2.23), 8.735 (4.29), 8.749 (2.17) .

- 187 040220

Example 141.

(+/-)-5-({[6-Bromo-3-methyl-2-(piperidin-1-yl)quinolin-4-yl]carbonyl}amino)-4-(2-chloro-3fluorophenyl)valeric acid (racemate)

To a solution of (+/-)-tert-butyl-5-({[6-bromo-3-methyl-2-(piperidin-1-yl)quinolin-4yl]carbonyl}amino)-4-(2-chloro -3-Fluorophenyl)pentanoate (172 mg, 272 µmol, racemate, example 156A) in dichloromethane (4.0 ml) TFA (310 µl, 4.1 mmol) was added and the mixture was stirred for 18 h at RT. Then TFA (155 µl, 2.05 mmol) was added again and the mixture was stirred at RT for 26 h. The mixture was then concentrated and mixed several times with dichloromethane and re-concentrated. The residue was purified by preparative HPLC (method 6). The combined target fractions were concentrated and the residue was lyophilized. 143 mg (100% pure, 91% th. y.) of the title compound were obtained.

LC-MS (method 1): Rt = 2.19 min; MS (ESIpos): m/z = 576/578 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 1.606 (4.25), 1.672 (8.45), 1.790 (0.50), 1.806 (0.96), 1.824 (1.50), 1.845 (1.97), 1.867 (1.12 ), 1.883 (0.52), 2.020 (0.49), 2.039 (1.16), 2.063 (3.60), 2.075 (1.70), 2.090 (4.80), 2.100 (8.16), 2.130 (16.00), 2.165 (1.21), 2.328 (0.48 ), 2.366 (0.44), 2.669 (0.52), 2.709 (0.44), 3.135 (11.08), 3.616 (1.87), 3.697 (3.00), 7.288 (1.68), 7.309 (3.78), 7.331 (2.61), 7.344 (2.90 ), 7.363 (4.95), 7.396 (2.49), 7.411 (2.98), 7.416 (3.42), 7.430 (3.39), 7.450 (1.62), 7.624 (2.09), 7.646 (11.69), 7.653 (7.79), 7.658 (6.74 ), 7.675 (1.30), 7.680 (1.47), 8.718 (2.07), 8.732 (4.17), 8.746 (2.03), 12.059 (0.63).

Separation of enantiomers.

The title target compound (125 mg) was dissolved in methanol (20 ml) and separated into enantiomers by chiral phase preparative HPLC (see Examples 142 and 143) [column: Daicel Chiralcel OX-H, 5 μm, 250 mm x 20 mm; flow: 80 ml/min; detection: 210 nm; temperature: 40°C; sample injection: 1.0 ml; eluent: 17% ethanol/83% carbon dioxide; duration of action 13 min, isocratic]. The combined target fractions were respectively concentrated and the corresponding residue was lyophilized.

Example 142.

(-)-5-({[6-Bromo-3-methyl-2-(piperidin-1-yl)quinolin-4-yl]carbonyl}amino)-4-(2-chloro-3fluorophenyl)valeric acid (enantiomer 1).

The separation of enantiomers described in Example 141 gave 43 mg (100% pure, >99% ee) of the title compound as the previously eluted enantiomer.

[a] _D20 = -13.8°, 589 nm, c = ^0.37 g/100 ml, methanol;

LC-MS (method 1): Rt = 2.20 min; MS (ESIpos): m/z = 576/578 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (2.03), 0.008 (2.00), 1.596 (3.88), 1.605 (4.29), 1.671 (8.19), 1.792 (0.54), 1.807 (1.05 ), 1.826 (1.62), 1.833 (1.58), 1.846 (2.10), 1.868 (1.23), 1.884 (0.62), 2.021 (0.60), 2.040 (1.29), 2.064 (3.77), 2.077 (1.88), 2.091 (4.95 ), 2.101 (8.41), 2.131 (16.00), 2.166 (1.27), 2.182 (0.56), 3.121 (7.95), 3.134 (10.68), 3.617 (1.89), 3.644 (1.14), 3.699 (2.96), 7.289 (1.83 ), 7.309 (3.92), 7.332 (2.80), 7.346 (2.97), 7.364 (5.02), 7.397 (2.62), 7.411 (3.07), 7.416 (3.55), 7.430 (3.51), 7.450 (1.68), 7.624 (2.18 ), 7.645 (11.92), 7.652 (7.95), 7.657 (7.09), 7.674 (1.32), 7.679 (1.53), 8.719 (2.03), 8.733 (4.07), 8.747 (2.01), 12.066 (5.30).

Example 143.

(+)-5-({[6-Bromo-3-methyl-2-(piperidin-1-yl)quinolin-4-yl]carbonyl}amino)-4-(2-chloro-3fluorophenyl)valeric acid (enantiomer 2).

The separation of enantiomers described in Example 141 gave 37 mg (100% pure, ee 95%) of the title compound as the later eluted enantiomer.

[a] _D20 = +13.4°, 589 nm ^, c = 0.35 g/100 mL, methanol;

LC-MS (method 1): Rt = 2.20 min; MS (ESIpos): m/z = 576/578 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.605 (4.31), 1.671 (8.37), 1.793 (0.53), 1.808 (1.01), 1.827 (1.61), 1.834 (1.61), 1.847 (2.06) , 1.869 (1.22), 1.885 (0.62), 2.023 (0.56), 2.041 (1.26), 2.065 (3.63) , 2.183 (0.60), 3.134 (10.81), 3.618 (1.95), 3.644 (1.18), 3.699 (3.03), 7.288 (1.74), 7.309 (3.75), 7.331 (2.65), 7.346 (2.89), 7.364 (4.84) . , 7.679 (1.36), 8.719 (1.99), 8.734 (3.94), 8.748 (1.97), 12.068 (3.84).

- 188 040220

Example 144.

(+/-)-5 -({[6-Bromo-3-methyl-2-(piperidin-1-yl)quinolin-4-yl]carbonyl}amino)-4-(6-chloro-2,3difluorophenyl) valeric acid (racemate)

To a solution of (+/-)-tert-butyl-5-({[6-bromo-3-methyl-2-(piperidin-1-yl)quinolin-4yl]carbonyl}amino)-4-(6-chloro -2,3-difluorophenyl)pentanoate (123 mg, 189 µmol, racemate, example 157A) in dichloromethane (3 ml) was added with TFA (220 µl, 2.8 mmol) and the mixture was stirred for 18 h at RT. Then TFA (110 μl, 1.4 mmol) was added again, and the mixture was stirred at RT for 26 h. The mixture was then concentrated and mixed several times with dichloromethane and re-concentrated. The residue was purified by preparative HPLC (method 6). The combined target fractions were concentrated and the residue was lyophilized. 124 mg (94% pure, 103% th. y.) of the title compound were obtained.

LC-MS (method 1): R _t = 2.22 min; MS (ESIpos): m/z = 594/596 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: -0.023 (0.44), -0.008 (2.46), 0.008 (2.14), 1.234 (0.89), 1.367 (4.68), 1.606 (2.38), 1.656 (4.36), 1.671 (4.64), 1.979 (0.61), 2.073 (2.70), 2.101 (1.76), 2.128 (2.50) (0.61), 2.366 (0.85), 2.670 (0.52), 2.710 (0.85), 3.135 (6.17), 3.734 (0.97), 3.770 (1.43), 7.376 (1.80) (1.39) (0.99).

Separation of enantiomers.

The title target compound (110 mg) was dissolved in methanol (15 ml) and separated into enantiomers by chiral phase preparative HPLC (see Examples 145 and 146) [column: Daicel Chiralpak AD, 5 μm, 250 mm x 20 mm; flow: 80 ml/min; detection: 210 nm; temperature: 40°C; sample injection: 2.0 ml; eluent: 30% isopropanol/70% carbon dioxide; duration of action 7 min, isocratic]. The combined target fractions were respectively concentrated and the corresponding residue was lyophilized.

Example 145.

(-)-5-({[6-Bromo-3-methyl-2-(piperidin-1-yl)quinolin-4-yl]carbonyl}amino)-4-(6-chloro-2,3difluorophenyl)valeric acid (enantiomer 1).

The separation of enantiomers described in Example 144 gave 43 mg (100% pure, >99% ee) of the title compound as the previously eluted enantiomer.

[a] _D20 = -31.8°, 589 nm, c = 0.41 g ^/ 100 ml, methanol;

LC-MS (method 2): Rt = 1.13 min; MS (ESIpos): m/z = 594/596 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 0.069 (0.50), 1.367 (3.93), 1.606 (2.74), 1.671 (5.29), 1.983 (0.77), 2.065 (1.26), 2.076 (1.30 ), 2.095 (1.33), 2.110 (1.94), 2.144 (16.00), 2.172 (2.18), 2.195 (0.93), 2.434 (0.58), 3.135 (6.96), 3.738 (1.19), 3.771 (1.70), 7.377 (2.00 ), 7.389 (2.43), 7.412 (1.72), 7.434 (1.70), 7.456 (1.02), 7.486 (0.51), 7.626 (1.66), 7.648 (6.84), 7.658 (4.26), 7.663 (4.01), 7.681 (0.93 ), 7.685 (1.02), 8.803 (1.17), 8.817 (2.27), 8.831 (1.13).

Example 146.

(+)-5-({[6-Bromo-3-methyl-2-(piperidin-1-yl)quinolin-4-yl]carbonyl}amino)-4-(6-chloro-2,3difluorophenyl)valeric acid (enantiomer 2).

Separation of the enantiomers as described in Example 144 gave 31 mg (98% pure, >99% ee) of the title compound as the later eluted enantiomer.

[a] _D20 = +34.1°, 589 nm, c = 0.40 g/100 mL ^, methanol;

LC-MS (method 2): Rt = 1.14 min; MS (ESIpos): m/z = 594/596 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: -0.008 (1.37), 0.008 (0.74), 1.368 (0.77), 1.596 (2.49), 1.606 (2.69), 1.671 (5.00), 1.982 ( 0.72), 2.067 (1.07), 2.079 (1.22), 2.097 (1.31), 2.116 (2.21), 2.145 (16.00), 2.178 (2.09), 2.200 (0.82), 3.122 (5.17), 3.135 (6.49), 1.21), 3.771 (1.63), 7.355 (0.86), 7.378 (2.03), 7.390 (2.38), 7.413 (1.64), 7.435 (1.43), 7.457 (0.74), 7.627 (1.88), 7.649 (7.16), 4.59), 7.664 (4.01), 7.681 (1.00), 7.686 (1.02), 8.802 (1.22), 8.816 (2.19), 8.830 (1.05).

Example 147.

(+/-)-5-({[6-Bromo-3-methyl-2-(piperidin-1-yl)quinolin-4-yl]carbonyl}amino)-4-(5-fluoro-2methylphenyl)valeric acid (racemate)

- 189 040220

To a solution of (+/-)-tert-butyl-5-({[6-bromo-3-methyl-2-(piperidin-1-yl)quinolin-4yl]carbonyl}amino)-4-(5-fluoro -2-methylphenyl)pentanoate (185 mg, 302 µmol, racemate, example 158A) in dichloromethane (4 ml) was added with TFA (350 µl, 4.5 mmol) and the mixture was stirred for 18 h at RT. The mixture was then concentrated and mixed several times with dichloromethane and re-concentrated. The residue was purified by preparative HPLC (method 6). The combined target fractions were concentrated and the residue was lyophilized. 149 mg (100% pure, 89% thor.) of the title compound were obtained.

LC-MS (method 1): R _t = 2.21 min; MS (ESIpos): m/z = 556/558 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (2.37), 0.008 (2.26), 1.606 (3.10), 1.670 (6.11), 1.739 (0.41), 1.756 (0.83), 1.772 (0.96 ), 1.797 (1.23), 1.828 (0.55), 1.993 (0.96), 2.006 (1.24), 2.023 (1.21), 2.043 (1.30), 2.063 (4.89), 2.079 (5.98), 2.100 (10.78), 2.293 (16.00 ), 2.327 (0.60), 2.669 (0.46), 3.135 (8.13), 3.460 (1.02), 3.473 (1.34), 3.493 (1.53), 3.507 (1.68), 3.521 (1.15), 3.725 (0.70), 6.921 (1.05 ), 6.928 (1.22), 6.942 (2.32), 7.139 (2.36), 7.159 (2.39), 7.166 (2.29), 7.197 (1.06), 7.626 (1.65), 7.648 (9.38), 7.654 (6.97), 7.659 (2.38 ), 8.740 (1.48).

(1.03), 3.653 (1.00), 3.672 (1.51), 3.690 (1.34) (2.51), 7.234 (2.07), 7.439 (5.99), 7.676 (1.07), 7.681 (1.21), 8.711 (1.47), 8.726

Separation of enantiomers.

The title target compound (135 mg) was dissolved in methanol (20 ml) and separated into enantiomers by chiral phase preparative HPLC (see Examples 148 and 149) [column: Daicel Chiralcel OX-H, 5 μm, 250 mm x 20 mm; flow: 80 ml/min; detection: 210 nm; temperature: 40°C; sample injection: 2.0 ml; eluent: 30% ethanol/70% carbon dioxide; duration of action 8 min, isocratic]. The combined target fractions were respectively concentrated and the corresponding residue was lyophilized.

Example 148.

(-)-5-({[6-Bromo-3-methyl-2-(piperidin-1-yl)quinolin-4-yl]carbonyl}amino)-4-(5-fluoro-2methylphenyl)valeric acid (enantiomer 1).

The separation of enantiomers described in Example 147 gave 57 mg (100% pure, >99% ee) of the title compound as the previously eluted enantiomer.

[a] _D20 = -13.8°, 589 nm, c = 0.49 ^g /100 ml, methanol;

LC-MS (method 2): Rt = 1.12 min; MS (ESIpos): m/z = 556/558 [M-H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.609 (3.14), 1.673 (6.11), 1.746 (0.41), 1.764 (0.84), 1.780 (1.02), 1.788 (1.06), 1.798 (1.19) , 1.803 (1.18), 1.818 (1.00), 1.836 (0.56), 1.980 (0.44), 1.999 (1.06), 2.012 (1.31), 2.030 (1.30), 2.049 (1.40), 2.062 (1.59), 2.075 (5.10) , 2.091 (7.94), 2.103 (10.32), 2.294 (16.00), 3.147 (7.87), 3.320 (1.45), 3.432 (0.41), 3.450 (0.52), 3.463 (1.20), 3.476 (1.60) . . , 7.236 (2.02), 7.444 (1.01), 7.638 (1.21), 7.660 (9.17), 7.664 (7.93),7.669 (5.88), 7.686 (0.75), 7.691 (0.88), 8.714 (1.52), 8.729 (2.41) , 8.743 (1.46).

Example 149.

(+)-5-({[6-Bromo-3-methyl-2-(piperidin-1-yl)quinolin-4-yl]carbonyl}amino)-4-(5-fluoro-2methylphenyl)valeric acid (enantiomer 2).

The separation of enantiomers described in Example 147 gave 51 mg (100% pure, ee 96%) of the title compound as the later eluted enantiomer.

[a] _D20 = +13.4°, 589 nm ^, c = 0.37 g/100 ml, methanol;

LC-MS (method 2): Rt = 1.13 min; MS (ESIpos): m/z = 556/558 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (1.34), 0.008 (1.21), 1.030 (0.40), 1.046 (0.41), 1.609 (3.05), 1.673 (5.95), 1.745 (0.41 ), 1.763 (0.85), 1.779 (1.01), 1.787 (1.04), 1.797 (1.17), 1.803 (1.15), 1.820 (1.02), 1.835 (0.58), 1.979 (0.43), 1.999 (1.03), 2.012 (1.29 ), 2.030 (1.29), 2.049 (1.38), 2.062 (1.54), 2.075 (5.05), 2.091 (7.75), 2.103 (10.14), 2.294 (16.00), 3.149 (7.64), 3.319 (1.39), 3.450 (0.41 ), 3.463 (1.08), 3.476 (1.46), 3.496 (1.72), 3.510 (1.90), 3.524 (1.28), 3.656 (1.43), 3.674 (1.91), 3.693 (1.69), 3.708 (1.48), 3.727 (0.98 ), 6.923 (1.08), 6.930 (1.25), 6.944 (2.29), 6.951 (2.50), 6.965 (1.28), 6.972 (1.31), 7.137 (2.34), 7.143 (2.38), 7.164 (2.38), 7.170 (2.30 ), 7.199 (2.38), 7.215 (2.66), 7.220 (2.45), 7.236 (2.05), 7.443 (0.99), 7.640

- 190 040220 (1.11), 7.662 (9.23), 7.669 (5.86), 7.687 (0.70), 7.692 (0.82), 8.715 (1.52), 8.730 (2.36), 8.744 (1.44).

Example 150.

(+/-)-5 -({[6-Bromo-2-(3,3-difluoropiperidin-1-yl)-3-methylquinolin-4-yl]carbonyl}amino)-4-(5-fluoro2-methylphenyl )valeric acid (racemate)

To a solution of (+/-)-tert-butyl-5-({[6-bromo-2-(3,3-difluoropiperidin-1-yl)-3-methylquinolin-4yl]carbonyl}amino)-4-( 5-Fluoro-2-methylphenyl)pentanoate (263 mg, 406 µmol, racemate, example 159A) in dichloromethane (4 ml) was added with TFA (620 µl, 8.1 mmol) and the mixture was stirred for 18 h at RT. The mixture was then concentrated and mixed several times with dichloromethane and re-concentrated. The residue was purified by preparative HPLC (method 6). The combined target fractions were concentrated and the residue was lyophilized. 211 mg (100% pure, 88% th. y.) of the title compound were obtained.

LC-MS (method 1): Rt = 2.17 min; MS (ESIpos): m/z = 592/594 [M+H]+.

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (2.15), 0.008 (1.52), 1.763 (0.87), 1.779 (1.10), 1.787 (1.11), 1.796 (1.27), 1.802 (1.23) ), 1.820 (1.00), 1.835 (0.72), 1.880 (3.31), 1.976 (0.53), 1.996 (1.11), 2.009 (1.35), 2.027 (1.46), 2.046 (2.40), 2.071 (6.38), 2.087 (8.11 ), 2.117 (10.60), 2.292 (16.00), 2.322 (0.52), 2.327 (0.56), 2.524 (1.64), 3.164 (4.06), 3.449 (2.71), 3.479 (5.41), 3.505 (3.74), 3.518 (2.18 ), 3.533 (1.13), 3.665 (1.08), 3.683 (1.64), 3.702 (1.40), 3.716 (1.20), 3.736 (0.71), 6.924 (1.18), 6.931 (1.33), 6.945 (2.41), 6.952 (2.57 ), 6.966 (1.34), 6.973 (1.35), 7.141 (2.55), 7.147 (2.54), 7.167 (2.57), 7.174 (2.42), 7.200 (2.58), 7.215 (2.84), 7.221 (2.58), 7.237 (2.16 ), 7.476 (0.90), 7.678 (1.75), 7.699 (10.07), 7.704 (7.52), 7.709 (6.08), 7.727 (0.97), 7.731 (1.10), 8.722 (1.71), 8.736 (2.53), 8.751 (1.53 ).

Example 151.

(+/-)-5-({[6-Bromo-3-methyl-2-(piperidin-1-yl)quinolin-4-yl]carbonyl}amino)-4-(2-chloro-3,6difluorophenyl) valeric acid (racemate)

To a solution of (+/-)-tert-butyl-5-({[6-bromo-3-methyl-2-(piperidin-1-yl)quinolin-4yl]carbonyl}amino)-4-(2-chloro -3,6-difluorophenyl)pentanoate (269 mg, 413 µmol, racemate, example 160A) in dichloromethane (5 ml) was added with TFA (480 µl, 6.2 mmol) and the mixture was stirred for 18 h at RT. TFA (240 μl, 3.1 mmol) was then added again and the mixture was stirred for an additional 24 h at RT. The mixture was then concentrated and mixed several times with dichloromethane and re-concentrated. The residue was purified by preparative HPLC (method 6). The combined target fractions were concentrated and the residue was lyophilized. 221 mg (100% pure, 90% thor.) of the title compound were obtained.

LC-MS (method 1): Rt = 2.19 min; MS (ESIpos): m/z = 594/596 [M+H]+.

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (2.84), 0.008 (2.84), 1.606 (3.28), 1.673 (6.38), 1.980 (0.76), 2.073 (2.12), 2.095 (2.56) ), 2.122 (4.17), 2.143 (16.00), 2.172 (1.53), 2.194 (0.58), 2.327 (0.55), 2.366 (0.54), 2.669 (0.59), 2.710 (0.57), 3.137 (8.46), 3.722 (1.94 ), 7.267 (0.88), 7.278 (1.02), 7.290 (1.81), 7.301 (1.87), 7.316 (1.43), 7.327 (1.33), 7.389 (1.13), 7.400 (1.34), 7.410 (1.91), 7.421 (1.92 ), 7.433 (1.20), 7.444 (1.12), 7.629 (2.29), 7.650 (9.72), 7.660 (6.52), 7.665 (5.84), 7.683 (1.37), 7.687 (1.47), 8.821 (2.50).

Separation of enantiomers.

The title target compound (200 mg) was dissolved in methanol (20 ml) and separated into enantiomers by chiral phase preparative HPLC (see Examples 152 and 153) [column: Daicel Chiralcel OJ-H, 5 μm, 250 mm x 20 mm; flow: 80 ml/min; detection: 210 nm; temperature: 40°C; sample injection: 0.5 ml; eluent: 17% methanol/83% carbon dioxide; duration of action 5 min, isocratic]. The combined target fractions were respectively concentrated and

- 191 040220 the remaining residue was lyophilized.

Example 152.

(-)-5-({[6-Bromo-3-methyl-2-(piperidin-1-yl)quinolin-4-yl]carbonyl}amino)-4-(2-chloro-3,6difluorophenyl)valeric acid (enantiomer 1).

The separation of enantiomers described in Example 151 gave 70 mg (99% pure, >99% ee) of the title compound as the previously eluted enantiomer.

[a]D ²⁰ = -35.9°, 589 nm, c = 0.45 g/100 ml, methanol;

LC-MS (method 2): R _t = 1.12 min; MS (ESIpos): m/z = 594/596 [M+H]+.

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (0.78), 0.008 (0.73), 1.597 (2.64), 1.607 (2.93), 1.673 (5.58), 1.980 (0.71), 2.073 (1.02 ), 2.082 (1.14), 2.089 (1.23), 2.103 (2.10), 2.144 (16.00), 2.161 (3.72), 2.179 (1.26), 2.201 (0.46), 3.125 (5.49), 3.137 (7.35), 3.726 (1.72 ), 7.268 (0.79), 7.279 (0.89), 7.291 (1.58), 7.302 (1.63), 7.317 (1.24), 7.328 (1.14), 7.390 (1.02), 7.401 (1.20), 7.411 (1.67), 7.422 (1.65 ), 7.433 (1.05), 7.445 (0.95), 7.629 (1.92), 7.651 (8.28), 7.661 (5.32), 7.665 (4.77), 7.683 (1.12), 7.688 (1.20), 8.804 (1.22), 8.819 (2.19) ), 12.101 (1.08).

Example 153.

(+)-5-({[6-Bromo-3-methyl-2-(piperidin-1-yl)quinolin-4-yl]carbonyl}amino)-4-(2-chloro-3,6difluorophenyl)valeric acid (enantiomer 2).

The separation of enantiomers described in Example 151 gave 67 mg (98% pure, 99% ee) of the title compound as the later eluted enantiomer.

[a] _D20 = +36.3°, 589 nm, c = 0.38 g/100 mL ^, methanol;

LC-MS (method 2): Rt = 1.13 min; MS (ESIpos): m/z = 594/596 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (1.16), 0.008 (1.02), 1.607 (2.99), 1.673 (5.69), 1.980 (0.73), 2.102 (2.13), 2.144 (16.00 ), 2.159 (3.78), 2.178 (1.27), 2.201 (0.47), 3.125 (5.63), 3.137 (7.50), 3.725 (1.78), 7.268 (0.83), 7.279 (0.95), 7.291 (1.66), 7.302 (1.69 ), 7.317 (1.28), 7.328 (1.17), 7.390 (1.09), 7.401 (1.28), 7.411 (1.75), 7.422 (1.72), 7.433 (1.10), 7.445 (0.99), 7.629 (2.00), 7.651 (8.50 ), 7.661 (5.45), 7.666 (4.83), 7.683 (1.13), 7.688 (1.20), 8.804 (1.26), 8.818 (2.23), 12.101 (0.71).

Example 154.

(+/-)-5-({[6-Bromo-3-methyl-2-(pyrrolidin-1-yl)quinolin-4-yl]carbonyl}amino)-4-(2-chloro-3,6difluorophenyl) valeric acid (racemate)

To a solution of (+/-)-tert-butyl-5-({[6-bromo-3-methyl-2-(pyrrolidin-1-yl)quinolin-4yl]carbonyl}amino)-4-(2-chloro -3,6-difluorophenyl)pentanoate (84 mg, 131 µmol, racemate, example 161A) in dichloromethane (1.1 ml) was added with TFA (220 µl, 2.9 mmol) and the mixture was left for 24 h at RT. The mixture was then concentrated and mixed several times with dichloromethane and re-concentrated. The residue was purified by preparative HPLC (method 7). The combined target fractions were concentrated and the residue was lyophilized. 24 mg (100% pure, 32% thor.) of the title compound were obtained.

LC-MS (method 1): R _t = 1.46 min; MS (ESIpos): m/z = 580/582 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.854 (0.47), 1.236 (2.28), 1.271 (0.43), 1.873 (16.00), 1.969 (1.55), 2.091 (4.87), 2.118 (6.28) . , 7.296 (3.55) , 7.551 (7.71), 7.556 (7.15), 7.573 (4.50), 7.579 (4.32), 8.756 (2.66), 8.770 (4.44).

Example 155.

(+/-)-5-({[6-Bromo-2-(3,3-difluoropiperidin-1-yl)-3-methylquinolin-4-yl]carbonyl}amino)-4-(2-chloro3,6 -difluorophenyl)valeric acid (racemate)

- 192 040220

To a solution of (+/-)-tert-butyl-5-({[6-bromo-2-(3,3-difluoropiperidin-1-yl)-3-methylquinolin-4yl]carbonyl}amino)-4-( 2-chloro-3,6-difluorophenyl)pentanoate (68 mg, 83% pure, 82.2 µmol, racemate, example 162A) in dichloromethane (690 µl) was added with TFA (140 µl, 1.8 mmol) and the mixture was left for 18 h at CT. The mixture was then concentrated and mixed several times with dichloromethane and re-concentrated. The residue was purified by preparative HPLC (method 7). The combined target fractions were concentrated and the residue was lyophilized. 35 mg (100% pure, 67% thor.) of the title compound were obtained.

LC-MS (method 1): Rt = 2.14 min; MS (ESIpos): m/z = 630/632 [M+H]+.

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (1.30), 0.008 (1.39), 1.236 (0.67), 1.885 (2.91), 1.980 (0.64), 2.082 (2.77), 2.100 (3.27 ), 2.106 (3.21), 2.134 (4.76), 2.147 (4.55), 2.165 (16.00), 3.170 (3.69), 3.451 (2.24), 3.480 (4.31), 3.509 (2.17), 3.736 (1.60), 7.271 (0.76 ), 7.282 (0.86), 7.295 (1.56), 7.305 (1.62), 7.320 (1.22), 7.331 (1.11), 7.392 (0.94), 7.403 (1.13), 7.414 (1.56), 7.425 (1.52), 7.436 (0.92 ), 7.447 (0.78), 7.680 (1.80), 7.702 (8.65), 7.710 (5.87), 7.715 (5.09), 7.733 (1.08), 7.738 (1.16), 8.818 (1.29), 8.833 (2.32), 12.100 (1.60 ).

Example 156.

5-[({6-Bromo-2-[3-fluoropiperidin-1-yl]-3-methylquinolin-4-yl}carbonyl)amino]-4-(2-chloro-3,6difluorophenyl)valeric acid (mixture of diastereoisomers )

To a solution of tert-butyl-5-[({6-bromo-2-[3-fluoropiperidin-1-yl]-3-methylquinolin-4yl}carbonyl)amino]-4-(2-chloro-3,6- difluorophenyl)pentanoate (85 mg, 127 µmol, mixture of diastereoisomers, example 163A) in dichloromethane (1.1 ml) was added with TFA (220 µl, 2.8 mmol) and the mixture was left for 18 h at RT. The mixture was then concentrated and mixed several times with dichloromethane and re-concentrated. The residue was purified by preparative HPLC (method 7). The combined target fractions were concentrated and the residue was lyophilized. 51 mg (100% pure, 65% thor.) of the title compound were obtained.

LC-MS (method 1): Rt = 2.09 min; MS (ESIpos): m/z = 612/614 [M+H]+.

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (1.33), 1.235 (0.52), 1.647 (1.14), 1.808 (1.08), 1.901 (1.96), 1.921 (1.82), 1.953 (1.67 ), 1.984 (1.23), 2.099 (2.21), 2.127 (3.58), 2.139 (4.40), 2.157 (16.00), 2.198 (0.59), 3.100 (1.31), 3.166 (1.35), 3.174 (1.35), 3.381 (1.62 ), 3.413 (0.83), 3.438 (1.26), 3.467 (0.80), 3.728 (1.77), 4.820 (0.94), 4.938 (0.95), 7.268 (0.78), 7.279 (0.90), 7.292 (1.63), 7.303 (1.69 ), 7.318 (1.28), 7.329 (1.18), 7.390 (0.96), 7.411 (1.63), 7.422 (1.63), 7.445 (0.87), 7.653 (1.94), 7.676 (8.85), 7.684 (5.74), 7.689 (5.25 ), 7.706 (1.15), 7.711 (1.24), 8.814 (1.27), 8.828 (2.28).

Example 157.

5-[({6-Bromo-3-methyl-2-[3-methylpiperidin-1-yl]quinolin-4-yl}carbonyl)amino]-4-(2-chloro-3,6 difluorophenyl)valeric acid ( mixture of diastereoisomers)

- 193 040220

To a solution of tert-butyl-5-[({6-bromo-3-methyl-2-[3-methylpiperidin-1-yl]quinolin-4yl}carbonyl)amino]-4-(2-chloro-3,6 -difluorophenyl)pentanoate (85 mg, 128 µmol, mixture of diastereoisomers, example 164A) in dichloromethane (1.1 ml) was added with TFA (220 µl, 2.8 mmol) and the mixture was left for 18 h at RT. The mixture was then concentrated and mixed several times with dichloromethane and re-concentrated. The residue was purified by preparative HPLC (method 7). The combined target fractions were concentrated and the residue was lyophilized. Received 53 mg (100% pure, 69% theoretical. yield.) specified in the title compound.

LC-MS (method 1): R _t = 2.33 min; MS (ESIpos): m/z = 608/610 [M+H]+.

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.922 (10.55), 0.938 (10.81), 1.051 (0.41), 1.080 (1.22), 1.108 (1.27), 1.131 (0.52), 1.235 (0.49) , 1.630 (0.96), 1.657 (1.13), 1.732 (2.16), 1.765 (2.08), 1.793 (2.57) , 2.179 (1.52), 2.203 (0.55), 2.461 (1.21), 2.679 (0.77), 2.711 (1.36), 2.741 (0.72), 3.436 (1.83), 3.464 (3.30), 3.493 (1.55), 3.725 (1.98) . , 7.433 (1.23), 7.445 (1.09), 7.632 (1.57), 7.654 (9.91), 7.658 (7.43), 7.663 (5.90), 7.681 (0.88), 7.685 (1.00), 8.796 (1.39), 8.811 (2.45) , 12.100 (2.08).

Example 158.

5-[({6-Bromo-2-[3-ethylpiperidin-1-yl]-3-methylquinolin-4-yl}carbonyl)amino]-4-(2-chloro-3,6difluorophenyl)valeric acid (mixture of diastereoisomers )

To a solution of tert-butyl-5-[({6-bromo-2-[3-ethylpiperidin-1-yl]-3-methylquinolin-4yl}carbonyl)amino]-4-(2-chloro-3,6- difluorophenyl)pentanoate (85 mg, 125 µmol, mixture of diastereoisomers, example 165A) in dichloromethane (1.1 ml) was added with TFA (210 µl, 2.8 mmol) and the mixture was left for 18 h at RT. The mixture was then concentrated and mixed several times with dichloromethane and re-concentrated. The residue was purified by preparative HPLC (method 7). The combined target fractions were concentrated and the residue was lyophilized. 59 mg (100% pure, 76% thor.) of the title compound were obtained.

LC-MS (method 1): R _t = 2.44 min; MS (ESIpos): m/z = 622/624 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.008 (2.12), 0.891 (5.97), 0.910 (13.55), 0.928 (7.25), 1.038 (0.57), 1.066 (1.50), 1.088 (1.54) , 1.096 (1.54), 1.117 (0.72), 1.241 (1.46), 1.259 (3.18), 1.277 (4.17), 1.294 (2.81), 1.566 (1.70), 1.600 (1.55), 1.633 (1.32), 1.748 (2.11) , 1.781 (1.43), 1.847 (1.75), 1.878 (1.71), 1.972 (0.97), 2.067 (1.41), 2.104 (3.81), 2.136 (16.00), 2.162 (4.53), 2.181 (1.63), 2.203 (0.64) , 2.327 (0.43), 2.423 (1.35), 2.670 (0.43), 2.745 (1.52), 3.488 (3.26), 3.518 (3.03), 3.725 (2.52), 7.266 (1.04), 7.277 (1.19), 7.290 (2.16) , 7.300 (2.21), 7.315 (1.62), 7.326 (1.46), 7.386 (1.42), 7.397 (1.68), 7.408 (2.33), 7.419 (2.32), 7.429 (1.44), 7.441 (1.30), 7.631 (1.77) , 7.653 (11.15), 7.684 (1.03), 8.794 (1.74), 8.809 (3.01), 12.096 (8.21).

Example 159.

(+/-)-5-({[2-(Azepan-1-yl)-6-bromo-3-methylquinolin-4-yl]carbonyl}amino)-4-(2-chloro-3,6difluorophenyl)valeric acid (racemate)

To a solution of (+/-)-tert-butyl-5-({[2-(azepan-1-yl)-6-bromo-3-methylquinolin-4-yl]carbonyl}amino)-4-(2- chloro-3,6-difluorophenyl)pentanoate (85 mg, 128 µmol, racemate, example 166A) in dichloromethane (1.1 ml) was added with TFA (210 µl, 2.8 mmol) and the mixture was left for 3.5 h at RT. The mixture was then concentrated and mixed several times with dichloromethane and re-concentrated. The residue was purified by preparative HPLC (method 7). The combined target fractions were concentrated and the residue was lyophilized. 54 mg (100% pure, 69% theoretical) of the title compound were obtained.

LC-MS (method 1): Rt = 2.22 min; MS (ESIpos): m/z = 608/610 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.603 (11.39), 1.781 (7.18), 1.972 (0.89), 2.104 (2.93), 2.134

- 194 040220 (16.00) 2.161 (4.26) 2.179 (1.62) 2.202 (0.64) 3.492 (8.81) 3.506 (13.30) 3.521 (8.69) 3.722 (2.42) ), 7.291 (2.00), 7.301 (2.10), 7.316 (1.57), 7.327 (1.47), 7.388 (1.42), 7.400 (1.68), 7.410 (2.19), 7.421 (2.12), 7.444 (1.08), 7.531 (4.68 ), 7.553 (8.36), 7.600 (4.67), 7.606 (4.40), 7.622 (2.52), 7.628 (2.47), 8.792 (2.66), 12.101 (1.23).

Example 160.

(+/-)-5-({[6-Bromo-3-methyl-2-(piperidin-1-yl)quinolin-4-yl]carbonyl}amino)-4-[2-fluoro-6(trifluoromethyl) phenyl]valeric acid (racemate)

To a solution of (+/-)-tert-butyl-5-({[6-bromo-3-methyl-2-(piperidin-1-yl)quinolin-4yl]carbonyl}amino)-4-[2-fluoro -6-(trifluoromethyl)phenyl]pentanoate (55 mg, 82.5 µmol, racemate, example 167A) in dichloromethane (1.1 ml) TFA (610 µl, 8.3 mmol) was added and the mixture was stirred at RT for 1.5 h. The mixture was then concentrated and the residue was dissolved in DMSO and purified by preparative HPLC (method 15). The combined desired fractions were concentrated and the residue was dried in vacuo. 45 mg (100% pure, 89% thor.) of the title compound were obtained.

LC-MS (method 1): Rt = 2.21 min; MS (ESIpos): m/z = 610/612 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.149 (1.21), -0.008 (15.78), 0.008 (11.37), 0.146 (1.24), 1.234 (1.30), 1.340 (0.44), 1.611 ( 5.24), 1.677 (10.32), 2.017 (1.79), 2.030 (3.50), 2.060 (4.14), 2.092 (2.65), 2.121 (5.79) 1.41), 2.366 (0.44), 2.670 (1.41), 3.148 (13.24),3.703 (1.54), 3.873 (1.46), 7.383 (0.58), 7.562 (5.88), 7.571 (5.05), 7.577 (4.94), 4.08) 2.21), 12.075 (1.49).

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 12.08 (br. s, 1H), 8.82 (t, 1H), 7.74-7.51 (m, 5H), 7.38 (br. s, 1H), 3.87 (br. s, 1H), 3.70 (br. s, 1H), 3.33-3.27 (1H, latent, empirical), 3.20-3.10 (m, 4H), 2.25-1.95 (m, 7H), 1.70- 1.55 (m, 6H).

Example 161.

(-)-5-({[6-Bromo-3-methyl-2-(piperidin-1-yl)quinolin-4-yl]carbonyl}amino)-4-[2-fluoro-6(trifluoromethyl)phenyl] valeric acid (enantiomer 1).

To a solution of tert-butyl-5-({[6-bromo-3-methyl-2-(piperidin-1-yl)quinolin-4-yl]carbonyl}amino)4-[2-fluoro-6-(trifluoromethyl )phenyl]pentanoate (85 mg, 128 µmol, enantiomer 1, example 168A) in dichloromethane (1.7 ml) was added with TFA (950 µl, 13 mmol) and the mixture was stirred at RT for 1 h. The mixture was then concentrated and the residue was adsorbed into DMSO and purified by preparative HPLC (method 20). The combined target fractions were concentrated and the respective residues were lyophilized. The lyophilizate was then adsorbed into methanol, combined, and the mixture was left to dry at ambient conditions. After subsequent drying of the residue in vacuo, 63 mg (98% pure, 79% theoretical) of the title compound were obtained.

[a] _D20 = -40.1°, 589 nm, c = 0.38 g/100 ml ^, methanol;

LC-MS (method 1): Rt = 2.24 min; MS (ESIpos): m/z = 610/612 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: -0.149 (0.84), 0.146 (0.81), 1.612 (5.48), 1.678 (10.55), 2.019 (1.74), 2.031 (3.64), 2.062 ( 4.46), 2.084 (2.72), 2.122 (6.02), 2.137 (5.09), 2.167 (16.00), 2.268 (0.57) 13.62) 5.14), 7.595 (7.85), 7.627 (5.54), 7.652 (14.78), 7.684 (1.70), 8.806 (2.22), 8.821 (4.53), 8.836 (2.38), 12.061 (1.47).

Example 162.

(+)-5-({[6-Bromo-3-methyl-2-(piperidin-1-yl)quinolin-4-yl]carbonyl}amino)-4-[2-fluoro-6(trifluoromethyl)phenyl] valeric acid (enantiomer 2).

To a solution of tert-butyl-5-({[6-bromo-3-methyl-2-(piperidin-1-yl)quinolin-4-yl]-carbonyl}amino)4-[2-fluoro-6-( trifluoromethyl)phenyl]pentanoate (93 mg, 140 μmol, enantiomer 2, example 169A) in dichloromethane (1.9 ml) was added with TFA (1.0 ml, 14 mmol) and the mixture was stirred at RT for 1 h. The mixture was then concentrated and the residue was adsorbed into DMSO and purified by preparative HPLC (method 20). The combined target fractions were concentrated and the respective residues were lyophilized. The lyophilizate was then adsorbed into methanol, combined, and the mixture was left to dry at ambient conditions. After subsequent drying of the residue in vacuo, 68 mg (98% pure, 78% theoretical) of the title compound were obtained.

- 195 040220

[a] ^D20 = +45.9°, 589 nm, c = 0.45 g/100 ml, methanol;

LC-MS (method 1): R _t = 2.21 min; MS (ESIpos): m/z = 610/612 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.149 (0.70), -0.008 (5.63), 0.008 (5.76), 0.146 (0.70), 1.613 (4.93), 1.679 (9.47), 2.019 ( 1.64), 2.032 (3.34), 2.062 (4.01), 2.093 (2.39), 2.122 (5.44), 2.137 (4.54) 1.02), 2.710 (0.56), 3.149 (12.27), 3.162 (10.30), 3.174 (4.19), 3.707 (1.42), 3.876 (1.33), 4.075 (0.66), 4.089 (0.66), 7.370 (0.56), 5.67) 1.70), 8.807 (2.26), 8.822 (4.55), 8.837 (2.29), 12.062 (1.62).

Example 163.

(+/-)-5-({[6-Bromo-3-methyl-2-(pyrrolidin-1-yl)quinolin-4-yl]carbonyl}amino)-4-[2-fluoro-6(trifluoromethyl) phenyl]valeric acid (racemate)

To a solution of (+/-)-tert-butyl-5-({[6-bromo-3-methyl-2-(pyrrolidin-1-yl)quinolin-4yl]carbonyl}amino)-4-[2-fluoro -6-(trifluoromethyl)phenyl]pentanoate (55 mg, 84.3 µmol, racemate, example 170A) in dichloromethane (1.1 ml) TFA (630 µl, 8.4 mmol) was added and the mixture was stirred at RT for 1.5 h. The mixture was then concentrated and the residue was dissolved in DMSO and purified by preparative HPLC (method 15). The combined desired fractions were concentrated and the residue was dried in vacuo. 41 mg (100% pure, 82% thor.) of the title compound were obtained.

LC-MS (method 1): Rt = 1.51 min; MS (ESIpos): m/z = 596/598 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: -0.149 (1.17), -0.008 (10.78), 0.008 (13.42), 0.146 (1.33), 1.879 (16.00), 2.012 (2.39), 2.026 (3.42), 2.056 (4.94), 2.085 (2.81), 2.118 (5.81), 2.125 (5.56), 2.154 (6.67), 2.171 (6.97), 2.328 (2.11), 2.366 (0.53) (11.19) 3.895 (1.53) 7.474 (8.50) 7.496 (14.53) 7.549 (8.83) 7.555 (10.11) 7.571 (10.28) 7.577 (8.56) 7.592 (8.33) (3.89), 7.640 (2.44), 8.139 (1.83), 8.748 (2.86), 8.763 (5.56), 8.778 (2.81), 12.088 (1.00).

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 12.09 (br. s, 1H), 8.76 (t, 1H), 7.72-7.52 (m, 4H), 7.51-7.39 (m, 1H) , 7.28 (br. s, 1H), 3.90 (br. s, 1H), 3.73-3.49 (m, 5H), 3.33-2.26 (1H, latent, experimental), 2.27-1.95 (m, 7H), 1.82 -1.83 (m, 4H).

Example 164.

(+)-5-({[6-Bromo-3-methyl-2-(pyrrolidin-1-yl)quinolin-4-yl]carbonyl}amino)-4-[2-fluoro-6(trifluoromethyl)phenyl] valeric acid (enantiomer 1).

To a solution of tert-butyl-5-({[6-bromo-3-methyl-2-(pyrrolidin-1-yl)quinolin-4-yl]carbonyl}amino)4-[2-fluoro-6-(trifluoromethyl )phenyl]pentanoate (75 mg, 115 µmol, enantiomer 7, example 171A) in dichloromethane (1.5 ml) was added with TFA (850 µl, 11 mmol) and the mixture was stirred at RT for 1 h. The mixture was then concentrated and the residue was adsorbed into DMSO and purified by preparative HPLC (method 22). The combined target fractions were concentrated and the respective residues were lyophilized. The lyophilizate was then adsorbed into methanol, combined, and the mixture was left to dry at ambient conditions. After subsequent drying of the residue in vacuo, 55 mg (99% pure, 79% theoretical) of the title compound were obtained.

[a] _D20 = +38.1°, 589 nm, c = 0.35 g/100 mL ^, methanol;

LC-MS (method 1): R _t = 1.54 min; MS (ESIpos): m/z = 596/598 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.149 (1.69), -0.008 (13.12), 0.146 (1.65), 1.880 (16.00), 2.012 (2.46), 2.027 (3.61), 2.056 ( 5.18), 2.089 (2.95), 2.118 (5.99), 2.125 (5.83), 2.154 (6.79), 2.176 (6.98), 2.328 (2.53), 2.366 (1.42), 2.670 (2.30), 2.710 (1.50), 0.42), 3.071 (2.07), 3.169 (2.76), 3.581 (11.20), 3.926 (2.19), 4.072 (0.42), 4.154 (3.65), 7.431 (0.58), 7.474 (7.60), 7.497 (13.47), 8.02), 7.555 (9.63), 7.571 (10.24), 7.577 (8.75), 7.592 (8.71), 7.617 (5.83), 7.629 (4.34) 5.76), 8.779 (2.88), 12.062 (1.73).

Example 165.

(-)-5-({[6-Bromo-3-methyl-2-(pyrrolidin-1-yl)quinolin-4-yl]carbonyl}amino)-4-[2-fluoro-6(trifluoromethyl)phenyl] valeric acid (enantiomer 2).

To a solution of tert-butyl-5-({[6-bromo-3-methyl-2-(pyrrolidin-1-yl)quinolin-4-yl]carbonyl}amino)4-[2-fluoro-6-(trifluoromethyl )phenyl]pentanoate (79 mg, 121 µmol, enantiomer 2, example 172A) in dichloromethane (1.6 ml) was added with TFA (900 µl, 12 mmol) and the mixture was stirred at RT for 1 h. The mixture was then concentrated and the residue was adsorbed into DMSO and purified by preparative HPLC (method 21). The pooled target fractions were concentrated and the corresponding residues were lyophilized.

- 196 040220 roval. The lyophilizate was then adsorbed into methanol, combined, and the mixture was left to dry at ambient conditions. After subsequent drying of the residue in vacuo, 49 mg (97% pure, 66% theoretical) of the title compound were obtained.

[a] _D20 = -41.4°, 589 nm, c = 0.35 ^g /100 ml, methanol;

LC-MS (method 1): R _t = 1.53 min; MS (ESIpos): m/z = 596/598 [M+H]+.

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: -0.150 (1.29), -0.008 (10.93), 0.008 (10.93), 0.146 (1.33), 1.879 (16.00), 2.012 (2.80), 2.026 (3.87) (2.22), 2.709 (1.29), 3.162 (0.62), 3.174 (0.71), 3.210 (0.58), 3.472 (0.93), 3.580 (11.02), 3.897 (1.87), 7.393 (0.58) (0.89), 7.474 (6.98), 7.496 (12.49), 7.549 (7.78), 7.555 (9.56), 7.571 (10.22), 7.592 (8.93) (3.11), 8.763 (5.69), 8.778 (2.89), 9.693 (0.44), 12.054 (6.53).

Example 166.

(+/-)-5-({[6-Bromo-2-(3,3-difluoropiperidin-1-yl)-3-methylquinolin-4-yl]carbonyl}amino)-4-[2-fluoro6-( trifluoromethyl)phenyl]valeric acid (racemate)

To a solution of (+/-)-tert-butyl-5-({[6-bromo-2-(3,3-difluoropiperidin-1-yl)-3-methylquinolin-4yl]carbonyl}amino)-4-[ 2-fluoro-6-(trifluoromethyl)phenyl]pentanoate (55 mg, 78.3 µmol, racemate, example 173A) in dichloromethane (1.0 ml) was added with TFA (580 µl, 7.8 mmol) and the mixture was stirred at RT for 1.5 h. The mixture was then concentrated and the residue was dissolved in DMSO and purified by preparative HPLC (method 15). The combined desired fractions were concentrated and the residue was dried in vacuo. Received 50 mg (100% pure, 99% theoretical. Y.) specified in the title compound.

LC-MS (method 1): R _t = 2.16 min; MS (ESIpos): m/z = 646/648 [M+H]+.

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.149 (0.66), -0.008 (8.90), 0.008 (6.39), 0.146 (0.64), 1.890 (5.53), 2.037 (4.19), 2.067 ( 7.01), 2.087 (6.21), 2.099 (6.24), 2.122 (8.03), 2.137 (6.44), 2.155 (5.81), 2.188 (14.73), 2.293 (0.54), 2.327 (0.78), 2.670 (0.80), 6.37), 3.186 (5.71), 3.462 (4.30), 3.491 (7.92), 3.520 (3.94), 3.699 (1.55), 3.891 (1.37) 5.08), 7.591 (4.30), 7.599 (7.83), 7.628 (5.37), 7.638 (3.85), 7.652 (2.57), 7.681 (2.59), 7.704 (16.00) 1.41), 7.734 (1.57), 8.820 (2.64), 8.835 (4.85), 8.850 (2.43), 12.072 (2.23).

1H-NMR (400 MHz, DMSO-d6): δ [ppm] = 12.07 (br. s, 1H), 8.84 (t, 1H), 7.77-7.52 (m, 5H), 7.52-7.17 (m, 1H) , 4.01-3.81 (m, 1H), 3.81-3.61 (m, 1H), 3.49 (t, 2H), 3.25-3.10 (m, 2H), 2.30-1.99 (m, 10H), 1.89 (br. s, 2H).

Example 167.

(-)-5-({[6-Bromo-2-(3,3-difluoropiperidin-1-yl)-3-methylquinolin-4-yl]carbonyl}amino)-4-[2-fluoro-6(trifluoromethyl )phenyl]valeric acid (enantiomer 1).

To a solution of tert-butyl-5-({[6-bromo-2-(3,3-difluoropiperidin-1-yl)-3-methylquinolin-4yl]carbonyl}amino)-4-[2-fluoro-6- (trifluoromethyl)phenyl]pentanoate (91 mg, 130 µmol, enantiomer 1, example 174A) in dichloromethane (1.7 ml) TFA (960 µl, 13 mmol) was added and the mixture was stirred at RT for 1 h. The mixture was then concentrated and the residue was adsorbed into DMSO and purified by preparative HPLC (method 19). The combined target fractions were concentrated and the respective residues were lyophilized. The lyophilizate was then adsorbed into methanol, combined, and the mixture was left to dry at ambient conditions. After subsequent drying of the residue in vacuo, 61 mg (97% pure, 71% theoretical) of the title compound was obtained.

[a] _D20 = -40.8°, 589 nm, c = 0.34 g ^/ 100 ml, methanol;

LC-MS (method 1): R _t = 2.16 min; MS (ESIpos): m/z = 646/648 [M+H]+.

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.149 (0.45), 0.146 (0.47), 1.891 (5.64), 2.038 (4.28), 2.068 (7.20), 2.088 (6.27), 2.099 (6.42 ), 2.123 (8.16), 2.137 (6.54), 2.155 (5.94), 2.189 (15.09), 2.293 (0.57), 2.328 (0.70), 2.366 (0.41), 2.670 (0.67), 2.710 (0.41), 3.163 (11.92 ), 3.175 (14.69), 3.462 (4.32), 3.491 (8.03), 3.520 (4.01), 3.703 (1.56), 3.895 (1.38), 4.063 (1.08), 4.076 (2.53), 4.089 (2.43), 4.102 (0.90 ), 7.422 (0.55), 7.566 (5.90), 7.575 (5.37), 7.581 (5.29), 7.591 (4.40), 7.599 (7.94), 7.628 (5.40), 7.638 (3.92), 7.651 (2.59), 7.681 (2.56 ), 7.703 (16.00), 7.712 (9.63), 7.730 (1.32), 7.734 (1.55), 8.819 (2.73), 8.834 (5.02), 8.849 (2.47), 12.066 (3.48).

Example 168.

(+)-5-({[6-Bromo-2-(3,3-difluoropiperidin-1-yl)-3-methylquinolin-4-yl]carbonyl}amino)-4-[2-fluoro-6-197 040220 (trifluoromethyl)phenyl]valeric acid (enantiomer 2).

To a solution of tert-butyl-5-({[6-bromo-2-(3,3-difluoropiperidin-1-yl)-3-methylquinolin-4yl]carbonyl}amino)-4-[2-fluoro-6- (trifluoromethyl)phenyl]pentanoate (93 mg, 132 µmol, enantiomer 2, Example 175A) in dichloromethane (1.8 mL) TFA (980 µL, 13 mmol) was added and the mixture was stirred at RT for 1 h. The mixture was then concentrated and the residue was adsorbed into DMSO and purified by preparative HPLC (method 19). The combined target fractions were concentrated and the respective residues were lyophilized. The lyophilizate was then adsorbed into methanol, combined, and the mixture was left to dry at ambient conditions. After subsequent drying of the residue in vacuo, 61 mg (98% pure, 70% theoretical) of the title compound was obtained.

[a] _D20 = -40.8°, 589 nm, c = 0.34 g ^/ 100 ml, methanol;

LC-MS (method 1): Rt = 2.16 min; MS (ESIpos): m/z = 646/648 [M+H]+.

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.149 (1.31), 0.146 (1.38), 1.890 (5.50), 2.034 (3.86), 2.067 (6.68), 2.086 (6.14), 2.097 (5.80 ), 2.121 (8.32), 2.136 (6.41), 2.153 (5.43), 2.188 (15.23), 2.292 (0.50), 2.327 (1.78), 2.366 (1.11), 2.670 (2.05), 2.710 (1.21), 3.162 (12.11 ), 3.175 (15.19), 3.462 (4.33), 3.491 (8.18), 3.519 (4.13), 3.708 (1.54), 3.894 (1.44), 4.063 (0.97), 4.074 (2.62), 4.088 (2.65), 4.100 (1.01 ), 7.424 (0.57), 7.566 (5.47), 7.575 (5.03), 7.599 (8.02), 7.628 (5.27), 7.638 (3.89), 7.651 (2.58), 7.680 (2.11), 7.703 (16.00), 7.734 (1.61 ), 8.821 (2.28), 8.837 (4.46), 8.851 (2.38), 12.068 (1.31).

Example 169.

5-[({6-Bromo-2-[3-fluoropiperidin-1-yl]-3-methylquinolin-4-yl}carbonyl)amino]-4-[2-fluoro-6(trifluoromethyl)phenyl]valeric acid ( mixture of diastereoisomers)

To a solution of tert-butyl-5-[({6-bromo-2-[3-fluoropiperidin-1-yl]-3-methylquinolin-4yl}carbonyl)amino]-4-[2-fluoro-6-(trifluoromethyl )phenyl]pentanoate (55 mg, 80.3 µmol, mixture of diastereoisomers, example 176A) in dichloromethane (1.1 ml) was added with TFA (600 µl, 8.0 mmol) and the mixture was stirred at RT for 1.5 h. The mixture was then concentrated and the residue was dissolved in DMSO and purified by preparative HPLC (method 15). The combined desired fractions were concentrated and the residue was dried in vacuo. 43 mg (100% pure, 85% thor.) of the title compound were obtained.

LC-MS (method 1): Rt = 2.11 min; MS (ESIpos): m/z = 628/630 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.149 (1.05), -0.008 (8.09), 0.008 (9.08), 0.146 (1.02), 1.654 (2.10), 1.811 (1.98), 1.907 ( 3.49), 1.927 (3.06), 1.957 (2.29), 2.002 (1.61), 2.021 (2.10), 2.035 (4.08), 2.065 (5.07), 2.087 (3.12), 2.123 (6.15), 2.137 (4.76), 5.44) 2.29) 8.93), 7.627 (5.93), 7.636 (4.26), 7.652 (3.37), 7.677 (15.14), 7.708 (1.64), 8.815 (2.44), 8.829 (4.76)

1H-NMR (400 MHz, DMSO-d6): δ [ppm] = 12.07 (br. s, 1H), 8.83 (t, 1H), 7.73-7.54 (m, 5H), 7.52-7.26 (m, 1H) , 4.88 (br. d, 1H), 4.00-3.80 (m, 1H), 3.77-3.60 (m, 1H), 3.52-3.33 (m, 3H, partially hidden, tentativ), 3.25-3.03 (m, 2H) , 2.26-1.72 (m, 10H), 1.70-1.57 (m, 1H).

Example 170.

5-[({6-Bromo-2-[3-ethylpiperidin-1-yl]-3-methylquinolin-4-yl}carbonyl)amino]-4-[2-fluoro-6(trifluoromethyl)phenyl]valeric acid ( mixture of diastereoisomers)

To a solution of tert-butyl-5-[({6-bromo-2-[3-ethylpiperidin-1-yl]-3-methylquinolin-4yl}carbonyl)amino]-4-[2-fluoro-6-(trifluoromethyl )phenyl]pentanoate (57 mg, 82 µmol, mixture of diastereoisomers, example 177A) in dichloromethane (1.1 ml) TFA (610 µl, 8.2 mmol) was added, and the mixture was changed for 1.5 h.

- 198 040220 stirred at RT. The mixture was then concentrated and the residue was dissolved in DMSO and purified by preparative HPLC (method 15). The combined desired fractions were concentrated and the residue was dried in vacuo. Received 51 mg (100% pure, 97% theoretical. yield.) specified in the title compound.

LC-MS (method 1): Rt = 2.46 min; MS (ESIpos): m/z = 638 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: -0.149 (1.26), -0.008 (16.00), 0.008 (10.04), 0.146 (1.32), 0.896 (5.78), 0.914 (13.57), 0.933 (6.59), 1.071 (1.05), 1.092 (1.14), 1.263 (2.01), 1.280 (2.73), 1.290 (2.22), 1.308 (1.53) (1.32) (0.81) (9.41), 7.680 (0.60), 8.813 (2.10), 12.069 (1.14).

1H-NMR (400 MHz, DMSO-d6): δ [ppm] = 12.07 (br. s, 1H), 8.81 (t, 1H), 7.70-7.52 (m, 5H), 7.51-7.19 (br. m, 1H), 3.99-3.82 (m, 1H), 3.76-3.62 (m, 1H), 3.58-3.45 (m, 2H), 2.84-2.69 (m, 1H), 2.50-2.37 (m, 1H, partially hidden) , 2.24-1.99 (m, 8H), 1.93-1.82 (m, 1H), 1.82-1.71 (m, 1H), 1.70-1.49 (m, 2H), 1.38-1.20 (m, 2H), 1.08 (br. q, 1H), 0.91 (t, 3H).

Example 171.

(+/-)-5-({[6-Bromo-3-methyl-2-(piperidin-1-yl)quinolin-4-yl]carbonyl}amino)-4-(2,3,6trichlorophenyl)valeric acid (racemate)

To a solution of (+/-)-tert-butyl-5-({[6-bromo-3-methyl-2-(piperidin-1-yl)quinolin-4yl]carbonyl}amino)-4-(2.3 ,6-trichlorophenyl)pentanoate (55 mg, 80.4 µmol, racemate, example 178A) in dichloromethane (1.1 ml) was added with TFA (600 µl, 8.0 mmol) and the mixture was stirred at RT for 1.5 h. The mixture was then concentrated and the residue was dissolved in DMSO and purified by preparative HPLC (method 15). The combined desired fractions were concentrated and the residue was dried in vacuo. 49 mg (100% pure, 97% thor.) of the title compound were obtained.

LC-MS (method 1): Rt = 2.34 min; MS (ESIpos): m/z = 626/628/630 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: -0.149 (1.91), -0.008 (16.00), 0.008 (14.22), 0.146 (1.95), 1.234 (0.51), 1.610 (3.52), 1.675 (6.66), 2.071 (1.40), 2.085 (1.95), 2.099 (2.63), 2.120 (3.18), 2.136 (7.09), 2.155 (3.52), 2.169 (14.39), 2.180 (3.35) (1.40) (3.18) (3.01), 7.689 (1.57), 8.813 (2.25), 12.108 (1.10).

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 12.10 (br. s, 1H), 8.92-8.69 (m, 1H), 7.77-7.39 (m, 5H), 4.203.92 (m, 2H ), 3.90-3.75 (m, 1H), 3.14 (br. s, 4H), 2.32-2.22 (m, 1H), 2.21-2.01 (m, 6H), 1.67 (br. s, 4H), 1.651.55 (m, 2H).

Example 172.

(+)-5-({[6-Bromo-3-methyl-2-(piperidin-1-yl)quinolin-4-yl]carbonyl}amino)-4-(2,3,6trichlorophenyl)valeric acid (enantiomer 1).

To a solution of tert-butyl-5-({[6-bromo-3-methyl-2-(piperidin-1-yl)quinolin-4-yl]carbonyl}amino)4-(2,3,6-trichlorophenyl) pentanoate (92 mg, 95% pure, 128 µmol, enantiomer 7, example 179A) in dichloromethane (1.1 ml) in TFA argon (960 µl, 13 mmol) and the mixture was stirred 2 h at RT. The mixture was then concentrated and the residue was dissolved in DMSO and purified by preparative HPLC (method 15). The combined desired fractions were concentrated and the residue was dried in vacuo. 68 mg (100% pure, 85% thor.) of the title compound were obtained.

[a] _D20 = +31.4°, 589 nm ^, c = 0.37 g/100 mL, methanol;

LC-MS (method 1): R _t = 2.36 min; MS (ESIpos): m/z = 626/628/630 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.149 (1.92), -0.008 (15.84), 0.146 (1.96), 1.609 (3.95), 1.676 (7.70), 2.075 (1.68), 2.101 ( 3.23), 2.122 (4.27), 2.136 (8.34), 2.169 (16.00), 2.183 (3.27), 2.206 (1.56) 2.31) 2.99), 7.631 (1.76), 7.654 (6.46), 7.658 (6.34), 7.668 (6.30), 7.691 (1.52), 8.808 (2.79), 12.101 (0.48).

Example 173.

(-)-5-({[6-Bromo-3-methyl-2-(piperidin-1-yl)quinolin-4-yl]carbonyl}amino)-4-(2,3,6trichlorophenyl)valeric acid (enantiomer 2).

- 199 040220

To a solution of tert-butyl-5-({[6-bromo-3-methyl-2-(piperidin-1-yl)quinolin-4-yl]-carbonyl}amino)4-(2,3,6-trichlorophenyl )pentanoate (96 mg, 95% pure, 133 µmol, enantiomer 2, example 180A) in dichloromethane (1.1 ml) in TFA argon (1.0 ml, 13 mmol) and the mixture was stirred 2 h at RT. The mixture was then concentrated and the residue was dissolved in DMSO and purified by preparative HPLC (method 15). The combined desired fractions were concentrated and the residue was dried in vacuo. 62 mg (100% pure, 74% thor.) of the title compound were obtained.

[a] _D20 = -28.8°, 589 nm, c = 0.35 ^g /100 ml, methanol;

LC-MS (method 1): R _t = 2.36 min; MS (ESIpos): m/z = 626/628/630 [M+H]+.

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.149 (1.14), 0.147 (1.14), 1.607 (4.08), 1.675 (8.11), 2.072 (1.61), 2.086 (2.39), 2.099 (3.19) ), 2.120 (4.11), 2.136 (8.64), 2.156 (4.33), 2.169 (16.00), 2.181 (3.50), 2.203 (1.67), 2.282 (1.64), 2.327 (2.25), 2.367 (1.03), 2.669 (1.69 ), 2.710 (1.14), 3.141 (10.56), 3.807 (1.42), 4.054 (2.42), 7.476 (2.58), 7.497 (3.81), 7.533 (3.39), 7.555 (5.50), 7.598 (4.42), 7.618 (3.11 ), 7.629 (2.06), 7.651 (6.64), 7.656 (6.81), 7.666 (6.50), 7.688 (1.56), 8.810 (2.67), 12.111 (1.14).

Example 174.

(+/-)-5-({[6-Bromo-3-methyl-2-(pyrrolidin-1-yl)quinolin-4-yl]carbonyl}amino)-4-(2,3,6trichlorophenyl)valeric acid (racemate)

To a solution of (+/-)-tert-butyl-5-({[6-bromo-3-methyl-2-(pyrrolidin-1-yl)quinolin-4yl]carbonyl}amino)-4-(2.3 ,6-trichlorophenyl)pentanoate (55 mg, 82.1 µmol, racemate, example 181A) in dichloromethane (1.1 ml) was added with TFA (610 µl, 8.2 mmol) and the mixture was stirred at RT for 1.5 h. The mixture was then concentrated and the residue was dissolved in DMSO and purified by preparative HPLC (method 15). The combined desired fractions were concentrated and the residue was dried in vacuo. 41 mg (100% pure, 81% d.Th.) of the title compound were obtained.

LC-MS (method 1): Rt = 1.66 min; MS (ESIpos): m/z = 612/614/616 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: -0.150 (1.74), -0.008 (16.00), 0.146 (1.82), 1.875 (15.55), 2.070 (2.64), 2.097 (4.97), 2.118 (5.12), 2.158 (8.72), 2.194 (15.11), 2.277 (2.23), 2.327 (2.78), 2.669 (2.04) (13.07), 7.499 (8.76), 7.522 (4.64), 7.544 (8.24), 7.552 (5.31), 7.558 (7.39), 7.580 (5.16), 7.590 (5.79), 7.611 (3.56), 8.146 (2.26), 8.757 (4.08).

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 12.06 (br. s, 1H), 8.76 (br. s, 1H), 7.73-7.15 (m, 5H), 4.23-3.92 (m, 2H ), 3.92-3.69 (m, 1H), 3.57 (br. s, 4H), 2.39-2.02 (m, 7H), 1.88 (br. s, 4H).

Example 175.

(+)-5-({[6-Bromo-3-methyl-2-(piperidin-1-yl)quinolin-4-yl]carbonyl}amino)-4-(2,3,6trichlorophenyl)valeric acid (enantiomer 1).

To a solution of tert-butyl-5-({[6-bromo-3-methyl-2-(pyrrolidin-1-yl)quinolin-4-yl]carbonyl}amino)4-(2,3,6-trichlorophenyl) pentanoate (92 mg, 97% pure, 133 µmol, enantiomer 7, example 182A) in dichloromethane (1.1 ml) in TFA argon (990 µl, 13 mmol) and the mixture was stirred 2 h at RT. The mixture was then concentrated and the residue was dissolved in DMSO and purified by preparative HPLC (method 15). The combined desired fractions were concentrated and the residue was dried in vacuo. 48 mg (100% pure, 59% thor.) of the title compound were obtained.

[a] _D20 = +31.4°, 589 nm ^, c = 0.37 g/100 mL, methanol;

LC-MS (method 1): Rt = 1.63 min; MS (ESIpos): m/z = 612/614/616 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: -0.149 (1.80), -0.008 (15.65), 0.008 (16.00), 0.147 (1.97), 1.875 (15.71), 2.067 (2.90), 2.096 (4.93) 2.108 (5.22) 2.157 (8.64) 2.194 (15.19) 2.276 (2.38) 2.327 (4.81) (2.09), 4.057 (3.36), 7.472 (9.10), 7.494 (14.03), 7.500 (8.93), 7.523 (5.28), 7.544 (9.28), 7.552 (5.74) (5.97), 7.611 (3.59), 8.206 (1.74), 8.759 (4.00), 12.141 (0.93).

Example 176.

(-)-5-({[6-Bromo-3-methyl-2-(piperidin-1-yl)quinolin-4-yl]carbonyl}amino)-4-(2,3,6trichlorophenyl)valeric acid-Formiat (enantiomer 2)

- 200 040220

To a solution of tert-butyl-5-({[6-bromo-3-methyl-2-(pyrrolidin-1-yl)quinolin-4-yl]carbonyl}amino)

4-(2,3,6-trichlorophenyl)pentanoate (98 mg, 94% pure, 138 µmol, enantiomer 2, example 183A) in dichloromethane (1.2 ml) in TFA argon (1.0 ml, 14 mmol) and the mixture was stirred 2 h at CT. The mixture was then concentrated and the residue was dissolved in DMSO and purified by preparative HPLC (method 15). The combined desired fractions were concentrated and the residue was dried in vacuo. 51 mg (100% pure, 56% thor.) of the title compound were obtained.

[a] _D20 = -29.4°, 589 nm, c = 0.36 g ^/ 100 ml, methanol;

LC-MS (method 1): R _t = 1.65 min; MS (ESIpos): m/z = 612/614/616 [M+H]+.

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.149 (0.68), -0.008 (6.08), 0.008 (5.30), 0.146 (0.67), 1.876 (7.64), 2.070 (1.42), 2.085 ( 1.86) 0.92), 4.102 (0.67), 7.472 (4.33), 7.477 (2.93), 7.495 (2.55), 2.118 (2.55), 2.131 (2.05), 2.159 (4.35), 2.194 (1.39), 2.366 (0.65), 2.670 ( 0.99) 2.80), 7.558 (3.90), 7.564 (1.99), 7.574 (1.77), 7.580 (2.63), 7.590 (2.85), 7.612 (1.83), 8.145 (16.00), 8.757 (2.02).

Example 177.

(+/-)-5-({[6-Bromo-2-(3,3-difluoropiperidin-1-yl)-3-methylquinolin-4-yl]carbonyl}amino)-4-(2,3,6trichlorophenyl )valeric acid (racemate)

To a solution of (+/-)-tert-butyl-5-({[6-bromo-2-(3,3-difluoropiperidin-1-yl)-3-methylquinolin-4yl]carbonyl}amino)-4-( 2,3,6-trichlorophenyl)pentanoate (56 mg, 77.8 µmol, racemate, Example 184A) in dichloromethane (1.0 mL) TFA (580 µL, 7.8 mmol) was added and the mixture was stirred at RT for 1.5 h. The mixture was then concentrated and the residue was dissolved in DMSO and purified by preparative HPLC (method 15). The combined desired fractions were concentrated and the residue was dried in vacuo. 48 mg (100% pure, 93% thor.) of the title compound were obtained.

LC-MS (method 1): Rt = 2.25 min; MS (ESIpos): m/z = 662/664/666 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 1.885 (3.71), 2.103 (4.93), 2.116 (5.04), 2.135 (3.96), 2.159 (9.28), 2.188 (16.00), 2.307 (1.63 ), 2.328 (1.61), 2.670 (1.01), 3.174 (4.63), 3.453 (2.74), 3.483 (5.27), 3.511 (2.65), 3.819 (1.27), 4.071 (2.16), 7.479 (2.26), 7.501 (3.20 ), 7.535 (3.02), 7.556 (5.36), 7.599 (4.05), 7.620 (2.74), 7.681 (1.38), 7.703 (6.38), 7.709 (6.79), 7.716 (6.35), 7.739 (1.34), 8.822 (2.49 ), 12.109 (1.24).

1H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.10 (br. s, 1H), 8.95-8.67 (m, 1H), 7.78-7.66 (m, 2H), 7.657.47 (m , 3H), 4.17-3.96 (m, 2H), 3.92-3.76 (m, 1H), 3.48 (br. t, 2H), 3.17 (br. s, 2H), 2.19 (s, 9H), 1.94-1.82 (m, 2H).

Example 178.

(+)-5-({[6-Bromo-2-(3,3-difluoropiperidin-1-yl)-3-methylquinolin-4-yl]carbonyl}amino)-4-(2,3,6trichlorophenyl)valeric acid (enantiomer 1).

To a solution of tert-butyl-5-({[6-bromo-2-(3,3-difluoropiperidin-1-yl)-3-methylquinolin-4yl]carbonyl}amino)-4-(2,3,6- trichlorophenyl)pentanoate (79 mg, 95% pure, 104 µmol, enantiomer 7, example 185A) in dichloromethane (890 µl) TFA (780 µl, 10 mmol) was added and the mixture was stirred at RT for 1 h. The mixture was then concentrated and the residue was adsorbed into DMSO and purified by preparative HPLC (method 19). The combined target fractions were concentrated and the respective residues were lyophilized. The lyophilizate was then adsorbed into methanol, combined, and the mixture was left to dry at ambient conditions. After subsequent drying of the residue in vacuo, 49 mg (98% pure, 69% theoretical) of the title compound were obtained.

- 201 040220

[a]D ²⁰ = +30.4°, 589 nm, c = 0.35 g/100 ml, methanol LC-MS (method 1): Rt = 2.28 min; MS (ESIpos): m/z = 662/664/666 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.149 (0.91), 0.146 (0.82), 1.886 (3.76), 2.102 (4.96), 2.117 (5.16), 2.136 (4.03), 2.158 (9.41 ), 2.188 (16.00), 2.229 (0.82), 2.307 (1.69), 2.328 (1.71), 2.366 (0.74), 2.669 (1.07), 2.710 (0.60), 3.162 (13.82), 3.175 (14.53), 3.453 (2.72 ), 3.483 (5.34), 3.512 (2.63), 3.819 (1.31), 3.833 (1.23), 4.062 (2.91), 4.076 (4.18), 4.088 (3.40), 7.479 (2.31), 7.500 (3.29), 7.534 (2.87 ), 7.556 (5.16), 7.598 (4.34), 7.620 (2.89), 7.685 (1.49), 7.703 (6.67), 7.709 (7.06), 7.716 (6.21), 7.738 (1.33), 8.822 (2.47), 12.100 (1.47 ).

Example 179.

(-)-5-({[6-Bromo-2-(3,3-difluoropiperidin-1-yl)-3-methylquinolin-4-yl]carbonyl}amino)-4-(2,3,6trichlorophenyl)valeric acid (enantiomer 2).

To a solution of tert-butyl-5-({[6-bromo-2-(3,3-difluoropiperidin-1-yl)-3-methylquinolin-4yl]carbonyl}amino)-4-(2,3,6- trichlorophenyl)pentanoate (100 mg, 97% pure, 134 µmol, enantiomer 2, example 186A) in dichloromethane (1.2 ml) was added with TFA (1.0 ml, 13 mmol) and the mixture was stirred at RT for 1 h. The mixture was then concentrated and the residue was adsorbed into DMSO and purified by preparative HPLC (method 19). The combined target fractions were concentrated and the respective residues were lyophilized. The lyophilizate was then adsorbed into methanol, combined, and the mixture was left to dry at ambient conditions. After subsequent drying of the residue in vacuo, 49 mg (98% pure, 69% theoretical) of the title compound were obtained.

[a] _D20 = -26.7°, 589 nm, c = 0.36 g ^/ 100 ml, methanol;

LC-MS (method 1): Rt = 2.25 min; MS (ESIpos): m/z = 662/664/666 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.149 (0.65), -0.008 (5.21), 0.008 (3.92), 0.146 (0.56), 1.884 (3.63), 2.065 (2.12), 2.078 ( 3.31), 2.103 (4.75), 2.117 (4.92), 2.136 (3.88), 2.158 (9.19), 2.188 (16.00), 2.206 (1.67), 2.229 (0.81), 2.279 (1.29), 2.307 (1.58), 1.60), 2.366 (0.65), 2.670 (1.04), 2.710 (0.56), 3.162 (6.10), 3.175 (6.79), 3.453 (2.73), 3.482 (5.23), 3.511 (2.58), 3.802 (0.90), 1.25), 3.833 (1.21),4.048 (1.81), 4.074 (2.58), 4.106 (0.85), 7.479 (2.23), 7.500 (3.19), 7.535 (2.83), 7.556 (5.19), 7.598 (4.19), 2.79), 7.680 (1.40), 7.685 (1.35), 7.703 (6.46), 7.709 (6.79), 7.716 (6.08), 7.738 (1.33), 8.821 (2.46), 12.100 (2.10).

Example 180.

5-[({6-Bromo-2-[3-fluoropiperidin-1-yl]-3-methylquinolin-4-yl}carbonyl)amino]-4-(2,3,6trichlorophenyl)valeric acid (Diastereomengemisch)

To a solution of tert-butyl-5-[({6-bromo-2-[3-fluoropiperidin-1-yl]-3-methylquinolin-4yl}carbonyl)amino]-4-(2,3,6-trichlorophenyl) pentanoate (55 mg, 78.4 µmol, mixture of diastereoisomers, example 187A) in dichloromethane (1.0 ml) TFA (580 µl, 7.8 mmol) was added and the mixture was stirred at RT for 1.5 h. The mixture was then concentrated and the residue was dissolved in DMSO and purified by preparative HPLC (method 15). The combined desired fractions were concentrated and the residue was dried in vacuo. 46 mg (100% pure, 91% thor.) of the title compound were obtained.

LC-MS (method 1): Rt = 2.22 min; MS (ESIpos): m/z = 644/646/648 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: -0.149 (1.84), -0.008 (16.00), 0.008 (15.66), 0.146 (1.80), 1.234 (0.68), 1.641 (1.24), 1.811 (1.24), 1.903 (1.88), 2.072 (1.33), 2.100 (2.40), 2.112 (2.70), 2.153 (7.06), 2.182 (12.62), 2.306 (1.37) (1.84), 2.709 (0.64), 3.105 (1.33), 3.171 (1.45), 3.385 (1.37), 3.441 (1.16) 7.477 (2.05), 7.499 (2.82), 7.533 (2.87), 7.555 (4.96), 7.597 (3.17), 7.617 (2.10), 7.654 (1.33), 7.676 (5.48), 7.680 (5.18), 7.690 (5.39), 7.712 (1.28), 8.819 (1.97), 12.102 (0.98).

Example 181.

5-[({6-Bromo-2-[3-ethylpiperidin-1-yl]-3-methylquinolin-4-yl}carbonyl)amino]-4-(2,3,6trichlorophenyl)valeric acid (mixture of diastereoisomers)

- 202 040220

To a solution of tert-butyl-5-[({6-bromo-2-[3-ethylpiperidin-1-yl]-3-methylquinolin-4yl}carbonyl)amino]-4-(2,3,6-trichlorophenyl) pentanoate (55 mg, 77.3 µmol, mixture of diastereoisomers, example 188A) in dichloromethane (1.0 ml) TFA (570 µl, 7.7 mmol) was added and the mixture was stirred at RT for 1.5 h. The mixture was then concentrated and the residue was dissolved in DMSO and purified by preparative HPLC (method 15). The combined desired fractions were concentrated and the residue was dried in vacuo. 45 mg (100% pure, 89% thor.) of the title compound were obtained.

LC-MS (method 1): Rt = 2.58 min; MS (ESIpos): m/z = 654/656/658 [M+H]+.

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.149 (1.89), -0.008 (16.00), 0.008 (15.48), 0.146 (1.85), 0.893 (5.12), 0.912 (12.22), 0.930 ( 6.41), 1.068 (1.29), 1.092 (1.25), 1.261 (2.41), 1.279 (3.14), 1.571 (1.42), 1.640 (1.20), 1.751 (1.76), 1.850 (1.42), 1.880 (1.46), 2.073 ( 1.46), 2.127 (5.85), 2.154 (11.44), 2.159 (9.81), 2.184 (2.37), 2.206 (1.29), 2.230 (0.82), 2.276 (1.38) 1.25) 3.74), 7.527 (3.35), 7.549 (5.59), 7.590 (3.44), 7.596 (3.61), 7.612 (2.37), 7.632 (1.25), 7.658 (8.82) 2.06), 12.107 (1.38).

Example 182.

(+/-)-5-({[6-Bromo-3-methyl-2-(piperidin-1-yl)quinolin-4-yl]carbonyl}amino)-4-[2(difluoromethoxy)-6-fluorophenyl ]valeric acid (racemate)

To a solution of (+/-)-tert-butyl-5-({[6-bromo-3-methyl-2-(piperidin-1-yl)quinolin-4yl]carbonyl}amino)-4-[2-( difluoromethoxy)-6-fluorophenyl]pentanoate (85 mg, 128 µmol, racemate, example 189A) in dichloromethane (1.1 ml) was added with TFA (220 µl, 2.8 mmol) and the mixture was left for 3.5 h at RT. The mixture was then concentrated and mixed several times with dichloromethane and re-concentrated. The residue was purified by preparative HPLC (method 7). The combined target fractions were concentrated and the residue was lyophilized. Received 52 mg (100% pure, 67% theoretical. yield.) indicated in the title compound.

LC-MS (method 1): R _t = 2.16 min; MS (ESIpos): m/z = 608/610 [M+H]+.

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: -0.008 (1.21), 1.608 (4.52), 1.673 (8.82), 1.908 (0.41), 1.924 (0.72), 1.941 (1.34), 1.963 ( 1.75), 1.986 (1.24), 2.004 (0.65), 2.036 (1.55), 2.055 (3.62), 2.093 (8.19), 2.134 (16.00), 3.139 (11.63), 3.534 (1.87), 3.665 (0.84), 1.39), 3.697 (2.25), 3.713 (2.67), 3.728 (1.44), 3.745 (1.52), 3.762 (2.00), 3.781 (1.70) 4.62) 0.95), 7.628 (2.91), 7.650 (13.17), 7.659 (8.54), 7.664 (7.65), 7.681 (1.71), 7.686 (1.86), 8.775 (2.20), 8.790 (4.37), 8.805 (2.16), 0.54).

Example 183.

(-)-5-({[6-Bromo-3-methyl-2-(piperidin-1-yl)quinolin-4-yl]carbonyl}amino)-4-[2-(difluoromethoxy)6-fluorophenyl]valeric acid (enantiomer 1).

To a solution of (-)-tert-butyl-5-({[6-bromo-3-methyl-2-(piperidin-1-yl)quinolin-4yl]carbonyl}amino)-4-[2-(difluoromethoxy) -6-Fluorophenyl]pentanoate (180 mg, 271 µmol, enantiomer 7, example 190A) in dichloromethane (2.1 ml) was added with TFA (460 µl, 6.0 mmol) and the mixture was left for 24 h at RT. The mixture was then concentrated and mixed several times with dichloromethane and re-concentrated. The residue was purified by preparative HPLC (method 7). The combined target fractions were concentrated and the residue was lyophilized. 121 mg (100% pure, 73% thor.) of the title compound were obtained.

[a] _D20 = -30.4°, 589 nm, c = ^0.33 g/100 ml, methanol;

LC-MS (method 1): R _t = 2.15 min; MS (ESIpos): m/z = 608/610 [M+H]+.

- 203 040220

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: -0.008 (1.66), 1.608 (4.73), 1.673 (9.37), 1.921 (0.69), 1.939 (1.41), 1.959 (1.86), 1.984 ( 1.30), 2.003 (0.64), 2.034 (1.58), 2.050 (3.83), 2.087 (8.86), 2.133 (16.00), 2.327 (0.43), 2.670 (0.46), 3.137 (12.32), 3.532 (1.88), 0.85), 3.678 (1.42), 3.696 (2.33), 3.711 (2.76), 3.726 (1.49), 3.744 (1.58), 3.761 (2.09), 3.780 (1.82), 3.793 (1.14), 3.814 (0.67), 4.17) 4.27), 7.474 (1.00), 7.626 (3.16), 7.648 (13.68), 7.658 (8.84), 7.662 (8.24), 7.680 (1.79), 7.685 (2.02) 2.18), 12.067 (0.62).

Example 184.

(+)-5-({[6-Bromo-3-methyl-2-(piperidin-1-yl)quinolin-4-yl]carbonyl}amino)-4-[2-(difluoromethoxy)6-fluorophenyl]valeric acid (enantiomer 2).

To a solution of (+)-tert-butyl-5-({[6-bromo-3-methyl-2-(piperidin-1-yl)quinolin-4yl]carbonyl}amino)-4-[2-(difluoromethoxy) -6-Fluorophenyl]pentanoate (145 mg, 218 µmol, enantiomer 2, example 191A) in dichloromethane (1.7 ml) was added with TFA (370 µl, 4.8 mmol) and the mixture was left for 24 h at RT. The mixture was then concentrated and mixed several times with dichloromethane and re-concentrated. The residue was purified by preparative HPLC (method 7). The combined target fractions were concentrated and the residue was lyophilized. 95 mg (100% pure, 72% of theory) of the title compound were obtained.

[a] _D20 = +29.9°, 589 nm, c = 0.30 g/100 ml ^, methanol;

LC-MS (method 1): Rt = 2.15 min; MS (ESIpos): m/z = 608/610 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.070 (0.53), 1.608 (4.56), 1.673 (9.01), 1.921 (0.70), 1.939 (1.37), 1.959 (1.76), 1.984 (1.24) , 2.000 (0.64), 2.034 (1.52), 2.052 (3.62), 2.090 (8.27), 2.133 (16.00), 2.669 (0.44), 3.137 (11.85), 3.532 (1.81), 3.664 (0.80) , 3.696 (2.21), 3.712 (2.64), 3.727 (1.46), 3.744 (1.54), 3.763 (2.00), 3.781 (1.73), 3.815 (0.63), 7.020 (4.01), 7.041 (4.64), 7.049 (3.41) , 7.091 (2.61) , 7.648 (12.70), 7.658 (7.83), 7.662 (7.47), 7.680 (1.63), 7.684 (1.80), 8.775 (2.16), 8.789 (4.27), 8.804 (2.14), 12.053 (1.06).

Example 185.

(-)-5-[({6-Bromo-2-[3-fluoropiperidin-1-yl]-3-methylquinolin-4-yl}carbonyl)amino]-4-(2chlorophenyl)valeric acid (diastereoisomer 1) [ see Example 78 (mixture of diastereoisomers) for the structural formula.

To a solution of (-)-tert-butyl-5-[({6-bromo-2-[3-fluoropiperidin-1-yl]-3-methylquinolin-4yl}carbonyl)amino]-4-(2-chlorophenyl) pentanoate (470 mg, 742 μmol, diastereoisomer 7, example 192A) in dichloromethane (13 ml) was added with TFA (1.3 ml, 16 mmol) and the mixture was left for 16 h at RT. The mixture was then concentrated and mixed several times with dichloromethane and re-concentrated. The residue was purified by preparative HPLC (method 32). The combined target fractions were concentrated and the residue was lyophilized from acetonitrile/water. 372 mg (100% pure, 68% thor.) of the title compound were obtained.

[a] _D20 = -9.3°, 589 nm, c = ^0.35 g/100 ml, methanol;

LC-MS (method 1): Rt = 2.06 min; MS (ESIpos): m/z = 576/578 [M+H] ⁺ .

1H-NMR (500 MHz, DMSO-d ₆ ) δ [ppm]: -0.007 (1.49), 0.006 (1.24), 1.640 (2.13), 1.775 (0.87), 1.793 (2.38), 1.801 (2.71), 1.818 ( 3.92), 1.835 (3.85), 1.853 (2.01), 1.906 (3.85), 1.916 (2.80), 1.923 (3.08), 1.944 (1.86), 1.966 (1.19), 1.973 (1.24), 1.990 (0.72), 0.95), 2.032 (1.71), 2.049 (6.03), 2.070 (5.11), 2.077 (5.53), 2.094 (4.64), 2.117 (3.43), 2.134 (7.30), 2.146 (15.75), 3.067 (1.67), 2.43) 1.66), 3.415 (1.66), 3.436 (2.25), 3.457 (1.57), 3.595 (2.39), 4.829 (1.80), 4.919 (1.56), 4.925 (1.81) 4.84), 7.287 (3.20), 7.289 (3.16), 7.358 (3.08), 7.373 (5.30), 7.387 (2.77) 6.24) 3.02), 8.731 (5.62), 8.743 (2.74).

Example 186.

(-)-5-[({6-Bromo-2-[3-fluoropiperidin-1-yl]-3-methylquinolin-4-yl}carbonyl)amino]-4-(2chlorophenyl)valeric acid (diastereoisomer 2).

To a solution of (-)-tert-butyl-5-[({6-bromo-2-[3-fluoropiperidin-1-yl]-3-methylquinolin-4yl}carbonyl)amino]-4-(2-chlorophenyl) pentanoate (420 mg, 664 μmol, diastereoisomer 2, example 193A) in dichloromethane (12 ml) was added with TFA (1.1 ml, 15 mmol) and the mixture was left for 16 h at RT. The mixture was then concentrated and mixed several times with dichloromethane and re-concentrated. The residue was purified by preparative HPLC (method 32). The combined target fractions were concentrated and the residue was lyophilized from acetonitrile/water. 331 mg (100% pure, 86% thor.) of the title compound were obtained.

[a] _D20 = -16.5°, 589 nm, c = 0.43 g ^/ 100 ml, methanol;

LC-MS (method 1): Rt = 2.06 min; MS (ESIpos): m/z = 576/578 [M+H] ⁺ .

- 204 040220

1H-NMR (500 MHz, DMSO-d ₆ ) δ [ppm]: -0.007 (1.47), 0.007 (1.09), 1.644 (1.88), 1.650 (1.80), 1.772 (0.62), 1.791 (2.00), 1.799 ( 1.815 (3.30), 1.833 (3.44), 1.851 (1.68), 1.905 (3.34), 1.922 (2.59), 1.943 (1.35), 1.949 (1.32), 1.967 (1.01), 1.975 (1.02), 1.983 ( 0.67), 1.991 (0.54), 2.019 (0.68), 2.029 (1.29), 2.038 (1.58), 2.046 (5.27), 2.066 (4.31), 2.073 (4.72), 2.090 (4.20), 2.113 (2.61), 5.56), 2.144 (12.88), 2.518 (0.57), 2.522 (0.43), 3.073 (1.31), 3.094 (2.18), 3.108 (1.92) 1.40), 3.297 (2.20), 3.309 (2.83), 3.322 (3.01), 3.337 (1.88), 3.385 (2.32), 3.406 (1.51), 3.411 (1.50), 3.427 (2.03), 3.432 (2.11), 1.48), 3.592 (2.08), 3.651 (1.20), 3.665 (2.13), 3.676 (2.72), 3.686 (2.31), 4.820 (1.33), 4.826 (1.57), 4.915 (1.34), 4.921 (1.57), 1.30), 7.257 (1.94), 7.260 (2.01), 7.273 (4.31), 7.288 (2.95), 7.290 (2.80), 7.359 (2.64), 7.374 (4.73), 7.388 (2.45), 7.442 (8.34), 7.88), 7.458 (7.21), 7.461 (6.59), 7 .482 (5.70), 7.484 (5.71), 7.497 (4.85), 7.651 (3.74), 7.668 (16.00), 7.675 (11.47), 7.679 (9.85), 7.693 (2.33), 7.697 (2.46), 8.720 (2.73) , 8.732 (5.23), 8.743 (2.55).

Example 187.

(+)-5-[({6-Bromo-2-[3-fluoropiperidin-1-yl]-3-methylquinolin-4-yl}carbonyl)amino]-4-(2chlorophenyl)valeric acid (diastereoisomer 3).

To a solution of (+)-tert-butyl-5-[({6-bromo-2-[3-fluoropiperidin-1-yl]-3-methylquinolin-4yl}carbonyl)amino]-4-(2-chlorophenyl) pentanoate (580 mg, 916 μmol, diastereoisomer 3, example 194A) in dichloromethane (8 ml) was added with TFA (1.4 ml, 18 mmol) and the mixture was left for 18 h at RT. The mixture was then concentrated and mixed several times with dichloromethane and re-concentrated. The residue was purified by preparative HPLC (method 6). The combined target fractions were concentrated and the residue was lyophilized from acetonitrile/water. 470 mg (100% pure, >99% ee, 89% thor.) of the title compound were obtained.

[a] _D20 = +10.0°, 589 nm, c = 0.37 g/100 mL ^, methanol;

LC-MS (method 1): Rt = 2.09 min; MS (ESIpos): m/z = 576/578 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (3.12), 0.008 (2.34), 1.641 (1.61), 1.793 (1.81), 1.811 (2.86), 1.835 (3.14), 1.858 (4.00 ), 2.079 (4.65), 2.088 (1.78), 3.158 (1.92), 3.175 (1.82), 3.680 (3.53), 4.817 (4.34), 7.392 (2.23), 7.441 (1.83), 1.898 (2.57), 1.917 (2.18 ), 1.948 (1.57), 1.982 (0.97), 2.012 (0.69), 2.045 (4.76), 2.143 (16.00), 2.327 (0.60), 2.366 (0.43), 2.670 (0.60), 3.060 (1.10), 3.093 (1.84 ), 3.202 (1.07), 3.380 (1.98), 3.406 (1.07), 3.438 (1.66), 3.464 (1.06), 3.594 (1.32), 4.937 (1.32), 7.256 (1.68), 7.274 (3.88), 7.291 (2.78 ), 7.356 (2.33), 7.374 (6.24), 7.444 (5.85), 7.461 (5.31), 7.464 (4.93), 7.484 (5.31), 7.500 (4.60), 7.647 (2.38), 7.668 (13.37), 7.675 (9.32 ), 7.680 (8.01), 7.698 (1.56), 7.702 (1.76), 8.716 (2.06), 8.730 (4.24), 8.745 (2.04), 12.062 (0.71).

Example 188.

(+)-5-[({6-Bromo-2-[3-fluoropiperidin-1-yl]-3-methylquinolin-4-yl}carbonyl)amino]-4-(2chlorophenyl)valeric acid (diastereoisomer 4).

To a solution of (+)-tert-butyl-5-[({6-bromo-2-[3-fluoropiperidin-1-yl]-3-methylquinolin-4yl}carbonyl)amino]-4-(2-chlorophenyl) pentanoate (609 mg, 962 μmol, diastereoisomer 4, example 195A) in dichloromethane (8 ml) was added with TFA (1.5 ml, 19 mmol) and the mixture was left for 18 h at RT. The mixture was then concentrated and mixed several times with dichloromethane and re-concentrated. The residue was purified by preparative HPLC (method 6). The combined target fractions were concentrated and the residue was lyophilized from acetonitrile/water.

485 mg (100% pure, >95% ee, 87% thor.) of the title compound were obtained.

LC-MS (method 1): Rt = 2.09 min; MS (ESIpos): m/z = 576/578 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.646 (1.83), 1.765 (0.56), 1.792 (1.99), 1.811 (3.13), 1.819 (2.79), 1.834 (3.36), 1.858 (2.09) , 1.901 (2.96), 1.921 (2.38), 1.948 (1.57), 1.983 (1.04), 2.011 (0.79), 2.045 (4.41), 2.080 (5.20), 2.088 (5.48), 2.101 (2.64), 2.142 (16.00) , 2.218 (0.42), 2.327 (0.45), 2.366 (0.42), 2.670 (0.47), 2.710 (0.44), 3.068 (1.11), 3.100 (2.08), 3.147 (2.16), 3.162 (2.10), 3.190 (1.11) . . 7.484 (5.92), 7.501 (4.82), 7.646 (2.35), 7.668 (13.36), 7.675 (9.12), 7.679 (7.80), 7.697 (1.46), 7.702 (1.63), 8.716 (2.26), 8.730 (4.52) , 8.744 (2.19), 12.050 (0.58).

Example 189.

(+)-5-[({6-Bromo-2-[3-fluoropiperidin-1-yl]-3-methylquinolin-4-yl}carbonyl)amino]-4-[2(trifluoromethyl)phenyl]valeric acid ( diastereoisomer 1) [for structural formula, see example 123 (mixture of diastereoisomers)].

To a solution of (+)-tert-butyl-5-[({6-bromo-2-[3-fluoropiperidin-1-yl]-3-methylquinolin-4yl}carbonyl)amino]-4-[2-(trifluoromethyl )phenyl]pentanoate (60 mg, 90 μmol, diastereoisomer 7, example 196A) in dichloromethane (690 μl) was added with TFA (150 μl, 2.0 mmol) and the mixture was left for 24 h at RT. The mixture was then concentrated and mixed several times with dichloromethane and re-concentrated. The residue was purified by preparative HPLC (method 7). The combined target fractions were concentrated and the residue was lyophilized from acetonitrile/water. Received 43 mg (100% pure

- 205 040220 you, 77% of theor. out) specified in the connection header.

[a] _D20 = +15.8°, 589 nm, c = 0.29 g/100 mL ^, methanol;

LC-MS (method 1): Rt = 2.11 min; MS (ESIpos): m/z = 610/612 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: -0.008 (2.36), 0.069 (0.58), 1.652 (1.85), 1.773 (0.52), 1.812 (1.73), 1.905 (4.46), 1.925 ( 4.44), 1.935 (3.90), 1.957 (3.44), 1.974 (3.09), 1.987 (2.33), 1.998 (3.21), 2.036 (1.48), 2.051 (2.71), 2.074 (2.78), 2.092 (1.69), 2.91) 2.51) 1.56), 7.463 (2.86), 7.482 (4.75), 7.500 (2.94), 7.658 (1.91), 7.680 (16.00), 7.687 (11.53), 7.706 (5.71) 6.70), 8.778 (2.25), 8.793 (4.51), 8.808 (2.24).

Example 190.

(+)-5-[({6-Bromo-2-[3-fluoropiperidin-1-yl]-3-methylquinolin-4-yl}carbonyl)amino]-4-[2(trifluoromethyl)phenyl]valeric acid ( diastereoisomer 2).

To a solution of (+)-tert-butyl-5-[({6-bromo-2-[3-fluoropiperidin-1-yl]-3-methylquinolin-4yl}carbonyl)amino]-4-[2-(trifluoromethyl )phenyl]pentanoate (60 mg, 90 μmol, diastereoisomer 2, example 197A) in dichloromethane (690 μl) was added with TFA (150 μl, 2.0 mmol) and the mixture was left for 24 h at RT. The mixture was then concentrated and mixed several times with dichloromethane and re-concentrated. The residue was purified by preparative HPLC (method 7). The combined target fractions were concentrated and the residue was lyophilized from acetonitrile/water. 38 mg (100% pure, 70% thor.) of the title compound were obtained.

[a] _D20 = +21.1°, 589 nm, c = 0.29 ^g /100 mL, methanol;

LC-MS (method 1): Rt = 2.11 min; MS (ESIpos): m/z = 610/612 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.069 (0.92), 1.651 (1.87), 1.771 (0.52), 1.811 (1.72), 1.903 (4.20), 1.923 (4.35), 1.952 (3.26) , 1.968 (3.32), 1.981 (2.34), 1.992 (3.53), 2.030 (1.48), 2.046 (2.71) . . , 4.824 (1.52), 4.944 (1.52), 7.463 (2.71), 7.482 (4.63), 7.500 (2.86), 7.657 (1.95), 7.679 (16.00), 7.686 (11.33), 7.708 (5.90) , 7.734 (7.42), 7.739 (7.24), 8.784 (2.18), 8.799 (4.37), 8.813 (2.19).

Example 191.

5-[({6-Bromo-2-[3-fluoropiperidin-1-yl]-3-methylquinolin-4-yl}carbonyl)amino]-4-[2(trifluoromethyl)phenyl]valeric acid (diastereoisomer 3)

Interaction and separation of mixed fractions from example 196A (peak 1):

The mixed fraction described in Example 196A (peak 1) was dissolved in dichloromethane (1.5 ml), mixed with TFA (340 μl, 4.4 mmol) and the mixture was left for 24 h at RT. The mixture was then concentrated and mixed several times with dichloromethane and re-concentrated. The residue was purified by preparative HPLC (method 7). The product-containing fractions were collected (with a loss of substance), combined, concentrated, and the residue was lyophilized from acetonitrile/water. 45 mg (100% pure) 5-[({6-bromo-2-[3-fluoropiperidin-1-yl]-3-methylquinolin-4-yl}carbonyl)amino]-4[2-(trifluoromethyl)- phenyl]valeric acid (mixture of diastereoisomers).

mg of this mixture of diastereoisomers was dissolved in a mixture (8 ml) of acetonitrile and methanol and purified by preparative SLC on a chiral phase (see examples 191 and 192) [column: Daicel Chiralcel OD-H, 5 μm, 250 mm x 20 mm; flow: 80 ml/min; sample injection: 2.0 ml; temperature 40°C, UV detection 210 nm, eluent: 80% carbon dioxide/20% ethanol; duration of action 6.5 min, isocratic]. The combined target fractions were suitably concentrated and the residue was suitably lyophilized.

(-)-5-[({6-Bromo-2-[3-fluoropiperidin-1-yl]-3-methylquinolin-4-yl}carbonyl)amino]-4-[2(trifluoromethyl)phenyl]valeric acid ( diastereoisomer 3).

The separation of the diastereoisomers as described gave 3 mg (100% pure) of the title compound as the primarily eluting diastereoisomer.

LC-MS (method 1): Rt = 2.12 min; MS (ESIpos): m/z = 610/612 [M+H] ⁺ .

1H-NMR (500 MHz, DMSO-d ₆ ) δ [ppm]: -0.007 (0.29), 0.006 (0.25), 0.069 (0.38), 0.843 (0.31), 1.033 (0.89), 1.045 (0.90), 1.236 (0.47), 1.296 (0.21), 1.483 (0.16), 1.498 (0.17), 1.652 (1.74), 1.813 (1.61), 1.829 (1.36), 1.907 (4.05), 1.914 (4.49), 1.924 (3.83), 1.947 (2.99), 1.965 (2.07), 1.979 (3.03), 1.989 (2.09), 1.998 (2.78), 2.007 (1.91), 2.045 (1.72), 2.057 (2.46), 2.076 (2.68), 2.090 (1.44), 2.107 (2.78), 2.118 (1.61), 2.133

(2.08), 2.177 (10.18), 2.215 (0.82), 2.359 (0.30), 2.363 (0.36), 2.432 (1.68), 2.637 (0.45), 2.640 (0.34) (2.21) 3.188 (2.24) 3.208 (1.55) 3.229 (3.57) 3.396 (3.72) 3.422 (2.39) (1.80) (1.65) (6.31), 7.724 (9.33), 7.735 (6.85), 7.740 (6.75), 7.749 (2.78), 7.826 (0.92), 8.777 (2.43), 8.789 (4.78), 8.801

- 206 040220 (2.35).

Example 192.

5-[({6-Bromo-2-[3-fluoropiperidin-1-yl]-3-methylquinolin-4-yl}carbonyl)amino]-4-[2(trifluoromethyl)phenyl]valeric acid (diastereoisomer 4).

Separation of diastereoisomers as described in Example 191 gave 3 mg (100% pure) of the title compound as the second eluting diastereoisomer.

LC-MS Method 1): Rt = 2.12 min; MS (ESIpos): m/z = 610/612 [M+H]+.

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.150 (0.03), 0.145 (0.03), 1.199 (0.06), 1.313 (0.08), 1.324 (0.10), 1.359 (16.00), 1.515 (0.07 ), 1.606 (1.36), 1.786 (0.95), 1.829 (0.23), 1.856 (0.12), 2.014 (0.07), 2.033 (0.72), 2.327 (0.04), 2.669 (0.04), 3.369 (0.20), 3.618 (0.27 ), 3.630 (0.26), 3.645 (0.64), 7.414 (0.61), 7.420 (0.72), 7.432 (0.62), 7.606 (0.59), 7.623 (0.33), 7.628 (0.27), 2.044 (0.29), (0.20) , 3.386 (0.20), (0.24), 3.663 (0.18), (0.19), 7.534 (0.65), (0.32), 8.703 (0.21), 8.718 (0.40), 8.732 (0.20).

2.065 (1.27), 2.089 (0.32), 2.096 (0.28), 2.128 3.496 (1.10), 3.511 (1.53), 3.525 (1.08), 3.602 7.358 (0.39), 7.384 (0.20), 7.397 (0.78), 7.408 7.546 (0.46), 7.556 (1.45), 7.569 (0.34), 7.600

Example 193.

(+)-5-[({6-Bromo-2-[3-ethylpiperidin-1-yl]-3-methylquinolin-4-yl}carbonyl)amino]-4-[2(trifluoromethyl)phenyl]valeric acid ( diastereoisomer 1) [for the structural formula, see example 124 (mixture of diastereoisomers)].

To a solution of (+)-tert-butyl-5-[({6-bromo-2-[3-ethylpiperidin-1-yl]-3-methylquinolin-4yl}carbonyl)amino]-4-[2-(trifluoromethyl )phenyl]pentanoate (45 mg, 67 μmol, diastereoisomer 7, example 198A) in dichloromethane (510 μl) was added with TFA (110 μl, 1.5 mmol) and the mixture was left for 24 h at RT. The mixture was then concentrated and mixed several times with dichloromethane and re-concentrated. The residue was purified by preparative HPLC (method 7). The combined target fractions were concentrated and the residue was lyophilized from acetonitrile/water. 33 mg (100% pure, 81% thor.) of the title compound were obtained.

[a] _D20 = +11.5°, 436 nm, c = 0.44 ^g /100 mL, methanol;

LC-MS (method 2): Rt = 1.28 min; MS (ESIpos): m/z = 620/622 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.895 (1.56), 0.913 (3.64), 0.932 (1.85), 1.263 (0.63), 1.281 (0.82), 1.298 (0.59), 1.571 (0.42) , 1.753 (0.48), 1.887 (0.65), 1.921 (0.41), 1.965 (0.46), 1.989 (0.49) , 2.501 (16.00) , 7.685 (0.50), 7.706 (0.96), 7.715 (1.30), 7.735 (2.15), 7.754 (0.48), 8.778 (0.74).

Example 194.

(-)-5-[({6-Bromo-2-[3-ethylpiperidin-1-yl]-3-methylquinolin-4-yl}carbonyl)amino]-4-[2(trifluoromethyl)phenyl]valeric acid ( diastereoisomer 2).

To a solution of (-)-tert-butyl-5-[({6-bromo-2-[3-ethylpiperidin-1-yl]-3-methylquinolin-4yl}carbonyl)amino]-4-[2-(trifluoromethyl )phenyl]pentanoate (40 mg, 59 µmol, diastereoisomer 2, example 199A) in dichloromethane (450 µl) was added with TFA (100 µl, 1.3 mmol) and the mixture was left for 24 h at RT. The mixture was then concentrated and mixed several times with dichloromethane and re-concentrated. The residue was purified by preparative HPLC (method 7). The combined target fractions were concentrated and the residue was lyophilized from acetonitrile/water. 33 mg (100% pure, 81% thor.) of the title compound were obtained.

[a] _D20 = -42.9°, 589 nm, c = ^0.34 g/100 ml, methanol;

LC-MS (method 2): Rt = 1.28 min; MS (ESIpos): m/z = 620/622 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.146 (0.17), 0.896 (6.44), 0.915 (16.00), 0.934 (7.90), 1.060 (0.48), 1.087 (3.26), 1.315 (1.58) , 1.895 (0.80), 2.041 (0.30), 2.671 (1.37), 3.634 (1.16), 1.113 (1.24), 1.139 (0.55), 1.234 (0.82), 1.247 (1.07), 1.264 (2.26), 1.281 (3.55) ,1.299 (1.91), 1.333 (0.76), 1.578 (1.42), 1.618 (1.33), 1.651 (1.17), 1.763 (1.74), 1.797 (1.17),1.858 (2.34), 1.927 (1.27), 1.945 (1.22) , 1.967 (0.98), 1.985 (1.74), 1.997 (1.06), 2.008 (2.11), 2.025 (1.12), 2.057 (2.00), 2.080 (2.04), 2.097 (1.20), 2.110 (2.27), 2.165 (10.84) , 2.328 (0.56), 2.367 (0.47), 2.711 (0.25), 2.779 (0.72), 2.809 (1.32), 3.326 (1.42), 3.546 (2.56), 3.577 (2.59) . , 8.792 (2.81), 8.807 (1.49).

Example 195.

5-[({6-Bromo-2-[3-ethylpiperidin-1-yl]-3-methylquinolin-4-yl}carbonyl)amino]-4-[2(trifluoromethyl)phenyl]valeric acid (diastereoisomer 3).

To a solution of (-)-tert-butyl-5-[({6-bromo-2-[3-ethylpiperidin-1-yl]-3-methylquinolin-4yl}carbonyl)amino]-4-[2-(trifluoromethyl )phenyl]pentanoate (55 mg, 81 μmol, diastereoisomer 3, example 200A) in dichloromethane (625 μl) was added with TFA (138 μl, 1.78 mmol) and the mixture was left for 24 h at RT. The mixture was then concentrated and mixed several times with dichloromethane and re-concentrated. The residue was purified by preparative HPLC (method 7). The combined target fractions were concentrated and the residue was lyophilized from acetonitrile/water. Received 33 mg (100% pure

- 207 040220 you, 81% theor. out) specified in the connection header.

LC-MS (method 2): Rt = 1.28 min; MS (ESIpos): m/z = 620/622 [M+H]+.

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.896 (6.71), 0.915 (16.00), 0.933 (7.95), 1.060 (0.50), 1.089

(1.32), 1.118 (2.79), 1.301 (0.58), 1.763 (1.14), 1.982 (6.50), 2.328 (1.56), 3.545 (1.68), 3.759

1.140 (0.62), 1.233 (0.74), 1.248 (1.12), 1.265 (2.52), (2.42), 1.310 (1.90), 1.344 (0.28), 1.580 (1.69), 1.606 (1.47), (1.92 ), 1.796 (1.31), 1.856 (1.82), 1.895 (2.61), 1.920 (1.46), (1.98), 1.995 (1.20), 2.006 (2.34), 2.023 (1.04), 2.044 (1.28), (0.40), 2.367 (0.31), 2.671 (0.37), 2.711 (0.24), 2.784 (0.87), (2.89), 3.576 (2.80), 3.609 (1.15), 3.626 (1.48), 3.643 (1.56), (1.21), 3.775 ( 0.66), 4.374 (0.60), 7.465 (2.03), 7.483 (3.62),

1.275

1.616

1.927

2.059

2.812

3.708

7.502 (2.32), 1.283 (3.35), 1.292 (1.53), 1.648 (1.30), 1.678 (1.46), 1.943 (1.42), 1.965 (2.27), 2.082 (2.50), 2.137 (1.60), 2.840 (0.89), 3.324 (1.13) 3.725 (1.89) 3.742 (2.29) 7.690 (1.98) 7.710 (13.25) 7.728 (4.42) 7.739 (8.10) 7.761 (2.15) 8.780 (1.62) 8.809 (1.68).

Example 196.

(+)-5-[({6-Bromo-2-[3-ethylpiperidin-1-yl]-3-methylquinolin-4-yl}carbonyl)amino]-4-[2(trifluoromethyl)phenyl]valeric acid ( diastereoisomer 4).

To a solution of (-)-tert-butyl-5-[({6-bromo-2-[3-ethylpiperidin-1-yl]-3-methylquinolin-4yl}carbonyl)amino]-4-[2-(trifluoromethyl )phenyl]pentanoate (45 mg, 67 µmol, diastereoisomer 4, example 201 A) in dichloromethane (512 µl) was added with TFA (113 µl, 1.46 mmol) and the mixture was left for 24 h at RT. The mixture was then concentrated and mixed several times with dichloromethane and re-concentrated. The residue was purified by preparative HPLC (method 7). The combined target fractions were concentrated and the residue was lyophilized from acetonitrile/water. 22 mg (100% pure, 54% thor.) of the title compound were obtained.

[a] _D20 = +36.5°, 589 nm, c = 0.44 g/100 mL ^, methanol;

LC-MS (method 2): Rt = 1.28 min; MS (ESIpos): m/z = 620/622 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.895 (6.49), 0.914 (16.00), 0.933 (7.87), 1.045 (0.48), 1.074 (1.22), 1.097 (1.27), 1.126 (0.56) , 1.245 (1.11), 1.262 (2.28), 1.279 (3.44), 1.296 (3.11), 1.312 (1.94), 1.330 (0.77), 1.572 (1.42), 1.615 (1.37), 1.644 (1.20), 1.755 (1.80) , 1.788 (1.19), 1.853 (1.63), 1.894 (2.29), 1.926 (1.31), 1.942 (1.33), 1.965 (1.02), 1.982 (1.75), 1.994 (1.19), 2.006 (2.13), 2.024 (0.84) . , 2.670 (0.49), 2.710 (0.42), 2.733 (0.86), 2.759 (1.56), 2.790 (0.85), 3.325 (1.61), 3.522 (5.03), 3.543 (4.60), 3.595 (2.21), 3.614 (2.34) . , 7.723 (6.19), 7.740 (7.10), 7.756 (1.65), 8.756 (1.60), 8.770 (3.12), 8.785 (1.58).

Example 197.

(+)-5-[({6-Bromo-3-methyl-2-[3-methylpiperidin-1-yl]quinolin-4-yl}carbonyl)amino]-4-[2(trifluoromethyl)phenyl]valeric acid (diastereoisomer 1) [for structural formula, see Example 125 (mixture of diastereoisomers)].

To a solution of (+)-tert-butyl-5-[({6-bromo-3-methyl-2-[3-methylpiperidin-1-yl]quinolin-4yl}carbonyl)amino]-4-[2-( trifluoromethyl)phenyl]pentanoate (70 mg, 106 µmol, diastereoisomer 1, example 202A) in dichloromethane (810 µl) TFA (180 µl, 2.32 mmol) was added and the mixture was left for 24 h at RT. The mixture was then concentrated and mixed several times with dichloromethane and re-concentrated. The residue was purified by preparative HPLC (method 7). The combined target fractions were concentrated and the residue was lyophilized from acetonitrile/water. 45 mg (100% pure, 70% thor.) of the title compound were obtained.

[a] _D20 = +22.2°, 589 nm, c = 0.27 ^g /100 mL, methanol;

LC-MS (method 1): Rt = 2.34 min; MS (ESIpos): m/z = 606/608 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.149 (0.18), -0.008 (1.58), 0.008 (1.81), 0.069 (0.44), 0.146 (0.19), 0.927 (10.77), 0.943 ( 10.98), 0.984 (0.16), 1.056 (0.36), 1.084 (1.12), 1.114 (1.17), 1.135 (0.48), 1.235 (0.33), 1.633 (0.97), (1.08), 1.902 (1.01) , 2.032 (0.90), (0.19), 2.436 (1.04), (3.26), 3.508 (1.63), (0.73), 7.462 (1.67),

1.663 1.924

2.047 2.465

3.608

7.481 (1.14), 1.691 (0.56), 1.737 (2.00), (1.40), 1.938 (1.28), 1.952 (1.21), (1.77), 2.071 (1.84), 2.088 (1.01), (1.69), 2.670 (0.37 ), 2.691 (0.96), (0.78), 3.625 (1.19), 3.641 (1.32),

1.771 (1.99), 1.797 1.968 (1.64), 1.981 2.108 (1.88), 2.162 2.718 (1.71), 2.747 3.696 (1.34), 3.712

(2.53), 1.827 (1.55), 1.893 (0.97), 1.992 (1.83), 2.001 (8.48), 2.328 (0.30), 2.367 (0.94), 3.452 (1.85) (2.99), 7.499 (1.81), 7.636 (0.90), 7.657 (16.00), 7.661 (8.05), 7.684 (1.57), 7.707 (3.18) (1.46), 8.781 (2.92), 8.795 (1.44), 12.101 (0.17).

Example 198.

(+)-5-[({6-Bromo-3-methyl-2-[3-methylpiperidin-1-yl]quinolin-4-yl}carbonyl)amino]-4-[2(trifluoromethyl)phenyl]valeric acid (diastereoisomer 2).

To a solution of (+)-tert-butyl-5-[({6-bromo-3-methyl-2-[3-methylpiperidin-1-yl]quinolin-4yl}carbonyl)amino]-4-[2-( trifluoromethyl)phenyl]pentanoate (70 mg, 106 µmol, diastereoisomer 2, example 203A) in dichloromethane (810 µl) TFA (180 µl, 2.3 mmol) was added and the mixture was left for 24 h at RT. The mixture was then concentrated and mixed several times with dichloromethane and re-concentrated

- 208 040220 rovali. The residue was purified by preparative HPLC (method 7). The combined target fractions were concentrated and the residue was lyophilized from acetonitrile/water. 47 mg (100% pure, 73% thor.) of the title compound were obtained.

[a] _D20 = +11.7°, 589 nm, c = 0.29 ^g /100 mL, methanol;

LC-MS (method 1): Rt = 2.34 min; MS (ESIpos): m/z = 606/608 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (1.27), 0.008 (1.49), 0.069 (0.30), 0.146 (0.17), 0.928 (11.12), 0.944 (11.35), 1.059 (0.37 ), 1.085 (1.15), 1.115 (1.18), 1.136 (0.47), 1.235 (0.19), 1.635 (0.98), 1.665 (1.19), 1.695 (0.56), 1.737 (2.01), 1.771 (1.99), 1.797 (2.48 ), 1.828 (1.54), 1.897 (1.09), 1.907 (1.03), 1.927 (1.25), 1.942 (1.18), 1.961 (1.04), 1.978 (1.67), 1.990 (1.02), 2.002 (1.92), 2.011 (1.17 ), 2.039 (1.00), 2.053 (1.87), 2.076 (1.89), 2.094 (1.09), 2.113 (1.91), 2.168 (10.24), 2.328 (0.43), 2.366 (0.20), 2.438 (1.20), 2.468 (1.84 ), 2.670 (0.48), 2.689 (0.90), 2.718 (1.63), 2.746 (0.89), 3.452 (1.81), 3.480 (3.20), 3.508 (1.54), 3.612 (1.12), 3.629 (1.22), 3.707 (1.17 ), 3.723 (1.04), 7.424 (0.65), 7.465 (1.63), 7.483 (2.97), 7.501 (1.79), 7.636 (0.89), 7.658 (16.00), 7.662 (7.92), 7.685 (1.30), 7.709 (3.20 ), 7.724 (6.78), 7.735 (4.84), 7.741 (4.46), 8.760 (1.53), 8.775 (3.04), 8.789 (1.47), 12.012 (0.45).

Example 199.

(-)-5-[({6-Bromo-3-methyl-2-[3-methylpiperidin-1-yl]quinolin-4-yl}carbonyl)amino]-4-[2(trifluoromethyl)phenyl]valeric acid (diastereoisomer 3).

Interaction and separation of mixed fractions from example 202A (peak 1).

The mixed fraction described in Example 202A (peak 1) was dissolved in dichloromethane (1.8 ml), mixed with TFA (390 μl, 5.05 mmol) and the mixture was left for 24 h at RT. The mixture was then concentrated and mixed several times with dichloromethane and re-concentrated. The residue was purified by preparative HPLC (method 7). The combined target fractions were concentrated and the residue was lyophilized from acetonitrile/water. Received 106 mg (100% pure) 5-[({6-bromo-3-methyl-2-[3methylpiperidin-1-yl]quinolin-4-yl}carbonyl)amino]-4-[2-(trifluoromethyl)phenyl ]valeric acid (mixture of diastereoisomers).

mg of this mixture of diastereoisomers was dissolved in a mixture (8 ml) of acetonitrile and methanol and purified by preparative SLC on a chiral phase (see examples 199 and 200) [column: Daicel Chiralcel OD-H, 5 μm, 250 mm x 20 mm; flow: 80 ml/min; sample injection: 2.0 ml; temperature 40°C, UV detection 210 nm, eluent: 80% carbon dioxide/20% ethanol; duration of action 6.5 min, isocratic]. The combined target fractions were suitably concentrated and the residue was suitably lyophilized.

(-)-5-[({6-Bromo-3-methyl-2-[3-methylpiperidin-1-yl]quinolin-4-yl}carbonyl)amino]-4-[2(trifluoromethyl)phenyl]valeric acid (diastereoisomer 3).

The separation of the diastereoisomers as described gave 24 mg (100% pure, >99% ee) of the title compound as the primarily eluting diastereoisomer.

LC-MS (method 2): Rt = 1.22 min; MS (ESIpos): m/z = 606/608 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (0.79), 0.008 (0.76), 0.069 (0.28), 0.927 (10.81), 0.943 (10.94), 1.056 (0.42), 1.084 (1.13) ), 1.108 (1.18), 1.136 (0.48), 1.237 (0.16), 1.633 (1.00), 1.663 (1.16), 1.737

(2.02), 1.744 (1.93), 1.772 (2.02), 1.797 (2.51), 1.828 (1.59), 1.898 (1.22), 1.909 (1.22), 1.929 (1.37), 1.942 (1.31), 1.963 (1.20), 1.979 (1.84), 1.992 (1.24), 2.004 (2.13), 2.012 (1.20), 2.040 (1.15), 2.055 (2.08), 2.079 (2.19), 2.096 (1.33), 2.114 (2.35), 2.162 (8.78), 2.328 (0.42), 2.366 (0.31), 2.436 (1.08), 2.466 (1.74), 2.670 (0.48), 2.691 (0.94), 2.718 (1.67), 2.747 (0.93), 3.452 (1.70), 3.479 (3.15), 3.509 (1.53), 3.628 (1.16), 3.644 (1.35), 3.697 (1.39), 3.713 (1.17), 7.432 (0.80), 7.464 (1.77), 7.483 (3.21), 7.502 (1.99), 7.636 (0.94), 7.658

(16.00), 7.662 (7.86), 7.685 (1.53), 7.709 (3.51), 7.724 (6.91), 7.740 (5.40), 7.754 (1.76) (2.34).

Example 200.

(-)-5-[({6-Bromo-3-methyl-2-[3-methylpiperidin-1-yl]quinolin-4-yl}carbonyl)amino]-4-[2(trifluoromethyl)phenyl]valeric acid (diastereoisomer 4).

Separation of diastereoisomers as described in Example 199 gave 23 mg (100% pure, >99% ee) of the title compound as the second eluted diastereoisomer.

LC-MS (method 2): Rt = 1.22 min; MS (ESIpos): m/z = 606/608 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.008 (0.84), 0.069 (0.29), 0.928 (11.23), 0.944 (11.35), 1.085 (1.20), 1.115 (1.22), 1.136 (0.52) , 1.634 (1.04), 1.665 (1.28), 1.692 (0.64), 1.737 (2.13), 1.771 (2.10), 1.797 (2.59), 1.828 (1.65), 1.897 (1.30), 1.909 (1.29), 1.929 (1.44) , 1.943 (1.42), 1.963 (1.22), 1.980 (1.93), 1.993 (1.27), 2.004 (2.23), 2.014 (1.33), 2.040 (1.25), 2.055 (2.17), 2.078 (2.26), 2.096 (1.43) . , 2.746 (0.93), 3.453 (1.89), 3.480 (3.27), 3.509 (1.63), 3.613 (1.27), 3.630 (1.33), 3.708 (1.29) 7.484 (3.29), 7.502 (2.08), 7.636 (0.78), 7.658 (16.00), 7.662 (8.26), 7.690 (1.53), 7.709 (3.65), 7.725 (7.44), 7.735 (5.58), 7.742 (5.23) , 8.758 (1.60), 8.773 (3.25), 8.788 (1.62), 12.029 (2.27).

- 209 040220

Example 201.

(-)-5-[({6-Bromo-2-[3-fluoropiperidin-1-yl]-3-methylquinolin-4-yl}carbonyl)amino]-4-[2(trifluoromethoxy)phenyl]valeric acid ( diastereoisomer 1) [for structural formula, see example

138 (mixture of diastereoisomers)].

To a solution of (-)-tert-butyl-5-[({6-bromo-2-[3-fluoropiperidin-1-yl]-3-methylquinolin-4yl}carbonyl)amino]-4-[2-(trifluoromethoxy )phenyl]pentanoate (70 mg, 101 µmol, diastereoisomer 7, example 204A) in dichloromethane (1.8 ml) was added with TFA (172 µl, 2.23 mmol) and the mixture was left for 16 h at RT. The mixture was then concentrated and mixed several times with dichloromethane and re-concentrated. The residue was purified by preparative HPLC (method 7). The combined target fractions were concentrated and the residue was lyophilized from acetonitrile/water. 40 mg (100% pure, 62% thor.) of the title compound were obtained.

[a] _D20 = -20.0°, 589 nm, c = 0.33 g ^/ 100 ml, methanol;

LC-MS (method 1): Rt = 2.15 min; MS (ESIpos): m/z = 626/628 [M+H]+.

1H-NMR (500 MHz, DMSO-d6) δ [ppm]: -0.007 (1.74), 0.006 (1.29), 0.117 (0.17), 1.234 (0.48), 1.358 (0.18), 1.647 (2.01), 1.777 (0.83 ), 1.794 (1.85), 1.807 (3.28), 1.815 (3.49), 1.825 (3.10), 1.833 (3.74), 1.851 (2.21), 1.910 (3.53), 1.926 (2.82), 1.948 (1.55), 1.970 (1.09 ), 1.978 (1.12), 1.995 (0.62), 2.010 (0.51), 2.031 (1.08), 2.042 (2.73), 2.068 (9.82), 2.072 (8.73), 2.093 (2.44), 2.106 (1.59), 2.153 (8.47 ), 2.242 (0.33), 2.358 (0.31), 2.362 (0.41), 2.519 (0.94), 2.523 (0.70), 2.632 (0.31), 2.636 (0.41), 2.639 (0.31), 3.079 (1.46), 3.100 (2.29 ), 3.163 (2.39), 3.177 (2.41), 3.198 (1.53), 3.292 (1.73), 3.305 (2.59), 3.318 (3.24), 3.331 (3.42), 3.345 (2.27), 3.390 (4.35), 3.395 (4.39 ), 3.415 (2.52), 3.441 (2.30), 3.463 (1.61), 3.594 (1.07), 3.605 (1.65), 3.620 (2.70), 3.632 (3.18), 3.645 (1.99), 3.656 (1.71), 3.670 (2.44 ), 3.684 (2.05), 3.696 (1.26), 3.711 (0.70), 4.831 (1.64), 4.920 (1.40), 4.926 (1.64), 4.932 (1.37), 7.343 (2.70), 7.347 (2.74), 7.351 (2.93 ), 7.355 (3.78), 7.359 (4.72), 7.362 (3.77), 7.384 (1.38), 7.389 (2.08), 7.399 (6.05), 7.403 (8.73), 7.410 (7.42), 7.417 (7.35) (3.30), 7.562 (3.39), 7.569 (3.42), 7.657 (3.58), 7.674 (16.00), 7.681 (10.84), 7.685 (9.37) (4.94), 8.769 (2.51).

Example 202.

(-)-5-[({6-Bromo-2-[3-fluoropiperidin-1-yl]-3-methylquinolin-4-yl}carbonyl)amino]-4-[2(trifluoromethoxy)phenyl]valeric acid ( diastereoisomer 2).

To a solution of (-)-tert-butyl-5-[({6-bromo-2-[3-fluoropiperidin-1-yl]-3-methylquinolin-4yl}carbonyl)amino]-4-[2-(trifluoromethoxy )phenyl]pentanoate (70 mg, 103 μmol, diastereoisomer 2, example 205A) in dichloromethane (1.8 ml) was added with TFA (174 μl, 2.26 mmol) and the mixture was left for 16 h at RT. The mixture was then concentrated and mixed several times with dichloromethane and re-concentrated. The residue was purified by preparative HPLC (method 7). The combined target fractions were concentrated and the residue was lyophilized from acetonitrile/water. 37 mg (100% pure, 58% thor.) of the title compound were obtained.

[a] _D20 = -14.2°, 589 nm, c = ^0.33 g/100 ml, methanol;

LC-MS (method 1): Rt = 2.15 min; MS (ESIpos): m/z = 626/628 [M+H] ⁺ .

1H-NMR (500 MHz, DMSO-d6) δ [ppm]: -0.120 (0.23), -0.007 (2.56), 0.006 (1.91), 0.070 (0.24), 0.117 (0.21), 1.234 (0.27), 1.249 ( 1.365 (0.16), 1.646 (1.97), 1.779 (0.86), 1.795 (1.89), 1.809 (3.39), 1.818 (3.31), 1.827 (3.12), 1.835 (3.65), 1.854 (2.25), 1.910 ( 3.52), 1.920 (2.49), 1.927 (2.86), 1.949 (1.66), 1.970 (1.11), 1.978 (1.13), 2.017 (0.45), 2.048 (2.62), 2.070 (10.21), 2.096 (2.46), 9.21) 1.56), 3.290 (1.92), 3.304 (2.85), 3.316 (3.52), 3.329 (3.62), 3.343 (2.38), 3.395 (4.37), 3.416 (2.57) 0.89), 3.611 (1.41), 3.625 (2.70), 3.638 (3.40), 3.650 (3.29), 3.664 (2.72), 3.678 (2.12), 3.690 (1.14), 3.705 (0.62), 4.826 (1.45), 1.71), 4.921 (1.45), 4.927 (1.72), 4.933 (1.42), 7.345 (2.69), 7.348 (2.70), 7.352 (2.89), 7.356 (3.79), 7.360 (4.70), 7.363 (3.78), 1.46), 7.389 (2.13), 7.399 (6.05), 7.4 03 (8.97), 7.410 (7.38), 7.417 (7.59), 7.431 (1.73), 7.480 (0.99), 7.551 (4.79), 7.555 (3.42) 7.675 (16.00), 7.682 (10.74), 7.686 (9.28), 7.700 (2.17), 7.704 (2.26), 8.743 (2.56), 8.755 (4.81), 8.766 (2.44), 12.171 (0.19).

Example 203.

(+)-5-[({6-Bromo-2-[3-fluoropiperidin-1-yl]-3-methylquinolin-4-yl}carbonyl)amino]-4-[2(trifluoromethoxy)phenyl]valeric acid ( diastereoisomer 3).

To a solution of (+)-tert-butyl-5-[({6-bromo-2-[3-fluoropiperidin-1-yl]-3-methylquinolin-4yl}carbonyl)amino]-4-[2-(trifluoromethoxy )phenyl]pentanoate (64 mg, 92 μmol, diastereoisomer 3, example 206A) in dichloromethane (1.62 ml) was added with TFA (156 μl, 2.02 mmol) and the mixture was left for 16 h at RT. The mixture was then concentrated and mixed several times with dichloromethane and re-concentrated. The residue was purified by preparative HPLC (method 7). The combined target fractions were concentrated and the residue was lyophilized from acetonitrile/water. 38 mg (100% pure, 65% thor.) of the title compound were obtained.

[a] _D20 = +14.9°, 589 nm, c = 0.32 g/100 mL ^, methanol;

LC-MS (method 1): Rt = 2.15 min; MS (ESIpos): m/z = 626/628 [M+H] ⁺ .

- 210 040220

1H-NMR (500 MHz, DMSO-d ₆ ) δ [ppm]: -0.007 (1.72), (0.22), 1.353 (0.39), 1.371 (0.25), 1.646 (2.02), 1.779 (0.85), (3.18) , 1.835 (3.82), 1.854 (2.40), 1.911 (3.61), 1.920 (2.55),

0.006 (1.14), 0.070 (0.25), 1.233 (0.53), 1.333

1.795 (1.93), 1.809 (3.59), 1.819 (3.45), 1.827

1.927 (2.93), 1.949 (1.71), 1.971 (1.13), 1.978 (1.15), 2.015 (0.49), 2.036 (1.12), 2.047 (2.88), 2.069 (10.49), 2.096 (2.64), 2.111 (1.57), 2.154 (9.53), 2.241 (0.34), 2.362 (0.36), 2.519 (0.74), 2.522 (0.54), 2.636 (0.34), 3.078 (1.52), 3.099 (2.33), 3.167 (2.56), 3.181 (2.58), 3.202 (1.69), 3.289 (1.77), 3.303 (2.69), 3.316 (3.34), 3.329 (3.53), 3.343 (2.33), 3.395 (4.62), 3.416 (2.75), 3.442 (2.37), 3.464 (1.65), 3.599 (0.94), 3.611 (1.50), 3.625 (2.85), 3.638 (3.63), 3.650 (3.47), 3.664 (2.87), 3.678 (2.24) 4.921 (1.49), 4.927 (1.76), 4.933 (1.46), 7.345 (2.68), 7.348 (2.69), 7.352 (2.86), 7.357 (3.85), 7.360 (4.78), 7.384 (1.37), 7.389 (2.04), 7.399 (6.17), 7.403 (9.14), 7.410 (7.53), 7.417 (7.95), 7.431 (1.82), 7.481 (1.02), 7.551 (5.06), 7.555 (3.52), 7.563 (3.66), 7.570 (3.84), 7.658 (3.63), 7.675 (16.00), 7.683 (10.62), 7.686 (9.13), 7.700 (2.21), 7.704 (2.30), 8.744 (2.82), 8.756 (5.44), 8.767 (2.75).

Example 204.

(+)-5-[({6-Bromo-2-[3-fluoropiperidin-1-yl]-3-methylquinolin-4-yl}carbonyl)amino]-4-[2(trifluoromethoxy)phenyl]valeric acid ( diastereoisomer 4).

To a solution of (+)-tert-butyl-5-[({6-bromo-2-[3-fluoropiperidin-1-yl]-3-methylquinolin-4yl}carbonyl)amino]-4-[2-(trifluoromethoxy )phenyl]pentanoate (64 mg, 94 μmol, diastereoisomer 4, example 207A) in dichloromethane (1.66 ml) was added with TFA (159 μl, 2.06 mmol) and the mixture was left for 16 h at RT. The mixture was then concentrated and mixed several times with dichloromethane and re-concentrated. The residue was purified by preparative HPLC (method 7). The combined target fractions were concentrated and the residue was lyophilized from acetonitrile/water. 31 mg (100% pure, 53% th. y.) of the title compound were obtained.

[a] _D20 = +20.0°, 589 nm, c = 0.35 g/100 mL ^, methanol;

LC-MS (method 1): Rt = 2.15 min; MS (ESIpos): m/z = 626/628 [M+H] ⁺ .

1H-NMR (500 MHz, DMSO-d ₆ ) δ [ppm]: -0.120 (0.20), -0.007 (2.68), (3.23), 1.235 (0.50), 1.353 (0.28), 1.386 (0.19), 1.646 ( 2.21), 1.778 (0.95), (3.73), 1.825 (3.47), 1.833 (4.07), 1.852 (2.39), 1.910 (3.89), 1.926 (3.11), (1.26), 2.047 (2.74) , 2.093 (2.58), 2.153 (9.32), 2.242 (0.35),

0.006 (1.93), 0.117 (0.20), 1.131

1.795 (2.07), 1.807 (3.59), 1.816

1.947 (1.73), 1.971 (1.24), 1.978

2.362 (0.50), 2.636 (0.46), 3.080 (3.33), 3.318 (4.05), 3.331 (1.14), 3.605 (1.76), 3.620 (1.38), 3.711 (0.77), 4.254 (0.26), 7.344 (2.98), 7.347 (9.12), 7.411 (7.68), 7.418

(1.61), 3.099 (2.52), 3.163 (2.63), 3.176 (2.67), 3.198 (1.69), 3.291 (2.30), (4.17), 3.345 (2.80), 3.390 (4.88), 3.415 (2.76), 3.441 (2.48), 3.462 (1.70), (2.90), 3.632 (3.47), 3.645 (2.18), 3.656 (1.95), 3.670 (2.71), 3.683 (2.24), (0.23), 4.265 (0.19), 4.831 (1.80), 4.926 (1.80), 7.213 (0.24), 7.286 (0.23), (3.03), 7.351 (3.22), 7.355 (4.05), 7.359 (4.92), 7.389 (2.26), 7.400 (6.52),

3.305

3.594

3.696

7.302

7.403 (7.84), 7.432 (1.90), 7.473 (1.07), 7.551 (4.79), 7.562 (3.74), 7.569 (3.59), 7.657 (3.65), 7.699 (2.19), 7.703 (2.29), 8.745 (2.59), 8.756 (4.66), 8.768 (2.45), 12.196 (0.18).

Example 205.

(+)-5-[({6-Bromo-2-[3-ethylpiperidin-1-yl]-3-methylquinolin-4-yl}carbonyl)amino]-4-[2(trifluoromethoxy)phenyl]valeric acid ( diastereoisomer 1) [for the structural formula, see example 139 (mixture of diastereoisomers)].

To a solution of (+)-tert-butyl-5-[({6-bromo-2-[3-ethylpiperidin-1-yl]-3-methylquinolin-4yl}carbonyl)amino]-4-[2-(trifluoromethoxy )phenyl]pentanoate (45 mg, 65 µmol, diastereoisomer 1, example 208A) in dichloromethane (0.5 ml) was added with TFA (110 µl, 1.43 mmol) and the mixture was left for 24 h at RT. The mixture was then concentrated and mixed several times with dichloromethane and re-concentrated. The residue was purified by preparative HPLC (method 7). The combined target fractions were concentrated and the residue was lyophilized from acetonitrile/water. 38 mg (100% pure, 92% thor.) of the title compound were obtained.

[a] _D20 = +12.7°, 436 nm, c = 0.30 g/100 mL ^, methanol;

LC-MS (method 2): Rt = 1.31 min; MS (ESIpos): m/z = 636/638 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.893 (6.77), 0.911 (16.00), 0.930 (8.24), 1.045 (0.61), 1.067 (1.37), 1.102 (1.47), 1.140 (0.77) , 1.242 (1.36), 1.260 (2.97), 1.278 (3.89), 1.296 (2.68), 1.567 (1.79), 1.603 (1.66), 1.636 (1.39), 1.753 (2.05), 1.785 (1.75), 1.812 (1.58) , 1.836 (2.59), 1.857 (2.73), 1.882 (1.90), 1.909 (1.96), 2.051 (2.59), 2.077 (12.08), 2.111 (7.17), 2.229 (0.46), 2.246 (0.53), 2.327 (0.72) , 2.675 (0.63), 2.739 (1.08), 2.769 (1.95), 2.799 (1.06), 3.390 (1.88), 3.510 (3.52), 3.540 (3.41), 3.567 (1.51), 3.584 (1.48) , 3.617 (2.79), 3.633 (3.32), 3.648 (2.34), 3.661 (2.48), 3.678 (3.22), 3.696 (2.83), 3.711 (2.05) . , 8.763 (1.76).

Example 206.

5-[({6-Bromo-2-[3-ethylpiperidin-1-yl]-3-methylquinolin-4-yl}carbonyl)amino]-4-[2(trifluoromethoxy)phenyl]valeric acid (diastereoisomer 2).

To a solution of (-)-tert-butyl-5-[({6-bromo-2-[3-ethylpiperidin-1-yl]-3-methylquinolin-4yl}carbonyl)amino]-4-[2-(trifluoromethoxy )phenyl]pentanoate (30 mg, 43 µmol, diastereoisomer 2,

- 211 040220 example 209A) in dichloromethane (330 μl) was added TFA (73 μl, 950 μmol) and the mixture was left for 24 h at RT. The mixture was then concentrated and mixed several times with dichloromethane and re-concentrated. The residue was purified by preparative HPLC (method 7). The combined target fractions were concentrated and the residue was lyophilized from acetonitrile/water. 14 mg (100% pure, 50% thor.) of the title compound were obtained.

LC-MS (method 2): Rt = 1.31 min; MS (ESIpos): m/z = 636/638 [M+H]+.

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.069 (0.21), 0.894 (6.49), 0.913 (16.00), 0.931 (8.01), 1.086 (1.30), 1.114 (1.33), 1.138 (0.60) 1.245 (1.15), 1.262 (2.51), 1.280 (3.24), 1.291 (2.89), 1.298 (2.89), 1.309 (1.93), 1.574 (1.48), 1.614 (1.40), 1.645 (1.26), 1.760 (1.81) , 1.792 (1.65), 1.815 (1.52), 1.838 (1.92),1.858 (2.48), 1.885 (1.73), 1.909 (0.69), 2.054 (2.32), 2.079 (10.90), 2.141 (9.25), 2.328 (0.48) , 2.367 (0.29), 2.671 (0.47), 2.710 (0.27), 2.803 (1.31), 3.406 (1.46), 3.536 (2.86), 3.566 (2.69), 3.603 (1.12), 3.621 (1.93), 3.637 (2.39) . , 7.437 (1.59), 7.554 (3.13), 7.566 (2.68), 7.577 (2.30), 7.702 (8.48), 8.747 (1.57), 8.762 (2.93).

Example 207.

(-)-5-[({6-Bromo-2-[3-ethylpiperidin-1-yl]-3-methylquinolin-4-yl}carbonyl)amino]-4-[2(trifluoromethoxy)phenyl]valeric acid ( diastereoisomer 3).

To a solution of (-)-tert-butyl-5-[({6-bromo-2-[3-ethylpiperidin-1-yl]-3-methylquinolin-4yl}carbonyl)amino]-4-[2-(trifluoromethoxy )phenyl]pentanoate (45 mg, 65 µmol, diastereoisomer 3, example 210A) in dichloromethane (0.5 ml) was added with TFA (110 µl, 1.43 mmol) and the mixture was left for 24 h at RT. The mixture was then concentrated and mixed several times with dichloromethane and re-concentrated. The residue was purified by preparative HPLC (method 7). The combined target fractions were concentrated and the residue was lyophilized from acetonitrile/water. 22 mg (100% pure, 53% thor.) of the title compound were obtained.

[a] _D20 = -10.6°, 436 nm, c = ^0.35 g/100 ml, methanol;

LC-MS (method 2): Rt = 1.31 min; MS (ESIpos): m/z = 636/638 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.893 (6.49), 0.912 (16.00), 0.930 (7.83), 1.069 (1.16), 1.098 (1.20), 1.121 (0.54), 1.243 (1.11) , 1.260 (2.52), 1.278 (3.35), 1.296 (2.24), 1.564 (1.46), 1.602 (1.36) , 1.836 (2.15), 1.857 (2.26), 1.883 (1.55), 2.050 (2.20), 2.077 (10.21), 2.109 (5.78), 2.328 (0.41), 2.367 (0.34), 2.404 (0.80), 2.430 (1.31) , 2.458 (0.96), 2.670 (0.35), 2.723 (0.91), (1.25), 3.617 (1.88), (0.63), 7.355 (2.78), (0.98), 7.555 (3.27), (0.77), 7.688 (0.90 ), 8.722 (1.55), 8.736 (2.95), 8.750 (1.56), 12.021 (0.18).

Example 208.

(+)-5-[({6-Bromo-2-[3-ethylpiperidin-1-yl]-3-methylquinolin-4-yl}carbonyl)amino]-4-[2(trifluoromethoxy)phenyl]valeric acid ( diastereoisomer 4).

To a solution of (+)-tert-butyl-5-[({6-bromo-2-[3-ethylpiperidin-1-yl]-3-methylquinolin-4yl}carbonyl)amino]-4-[2-(trifluoromethoxy )phenyl]pentanoate (50 mg, 72 μmol, diastereoisomer 4, example 211A) in dichloromethane (550 μl) was added with TFA (122 μl, 1.60 mmol) and the mixture was left for 24 h at RT. The mixture was then concentrated and mixed several times with dichloromethane and re-concentrated. The residue was purified by preparative HPLC (method 7). The combined target fractions were concentrated and the residue was lyophilized from acetonitrile/water. 29 mg (100% pure, 64% thor.) of the title compound were obtained.

[a] _D20 = +33.2°, 589 nm, c = 0.33 g/100 mL ^, methanol;

2.755 (1.66), 2.783 (0.94), 3.409 (2.32), 3.498 (3.72), 3.528 (3.05), 3.584 (0.97), 3.599 3.633 (2.25), 3.648 (1.36), 3.660 (1.49), 3.677 (1.98), 3.696 (1.66), 3.712 (0.97), 3.730 7.384 (1.19), 7.399 (4.88), 7.410 (4.38), 7.417 (3.92), 7.421 (4.57), 7.434 (1.17), 7.472 7.560 (2.08), 7.567 (2.60), 7.578 (2.44), 7.637 (1.08), 7.660 (13.23), 7.665 (7.07), 7.683

LC-MS (method 2): Rt = 1.31 min; MS (ESIpos): m/z = 636/638 [M+H]+.

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: (0.60), 1.098 (0.62), 1.120 (0.28), 1.242 (0.50), (0.36), 1.565 (0.68), 1.608 (0.66), 1.638 (0.61), (0.64), 1.837 (1.03), 1.857 (1.17), 1.883 (0.79),

0.893 (2.80), 0.911 (6.69), 0.930 1.260 (1.07), 1.277 (1.46), 1.288 1.669 (0.27), 1.749 (0.86), 1.783 2.052 (0.97), 2.078 (4.80), 2.104

(3.44), 1.040 (0.22), 1.068 (1.30), 1.306 (0.89), 1.323 (0.69), 1.813 (0.64), 1.825 (0.89) (16.00), 2.711 (0.49), 2.743 (0.82), 2.772 (0.45), 3.391 (0.71), 3.405 (0.71), 3.495 (1.33), 3.525 (1.23), 3.585 (0.29), (0.68), 3.702 ( 0.37), 3.721 (0.20), (0.73), 7.551 (1.40), 7.564 (1.20), (1.55), 8.747 (0.78), 12.050 (0.93).

3.600 (0.45), 3.618 (0.88), 3.633 (1.10), 3.650 (1.01), 3.668 (0.85), 3.686

7.357 (1.35), 7.385 (0.60), 7.400 (2.46), 7.410 (2.05), 7.422 (2.29), 7.435

7.574 (1.03), 7.630 (0.49), 7.653 (5.71), 7.681 (0.35), 8.718 (0.80), 8.733

Example 209.

(-)-5-[({6-Bromo-3-methyl-2-[3-methylpiperidin-1-yl]quinolin-4-yl}carbonyl)amino]-4-[2(trifluoromethoxy)phenyl]valeric acid (diastereoisomer 1) [for structural formula, see example 140 (mixture of diastereoisomers)].

- 212 040220

To a solution of tert-butyl-5-[({6-bromo-3-methyl-2-[3-methylpiperidin-1-yl]quinolin-4 yl}carbonyl)amino]-4-[2-(trifluoromethoxy)phenyl ]pentanoate (55 mg, 81 μmol, diastereoisomer 7, example 212A) in dichloromethane (620 μl) was added with TFA (140 μl, 1.78 mmol) and the mixture was left for 24 h at RT. The mixture was then concentrated and mixed several times with dichloromethane and re-concentrated. The residue was purified by preparative HPLC (method 11). The combined target fractions were concentrated and the residue was lyophilized from acetonitrile/water. 31 mg (100% pure, 62% thor.) of the title compound were obtained.

[a] _D20 = -10.3°, 589 nm, c = 0.32 g ^/ 100 ml, methanol;

LC-MS (method 1): Rt = 2.38 min; MS (ESIpos): m/z = 622/624 [M+H]+.

1H-NMR (600 MHz, DMSO-d6) δ [ppm]: 0.926 (16.00), 0.936 (15.61), 1.064 (0.58), 1.078 (1.42), 1.084 (1.41), 1.097 (1.41), 1.102 (1.47) , 1.117 (0.60), 1.123 (0.56), 1.231 (0.22), 1.613 (0.50), 1.634 (1.34) , 1.782 (1.39), 1.798 (2.50), 1.805 (2.60), 1.814 (2.76), 1.821 (2.68), 1.828 (2.74), 1.844 (1.25), 1.863 (0.27), 2.010 (0.25), 2.020 (0.39) . . . , 7.556 (3.06), 7.567 (2.56), 7.572 (2.44), 7.641 (2.35), 7.655 (10.60), 7.661 (6.80), 7.665 (6.00), 7.676 (1.43), 7.679 (1.49), 8.756 (2.07) , 8.765 (3.88), 8.775 (2.04).

Example 210.

(-)-5-[({6-Bromo-3-methyl-2-[3-methylpiperidin-1-yl]quinolin-4-yl}carbonyl)amino]-4-[2(trifluoromethoxy)phenyl]valeric acid (diastereoisomer 2).

To a solution of tert-butyl-5-[({6-bromo-3-methyl-2-[3-methylpiperidin-1-yl]quinolin-4yl}carbonyl)amino]-4-[2-(trifluoromethoxy)phenyl] pentanoate (54 mg, 80 µmol, diastereoisomer 2, example 213A) in dichloromethane (612 µl) TFA (135 µl, 1.75 mmol) was added and the mixture was left for 24 h at RT. The mixture was then concentrated and mixed several times with dichloromethane and re-concentrated. The residue was purified by preparative HPLC (method 11). The combined target fractions were concentrated and the residue was lyophilized from acetonitrile/water. 32 mg (100% pure, 65% thor.) of the title compound were obtained.

[a] _D20 = -21.8°, 589 nm, c = 0.36 g ^/ 100 ml, methanol;

LC-MS (method 1): Rt = 2.38 min; MS (ESIpos): m/z = 622/624 [M+H] ⁺ .

1H-NMR (600 MHz, DMSO-d6) δ [ppm]: 0.924 (16.00), 0.935 (15.74), 1.056 (0.52), 1.063 (0.63), 1.076 (1.57), 1.082 (1.58), 1.096 (1.60) , 1.100 (1.67), 1.115 (0.68), 1.121 (0.63), 1.231 (0.24), 1.630 (1.33), 1.650 (1.46), 1.736 (2.56), 1.741 (2.31), 1.758 (2.71), 1.777 (1.77) , 1.783 (1.70), 1.803 (3.04), 1.812 (3.22),1.820 (3.18), 1.827 (3.32), 1.843 (1.39), 1.861 (0.33), 1.912 (0.18), 2.015 (0.47), 2.033 (1.03) . , 2.616 (0.22), 2.689 (1.13), 2.707 (2.01), 2.727 (1.10), 3.444 (3.52), 3.470 (3.91), 3.494 (2.73), 3.596 (0.97), 3.606 (1.40), 3.617 (1.98) . . , 7.676 (1.83), 7.679 (1.86), 7. 691 (0.24), 7.694 (0.24), 8.756 (1.89), 8.765 (3.35), 8.774 (1.84).

Example 211.

(+)-5-[({6-Bromo-3-methyl-2-[3-methylpiperidin-1-yl]quinolin-4-yl}carbonyl)amino]-4-[2(trifluoromethoxy)phenyl]valeric acid (diastereoisomer 3).

To a solution of tert-butyl-5-[({6-bromo-3-methyl-2-[3-methylpiperidin-1-yl]quinolin-4yl}carbonyl)amino]-4-[2-(trifluoromethoxy)phenyl] pentanoate (43 mg, 63 µmol, diastereoisomer 3, example 214A) in dichloromethane (490 µl) TFA (107 µl, 1.39 mmol) was added and the mixture was left for 24 h at RT. The mixture was then concentrated and mixed several times with dichloromethane and re-concentrated. The residue was purified by preparative HPLC (method 11). The combined target fractions were concentrated and the residue was lyophilized from acetonitrile/water. 32 mg (100% pure, 65% thor.) of the title compound were obtained.

[a] _D20 = +28.2°, 589 nm, c = 0.32 g/100 mL ^, methanol;

LC-MS (method 1): Rt = 2.38 min; MS (ESIpos): m/z = 622/624 [M+H] ⁺ .

1H-NMR (600 MHz, DMSO-d6) δ [ppm]: 0.926 (16.00), 0.937 (15.62), 1.073 (0.62), 1.087 (1.54), 1.092 (1.54), 1.111 (1.60), 1.126 (0.64) , 1.132 (0.60), 1.232 (0.37), 1.635 (1.27), 1.654 (1.37), 1.742 (2.59), 1.747 (2.38), 1.753 (1.94), 1.764 (2.85), 1.770 (2.57), 1.782 (1.70) , 1.788 (1.71), 1.802 (2.90), 1.810 (2.73), 1.825 (3.13), 1.832 (3.13), 1.848 (1.67), 1.866 (0.40), 2.030 (0.47), 2.048 (1.13), 2.057 (2.98) , 2.075 (10.52), 2.082 (8.56), 2.096 (3.00), 2.104 (2.18), 2.110 (2.35), 2.128 (2.72), 2.216 (0.36), 2.389 (0.23), 2.478 (1.40) , 2.720 (1.08), 2.739 (1.95), 2.759 (1.06), 3.394 (1.70), 3.466 (1.91), 3.496 (2.75), 3.518 (2.09) . , 7.415 (5.55), 7.422 (5.89), 7.434 (1.58), 7.562

- 213 040220 (3.71), 7.573 (3.06), 7.577 (3.13), 7.662 (2.25), 7.677 (12.80), 7.681 (8.38), 7.684 (7.38), 7.696 (1.44), 7.699 (1.60), 8.763 (1.83) ), 8.773 (3.46), 8.783 (1.97).

Example 212.

(+)-5-[({6-Bromo-3-methyl-2-[3-methylpiperidin-1-yl]quinolin-4-yl}carbonyl)amino]-4-[2(trifluoromethoxy)phenyl]valeric acid (diastereoisomer 4).

To a solution of tert-butyl-5-[({6-bromo-3-methyl-2-[3-methylpiperidin-1-yl]quinolin-4yl}carbonyl)amino]-4-[2-(trifluoromethoxy)phenyl] pentanoate (53 mg, 78 µmol, diastereoisomer 4, example 215A) in dichloromethane (600 µl) TFA (132 µl, 1.72 mmol) was added and the mixture was left for 24 h at RT. The mixture was then concentrated and mixed several times with dichloromethane and re-concentrated. The residue was purified by preparative HPLC (method 11). The combined target fractions were concentrated and the residue was lyophilized from acetonitrile/water. 26 mg (100% pure, 53% thor.) of the title compound were obtained.

[a] _D20 = +11.8°, 589 nm, c = 0.34 ^g /100 mL, methanol;

LC-MS (method 1): Rt = 2.38 min; MS (ESIpos): m/z = 622/624 [M+H] ⁺ .

1H-NMR (600 MHz, DMSO-d6) δ [ppm]: 0.925 (16.00), 0.936 (15.89), 1.064 (0.59), 1.078 (1.47), 1.083 (1.49), 1.097 (1.49), 1.102 (1.54) , 1.675 (0.66), 1.735 (2.92), 1.821 (2.88), 1.828 (6.09), 2.068 (7.27), 2.086 (1.12), 2.457 (1.81), 2.476 (3.99), 3.495 (2.22), 3.599 (1.49) , 7.407 (5.12), 7.412 (0.61), 1.230 (0.21), 1.613 (2.49), 1.781 (1.46), 1.798 (0.30), 2.018 (0.36), 2.035 (1.65), 2.140 (3.69), 2.222 (0.89) , 2.704 (1.50), 2.722 (1.95), 3.670 (1.33), 7.349 (1.38), 7.556 (3.17), 7.567 (0.51), 1.634 (1.38), 1.655 (2.63), 1.804 (2.79), 1.813 (0.83) 2.044 (2.11), 2.063 (0.30), 2.388 (0.20), 2.438 (0.88), 3.447 (3.51), 3.470 (2.41), 7.361 (3.73), 7.393 (2.64), 7.571 (2.47), 7.640 (1.57) , 1.116 (0.65), 1.123 (2.39), 1.740 (2.19), 1.757 (2.98), 1.843 (1.28), 1.862 (2.04), 2.089 (2.21), 2.099 (1.13), 2.616 (0.20), 2.684 (1.31) , 3.610 (1.79), 3.620 (5.06), 7.419 (5.28), 7.431 (2.43), 7.655 (10.78), 7.661 (6.89), 7.664 (6.03), 7.676 (1.37), 7.679 (1.44) , 8.766 (3.93), 8.776 (2.0 2).

Example 213.

(-)-5-({[6-Bromo-2-(3,3-difluoropiperidin-1-yl)-3-methylquinolin-4-yl]carbonyl}amino)-4-(5-fluoro-2methylphenyl)valeric acid (enantiomer 1) [for structural formula, see example 150 (racemate)].

Separation of enantiomers from example 150.

(+/-)-5-({[6-Bromo-2-(3,3-difluoropiperidin-1-yl)-3-methylquinolin-4-yl]carbonyl}amino)-4-(5-fluoro2-methylphenyl valeric acid (racemate, 183 mg, 309 µmol, example 150) was separated into enantiomers by preparative SLC on the chiral phase (see examples 213 and 214) [column: Daicel Chiral cel OX-H, 5 µm, 250 mm x 20 mm; flow: 60 ml/min; UV detection: 230 nm, temperature: 25°C; eluent: 80% carbon dioxide/20% ethanol; isocratic]. The combined desired fractions were concentrated at 30° C./30 mbar, respectively.

(-)-5-({[6-Bromo-2-(3,3-difluoropiperidin-1-yl)-3-methylquinolin-4-yl]carbonyl}amino)-4-(5-fluoro-2methylphenyl)valeric acid (enantiomer 1).

Separation of the enantiomers as described gave 90 mg (>99% pure, >97% ee) of the title compound as the previously eluted enantiomer.

[a] _D20 = -10.8°, 589 nm, c = 0.46 g ^/ 100 ml, methanol;

LC-MS (method 2): Rt = 1.12 min; MS (ESIpos): m/z = 592/594 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.149 (0.17), 0.069 (0.30), 0.146 (0.19), 1.235 (0.96), 1.745 (0.36), 1.763 (0.84), 1.779 (1.06 ), 1.797 (1.31), 1.819 (1.05), 1.835 (0.71), 1.880 (3.50), 1.976 (0.55), 1.997 (1.12), 2.009 (1.39), 2.028 (1.49), 2.046 (2.35), 2.072 (5.97 ), 2.088 (7.64), 2.117 (11.26), 2.293 (16.00), 2.366 (0.29), 2.670 (0.41), 2.710 (0.21), 3.165 (4.29), 3.450 (2.65), 3.479 (5.58), 3.506 (3.83 ), 3.533 (1.13), 3.665 (1.00), 3.683 (1.61), 3.702 (1.43), 3.717 (1.21), 3.736 (0.69), 6.930 (1.26), 6.945 (2.35), 6.951 (2.51), 6.966 (1.32 ), 6.972 (1.35), 7.141 (2.38), 7.147 (2.44), 7.168 (2.44), 7.174 (2.35), 7.200 (2.42), 7.216 (2.84), 7.237 (2.08), 7.479 (1.02), 7.677 (1.46 ), 7.699 (9.77), 7.708 (5.87), 7.731 (0.97), 8.722 (1.64), 8.736 (2.62), 8.749 (1.57), 12.074 (0.51).

Example 214.

(+)-5-({[6-Bromo-2-(3,3-difluoropiperidin-1-yl)-3-methylquinolin-4-yl]carbonyl}amino)-4-(5-fluoro-2methylphenyl)valeric acid (enantiomer 2).

The separation of enantiomers described in Example 213 gave 91 mg (>99% pure, ee >95%) of the title compound as the later eluted enantiomer.

[a] _D20 = +15.6°, 589 nm, c = 0.46 ^g /100 ml, methanol;

LC-MS (method 2): Rt = 1.12 min; MS (ESIpos): m/z = 592/594 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.149 (0.22), 0.069 (0.40), 0.146 (0.25), 0.854 (0.28), 1.236 (1.91), 1.743 (0.33), 1.761 (0.79 ), 1.776 (1.03), 1.795 (1.26), 1.817 (1.00), 1.833 (0.64), 1.880 (3.52), 1.974 (0.55), 1.995 (1.09), 2.008 (1.35), 2.025 (1.40), 2.044 (2.36 ), 2.067 (5.71), 2.083 (7.36), 2.117 (11.16), 2.292 (16.00), 2.327 (0.76), 2.366 (0.39), 2.669 (0.53), 2.710 (0.36), 3.164 (4.38), 3.449 (2.80 ), 3.479 (5.80), 3.506 (3.89), 3.532 (1.17), 3.665 (1.03), 3.683 (1.64), 3.701 (1.45), 3.717 (1.24), 3.736 (0.71), 6.924 (1.15), 6.930 (1.27 ), 6.945 (2.41), 6.951 (2.58), 6.966 (1.37), 6.972 (1.37), 7.140 (2.43), 7.146 (2.46), 7.167 (2.48), 7.173

- 214 040220 (2.37), 7.199 (2.53), 7.215 (2.93), 7.220 (2.73), 7.236 (2.18), 7.477 (1.00), 7.677 (1.54), 7.699 (10.24), 7.704 (7.44), 7.708 (5.90) ), 7.727 (0.92), 7.731 (1.00), 8.724 (1.65), 8.737 (2.63), 8.752 (1.58), 12.098 (0.31).

Example 215.

(+)-5-({[6-Bromo-3-methyl-2-(pyrrolidin-1-yl)quinolin-4-yl]carbonyl}amino)-4-(2-chloro-3,6difluorophenyl)valeric acid (enantiomer 1) [for structural formula, see example 154 (racemate)].

To a mixture of (+)-tert-butyl-5-{[(6-bromo-2-chloro-3-methylquinolin-4-yl)carbonyl]amino}-4-(2-chloro3,6-difluorophenyl)pentanoate ( 301 mg, 500 µmol, example 48A) in NMP (2.0 ml) was added pyrrolidine (125 µl, 1.50 mmol) and the mixture was stirred for 2 h at 110°C. After cooling to RT, the mixture with ethyl acetate (100 ml) was mixed and washed once with water (100 ml). The aqueous phase was extracted once with ethyl acetate (100 ml). The combined organic phases were washed once with saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated, and the residue was purified by preparative HPLC (method 33). The combined target fractions were concentrated and the residue was lyophilized from acetonitrile/water. The title compound was obtained directly (without isolation of the tert-butyl ether and subsequent hydrolysis step), since it is clear that the educt used has already been partially hydrolysed. 27 mg (100% pure, 9% thor.) of the title compound were obtained.

[a] _D20 = +25.1°, 589 nm, c = 0.37 ^g /100 ml, methanol;

LC-MS (method 1): Rt = 1.45 min; MS (ESIpos): m/z = 580/582 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (1.81), 1.020 (0.81), 1.029 (0.43), 1.036 (0.81), 1.245 (0.78), 1.261 (0.79), 1.277 (0.42 ), 1.402 (0.68), 1.838 (0.86), 1.898 (16.00), 1.938 (2.12), 2.066 (2.00), 2.077 (2.29), 2.102 (4.07), 2.129 (6.46), 2.142 (7.04), 2.159 (7.73 ), 2.178 (7.47), 2.196 (11.68), 2.328 (0.69), 2.367 (0.78), 2.667 (0.96), 2.686 (1.84), 2.695 (8.17), 2.710 (0.72), 3.285 (2.20), 3.303 (3.04 ), 3.321 (2.14), 3.718 (7.64), 3.816 (7.02), 7.266 (1.61), 7.277 (1.87), 7.290 (3.14), 7.301 (3.22), 7.315 (2.42), 7.326 (2.20), 7.386 (2.00 ), 7.407 (3.05), 7.418 (2.99), 7.566 (1.86), 7.588 (3.77), 7.615 (5.18), 7.635 (2.29), 8.817 (3.70).

Example 216.

(-)-5-({[6-Bromo-3-methyl-2-(pyrrolidin-1-yl)quinolin-4-yl]carbonyl}amino)-4-(2-chloro-3,6difluorophenyl)valeric acid (enantiomer 2).

To a mixture of (-)-tert-butyl-5-{[(6-bromo-2-chloro-3-methylquinolin-4-yl)carbonyl]amino}-4-(2-chloro-3,6difluorophenyl)pentanoate ( 301 mg, 500 µmol, example 49A) in NMP (2.0 ml) was added pyrrolidine (125 µl, 1.50 mmol) and the mixture was stirred for 2 h at 110°C. After cooling to RT, the mixture with ethyl acetate (100 ml) was mixed and washed once with water (100 ml). The aqueous phase was extracted once with ethyl acetate (100 ml). The combined organic phases were washed once with saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated, and the residue was purified by preparative HPLC (method 33). The combined target fractions were concentrated and the residue was lyophilized from acetonitrile/water. The title compound was obtained directly (without isolation of the tert-butyl ether and subsequent hydrolysis step), since it is clear that the educt used was already partially hydrolyzed. 15 mg (100% pure, 5% thor.) of the title compound were obtained.

[a] _D20 = -26.9°, 589 nm, c = 0.32 g ^/ 100 ml, methanol;

LC-MS (method 1): Rt = 1.45 min; MS (ESIpos): m/z = 580/582 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.024 (3.21), 0.853 (0.68), 1.120 (0.42), 1.135 (0.88), 1.150 (0.46), 1.234 (8.39), 1.606 (0.89 ), 1.667 (1.32), 1.689 (2.77), 1.713 (2.12), 1.872 (16.00), 1.919 (2.19), 1.938 (1.34), 1.987 (2.25), 2.174 (10.50), 2.227 (1.01), 2.248 (0.88 ), 2.328 (0.52), 2.346 (0.56), 2.366 (0.42), 2.670 (0.49), 2.694 (6.62), 2.710 (0.54), 3.285 (4.71), 3.303 (8.01), 3.526 (6.69), 3.571 (9.55 ), 3.653 (3.61), 3.822 (1.24), 7.226 (1.39), 7.236 (1.65), 7.249 (2.96), 7.258 (3.79), 7.274 (2.59), 7.279 (2.66), 7.285 (2.57), 7.336 (2.05 ), 7.348 (2.38), 7.358 (3.09), 7.369 (2.96), 7.391 (1.71), 7.466 (7.59), 7.488 (12.49), 7.544 (6.80), 7.549 (6.31), 7.566 (3.94), 7.571 (3.80 ), 7.589 (0.63), 7.615 (0.53), 8.526 (0.60), 8.859 (0.49), 8.938 (3.00).

Example 217.

(+)-5-({[6-Bromo-2-(3,3-difluoropiperidin-1-yl)-3-methylquinolin-4-yl]carbonyl}amino)-4-(2-chloro3,6-difluorophenyl )valeric acid (enantiomer 1) [for structural formula, see Example 155 (racemate)].

To a solution of (+)-tert-butyl-5-({[6-bromo-2-(3,3-difluoropiperidin-1-yl)-3-methylquinolin-4yl]carbonyl}amino)-4-(2- chloro-3,6-difluorophenyl)pentanoate (70 mg, 99 µmol, enantiomer 1, example 216A) in dichloromethane (1.8 ml) was added with TFA (169 µl, 2.19 mmol) and the mixture was left for 16 h at RT. The mixture was then concentrated and mixed several times with dichloromethane and re-concentrated. The residue was purified by preparative HPLC (method 7). The combined target fractions were concentrated and the residue was lyophilized from acetonitrile/water. 18 mg (100% pure, 28% thor.) of the title compound were obtained.

[a] _D20 = +33.1°, 589 nm, c = 0.31 g/100 mL ^, methanol;

LC-MS (method 1): Rt = 2.11 min; MS (ESIpos): m/z = 630/632 [M+H] ⁺ .

1H-NMR (500 MHz, DMSO-d6) δ [ppm]: -0.007 (1.41), 0.006 (1.38), 0.071 (0.81), 1.235 (0.63), 1.353

- 215 040220 (0.24), 1.361 (0.68), 1.885 (4.28), 1.969 (0.95), 2.070 (2.84), 2.097 (5.30), 2.111 (4.98), 2.122 (5.25), 2.165 (16.00), 2.292 (0.18) ), 2.304 (0.18), 2.362 (0.41), 2.523 (0.97), 2.636 (0.39), 3.170 (5.56), 3.317 (1.07), 3.457 (3.41), 3.480 (6.14), 3.503 (3.20), 3.727 (2.01 ), 7.274 (1.01), 7.283 (1.19), 7.293 (2.09), 7.302 (2.18), 7.313 (1.54), 7.322 (1.36), 7.411 (2.06), 7.419 (2.03), 7.683 (3.35), 7.701 (12.28 ), 7.711 (8.00), 7.715 (7.27), 7.728 (2.00), 7.732 (2.13), 8.838 (2.94).

Example 218.

(-)-5-({[6-Bromo-2-(3,3-difluoropiperidin-1-yl)-3-methylquinolin-4-yl]carbonyl}amino)-4-(2-chloro3,6-difluorophenyl )valeric acid (enantiomer 2).

To a solution of (-)-tert-butyl-5-({[6-bromo-2-(3,3-difluoropiperidin-1-yl)-3-methylquinolin-4yl]carbonyl}amino)-4-(2- chloro-3,6-difluorophenyl)pentanoate (70 mg, 102 µmol, enantiomer 2, example 217A) in dichloromethane (1.8 ml) was added with TFA (173 µl, 2.24 mmol) and the mixture was left for 16 h at RT. The mixture was then concentrated and mixed several times with dichloromethane and re-concentrated. The residue was purified by preparative HPLC (method 7). The combined target fractions were concentrated and the residue was lyophilized from acetonitrile/water. 27 mg (100% pure, 42% thor.) of the title compound were obtained.

[a] _D20 = -33.8°, 589 nm, c = ^0.34 g/100 ml, methanol;

LC-MS (method 1): Rt = 2.11 min; MS (ESIpos): m/z = 630/632 [M+H]+.

1H-NMR (500 MHz, DMSO-d6) δ [ppm]: -0.120 (0.21), -0.007 (2.56), 0.006 (1.56), 0.069 (0.21), 0.117 (0.20), 1.234 (0.54), 1.353 ( 0.21), 1.361 (0.19), 1.370 (0.20), 1.885 (4.23), 1.967 (0.93), 2.069 (2.85), 2.084 (4.22), 2.094 (5.84), 2.114 (4.95), 2.127 (5.76), 16.00), 2.304 (0.18), 2.358 (0.39), 2.362 (0.50), 2.519 (1.30), 2.522 (0.91), 2.635 (0.48), 3.169 (5.45), 3.314 (1.22), 3.457 (3.35), 6.01), 3.503 (3.07),3.730 (1.95), 7.274 (1.09), 7.283 (1.25), 7.293 (2.14), 7.302 (2.17), 7.313 (1.56), 7.322 (1.38), 7.411 (2.05), 1.97), 7.683 (3.38), 7.701 (12.40), 7.710 (8.28), 7.715 (7.26), 7.728 (2.01), 7.732 (2.08), 8.826 (1.80), 8.837 (3.09).

Example 219.

(+)-5-({[2-(Azepan-1-yl)-6-bromo-3-methylquinolin-4-yl]carbonyl}amino)-4-(2-chloro-3,6difluorophenyl)valeric acid ( enantiomer 1) [for structural formula, see example 159 (racemate)].

To a solution of tert-butyl-5-({[2-(azepan-1-yl)-6-bromo-3-methylquinolin-4-yl]carbonyl}amino)-4-(2chloro-3,6-difluorophenyl) pentanoate (35 mg, 49 µmol, enantiomer 7, example 218A) in dichloromethane (378 µl) TFA (83 µl, 1.08 mmol) was added and the mixture was left for four days at RT. The mixture was then concentrated and mixed several times with dichloromethane and re-concentrated. The residue was purified by preparative HPLC (method 6). The combined target fractions were concentrated and the residue was lyophilized from acetonitrile/water. Received 15 mg (100% pure, 51% theoretical. yield.) specified in the title compound.

[a] _D20 = +31.4°, 589 nm ^, c = 0.38 g/100 mL, methanol;

LC-MS (method 1): Rt = 2.21 min; MS (ESIpos): m/z = 608/610 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.150 (0.18), 1.234 (0.71), 1.259 (0.35), 1.298 (0.28), 1.360 (1.00), 1.602 (13.68), 1.781 (8.50 ), 1.891 (0.92), 1.965 (1.10), 2.071 (3.58), 2.107 (7.74), 2.133 (15.66), 2.272 (0.34), 2.327 (0.34), 2.366 (0.31), 2.669 (0.32), 2.710 (0.31 ), 3.318 (2.40), 3.491 (10.92), 3.505 (16.00), 3.520 (10.56), 3.711 (2.90), 7.262 (1.06), 7.273 (1.27), 7.285 (2.29), 7.296 (2.42), 7.311 (1.84 ), 7.322 (1.74), 7.384 (1.63), 7.395 (1.94), 7.405 (2.60), 7.416 (2.58), 7.438 (1.37), 7.529 (5.55), 7.551 (10.09), 7.599 (5.55), 7.604 (5.36 ), 7.621 (3.13), 7.626 (3.13), 8.804 (3.10).

Example 220.

5-({[2-(Azepan-1-yl)-6-bromo-3-methylquinolin-4-yl]carbonyl}amino)-4-(2-chloro-3,6difluorophenyl)valeric acid (enantiomer 2).

To a solution of tert-butyl-5-({[2-(azepan-1-yl)-6-bromo-3-methylquinolin-4-yl]carbonyl}amino)-4-(2chloro-3,6-difluorophenyl) pentanoate (28 mg, 39 µmol, enantiomer 2, example 219A) in dichloromethane (300 µl) was added with TFA (66 µl, 858 µmol) and the mixture was left for 4 days at RT. The mixture was then concentrated and mixed several times with dichloromethane and re-concentrated. The residue was purified by preparative HPLC (method 6). The combined target fractions were concentrated and the residue was lyophilized from acetonitrile/water. 9 mg (100% pure, 39% thor.) of the title compound were obtained.

LC-MS (method 1): Rt = 2.21 min; MS (ESIpos): m/z = 608/610 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.235 (0.90), 1.259 (0.51), 1.298 (0.35), 1.360 (0.94), 1.602 (13.49), 1.781 (8.38), 1.880 (2.79) , 1.946 (1.09), 2.055 (3.52), 2.085 (6.46), 2.132 (15.36), 2.274 (0.37), 2.326 (0.42), 2.366 (0.38), 2.669 (0.41), 2.710 (0.34), 3.320 (1.46) , 3.490 (10.99), 3.505 (16.00), 3.519 (10.58), 3.703 (2.91), 7.259 (1.22), 7.270 (1.40), 7.282 (2.43), 7.293 (2.56), 7.308 (1.90) , 7.401 (2.69), 7.412 (2.69), 7.528 (6.05), 7.551 (10.65), 7.598 (5.94), 7.603 (5.52), 7.620 (3.18), 7.625 (3.14), 8.810 (3.11).

Example 221.

5-[({6-Bromo-2-[3-fluoropiperidin-1-yl]-3-methylquinolin-4-yl}carbonyl)amino]-4-(2,3,6trichlorophenyl)valeric acid (diastereoisomer 1) [ structural formula see example 180

- 216 040220 (mixture of diastereoisomers)].

To a solution of tert-butyl-5-[({6-bromo-2-[3-fluoropiperidin-1-yl]-3-methylquinolin-4yl}carbonyl)amino]-4-(2,3,6-trichlorophenyl) pentanoate (14 mg, 20 µmol, diastereoisomer 1, example 220A) in dichloromethane (153 µl) was added with TFA (34 µl, 439 µmol) and the mixture was left for 24 h at RT. The mixture was then concentrated and mixed several times with dichloromethane and re-concentrated. The residue was purified by preparative HPLC (method 11). The combined target fractions were concentrated and the residue was lyophilized from acetonitrile/water. 7 mg (100% pure, 51% th. y.) of the title compound were obtained.

LC-MS (method 1): Rt = 2.20 min; MS (ESIpos): m/z = 644/646/648 [M+H]+.

1H-NMR (600 MHz, DMSO-d6) δ [ppm]: -0.024 (0.18), 0.852 (0.29), 0.923 (0.20), 1.232 (1.22), 1.369 (0.28), 1.648 (2.02), 1.723 (1.34 ), 1.809 (1.91), 1.910 (3.93), 1.924 (3.45), 2.040 (1.60), 2.154 (4.33), 2.183 (8.36), 2.299 (0.27), 2.388 (0.31), 2.618 (0.25), 2.695 (0.22 ), 3.097 (2.45), 3.164 (2.36), 3.330 (5.54), 3.413 (16.00), 3.765 (1.57), 4.002 (1.26), 4.100 (1.07), 4.839 (1.36), 4.919 (1.34), 7.459 (1.70 ), 7.473 (1.94), 7.519 (2.29), 7.533 (3.23), 7.573 (2.41), 7.658 (2.35), 7.673 (5.57), 7.689 (4.72), 7.704 (1.81), 8.972 (1.67).

Example 222.

5-[({6-Bromo-2-[3-fluoropiperidin-1-yl]-3-methylquinolin-4-yl}carbonyl)amino]-4-(2,3,6trichlorophenyl)valeric acid (diastereoisomer 2).

To a solution of tert-butyl-5-[({6-bromo-2-[3-fluoropiperidin-1-yl]-3-methylquinolin-4yl}carbonyl)amino]-4-(2,3,6-trichlorophenyl) pentanoate (17 mg, 24 μmol, diastereoisomer 2, example 220A) in dichloromethane (186 μl) was added with TFA (41 μl, 533 μmol) and the mixture was left for 24 h at RT. The mixture was then concentrated and mixed several times with dichloromethane and re-concentrated. The residue was purified by preparative HPLC (method 11). The combined target fractions were concentrated and the residue was lyophilized from acetonitrile/water. 7 mg (100% pure, 51% th. y.) of the title compound were obtained.

LC-MS (method 1): Rt = 2.20 min; MS (ESIpos): m/z = 644/646/648 [M+H] ⁺ .

1H-NMR (600 MHz, DMSO-d6) δ [ppm]: 0.854 (0.19), 1.233 (0.77), 1.645 (1.59), 1.817 (1.51), 1.912 (2.83), 1.925 (2.37), 1.945 (1.40) , 1.968 (0.93), 2.060 (0.51), 2.073 (1.19), 2.083 (1.71), 2.097 (3.37), 2.108 (3.12), 2.114 (3.29), 2.128 (2.50), 2.151 (3.80), 2.160 (4.09) . . , 3.912 (6.65), 4.040 (3.28), 4.055 (3.16), 4.064 (3.35), 4.073 (3.57), 4.079 (3.71), 4.088 (2.70) . , 7.686 (5.41), 7.694 (3.96), 7.697 (4.31), 7.703 (3.05), 7.709 (1.79), 7.712 (1.82), 7.718 (1.29), 8.838 (2.29), 8.848 (2.59).

Example 223.

5-[({6-Bromo-2-[3-fluoropiperidin-1-yl]-3-methylquinolin-4-yl}carbonyl)amino]-4-(2,3,6trichlorophenyl)valeric acid (diastereoisomer 3).

To a solution of tert-butyl-5-[({6-bromo-2-[3-fluoropiperidin-1-yl]-3-methylquinolin-4yl}carbonyl)amino]-4-(2,3,6-trichlorophenyl) pentanoate (32 mg, 46 μmol, diastereoisomer 3, example 220A) in dichloromethane (351 μl) TFA (77 μl, 1.0 mmol) was added and the mixture was left for 24 h at RT. The mixture was then concentrated and mixed several times with dichloromethane and re-concentrated. The residue was purified by preparative HPLC (method 11). The combined target fractions were concentrated and the residue was lyophilized from acetonitrile/water. 15 mg (100% pure, 52% thor.) of the title compound were obtained.

LC-MS (method 1): Rt = 2.20 min; MS (ESIpos): m/z = 644/646/648 [M+H] ⁺ .

1H-NMR (600 MHz, DMSO-d6) δ [ppm]: 1.232 (0.37), 1.244 (0.46), 1.255 (0.44), 1.259 (0.38), 1.270 (0.31), 1.646 (1.40), 1.817 (1.34) , 1.912 (2.53), 1.926 (2.11), 1.944 (1.31), 1.968 (0.82), 2.009 (0.20), 2.060 (0.58), 2.074 (1.12), 2.083 (1.63), 2.097 (3.20), 2.109 (2.88) . , 2.389 (0.24), 2.617 (0.21), 3.074 (1.12), (1.66), 3.351 (0.95), (1.71), 3.834 (1.57), (5.09), 4.099 (4.83), (1.95), 7.501 (2.41 ), (6.65), 7.689 (5.63),

3.089 (1.58), 3.185 (1.49), 3.197 (1.59), 3.214 (1.04), 3.320 (1.20), 3.330 (1.56), 3.340 3.398 (1.52), 3.420 (1.00), 3.437 (1.49), 3.456 (1.05), 3.806 (1.52), 3.817 (1.72), 3.827 4.040 (4.13), 4.049 (4.31), 4.056 (4.60), 4.064 (5.06), 4.071 (5.46), 4.079 (5.82), 4.088 4.113 (4.27), 4.847 (1.34), 4.926 (1.33), 7.028 (0.27), 7.113 (0.32), 7.198 (0.28), 7.486 7.543 (3.07), 7.558 (4.54), 7.605 (2.56), 7.619 (2.13), 7.668 (2.51), 7.674 (2.27), 7.683 7.696 (4.24), 7.700 (4.26), 7.702 (3.33), 7.706 (2.72), 7.711 (1.61), 7.715 (1.64), 7.717

(1.20), 7.721 (1.08), 8.835 (2.19), 8.846 (2.41), 9.683 (0.16).

Example 224.

5-[({6-Bromo-2-[3-fluoropiperidin-1-yl]-3-methylquinolin-4-yl}carbonyl)amino]-4-(2,3,6trichlorophenyl)valeric acid (diastereoisomer 4).

To a solution of tert-butyl-5-[({6-bromo-2-[3-fluoropiperidin-1-yl]-3-methylquinolin-4yl}carbonyl)amino]-4-(2,3,6-trichlorophenyl) pentanoate (27 mg, 38 µmol, diastereoisomer 4, example

- 217 040220

220A) in dichloromethane (296 μl) TFA (65 μl, 846 μmol) was added and the mixture was left for 24 h at RT. The mixture was then concentrated and mixed several times with dichloromethane and re-concentrated. The residue was purified by preparative HPLC (method 11). The combined target fractions were concentrated and the residue was lyophilized from acetonitrile/water. 9 mg (100% pure, 36% thor.) of the title compound were obtained.

LC-MS (method 1): Rt = 2.20 min; MS (ESIpos): m/z = 644/646/648 [M+H]+.

1H-NMR (600 MHz, DMSO-d ₆ ) δ [ppm]: 0.841 (0.19), 0.853 (0.24), 0.913 (0.21), 1.231 (0.86), 1.552 (0.61), 1.648 (2.28), 1.674 (0.65 ), 1.812 (2.09), 1.825 (1.79), 1.910 (4.02), 1.924 (2.87), 1.947 (1.51), 1.970 (1.30), 2.061 (1.95), 2.076 (2.56), 2.083 (3.02), 2.096 (3.15 ), 2.109 (2.63), 2.121 (2.60), 2.145 (5.67), 2.166 (4.32), 2.180 (16.00), 2.278 (1.99), 2.389 (0.46), 2.616 (0.26), 3.077 (1.94), 3.093 (2.84 ), 3.174 (2.89), 3.427 (5.68), 3.449 (3.64), 3.783 (0.87), 3.791 (1.60), 3.802 (1.66), 3.812 (1.93), 3.822 (1.47), 4.054 (1.96), 4.062 (1.76 ), 4.070 (1.68), 4.077 (1.98), 4.088 (1.51), 4.099 (1.29), 4.109 (1.07), 4.124 (0.59), 4.839 (1.68), 4.919 (1.66), 7.484 (2.30), 7.498 (2.76 ), 7.539 (4.21), 7.554 (6.01), 7.603 (3.12), 7.617 (2.69), 7.662 (3.82), 7.667 (2.96), 7.677 (9.70), 7.682 (7.07), 7.690 (6.12), 7.694 (6.22 ), 7.700 (3.79), 7.705 (2.38), 7.709 (2.46), 7.715 (1.52), 8.837 (2.65), 8.846 (3.25).

Example 225.

5-[({6-Bromo-2-[3-ethylpiperidin-1-yl]-3-methylquinolin-4-yl}carbonyl)amino]-4-(2,5difluorophenyl)valeric acid (mixture of diastereoisomers)

tert-Butyl 5-[({6-bromo-2-(3-ethylpiperidin-1-yl)-3-methylquinolin-4-yl}carbonyl)amino]-4-(2,5difluorophenyl)pentanoate (mixture of diastereoisomers, 56 mg, 86.9 µmol, example 227A) was dissolved in dichloromethane (1.2 ml). TFA (650 µl, 8.7 mmol) was added at RT and the reaction mixture was stirred at RT for 90 min. The volatile components were removed on a rotary evaporator. The residue was dissolved in a small amount of DMSO and purified by preparative HPLC (method 15). The desired fractions were evaporated together and the residue was dried in vacuo. 48 mg (100% pure, 94% th. y.) of the title compound were obtained.

LC-MS (method 1): Rt = 2.37 min; MS (ESIpos): m/z = 588/590 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (3.01), 0.890 (6.60), 0.908 (16.00), 0.927 (8.11), 1.035 (0.56), 1.064 (1.36), 1.093 (1.40 ), 1.116 (0.62), 1.238 (1.14), 1.256 (2.65), 1.275 (3.54), 1.292 (2.47), 1.560 (1.54), 1.602 (1.47), 1.632 (1.31), 1.747 (1.98), 1.786 (1.98 ), 1.809 (1.45), 1.842 (1.85), 1.877 (1.52), 2.002 (1.18), 2.015 (1.54), 2.034 (1.67), 2.054 (1.89), 2.063 (1.63), 2.108 (12.92), 2.119 (6.84 ), 2.139 (2.27), 2.160 (0.71), 2.327 (0.67), 2.422 (1.36), 2.670 (0.80), 2.709 (1.23), 2.737 (1.87), 2.766 (1.05), 3.481 (2.87), 3.513 (2.74 ), 3.616 (1.09), 3.634 (1.63), 3.649 (2.32), 3.662 (1.38), 3.677 (1.11), 3.696 (1.45), 7.122 (2.01), 7.143 (1.43), 7.198 (1.72), 7.209 (1.78 ), 7.221 (2.79), 7.232 (2.72), 7.244 (1.31), 7.256 (1.20), 7.291 (1.65), 7.300 (2.36), 7.315 (1.65), 7.426 (0.71), 7.624 (1.40), 7.647 (11.57 ), 7.654 (6.46), 7.677 (1.03), 8.729 (2.85), 12.061 (5.15).

Example 226.

(-)-5-[({6-Bromo-2-[3-ethylpiperidin-1-yl]-3-methylquinolin-4-yl}carbonyl)amino]-4-(2,5difluorophenyl)valeric acid (mixture of two diastereoisomers).

To a solution of tert-butyl 5-[({6-bromo-2-[3-ethylpiperidin-1-yl]-3-methylquinolin-4yl}carbonyl)amino]-4-(2,5-difluorophenyl)pentanoate ( 118 mg, 183 µmol, mixture of two diastereoisomers, example 228A) in dichloromethane (1.4 ml) was added with TFA (310 µl, 4.03 mmol) and the mixture was left for 24 h at RT. The mixture was then concentrated and mixed several times with dichloromethane and re-concentrated. The residue was purified by preparative HPLC (method 11). The combined target fractions were concentrated and the residue was lyophilized. Received 88 mg (100% pure, 81% theoretical. yield.) specified in the title compound.

[a] _D20 = -32.2°, 589 nm, c = 0.46 g ^/ 100 ml, methanol;

LC-MS (method 1): Rt = 2.35 min; MS (ESIpos): m/z = 588/590 [M+H]+.

1H-NMR (600 MHz, DMSO-d6) δ [ppm]: -0.021 (1.21), 0.839 (0.16), 0.851 (0.32), 0.862 (0.18), 0.895 (7.27), 0.907 (16.00), 0.919 (8.17 ), 1.036 (0.49), 1.042 (0.58), 1.057 (1.40), 1.062 (1.43), 1.076 (1.48), 1.081 (1.49), 1.096 (0.64), 1.103 (0.57), 1.227 (2.36), 1.245 (1.25 ), 1.257 (2.57), 1.269 (3.67), 1.280 (3.10), 1.292 (1.60), 1.551 (1.33), 1.556 (1.48), 1.574 (0.99), 1.585 (0.77), 1.606 (1.26), 1.627 (1.34 ), 1.647 (0.55), 1.748 (2.00), 1.769 (1.82), 1.775 (1.61), 1.791 (1.33), 1.805 (1.44), 1.814 (1.08), 1.829 (0.61), 1.853 (1.68), 1.870 (1.64 ), 1.997 (0.58), 2.010 (1.28), 2.018 (1.73), 2.032 (1.83), 2.041 (1.27), 2.053 (1.10), 2.064 (1.27), 2.073

- 218 040220 (1.48), 2.078 (1.64), 2.091 (4.12), 2.104 (7.92), 2.116 (7.21), 2.130 (3.21), 2.144 (1.34), 2.157 (0.68), 2.414 (0.84), 2.714 (0.86) ), 2.733 (1.45), 2.752 (0.82), 3.494 (3.60), 3.510 (2.68), 3.627 (1.33), 3.637 (1.69), 3.640 (1.59), 3.649 (2.00), 3.709 (1.15), 7.127 (1.84 ), 7.140 (1.20), 7.211 (1.72), 7.219 (1.85), 7.226 (2.96), 7.234 (2.92), 7.242 (1.44), 7.250 (1.30), 7.301 (1.79), 7.309 (2.30), 7.317 (1.78 ), 7.448 (0.24), 7.635 (2.37), 7.649 (9.88), 7.657 (5.87), 7.672 (1.32), 8.744 (1.47), 8.754 (2.67).

Example 227.

(+)-5-[({6-Bromo-2-[3-ethylpiperidin-1-yl]-3-methylquinolin-4-yl}carbonyl)amino]-4-(2,5difluorophenyl)valeric acid (diastereoisomer 1 ).

To a solution of tert-butyl 5-[({6-bromo-2-[3-ethylpiperidin-1-yl]-3-methylquinolin-4yl}carbonyl)amino]-4-(2,5-difluorophenyl)pentanoate ( 37 mg, 57 µmol, diastereoisomer 1, example 229A) in dichloromethane (442 µl) was added with TFA (97 µl, 1.26 mmol) and the mixture was left for 24 h at RT. The mixture was then concentrated and mixed several times with dichloromethane and re-concentrated. The residue was purified by preparative HPLC (method 11). The combined target fractions were concentrated and the residue was lyophilized. 20 mg (100% pure, 60% thor.) of the title compound were obtained.

[a] _D20 = +17.1°, 589 nm, c = 0.31 g/100 mL ^, methanol;

LC-MS (method 1): Rt = 2.38 min; MS (ESIpos): m/z = 588/590 [M+H] ⁺ .

1H-NMR (600 MHz, DMSO-d6) δ [ppm]: -0.021 (1.57), 0.839 (0.20), 0.851 (0.40), 0.862 (0.20), 0.895 (6.95), 0.908 (16.00), 0.920 (7.91 ), 1.036 (0.39), 1.042 (0.45), 1.057 (1.08), 1.062 (1.11), 1.076 (1.14), 1.081 (3.04), 1.280 (2.59), 1.292 (0.82), 1.605 (0.92), 1.626 (1.36 ), 1.787 (1.08), 1.796 (0.90), 1.870 (1.27), 1.993 (1.23), 2.062 (1.16), 2.079 (0.69), 2.695 (0.28), 2.713 (0.89), 3.621 (1.38), 3.634 (1.39 ), 7.225 (2.20), 7.232 (1.91), 7.310 (1.40), 7.314 (4.64), 7.671 (1.16), 7.674 (1.13), 1.256 (2.13), 1.268 (1.21), 1.562 (1.04), 1.574 (1.31 ), 1.769 (1.42), 1.774 (0.52), 1.854 (1.30), 1.862 (0.99), 2.041 (1.03), 2.053 (1.28), 2.148 (0.71), 2.417 (3.09), 3.511 (2.04), 3.612 (1.33 ), 7.209 (1.28), 7.217 (1.34), 7.299 (1.42), 7.305 (9.46), 7.656 (5.17), 7.659

(1.15), 1.096 (0.50), 1.103 (0.45), 1.228 (3.22), 1.245 (1.39), 1.539 (0.79), 1.545 (0.94), 1.550 (1.07), 1.557 (0.99), 1.646 (0.43), 1.747 (1.60), 1.752 (1.34), 1.764 (1.06), 1.802 (1.15), 1.811 (0.88), 1.817 (0.65), 1.826 (0.47), 2.006 (1.01), 2.014 (1.35), 2.027 (1.49), 2.036 (2.91), 2.094 (4.55), 2.108 (4.56), 2.121 (2.74), 2.135 (0.72), 2.733 (1.24), 2.752 (0.70), 3.478 (2.03), 3.495 (1.50), 3.643 (1.98), 3.652 (1.12), 3.709 (1.00), 7.125 (2.18), 7.240 (1.10), 7.247 (0.98), 7.290 (1.07), 7.295 (1.34), 7.320 (1.05), 7.499 (0.20), 7.634 (2.33), 7.649

(1.22), 8.745 (1.67), 8.755 (2.75), 8.764 (1.62).

Example 228.

(+)-5-[({6-Bromo-2-[3-ethylpiperidin-1-yl]-3-methylquinolin-4-yl}carbonyl)amino]-4-(2,5difluorophenyl)valeric acid (diastereoisomer 2 ).

To a solution of tert-butyl 5-[({6-bromo-2-[3-ethylpiperidin-1-yl]-3-methylquinolin-4yl}carbonyl)amino]-4-(2,5-difluorophenyl)pentanoate ( 43 mg, 67 µmol, diastereoisomer 2, example 230A) in dichloromethane (513 µl) was added with TFA (113 µl, 1.47 mmol) and the mixture was left for 24 h at RT. The mixture was then concentrated and mixed several times with dichloromethane and re-concentrated. The residue was purified by preparative HPLC (method 11). The combined target fractions were concentrated and the residue was lyophilized. 25 mg (100% pure, 63% th. y.) of the title compound were obtained.

[a] _D20 = +47.3°, 589 nm, c = 0.32 g/100 mL ^, methanol;

LC-MS (method 1): Rt = 2.38 min; MS (ESIpos): m/z = 588/590 [M+H] ⁺ .

1H-NMR (600 MHz, DMSO-d6) δ [ppm]: -0.022 (1.15), 0.852 (0.27), 0.895 (6.90), 0.907 (16.00), 0.919 (7.82), 1.037 (0.38), 1.043 (0.44 ), 1.058 (1.06), 1.063 (1.08), 1.077 (1.11), 1.083 (1.12), 1.097 (0.50), 1.104 (0.44), 1.230 (2.23), 1.247 (0.91), 1.258 (1.89), 1.270 (2.65 ), 1.281 (2.16), 1.290 (1.20), 1.557 (1.06), 1.586 (0.60), 1.606 (1.01), 1.628 (1.08), 1.648 (0.45), 1.750 (1.53), 1.755 (1.31), 1.760 (1.16 ), 1.771 (1.65), 1.783 (1.27), 1.791 (1.07), 1.799 (1.12), 1.807 (0.84), 1.813 (0.64), 1.822 (0.50), 1.855 (1.27), 1.871 (1.24), 1.990 (0.41 ), 2.003 (0.94), 2.012 (1.23), 2.025 (1.35), 2.034 (0.86), 2.038 (0.86), 2.046 (0.75), 2.055 (0.78), 2.064 (0.82), 2.082 (2.33), 2.095 (4.70 ), 2.108 (7.35), 2.121 (2.98), 2.135 (1.06), 2.148 (0.51), 2.412 (0.62), 2.730 (0.98), 3.491 (2.76), 3.509 (2.34), 3.614 (0.80), 3.623 (1.33 ), 3.636 (1.50), 3.645 (2.05), 3.654 (1.10), 3.701 (0.84), 7.126 (1.43), 7.140 (0.93), 7.210 (1.32), 7.217 (1.42), 7.225 (2.26), 7.233 (2.23 ), 7.240 (1.11), 7.248 (1.00), 7.29 2 (1.09), 7.297 (1.34), 7.301 (1.40), 7.307 (1.90), 7.313 (1.37), 7.317 (1.32), 7.322 (1.04), 7.632 (1.89), 7.647 (7.35), 7.654 (4.76), 7.658 (4.23), 7.669 (1.08), 7.672 (1.12), 8.748 (1.37), 8.757 (2.29), 8.767 (1.29).

Example 229.

(+/-)-5-({[6-Bromo-2-(3,3-difluoropiperidin-1-yl)-3-methylquinolin-4-yl]carbonyl}amino)-4-(2methylphenyl)valeric acid ( racemate)

- 219 040220

To (+/-)-5-{[(6-bromo-2-chloro-3-methylquinolin-4-yl)carbonyl]amino}-4-(2-methylphenyl)valeric acid (racemate, 500 mg, 86% purity, 0.88 mmol, example 234A) and 3,3-difluoropiperidine hydrochloride (804 mg, 5.10 mmol) in NMP (2.6 ml) were added DIPEA (2.1 ml, 12 mmol) and the mixture was stirred for 4 days at 120°C. Then cooled to RT, and the reaction mixture was added to 1 M hydrochloric acid. The mixture was extracted with dichloromethane, the organic phase was dried over sodium sulfate and concentrated on a rotary evaporator. The residue was previously purified by column chromatography (Isolera, KP-Sil, eluent: dichloromethane/methanol, gradient: 0-40% methanol) and then further purified by preparative HPLC (method 27). 212 mg (99% pure, 42% thor.) of the title compound were obtained.

LC-MS (method 26): R _t = 0.80 min; MS (ESIpos): m/z = 574/576 [M+H]+.

1H-NMR (400 MHz, chloroform-d) δ [ppm]: 1.262 (1.33), 1.935 (1.64), 1.950 (1.86), 1.957 (1.72), 1.967 (1.54), 1.974 (1.08), 1.985 (0.60) , 1.991 (0.70), 2.009 (0.48), 2.022 (0.57), 2.039 (0.67), 2.055 (1.10),2.071 (1.05), 2.087 (0.88), 2.106 (0.65), 2.121 (0.52), 2.142 (0.63) . , 2.389 (2.69), 2.628 (2.33), 3.127 (1.35), 3.138 (1.70), (0.50), 3.461 (2.58), 3.489 (1.35), (0.61), 3.746 (0.54), 3.933 (0.69), ( 1.00), 5.977 (0.56), 7.114 (0.46), (2.44), 7.185 (0.96), 7.193 (0.71), (3.85), 7.234 (3.60), 7.602 (1.21), (3.39), 7.697 (2.97).

Separation of enantiomers.

3.389

3.677

3.949

7.122

7.199

7.607 (0.46), 3.396 (0.53), 3.402 (0.53), 3.410 (0.81), (0.49), 3.690 (0.54), 3.699 (0.48), 3.711 (1.03), (1.16), 3.965 (0.97), 3.982 ( 0.92), 3.998 (0.46), (0.56), 7.127 (0.44), 7.133 (1.21), 7.142 (1.42), (0.74), 7.204 (0.97), 7.208 (0.67), 7.219 (2.04), (1.30), 7.624 (2.59), 7.629 (2.96), 7.659 (4.47),

3.433 (1.79), 3.447 3.725 (0.66), 3.732 5.949 (0.59), 5.963 7.154 (1.65), 7.167 7.223 (3.71), 7.231 7.682 (2.17), 7.692

The title title compound (197 mg) was dissolved in dichloromethane/methanol (1:1, 3.3 ml) and separated into enantiomers by preparative HPLC on chiral phase (see examples 230 and 231) [column: Chiralpak IA, 5 µm, 250 mmx30 mm; flow: 50 ml/min; detection: UV 254 nm; sample injection: 0.3 ml; eluent: hexane + 0.1 vol% TFA (80%)/isopropanol (20%), isocratic]. The pooled target fractions were respectively concentrated and the corresponding residue was lyophilized.

Example 230.

(-)-5-({[6-Bromo-2-(3,3-difluoropiperidin-1-yl)-3-methylquinolin-4-yl]carbonyl}amino)-4-(2methylphenyl)valeric acid (enantiomer 1 ).

Separation of enantiomers as described in Example 229 gave 71 mg (98% pure, >99% ee) of the title compound as the previously eluted enantiomer.

[a] _D20 = -5.0°, 589 nm, c = 0.34 g ^/ 100 ml, methanol.

Example 231.

(+)-5-({[6-Bromo-2-(3,3-difluoropiperidin-1-yl)-3-methylquinolin-4-yl]carbonyl}amino)-4-(2methylphenyl)valeric acid (enantiomer 2 ).

The separation of enantiomers described in Example 229 gave 85 mg (88% pure, 87% ee) of the title compound as the later eluted enantiomer.

[a] _D20 = +7.8°, 589 nm, c = 0.28 ^g /100 ml, methanol.

Example 232.

(+/-)-5-({[6-Bromo-3-methyl-2-(pyrrolidin-1-yl)quinolin-4-yl]carbonyl}amino)-4-(2methylphenyl)valeric acid (racemate)

(+/-)-5-{[(6-Bromo-2-chloro-3-methylquinolin-4-yl)carbonyl]amino}-4-(2-methylphenyl)valeric

- 220 040220 acid (racemate, 500 mg, 86% purity, 0.88 mmol, example 234A) was stirred in pyrrolidine (3.0 ml,

2.2 mmol) 2 h at 100°C. After cooling to RT, the reaction mixture was added to 1M hydrochloric acid and the mixture was extracted with dichloromethane. The organic phase was dried over sodium sulfate and concentrated on a rotary evaporator. The residue was previously purified by column chromatography (Isolera, KP-Sil, Laufmittel dichloromethane/methanol, gradient: 0-40% methanol) and further purified by preparative HPLC (method 27). 375 mg (99% pure, 80% thor.) of the title compound were obtained.

LC-MS (method 26): Rt = 0.77 min; MS (ESIpos): m/z = 524/526 [M+H]+.

1H-NMR (400 MHz, chloroform-d) δ [ppm]: 0.084 (0.46), 0.087 (0.42), 0.838 (0.57), 0.850 (0.55), 0.871 (0.52), 0.888 (0.83), 1.184 (0.44) , 1.217 (0.82), 1.262 (7.00), 1.391 (0.53), 1.918 (2.72), 1.927 (3.16), 1.935 (8.00), 1.942 (3.26), 1.951 (3.35), 1.968 (1.08), 1.977 (0.98) , 1.987 (0.95), 1.993 (0.93), 2.012 (0.96),2.028 (0.87), 2.037 (0.70), 2.049 (0.87), 2.054 (0.66), 2.063 (0.63), 2.075 (0.71), 2.090 (0.74) . , 2.282 (0.60), 2.301 (2.74), 2.320 (3.62), 2.339 (1.34), 2.368 (16.00), 2.385 (1.42), 2.392 (11.83), 2.518 (0.66), 2.535 (0.58), 2.545 (0.67) , 2.560 (1.05), 2.567 (0.84), 2.574 (0.82), 2.582 (0.76), 2.629 (3.84) . , 3.459 (0.48), 3.586 (2.41) . , 3.949 (0.98), 3.966 (0.89), 3.983 (0.81), 3.999 (0.42), 5.785 (0.65) , 7.141(1.26), 7.146(1.19), 7.154(1.89),7.166(2.94), 7.181(1.44), 7.193(2.67), 7.198(2.32), 7.207(4.20), 7.221(2.42), 7.229(3.00) , 7.235 (4.04), 7.238 (3.76), 7.249 (0.51), 7.507 (5.43), 7.528 (0.70), 7.576 (2.43), 7.579 (3.98).

Separation of enantiomers.

The title target compound (360 mg) was dissolved in DMSO/dichloromethane/methanol (1:1:1, 6 ml) and separated into enantiomers by chiral phase preparative HPLC (see

examples 233 and 234) [column: Chiralpak IG, 5 µm, 250 mm x 30 mm; flow: 100 ml/min; detection: MWD 220 nm; sample injection: 1.0 ml; eluent: 28% methanol/72% carbon dioxide, isocratic]. The pooled target fractions were appropriately concentrated and the corresponding residue was lyophilized.

Example 233.

(+)-5-({[6-Bromo-3-methyl-2-(pyrrolidin-1-yl)quinolin-4-yl]carbonyl}amino)-4-(2methylphenyl)valeric acid (enantiomer 1).

The separation of enantiomers described in Example 232 gave 190 mg (98% pure, ee 98%) of the title compound as the previously eluted enantiomer.

[a] _D20 = +12.7°, 589 nm, c = 0.27 g/100 mL ^, methanol.

Example 234.

(-)-5-({[6-Bromo-3-methyl-2-(pyrrolidin-1-yl)quinolin-4-yl]carbonyl}amino)-4-(2methylphenyl)valeric acid (enantiomer 2).

The separation of enantiomers described in Example 232 gave 135 mg (96% pure, ee 96%) of the title compound as the later eluted enantiomer.

[a] _D20 = -4.43°, 589 nm, c = 0.35 g ^/ 100 ml, methanol.

Example 235.

(+)-5-({[6-Bromo-3-methyl-2-(piperidin-1-yl)quinolin-4-yl]carbonyl}amino)-4-(2methoxyphenyl)valeric acid (enantiomer 1)

L^ ^he O^NH O

Br С Н s

Mixture of 5-{[(6-bromo-2-chloro-3-methylquinolin-4-yl)carbonyl]amino}-4-(2methoxyphenyl)valeric acid (enantiomer 1, 200 mg, 85% pure, 336 µmol, example 241A) and piperidine (5.0 ml) were stirred for 2 h at 100°С. After cooling to RT, the reaction mixture was added to 1M hydrochloric acid and extracted with dichloromethane. The organic phase was dried over sodium sulfate and concentrated. The starting material was purified by preparative HPLC (method 28). 160 mg (99% pure, 85% thor.) of the title compound were obtained.

[a] _D20 = +4.73°, 589 nm, c = 0.36 g/100 mL ^, chloroform;

LC-MS (method 25): Rt = 1.29 min; MS (ESIpos): m/z = 554/556 [M+H] ⁺ .

- 221 040220

1H-NMR (400 MHz, chloroform-d) δ [ppm]: 1.643 (1.02), 1.653 (1.13), 1.711 (2.01), 1.721 (2.28), 2.018 (0.40), 2.031 (0.46), 2.039 (0.46) , 2.054 (0.43), 2.131 (0.52), 2.144 (0.65), 2.151 (0.45), 2.165 (0.67), 2.189 (8.51), 2.279 (0.84), 2.293 (1.56), 2.299 (0.99), 2.313 (1.58) , 2.323 (0.57), 2.334 (0.69), 3.173 (2.55), 3.447 (0.48), 3.460 (0.61), 3.472 (0.51), 3.551 (0.42), 3.709 (0.51), 3.740 (16.00), 3.815 (0.58) . , 6.958 (0.68), 6.960 (0.70), 6.979 (1.59), 6.995 (0.95), 6.998 (0.90), 7.210 (1.95), 7.212 (1.90), 7.230 (2.18), 7.251 (0.81), 7.255 (0.63) , 7.561 (0.88), 7.566 (1.02), 7.583 (1.45), 7.589 (1.81), 7.630 (2.05), 7.635 (1.95), 7.664 (0.46).

Example 236.

(-)-5-({[6-Bromo-3-methyl-2-(piperidin-1-yl)quinolin-4-yl]carbonyl}amino)-4-(2methoxyphenyl)valeric acid (enantiomer 2).

Mixture of 5-{[(6-bromo-2-chloro-3-methylquinolin-4-yl)carbonyl]amino}-4-(2methoxyphenyl)valeric acid (enantiomer 2, 200 mg, 87% pure, 344 µmol, example 242A) and piperidine (5.0 ml) were stirred for 1.5 h at 100°С. After cooling to RT, the reaction mixture was added to 1M hydrochloric acid and extracted with dichloromethane. The organic phase was dried over sodium sulfate and concentrated. The starting material was purified by preparative HPLC (method 28). 166 mg (99% pure, 86% thor.) of the title compound were obtained.

[a]D ²⁰ = -2.58°, 589 nm, c = 0.8 g/100 ml, chloroform.

LC-MS (method 25): Rt = 1.35 min; MS (ESIpos): m/z = 554/556 [M+H]+.

1H-NMR (400 MHz, chloroform-d) δ [ppm]: 1.036 (0.66), 1.194 (0.73), 1.261 (0.62), 1.276 (16.00), 1.282 (1.00), 1.295 (0.60), 1.610 (0.44) , 1.623 (0.62), 1.638 (0.83), 1.650 (0.82), 1.707 (1.46), 1.717 (1.68), 1.745 (0.88), 1.760 (0.72), 2.179 (6.04), 2.225 (0.48), 2.238 (0.80) , 2.258 (0.82), 2.299 (0.42), 2.995 (0.57), 3.009 (0.76), 3.023 (0.54), 3.148 (1.64), 3.162 (2.07), 3.173 (1.50), 3.439 (0.43), 3.729 (11.07) , 3.791 (0.41), 3.924 (0.61), 3.957 (0.41), 5.978 (0.72), 6.832 (0.97), 6.853 (1.08), 6.942 (0.51), 6.945 (0.50), 6.962 (1.06), 6.963 (1.09) , 6.980 (0.68), 6.982 (0.65), 7.199 (2.09), 7.218 (2.39), 7.235 (0.57), 7.552 (0.71), 7.557 (0.73), 7.574 (1.23), 7.579 (1.51), 7.625 (2.89) , 7.628 (1.65), 7.634 (1.32), 7.646 (1.30).

Example 237.

(+)-5-({[6-Bromo-3-methyl-2-(pyrrolidin-1-yl)quinolin-4-yl]carbonyl}amino)-4-(2methoxyphenyl)valeric acid (enantiomer 1) (λ ΝΗ O ^Br ^^UcH ₃ mm χ

Mixture of 5-{[(6-bromo-2-chloro-3-methylquinolin-4-yl)carbonyl]amino}-4-(2methoxyphenyl)valeric acid (enantiomer 1, 200 mg, 85% pure, 336 µmol, example 241A) and pyrrolidine (1.5 ml) were stirred for 2 h at 100°C. After cooling to RT, the reaction mixture was added to 1M hydrochloric acid and extracted with dichloromethane. The organic phase was dried over sodium sulfate and concentrated. The starting material was purified by preparative HPLC (method 28). 65 mg (99% pure, 35% thor.) of the title compound were obtained.

[a]D ²⁰ = +5.19°, 589 nm, c = 0.24 g/100 ml, chloroform;

LC-MS (method 25): R _t = 0.85 min; MS (ESIpos): m/z = 540/542 [M+H] ⁺ .

1H-NMR (400 MHz, chloroform-d) δ [ppm]: 1.914 (1.96), 1.923 (2.41), 1.930 (5.41), 1.937 (2.38), 1.946 (2.04), 1.962 (0.41), 1.973 (0.52) , 1.993 (0.40), 2.007 (0.47), 2.015 (0.41), 2.019 (0.50), 2.028 (0.51), 2.032 (0.50), 2.043 (0.45), 2.126 (0.75), 2.150 (4.86), 2.172 (0.56) , 2.179 (0.40) . , 3.841 (0.44), 3.896 (0.41), 3.911 (0.69), 3.926 (0.48), 6.082 (0.69), 6.847 (1.55), 6.867 (1.61) , 6.991 (1.01), 6.993 (0.94), 7.211 (3.38), 7.230 (3.74), 7.249 (0.85), 7.253 (0.61), 7.408 (0.72), 7.430 (1.91), 7.450 (1.96), 7.456 (2.06) , 7.473 (0.66), 7.478 (0.82), 7.528 (1.65).

Example 238.

(-)-5-({[6-Bromo-3-methyl-2-(pyrrolidin-1-yl)quinolin-4-yl]carbonyl}amino)-4-(2methoxyphenyl)valeric acid (enantiomer 2).

Mixture of 5-{[(6-bromo-2-chloro-3-methylquinolin-4-yl)carbonyl]amino}-4-(2methoxyphenyl)valeric acid (enantiomer 2, 127 mg, 87% pure, 218 µmol, example 242A) and pyrrolidine (1.0 ml) were stirred for 1.5 h at 100°C. After cooling to RT, the reaction mixture was added to 1M hydrochloric acid and extracted with dichloromethane. The organic phase was dried over sodium sulfate and concentrated. The starting product was purified by preparative HPLC (me

- 222 040220 tod 28). 24 mg (99% pure, 20% theoretical) of the title compound were obtained.

To determine the specific rotation value, a sample of the title compound was dissolved in dichloromethane and washed with water. The organic phase was concentrated and the residue was dried and dissolved in chloroform to measure the specific rotation.

[a] ^D20 = -2.0°, 589 nm, c = 0.33 g/100 ml, chloroform;

LC-MS (method 25): R _t = 0.85 min; MS (ESIpos): m/z = 540/542 [M+H]+.

¹ H-NMR (400 MHz, chloroform-d) δ [ppm]: 1.260 (1.06), 1.649 (2.69), 1.790 (1.96), 1.911 (2.71), 1.928 (7.02), 1.944 (3.21), 1.978 (0.87 ), 1.998 (0.87), 2.016 (0.86), 2.035 (0.46), 2.085 (0.76), 2.099 (0.91), 2.118 (0.91), 2.139 (0.64), 2.171 (6.76), 2.220 (1.98), 2.238 (1.97 ), 2.257 (0.91), 3.028 (2.58), 3.042 (3.03), 3.056 (2.57), 3.423 (0.94), 3.435 (1.21), 3.448 (1.02), 3.568 (3.20), 3.584 (7.25), 3.665 (0.70 ), 3.727 (16.00), 3.767 (0.91), 3.786 (1.16), 3.799 (1.04), 3.822 (0.82), 3.884 (0.81), 3.899 (1.23), 3.913 (0.97), 3.931 (0.85), 6.149 (1.09 ), 6.827 (1.86), 6.848 (2.18), 6.935 (1.01), 6.953 (2.11), 6.971 (1.26), 7.192 (1.35), 7.206 (3.26), 7.225 (2.36), 7.452 (0.52), 7.476 (4.64 ), 7.504 (0.56), 7.551 (2.52).

Example 239.

(+)-5-({[2-(Azepan-1-yl)-6-bromo-3-methylquinolin-4-yl]carbonyl}amino)-4-(2methoxyphenyl)valeric acid (enantiomer 1)

Mixture of 5-{[(6-bromo-2-chloro-3-methylquinolin-4-yl)carbonyl]amino}-4-(2methoxyphenyl)valeric acid (enantiomer 7, 200 mg, 85% pure, 336 µmol, example 241A) and azepane (1.5 ml) were stirred for 2 h at 100°C. After cooling to RT, the reaction mixture was added to 1M hydrochloric acid and extracted with dichloromethane. The organic phase was dried over sodium sulfate and concentrated. The starting material was purified by preparative HPLC (method 28). 65 mg (99% pure, 34% thor.) of the title compound were obtained.

To determine the specific rotation value, a sample of the title compound was dissolved in dichloromethane and washed with water. The organic phase was concentrated and the residue was dried and dissolved in methanol to determine the specific rotation value.

[a]D ²⁰ = +11.0°, 589 nm, c = 0.47 g/100 ml, methanol.

LC-MS (method 25): R _t = 1.26 min; MS (ESIpos): m/z = 568/570 [M+H] ⁺ .

1H-NMR (400 MHz, chloroform-d) δ [ppm]: 1.261 (0.55), 1.654 (1.36), 1.660 (2.71), 1.669 (3.59), 1.677 (3.06), 1.684 (2.08), 1.815 (2.31) 2.019 (0.45), 2.032 (0.49), 2.041 (0.52), 2.055 (0.47), 2.066 (0.43), 2.130 (0.58), 2.144 (0.76), 2.151 (0.58), 2.171 (7.20), 2.278 (0.94) . . , 3.951 (0.55), 3.969 (0.59), 5.825 (0.48), 6.843 (1.57), 6.863 (1.56), 6.956 (0.77), 6.958 (0.74) , 7.229 (3.12), 7.249 (0.85), 7.253 (0.63), 7.523 (0.48), 7.528 (0.63), 7.545 (1.76), 7.549 (1.96), 7.561 (0.89), 7.590 (1.96).

Example 240.

(-)-5-({[2-(Azepan-1-yl)-6-bromo-3-methylquinolin-4-yl]carbonyl}amino)-4-(2methoxyphenyl)valeric acid (enantiomer 2).

Mixture of 5-{[(6-bromo-2-chloro-3-methylquinolin-4-yl)carbonyl]amino}-4-(2methoxyphenyl)valeric acid (enantiomer 2, 70 mg, 87% pure, 120 µmol, example 242A) and azepane (0.5 ml) were stirred for 1.5 h at 100°С. After cooling to RT, the reaction mixture was added to 1M hydrochloric acid and extracted with dichloromethane. The organic phase was dried over sodium sulfate and concentrated. The starting material was purified by preparative HPLC (method 28). 58 mg (99% pure, 84% thor.) of the title compound were obtained.

To determine the specific rotation value, a sample of the title compound was dissolved in dichloromethane and washed with water. The organic phase was concentrated and the residue was dried and dissolved in methanol to determine the specific rotation value.

[a]D ²⁰ = -8.8°, 589 nm, c = 0.40 g/100 ml, methanol.

LC-MS (method 25): R _t = 1.38 min; MS (ESIpos): m/z = 568/570 [M+H] ⁺ .

1H-NMR (400 MHz, chloroform-d) δ [ppm]: 1.287 (0.66), 1.430 (0.60), 1.435 (0.60), 1.440 (0.59), 1.447 (0.68), 1.451 (0.68), 1.459 (0.66) , 1.464 (0.82), 1.475 (0.64), 1.480 (0.66), 1.487 (0.79), 1.589 (0.72), 1.620 (0.90), 1.671 (2.26), 1.676 (2.27), 1.681 (2.15), 1.688 (2.69) , 1.692 (2.40), 1.700 (2.08), 1.706 (2.52), 1.710

- 223 040220 (2.46), 1.715 (1.42), 1.722 (1.23), 1.728 (1.45), 1.739 (0.58), 1.746 (0.66), 2.074 (9.60), 2.080 (9.89), 2.088 (10.03), 2.225 (8.25) ), 2.392 (1.01), 2.413 (1.28), 2.427 (1.51), 2.449 (1.17), 2.463 (0.78), 2.508 (1.34), 2.523 (1.47), 2.542 (1.59), 2.562 (3.91), 2.583 (5.23 ), 2.597 (6.79), 2.607 (4.51), 2.618 (6.43), 2.636 (2.19), 2.653 (2.10), 2.673 (1.04), 3.403 (1.36), 3.408 (1.53), 3.413 (1.92), 3.427 (2.90 ), 3.432 (3.63), 3.437 (4.40), 3.442 (4.50), 3.448 (3.86), 3.453 (4.66), 3.460 (4.20), 3.467 (3.15), 3.476 (2.60), 3.481 (1.25), 3.488 (1.49 ), 3.852 (1.68), 3.879 (2.23), 3.885 (2.31), 3.915 (6.23), 3.930 (6.53), 3.944 (4.69), 3.966 (2.11), 4.116 (4.77), 4.120 (4.83), 4.126 (4.65 ), 4.133 (5.54), 4.136 (5.90), 4.139 (5.58), 4.144 (5.35), 4.150 (8.43), 4.154 (7.75), 4.160 (4.77), 4.166 (5.01), 4.173 (7.65), 4.188 (0.85 ), 4.202 (1.00), 4.223 (0.87), 4.324 (0.95), 4.338 (1.27), 4.358 (1.14), 4.372 (0.79), 6.547 (1.48), 7.235 (1.36), 7.251 (1.79), 7.292 (1.11 ), 7.347 (1.00), 7.3 64 (1.59),7.382 (2.13), 7.400 (1.78), 7.420 (0.70), 7.580 (0.44), 7.585 (0.42), 7.599 (1.69), 7.604 (1.77), 7.609 (1.76), 7.620 (2.87), 7.628 (2.62), 7.635 (3.96), 7.660 (12.32), 7.664 (11.67), 7.670 (10.66), 7.677 (12.09), 7.680 (12.39),

7.683 (11.15), 7.688 (11.09), 7.694 (15.57), 7.699 (14.56), 7.702 (2.63), 7.704 (10.36), 7.710 (10.63), 7.715 (12.08), 7.717 (16.00), 7.931 (0.88), 7.936 (1.58), 7.942 (1.97), 7.948 (2.49), 7.954 (2.68), 7.960 (2.75), 7.965 (3.65), 7.970 (3.52), 7.981 (3.59), 7.988 (3.08) 8.001 (3.64), 8.015 (1.81), 8.031 (2.10), 8.049 (1.69).

Example 241.

(+/-)-5-({[6-Bromo-3-methyl-2-(piperidin-1-yl)quinolin-4-yl]carbonyl}amino)-4-(2,6dichlorophenyl)valeric acid ( racemate)

Method A.

(+/-)-5-{[(6-Bromo-2-chloro-3-methylquinolin-4-yl)carbonyl]amino}-4-(2,6-dichloro-phenyl)valeric acid (racemate, 45.0 mg , 72% pure, 59.5 µmol, example 246A) and piperidine (1.0 ml, 180 µmol) were stirred for 1.5 h at 100°C.

Method B.

(+/-)-5-{[(6-Bromo-2-chloro-3-methylquinolin-4-yl)carbonyl]amino}-4-(2,6-dichlorophenyl)valeric acid (racemate, 123mg, 72 % purity, 163 µmol, example 246A) and piperidine (50 µl, 500 µmol) were stirred in 1-butanol (6 ml) for 8 h at 100°C.

The combined reaction mixtures from Method A and Method B were added to 1M hydrochloric acid and extracted with dichloromethane. The organic phase was dried over sodium sulfate and concentrated on a rotary evaporator. The starting material was purified by preparative HPLC (Chromatorex C-18, 10 µm, 125 mm x 30 mm, eluent A: water + 0.1% formic acid, eluent B: acetonitrile; gradient: 50-95% B). 69 mg (97% pure, 50% theoretical) of the title compound were obtained.

LC-MS (method 25): Rt = 1.39 min; MS (ESIpos): m/z = 592/594/596 [M+H] ⁺ .

1H-NMR (400 MHz, chloroform-d) δ [ppm]: 0.959 (0.56), 1.185 (1.50), 1.200 (2.54), 1.205 (0.61), 1.219 (0.63), 1.370 (12.44), 1.561 (0.53) , 1.604 (1.80), 1.614 (1.57), 1.650 (3.36), 1.659 (3.52), 2.069 (0.76), 2.079 (0.72), 2.085 (0.73), 2.088 (0.75), 2.102 (1.06), 2.113 (0.71) 2.121 (0.58), 2.133 (1.46), 2.158 (16.00), 2.172 (1.46), 2.187 (1.38), 2.205 (1.47), 2.223 (1.78), 2.242 (1.01), 2.264 (0.61), 2.283 (0.41) . , 2.931 (0.65), 3.214 (4.22), 3.783 (3.91), 3.991 (0.77), 4.006 (0.82), 4.019 (1.17), 4.033 (1.38) , 4.083 (0.65), 4.090 (0.95), 4.107 (0.60), 4.118 (0.79), 4.133 (0.70),6.816 (0.42), 6.836 (0.47), 7.049 (1.92), 7.070 (4.35), 7.089 (2.79) , 7.219 (2.59) , 7.527 (1.62), 7.532 (1.85), 7.549 (2.11), 7.554 (2.61), 7.587 (2.49), 7.636 (3.49), 7.658 (2.29).

Example 242.

(+/-)-5-({[6-Bromo-3-methyl-2-(piperidin-1-yl)quinolin-4-yl]carbonyl}amino)-4-(2methylphenyl)valeric acid (racemate)

- 224 040220

(+/-)-5-{[(6-Bromo-2-chloro-3-methylquinolin-4-yl)carbonyl]amino}-4-(2-methylphenyl)valeric acid (racemate, 500mg, 86% pure , 0.88 mmol, example 234A) and piperidine (3.0 ml, 2.2 mmol) were stirred for 2 h at 100°C. After cooling to RT, the reaction mixture was added to 1M hydrochloric acid and extracted with dichloromethane. The organic phase was dried over sodium sulfate and concentrated. The starting material was previously purified by column chromatography (Isolera, KP-Sil, eluent: dichloromethane/methanol, gradient: 0-40% methanol) and further purified by preparative HPLC (method 27). 330 mg (99% pure, 69% theoretical) of the title compound were obtained.

LC-MS (method 26): Rt = 0.82 min; MS (ESIpos): m/z = 538/540 [M+H] ⁺ .

1H-NMR (400 MHz, chloroform-d) δ [ppm]: 1.565 (0.89), 1.577 (0.89), 1.660 (2.48), 1.672 (2.38), 1.689 (2.28), 1.704 (2.76), 1.716 (2.87) , 1.885 (0.46), 1.907 (0.57), 1.913 (0.68), 1.920 (0.65), 1.942 (0.49), 2.079 (0.56), 2.092 (0.70), 2.111 (0.70), 2.130 (0.42), 2.180 (2.18) 2.198 (3.83), 2.207 (16.00), 2.218 (1.80), 2.262 (0.53), 2.356 (14.53), 2.391 (4.38), 2.874 (2.02), 2.888 (2.61), 2.902 (1.88), 3.145 (2.77) , 3.159 (3.54), 3.169 (2.59), 3.316 (0.45), 3.343 (0.53), 3.352 (0.51), 3.369 (0.68), 3.382 (0.54), 3.652 (0.46), 3.665 (0.52) . , 6.179 (1.00), 6.193 (0.56), 7.087 (0.47), 7.091 (0.49), 7.107 (1.30), 7.111 (1.31), 7.122 (1.34), 7.126 (1.68), 7.141 (2.27), 7.155 (0.79) 7.178 (0.74), 7.183 (0.61), 7.190 (1.05), 7.197 (1.99), 7.202 (1.60), 7.205 (1.91), 7.217 (3.58), 7.221 (2.59), 7.237 (0.66), 7.554 (1.42) , 7.559 (1.49), 7.577 (2.49 ), 7.582 (2.70), 7.628 (4.42), 7.650 (2.37), 7.664 (3.39), 7.669 (3.15).

Example 243.

(+/-)-5-({[2-(azepan-1-yl)-6-bromo-3-methylquinolin-4-yl]carbonyl}amino)-4-(2methylphenyl)valeric acid (racemate)

(+/-)-5-{[(6-Bromo-2-chloro-3-methylquinolin-4-yl)carbonyl]amino}-4-(2-methylphenyl)valeric acid (racemate, 500mg, 86% pure , 0.88 mmol, example 234А) and azepane (3.0 mL, 2.2 mmol) were stirred for 2 h at 100°С. After cooling to RT, the reaction mixture was added to 1 M hydrochloric acid and extracted with dichloromethane. The organic phase was dried over sodium sulfate and concentrated.

The starting material was purified by preparative HPLC (method 27). 315 mg (99% pure, 64% theoretical) of the title compound were obtained.

LC-MS (method 26): R _t = 0.87 min; MS (ESIpos): m/z = 552/554 [M+H] ⁺ .

1H-NMR (400 MHz, chloroform-d) δ [ppm]: 1.262 (0.44), 1.622 (0.65), 1.629 (1.23), 1.637 (1.69), 1.652 (2.55), 1.657 (3.68), 1.665 (4.74) , 1.674 (4.04), 1.680 (2.70), 1.812 (3.00), 1.898 (0.58), 1.908 (0.52), 1.924 (0.51), 1.931 (0.58), 1.942 (0.65), 1.965 (0.57), 2.111 (0.66) , 2.125 (0.74), 2.144 (0.71), 2.160 (0.48), 2.177 (0.48), 2.194 (16.00), 2.207 (0.84), 2.230 (2.25), 2.248 (3.63) , 2.390 (2.68), 2.626 (1.58), 3.005 (1.99), 3.020 (1.81), 3.034 (1.87), 3.369 (0.52), 3.385 (0.72), 3.398 (0.58), 3.406 (0.49) . , 3.907 (0.61), 3.923 (1.16), 3.940 (1.00), 3.957 (0.93), 3.973 (0.47), 5.949 (0.63), 5.963 (1.10), 5.977 (0.62), 7.096 (0.45), 7.102 (0.49) , 7.116 (1.30), 7.122 (1.17), 7.129 (1.28), 7.136 (1.72), 7.148 (2.58), 7.165 (0.88), 7.185 (0.51), 7.192 (0.68), 7.197 (0.67), 7.205 (2.43) , 7.208 (2.22), 7.215 (2.91 ), 7.219 (3.74), 7.222 (3.61), 7.234 (0.49), 7.519 (0.65), 7.523 (0.61), 7.541 (3.29), 7.546 (3.86), 7.553 (5.15), 7.574 (0.96), 7.608 (0.42 ), 7.616 (3.08), 7.620 (2.89).

Example 244.

(+/-)-5-({[6-Bromo-3-methyl-2-(piperidin-1-yl)quinolin-4-yl]carbonyl}amino)-4-(2,6difluorophenyl)valeric acid (racemate )

- 225 040220

Based on (+/-)-tert-butyl-5-({[6-bromo-3-methyl-2-(piperidin-1-yl)quinolin-4-yl]carbonyl}amino)4-(2.6 -difluorophenyl)pentanoate (racemate, 55 mg, 89.2 µmol, example 250A) was reacted with TFA and the product was purified as described for 5-[({6-bromo-2-[3-ethylpiperidin-1-yl]-3- methylquinolin4-yl}carbonyl)amino]-4-(2,5-difluorophenyl)valeric acid (Example 225). 44 mg (100% pure, 88% thor.) of the title compound were obtained.

LC-MS (method 1): R _t = 2.10 min; MS (ESIpos): m/z = 560/562 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.149 (0.65), -0.008 (5.92), 0.008 (5.82), 0.146 (0.65), 1.607 (3.47), 1.671 (6.81), 1.873 ( 0.73), 1.888 (0.94), 1.905 (1.25), 2.051 (1.10), 2.065 (1.33), 2.082 (1.41), 2.101 (1.80), 2.116 (7.07), 2.135 (16.00), 2.327 (0.73), 0.89), 3.133 (9.00), 3.489 (1.25), 3.677 (0.84), 3.695 (1.88), 3.710 (3.03), 3.724 (2.17), 7.057 (3.63), 7.079 (6.66), 7.102 (4.28), 0.57) 1.46), 7.683 (1.59), 8.798 (1.62), 8.813 (3.26), 8.827 (1.67), 12.078 (4.36).

Example 245.

(+)-5-({[6-Bromo-3-methyl-2-(piperidin-1-yl)quinolin-4-yl]carbonyl}amino)-4-(2,6difluorophenyl)valeric acid (enantiomer 1) .

tert-Butyl 5-({[6-bromo-3-methyl-2-(piperidin-1-yl)quinolin-4-yl]carbonyl}amino)-4-(2,6difluorophenyl)pentanoate (enantiomer 1, 85 mg, 138 µmol, example 251A) was dissolved in dichloromethane (1.8 ml). TFA (1.0 ml, 14 mmol) was added at RT and the reaction mixture was stirred for 1 h at RT. The volatile components were removed on a rotary evaporator. The residue was dissolved in a small amount of DMSO and purified by preparative HPLC (method 31). The combined desired fractions were concentrated and the residue was dried in vacuo. 64 mg (99% pure, 82% thor.) of the title compound were obtained.

[a] _D20 = +40.8°, 589 nm ^, c = 0.32 g/100 mL, methanol;

LC-MS (method 1): R _t = 2.09 min; MS (ESIpos): m/z = 560/562 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: -0.149 (0.63), 0.008 (3.76), 0.146 (0.46), 0.839 (0.69), 1.234 (0.67), 1.607 (3.61), 1.671 ( 6.99), 1.903 (1.28), 2.051 (1.15), 2.064 (1.45), 2.081 (1.45), 2.116 (7.35), 2.135 (16.00), 2.327 (1.49), 2.366 (0.97), 2.670 (1.49), 2.710 ( 0.92), 3.133 (9.28), 3.162 (1.97), 3.175 (1.74), 3.496 (1.22), 3.677 (0.82), 3.695 (1.89), 3.710 (3.13), 3.725 (2.14), 7.057 (3.84), 7.079 7.06) 1.72), 7.683 (1.72), 8.798 (1.66), 8.813 (3.38), 8.827 (1.76), 12.080 (2.94).

Example 246.

(-)-5-({[6-Bromo-3-methyl-2-(piperidin-1-yl)quinolin-4-yl]carbonyl}amino)-4-(2,6difluorophenyl)valeric acid (enantiomer 2) .

Starting from tert-butyl 5-({[6-bromo-3-methyl-2-(piperidin-1-yl)quinolin-4-yl]carbonyl}amino)-4(2,6-difluorophenyl)pentanoate (enantiomer 2, 63 mg, 102 µmol, example 252A) reacted and worked up the product as described for tert-butyl-5-({[6-bromo-3-methyl-2-(piperidin-1yl)quinolin-4-yl] carbonyl}amino)-4-(2,6-difluorophenyl)pentanoate (enantiomer 1, example 245). 48 mg (100% pure, 84% thor.) of the title compound were obtained.

[a] _D20 = -46.7°, 589 nm, c = 0.30 ^g /100 ml, methanol;

LC-MS (method 1): R _t = 2.09 min; MS (ESIpos): m/z = 560/562 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.149 (0.52), -0.008 (3.81), 0.008 (3.85), 0.146 (0.46), 1.606 (3.56), 1.671 (7.01), 1.902 ( 1.29), 2.050 (1.14), 2.063 (1.35), 2.081 (1.41), 2.115 (7.45), 2.135 (16.00), 2.327 (1.39), 2.366 (0.73), 2.669 (1.60), 2.710 (0.92), 9.32), 3.493 (1.29), 3.676 (0.87), 3.694 (1.89), 3.710 (3.14), 3.724 (2.23), 7.057 (3.85), 7.079 (7.03), 7.101 (4.51), 7.340 (1.48), 7.359 ( 2.10) 1.69), 8.813 (3.39), 8.828 (1.75), 12.083 (2.29).

Example 247.

(+/-)-5-({[6-Bromo-3-methyl-2-(pyrrolidin-1-yl)quinolin-4-yl]carbonyl}amino)-4-(2,6difluorophenyl)valeric acid hydroformate (racemate)

- 226 040220

Based on (+/-)-tert-butyl-5-({[6-bromo-3-methyl-2-(pyrrolidin-1-yl)quinolin-4yl]carbonyl}amino)-4-(2,6- difluorophenyl)pentanoate (racemate, 56 mg, 92.9 µmol, Example 253A) was reacted and worked up as described for 5-[({6-bromo-2-[3-ethylpiperidin-1-yl]-3methylquinolin-4-yl }carbonyl)amino]-4-(2,5-difluorophenyl)valeric acid (Example 225). 20 mg (100% pure, 36% thor. y.) of the title compound (contained formic acid obtained from HPLC method) was obtained.

LC-MS (method 1): Rt = 1.39 min; MS (ESIpos): m/z = 546/548 [M+H]+.

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.149 (1.79), 0.008 (16.00), 0.146 (1.79), 1.872 (13.83), 2.061 (1.98), 2.079 (2.02), 2.114 (8.78) ), 2.129 (7.73), 2.163 (9.28), 2.328 (2.17), 2.670 (2.10), 3.566 (8.93), 3.680 (2.52), 3.695 (3.53), 3.709 (2.80), 7.050 (5.01), 7.072 (9.09 ), 7.095 (5.79), 7.354 (2.87), 7.372 (2.14), 7.466 (7.03), 7.488 (11.61), 7.547 (6.21), 7.553 (5.86), 7.570 (3.77), 7.575 (3.61), 8.137 (14.49 ), 8.750 (2.29), 8.765 (4.50), 8.779 (2.29), 12.103 (0.50).

Example 248.

5-({[6-Bromo-3-methyl-2-(pyrrolidin-1-yl)quinolin-4-yl]carbonyl}amino)-4-(2,6difluorophenyl)valeric acid (enantiomer 1) jOl

Ν Η O

CH ₃

ULAq

Starting from tert-butyl 5-({[6-bromo-3-methyl-2-(pyrrolidin-1-yl)quinolin-4-yl]carbonyl}amino)-4(2,6-difluorophenyl)pentanoate (enantiomer 1, 54 mg, 89.6 µmol, example 254A) reacted and worked up the product as described for (+)-5-({[6-bromo-3-methyl-2-(piperidin-1-yl)quinolin-4yl] carbonyl}amino)-4-(2,6-difluorophenyl)valeric acid (Example 245). 20 mg (96% pure, 39% thor.) of the title compound were obtained.

LC-MS (method 1): Rt = 1.39 min; MS (ESIpos): m/z = 546/548 [M+H]+.

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.149 (1.41), 0.146 (1.22), 1.141 (5.31), 1.235 (3.97), 1.356 (1.09), 1.872 (13.06), 2.086 (16.00 ), 2.115 (9.79), 2.130 (8.19), 2.165 (8.58), 2.328 (3.90), 2.366 (2.69), 2.669 (4.54), 2.710 (3.14), 3.564 (8.13), 3.694 (3.65), 4.538 (0.83 ), 7.051 (4.99), 7.073 (8.96), 7.095 (5.44), 7.354 (3.14), 7.466 (6.53), 7.489 (10.50), 7.548 (5.63), 7.553 (5.31), 7.570 (3.39), 7.575 (3.14 ), 7.838 (0.96), 8.133 (5.63), 8.750 (2.43), 8.765 (4.10), 12.071 (1.73).

Example 249.

(-)-5-({[6-Bromo-3-methyl-2-(pyrrolidin-1-yl)quinolin-4-yl]carbonyl}amino)-4-(2,6difluorophenyl)valeric acid (enantiomer 2) .

Starting from tert-butyl 5-({[6-bromo-3-methyl-2-(pyrrolidin-1-yl)quinolin-4-yl]carbonyl}amino)-4(2,6-difluorophenyl)pentanoate (enantiomer 2, 47 mg, 78.0 µmol, example 255A) reacted and worked up the product as described for (+)-5-({[6-bromo-3-methyl-2-(piperidin-1-yl)quinolin-4yl] carbonyl}amino)-4-(2,6-difluorophenyl)valeric acid (Example 245). 33 mg (96% pure, 74% thor.) of the title compound were obtained.

[a] _D20 = -41.1°, 589 nm, c = 0.30 ^g /100 ml, methanol;

LC-MS (method 1): Rt = 1.39 min; MS (ESIpos): m/z = 546/548 [M+H]+.

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.149 (1.73), 0.146 (1.64), 1.147 (0.95), 1.872 (16.00), 2.114 (10.29), 2.129 (9.25), 2.162 (10.64) ), 2.327 (5.88), 2.366 (2.34), 2.669 (5.71), 2.710 (2.51), 3.565 (9.95), 3.693 (3.98), 7.050 (5.79), 7.072 (10.81), 7.095 (6.40), 7.351 (3.11 ), 7.466 (8.13), 7.488 (13.15), 7.547 (6.83), 7.553 (6.66), 7.575 (4.15), 8.134 (10.90), 8.763 (4.84), 12.069 (1.38).

Example 250.

(+/-)-5-({[6-Bromo-2-(3,3-difluoropiperidin-1-yl)-3-methylquinolin-4-yl]carbonyl}amino)-4-(2,6difluorophenyl)valeric acid (racemate)

- 227 040220

Based on (+/-)-tert-butyl-5-({[6-bromo-2-(3,3-difluoropiperidin-1-yl)-3-methylquinolin-4yl]carbonyl}amino)-4-(2 ,6-difluorophenyl)pentanoate (racemate, 55 mg, 84.3 µmol, Example 256A) was reacted and worked up as described for 5-[({6-bromo-2-[3-ethylpiperidin-1-yl]-3methylquinolin- 4-yl}carbonyl)amino]-4-(2,5-difluorophenyl)valeric acid (Example 255). 48 mg (100% pure, 95% thor.) of the title compound were obtained.

LC-MS (method 1): R _t = 2.07 min; MS (ESIpos): m/z = 596/598 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: -0.149 (0.57), -0.008 (4.89), 0.146 (0.61), 1.234 (0.46), 1.890 (4.70), 2.064 (2.82), 2.082 (3.71) (4.20) (2.22) (1.90), 8.828 (3.82), 8.842 (1.95), 12.091 (1.33).

Example 251.

(+)-5-({[6-Bromo-2-(3,3-difluoropiperidin-1-yl)-3-methylquinolin-4-yl]carbonyl}amino)-4-(2,6difluorophenyl)valeric acid ( enantiomer 1).

Starting from tert-butyl 5-({[6-bromo-3-methyl-2-(piperidin-1-yl)quinolin-4-yl]carbonyl}amino)-4(2,6-difluorophenyl)pentanoate (enantiomer 7 , 82 mg, 126 µmol, Example 257A) was reacted with TFA as described for (+)-5-({[6-bromo-3-methyl-2-(piperidin-1-yl)quinolin-4yl]carbonyl} amino)-4-(2,6-difluorophenyl)valeric acid (Example 245). The product was purified by preparative HPLC (method 19). 48 mg (98% pure, 63% thor.) of the title compound were obtained.

[a] _D20 = +44.1°, 589 nm, c = 0.48 g/100 mL ^, methanol;

LC-MS (method 1): Rt = 2.09 min; MS (ESIpos): m/z = 596/598 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.150 (0.59), 0.146 (0.64), 1.889 (4.78), 2.081 (3.71), 2.100 (3.95), 2.118 (8.73), 2.133 (9.08 ), 2.154 (16.00), 2.365 (0.46), 2.709 (0.55), 3.162 (10.75), 3.174 (9.58), 3.446 (3.22), 3.476 (6.83), 3.504 (4.20), 3.703 (2.08), 3.719 (3.25 ), 4.063 (0.59), 4.075 (1.40), 4.087 (1.37), 7.058 (3.98), 7.080 (7.57), 7.103 (4.68), 7.342 (1.63), 7.360 (2.24), 7.377 (1.44), 7.501 (0.70 ), 7.673 (2.24), 7.695 (10.13), 7.705 (6.46), 7.731 (1.48), 8.812 (1.86), 8.827 (3.59), 8.841 (1.87), 12.083 (1.83).

Example 252.

(-)-5-({[6-Bromo-2-(3,3-difluoropiperidin-1-yl)-3-methylquinolin-4-yl]carbonyl}amino)-4-(2,6difluorophenyl)valeric acid ( enantiomer 2).

Starting from tert-butyl 5-({[6-bromo-3-methyl-2-(piperidin-1-yl)quinolin-4-yl]carbonyl}amino)-4(2,6-difluorophenyl)pentanoate (enantiomer 2, 73 mg, 112 µmol, example 258A) was reacted with TFA as described for (+)-5-({[6-bromo-3-methyl-2-(piperidin-1-yl)quinolin-4yl]carbonyl }amino)-4-(2,6-difluorophenyl)valeric acid (Example 245). The product was purified by preparative HPLC (method 19). 40 mg (98% pure, 59% thor.) of the title compound were obtained.

[a] _D20 = -38.2°, 589 nm, c = 0.37 ^g /100 ml, methanol;

LC-MS (method 1): Rt = 2.06 min; MS (ESIpos): m/z = 596/598 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 1.890 (4.67), 2.065 (2.78), 2.082 (3.62), 2.101 (3.76), 2.119 (8.55), 2.135 (9.19), 2.155 (16.00) ), 2.327 (0.66), 2.670 (0.70), 2.710 (0.43), 3.162 (9.09), 3.175 (8.05), 3.447 (3.23), 3.476 (6.83), 3.504 (4.13), 3.687 (0.97), 3.703 (2.09 ), 3.719 (3.30), 3.734 (2.38), 4.062 (0.43), 4.075 (1.22), 4.088 (1.19), 4.102 (0.40), 7.059 (4.21), 7.081 (7.74), 7.104 (4.91), 7.323 (0.64 ), 7.342 (1.64), 7.361 (2.27), 7.378 (1.46), 7.398 (0.56), 7.511 (0.67), 7.674 (2.44), 7.696 (11.21), 7.705 (6.99), 7.710 (6.16), 7.728 (1.40 ), 7.732 (1.46), 8.812 (1.93), 8.827 (3.80), 8.841 (1.89), 12.081 (4.01).

Example 253.

5-[({6-Bromo-2-(3-fluoropiperidin-1-yl)-3-methylquinolin-4-yl}carbonyl)amino]-4-(2,6difluorophenyl)valeric acid (mixture of diastereoisomers)

- 228 040220

Starting from tert-butyl 5-[({6-bromo-2-(3-fluoropiperidin-1-yl)-3-methylquinolin-4yl}carbonyl)amino]-4-(2,6-difluorophenyl)pentanoate (56 mg, 88 µmol, Example 259A) reacted and worked up the product as described for 5-[({6-bromo-2-[3-ethylpiperidin-1-yl]-3methylquinolin-4-yl}carbonyl)amino]-4 -(2,5-difluorophenyl)valeric acid (Example 255). 44 mg (100% pure, 88% thor.) of the title compound were obtained.

LC-MS (method 1): Rt = 2.01 min; MS (ESIpos): m/z = 578/580 [M+H]+.

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: -0.149 (1.03), -0.008 (8.38), 0.008 (8.14), 0.146 (0.93), 1.644 (1.51), 1.806 (1.39), 1.902 (3.86), 2.051 (1.37), 2.064 (1.63), 2.082 (1.68), 2.116 (7.76), 2.132 (8.29) (1.75), 3.379 (1.96), 3.405 (1.08), 3.437 (1.77), 3.470 (1.84), 3.714 (2.97), 4.817 (1.29), 4.937 (1.20) (5.17) (1.80), 8.807 (1.82), 8.822 (3.74), 8.836 (1.96), 12.087 (1.51).

Example 254.

5-[({6-Bromo-2-(3-ethylpiperidin-1-yl)-3-methylquinolin-4-yl}carbonyl)amino]-4-(2,6difluorophenyl)valeric acid (mixture of diastereoisomers)

XjL

Ο^ΝΗ Oh

Br^lc^ XX Λ

Starting from tert-butyl 5-[({6-bromo-2-(3-ethylpiperidin-1-yl)-3-methylquinolin-4yl}carbonyl)amino]-4-(2,6-difluorophenyl)pentanoate (mixture diastereoisomers, 55 mg, 85.3 µmol, example 260A) reacted and worked up the product as described for 5-[({6-bromo-2-[3-ethylpiperidin-1-yl]-3-methylquinolin-4-yl}carbonyl)amino ]-4-(2,5-difluorophenyl)valeric acid (Example 255). 48 mg (100% pure, 96% thor.) of the title compound were obtained.

LC-MS (method 1): Rt = 2.37 min; MS (ESIpos): m/z = 588/590 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.149 (0.62), -0.008 (5.31), 0.008 (4.88), 0.146 (0.62), 0.892 (5.28), 0.909 (12.18), 0.911 ( 12.13), 0.928 (6.42), 1.035 (0.46), 1.065 (1.21), 1.086 (1.24), 1.116 (0.56), 1.240 (1.12) 0.50), 1.563 (1.35), 1.603 (1.26), 1.632 (1.09), 1.747 (1.69), 1.780 (1.17), 1.854 (1.61), 1.887 (2.01), 2.030 (0.44), 2.049 (1.06), 2.063 ( 1.30) 0.71), 2.710 (0.96), 2.738 (1.43), 2.768 (0.80), 3.493 (3.67), 3.515 (2.99), 3.679 (0.74), 3.696 (1.61), 3.712 (2.60), 3.726 (1.88), 3.55), 7.075 (6.48), 7.097 (4.26), 7.319 (0.53), 7.338 (1.33), 7.357 (1.92), 7.376 (1.26), 7.394 (0.56), 7.473 (0.53), 7.625 (1.61), 9.98), 7.654 (6.34), 7.658 (5.28), 7.676 (0.99), 7.680 (1.02), 8.790 (1.48), 8.805 (2.94), 8.819 (1.52), 12.082 (1.72).

Example 255.

(+/-)-5-({[6-Bromo-3-methyl-2-(piperidin-1-yl)quinolin-4-yl]carbonyl}amino)-4-(2,5difluorophenyl)valeric acid (racemate )

Based on (+/-)-tert-butyl-5-({[6-bromo-3-methyl-2-(piperidin-1-yl)quinolin-4-yl]carbonyl}amino)4-(2.5 -difluorophenyl)pentanoate (racemate, 56 mg, 90.8 µmol, example 261A) was reacted with TFA (reaction time 45 min) and the product was purified as described for 5-[({6-bromo-2-[3-ethylpiperidine

- 229 040220

1-yl]-3-methylquinolin-4-yl}carbonyl)amino]-4-(2,5-difluorophenyl)valeric acid (Example 255). 49 mg (100% pure, 96% thor.) of the title compound were obtained.

LC-MS (method 1): Rt = 2.11 min; MS (ESIpos): m/z = 560/562 [M+H]+.

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: -0.150 (0.88), 0.146 (0.88), 1.371 (0.59), 1.605 (4.49), 1.670 (8.78), 1.805 (1.66), 2.003 ( 1.56), 2.015 (2.05), 2.035 (1.95), 2.054 (2.24), 2.090 (5.07), 2.117 (16.00), 2.327 (1.76), 2.366 (0.54), 2.669 (1.95), 3.132 (11.56), 1.46), 3.631 (2.10), 3.645 (3.02), 3.695 (1.76), 7.127 (2.54), 7.204 (2.05), 7.215 (2.24), 7.227 (3.32), 7.239 (3.32), 7.250 (1.61), 1.46) 2.10), 12.064 (1.46).

Example 256.

(-)-5-({[6-Bromo-3-methyl-2-(piperidin-1-yl)quinolin-4-yl]carbonyl}amino)-4-(2,5difluorophenyl)valeric acid (enantiomer 1) .

Starting from tert-butyl 5-({[6-bromo-3-methyl-2-(piperidin-1-yl)quinolin-4-yl]carbonyl}amino)-4(2,5-difluorophenyl)pentanoate (enantiomer 1, 81 mg, 131 µmol, example 262A) was reacted with TFA as described for (+)-5-({[6-bromo-3-methyl-2-(piperidin-1-yl)quinolin-4yl]carbonyl }amino)-4-(2,6-difluorophenyl)valeric acid (Example 245). The product was purified by preparative HPLC (method 20). 40 mg (98% pure, 59% thor.) of the title compound were obtained.

[a] _D20 = -28.8°, 589 nm, c = 0.32 ^g /100 ml, methanol;

LC-MS (method 1): R _t = 2.10 min; MS (ESIpos): m/z = 560/562 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: -0.149 (1.04), 0.146 (0.87), 1.606 (4.57), 1.670 (8.65), 1.807 (1.78), 2.003 (1.72), 2.016 ( 2.23), 2.035 (2.23), 2.055 (2.53), 2.063 (2.20), 2.090 (5.31), 2.117 (16.00), 2.137 (3.69), 2.327 (1.78) 0.81), 3.132 (11.40), 3.162 (5.70), 3.175 (5.54), 3.612 (1.49), 3.631 (2.07), 3.646 (2.98), 3.659 (1.68), 3.694 (1.65), 4.062 (0.52), 1.49), 4.088 (1.43),4.100 (0.49), 7.127 (2.49), 7.147 (1.68), 7.204 (2.23), 7.216 (2.36), 7.227 (3.47), 7.239 (3.43), 7.250 (1.65), 1.59), 7.278 (1.78), 7.287 (2.11), 7.293 (2.17), 7.301 (3.01), 7.316 (2.11), 7.324 (1.68), 7.422 (0.94), 7.622 (2.66), 7.644 (12.70), 7.90), 7.658 (7.13), 7.675 (1.46), 7.680 (1.68), 8.724 (2.17), 8.739 (3.92), 8.753 (2.14), 12.061 (2.36).

Example 257.

(+)-5 -({[6-Bromo-3-methyl-2-(piperidin-1-yl)quinolin-4-yl]carbonyl}amino)-4-(2,5difluorophenyl)valeric acid (enantiomer 2) .

Starting from tert-butyl 5-({[6-bromo-3-methyl-2-(piperidin-1-yl)quinolin-4-yl]carbonyl}amino)-4(2,5-difluorophenyl)pentanoate (enantiomer 2, 90 mg, 146 µmol, example 263A) was reacted with TFA as described for (+)-5-({[6-bromo-3-methyl-2-(piperidin-1-yl)quinolin-4yl]carbonyl }amino)-4-(2,6-difluorophenyl)valeric acid (Example 245). The product was purified by preparative HPLC (method 20). 69 mg (97% pure, 82% thor.) of the title compound were obtained.

[a] _D20 = +34.2°, 589 nm, c = 0.33 g/100 mL ^, methanol;

LC-MS (method 1): R _t = 2.11 min; MS (ESIpos): m/z = 560/562 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: -0.149 (0.51), -0.008 (4.19), 0.008 (4.29), 0.146 (0.51), 1.605 (4.49), 1.670 (8.69), 1.750 (0.60), 1.773 (1.12), 1.785 (1.50), 1.808 (1.80), 1.984 (0.65), 2.003 (1.58) (5.24) (9.18) 7.136 (2.01), 7.147 (1.69), 7.204 (2.06), 7.215 (2.25), 7.227 (3.34), 7.239 (3.26), 7.250 (1.60), 7.262 (1.46), 7.278 (1.77), 7.286 (2.06) (1.68), 7.422 (0.90), 7.622 (2.45), 7.644 (12.19), 7.653 (7.77), 7.657 (6.84), 7.675 (1.47) (2.14), 12.060 (2.50).

Example 258.

(+/-)-5-({[6-Bromo-3-methyl-2-(pyrrolidin-1-yl)quinolin-4-yl]carbonyl}amino)-4-(2,5difluorophenyl)valeric acid (racemate )

Based on (+/-)-tert-butyl-5-({[6-bromo-3-methyl-2-(pyrrolidin-1-yl)quinolin-4yl]carbonyl}amino)-4-(2,5- difluorophenyl)pentanoate (racemate, 55 mg, 91.3 µmol, example 264A)

- 230 040220 reacted and worked up the product as described for 5-[({6-bromo-2-[3-ethylpiperidin-1-yl]-3methylquinolin-4-yl}carbonyl)amino]-4-(2.5 -difluorophenyl)valeric acid (Example 255). 29 mg (100% pure, 58% thor.) of the title compound were obtained.

LC-MS (method 1): Rt = 1.41 min; MS (ESIpos): m/z = 546/548 [M+H]+.

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.149 (0.78), -0.008 (5.94), 0.008 (6.57), 0.146 (0.78), 1.235 (0.57), 1.750 (0.63), 1.773 ( 1.30), 1.786 (1.77), 1.806 (2.19), 1.830 (1.93), 1.871 (16.00), 1.981 (0.83), 2.001 (1.98), 2.013 (2.61), 2.033 (2.81), 2.052 (3.07) 2.66), 2.088 (5.37), 2.102 (7.09), 2.118 (8.44), 2.138 (9.07), 2.323 (0.99), 2.327 (1.25), 2.332 (0.94) 1.04), 2.710 (0.42), 3.566 (11.15), 3.597 (3.80), 3.617 (3.28), 3.631 (4.12), 3.644 (2.35), 3.688 (2.08), 7.099 (1.41), 7.120 (2.87), 2.03), 7.196 (2.92), 7.208 (3.07), 7.219 (4.53), 7.231 (4.59), 7.242 (2.40), 7.254 (2.24) 7.303 (3.02), 7.309 (3.02), 7.317 (2.61), 7.465 (8.55), 7.488 (14.59), 7.544 (7.35), 7.549 (6.98), 7.566 (4.33), 7.571 (4.27), 1.98), 8.678 (2.76), 8.693 (4.95), 8.707 (2.76), 12.057 (2.24).

Example 259.

(+)-5-({[6-Bromo-3-methyl-2-(pyrrolidin-1-yl)quinolin-4-yl]carbonyl}amino)-4-(2,5difluorophenyl)valeric acid (enantiomer 1) .

Starting from tert-butyl 5-({[6-bromo-3-methyl-2-(pyrrolidin-1-yl)quinolin-4-yl]carbonyl}amino)-4(2,5-difluorophenyl)pentanoate (enantiomer 1, 80 mg, 133 µmol, example 265A) reacted and worked up the product as described for (+)-5-({[6-bromo-3-methyl-2-(piperidin-1-yl)quinolin-4yl] carbonyl}amino)-4-(2,6-difluorophenyl)valeric acid (Example 245). Received 59 mg (100% pure, 81% theoretical. yield.) specified in the title compound.

[a] _D20 = +30.2°, 589 nm, c = 0.30 g/100 mL ^, methanol;

LC-MS (method 1): Rt = 1.42 min; MS (ESIpos): m/z = 546/548 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.149 (1.42), -0.008 (10.42), 0.008 (9.95), 0.146 (1.26), 1.148 (0.74), 1.806 (2.42), 1.871 ( 16.00), 2.001 (2.11), 2.013 (2.68), 2.033 (2.95), 2.052 (3.21), 2.060 (2.74), 2.088 (5.53), 2.101 (7.47), 2.118 (8.79), 2.137 (9.00), 2.327 ( 3.63), 2.332 (2.74), 2.366 (1.95), 2.669 (4.11), 2.710 (2.11), 3.169 (0.74), 3.566 (10.89), 3.617 (3.47), 3.631 (4.32) 2.26) 4.32), 7.303 (3.21), 7.317 (2.74), 7.466 (5.63), 7.488 (9.68), 7.544 (5.95), 7.550 (5.58), 7.567 (3.53) 2.00), 8.679 (2.74), 8.693 (4.84), 8.707 (2.74), 12.057 (2.84), 12.732 (0.58).

Example 260.

(-)-5-({[6-Bromo-3-methyl-2-(pyrrolidin-1-yl)quinolin-4-yl]carbonyl}amino)-4-(2,5difluorophenyl)valeric acid (enantiomer 2) .

Starting from tert-butyl 5-({[6-bromo-3-methyl-2-(pyrrolidin-1-yl)quinolin-4-yl]carbonyl}amino)-4(2,5-difluorophenyl)pentanoate (enantiomer 2, 83 mg, 138 µmol, example 266A) reacted and worked up the product as described for (+)-5-({[6-bromo-3-methyl-2-(piperidin-1-yl)quinolin-4yl] carbonyl}amino)-4-(2,6-difluorophenyl)valeric acid (Example 245). Received 56 mg (100% pure, 74% theoretical. yield.) specified in the title compound.

[a] _D20 = -28.6°, 589 nm, c = 0.30 ^g /100 ml, methanol;

LC-MS (method 1): Rt = 1.42 min; MS (ESIpos): m/z = 546/548 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.149 (1.11), -0.008 (8.91), 0.008 (10.55), 0.146 (1.15), 1.147 (0.53), 1.806 (2.44), 1.871 ( 16.00), 2.001 (1.99), 2.013 (2.61), 2.033 (2.75), 2.052 (3.10), 2.088 (5.50), 2.102 (7.31), 2.118 (8.60), 2.138 (9.00), 2.327 (2.75), 2.366 ( 1.60), 2.669 (3.01), 2.710 (1.68), 3.207 (0.58), 3.565 (11.21), 3.617 (3.28), 3.631 (4.08), 3.644 (2.30), 3.686 (2.13), 7.120 (3.01), 2.75), 7.208 (3.06), 7.219 (4.43), 7.231 (4.43), 7.242 (2.26), 7.254 (2.26), 7.271 (2.57), 7.285 (3.19) 2.48), 7.465 (7.40), 7.487 (12.59), 7.544 (6.47), 7.549 (6.12), 7.566 (3.81), 7.571 (3.77) 2.57), 12.055 (6.43).

Example 261.

(+/-)-5-({[6-Bromo-2-(3,3-difluoropiperidin-1-yl)-3-methylquinolin-4-yl]carbonyl}amino)-4-(2,5difluorophenyl)valeric acid (racemate)

Based on (+/-)-tert-butyl-5-({[6-bromo-2-(3,3-difluoropiperidin-1-yl)-3-methylquinolin-4yl]carbonyl}amino)-4-(2 ,5-difluorophenyl)pentanoate (racemate, 55 mg, 84.3 µmol, example 267A) was reacted with TFA (reaction time 40 min) and the product was purified as described for 5-[({6-bromo

- 231 040220

2-[3-ethylpiperidin-1-yl]-3-methylquinolin-4-yl}carbonyl)amino]-4-(2,5-difluorophenyl)valeric acid (Example 255). 47 mg (100% pure, 93% thor.) of the title compound were obtained.

LC-MS (method 1): Rt = 2.07 min; MS (ESIpos): m/z = 596/598 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.149 (0.53), -0.008 (4.53), 0.008 (4.37), 0.146 (0.53), 1.372 (1.58), 1.788 (1.68), 1.811 ( 1.95), 1.881 (5.11), 2.004 (1.84), 2.017 (2.37), 2.037 (2.95), 2.056 (4.21), 2.063 (3.89), 2.092 (8.63), 2.106 (8.47), 2.119 (10.53), 15.47) 2.42), 3.655 (3.42),3.670 (2.00), 3.701 (1.79), 7.107 (1.21), 7.128 (2.79), 7.138 (2.26), 7.149 (1.95), 7.206 (2.53), 7.217 (2.74), 4.11), 7.241 (4.16), 7.252 (2.00), 7.264 (1.84), 7.285 (2.05), 7.292 (2.42), 7.298 (2.58), 7.307 (3.58) 2.16), 7.469 (0.89), 7.673 (2.89), 7.695 (16.00), 7.702 (10.95), 7.707 (9.63), 7.724 (1.95), 7.729 (2.11) 2.58), 12.069 (1.58).

Example 262.

(-)-5-({[6-Bromo-2-(3,3-difluoropiperidin-1-yl)-3-methylquinolin-4-yl]carbonyl}amino)-4-(2,5difluorophenyl)valeric acid ( enantiomer 1).

Starting from tert-butyl 5-({[6-bromo-2-(3,3-difluoropiperidin-1-yl)-3-methylquinolin-4yl]carbonyl}amino)-4-(2,5-difluorophenyl)pentanoate (enantiomer 1, 55 mg, 84.3 µmol, example 268A) was reacted with TFA as described for (+)-5-({[6-bromo-3-methyl-2-(piperidin-1yl)quinolin-4-yl ]carbonyl}amino)-4-(2,6-difluorophenyl)valeric acid (Example 245). The product was purified by preparative HPLC (method 20). 23 mg (98% pure, 35% thor.) of the title compound were obtained.

[a] _D ²⁰ = -30.7°, 589 nm, c = 0.33 g/100 ml, methanol;

LC-MS (method 1): Rt = 2.07 min; MS (ESIpos): m/z = 596/598 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: -0.149 (0.99), -0.008 (12.44), 0.146 (0.96), 1.812 (2.13), 1.882 (5.42), 2.005 (2.03), 2.017 (2.55), 2.037 (3.26), 2.057 (4.72), 2.093 (9.47), 2.109 (9.62), 2.119 (11.50), 2.136 (16.00) (0.82) (2.28) (2.05), 7.264 (1.85), 7.285 (2.23), 7.298 (2.74), 7.307 (3.66), 7.316 (2.60), 7.322 (2.57), 7.330 (2.08) (15.06), 7.702 (10.51), 7.707 (9.15), 7.725 (1.76), 7.729 (1.98), 8.739 (2.72), 8.753 (4.77), 8.768 (2.62), 12.065 (1.78).

Example 263.

(+)-5-({[6-Bromo-2-(3,3-difluoropiperidin-1-yl)-3-methylquinolin-4-yl]carbonyl}amino)-4-(2,5difluorophenyl)valeric acid ( enantiomer 2).

Starting from tert-butyl 5-({[6-bromo-2-(3,3-difluoropiperidin-1-yl)-3-methylquinolin-4yl]carbonyl}amino)-4-(2,5-difluorophenyl)pentanoate (enantiomer 2, 71 mg, 95% pure, 103 µmol, example 269A) was reacted with TFA as described for (+)-5-({[6-bromo-3-methyl-2(piperidin-1-yl) quinolin-4-yl]carbonyl}amino)-4-(2,6-difluorophenyl)valeric acid (Example 245).

The product was purified by preparative HPLC (method 20). 28 mg (99% pure, 45% theoretical) of the title compound were obtained.

[a] _D ²⁰ = +34.0°, 589 nm, c = 0.33 g/100 ml, methanol;

LC-MS (method 1): Rt = 2.06 min; MS (ESIpos): m/z = 596/598 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.149 (0.62), 0.146 (0.69), 1.371 (0.58), 1.754 (0.65), 1.790 (1.79), 1.810 (2.06), 1.881 (5.45 ), 2.004 (1.92), 2.017 (2.47), 2.038 (3.17), 2.056 (4.63), 2.092 (9.35), 2.108 (9.58), 2.119 (11.35), 2.136 (16.00), 2.327 (0.91), 2.366 (0.44 ), 2.669 (1.00), 2.709 (0.49), 3.163 (7.70), 3.447 (4.16), 3.475 (7.62), 3.504 (3.78), 3.622 (1.83), 3.642 (2.58), 3.655 (3.47), 3.669 (2.14 ), 3.703 (1.99), 7.128 (2.87), 7.148 (1.86), 7.206 (2.42), 7.217 (2.60), 7.229 (3.79), 7.240 (3.68), 7.252 (1.83), 7.263 (1.66), 7.285 (2.14 ), 7.298 (2.63), 7.307 (3.52), 7.316 (2.47), 7.329 (1.86), 7.467 (0.96), 7.673 (2.87), 7.695 (14.19), 7.702 (9.23), 7.706 (8.04), 7.729 (1.64 ), 8.739 (2.76), 8.753 (4.69), 8.767 (2.46), 12.063 (1.15).

Example 264.

5-[({6-Bromo-2-(3-fluoropiperidin-1-yl)-3-methylquinolin-4-yl}carbonyl)amino]-4-(2,5difluorophenyl)valeric acid (mixture of diastereoisomers)

- 232 040220

Starting from tert-butyl 5-[({6-bromo-2-(3-fluoropiperidin-1-yl)-3-methylquinolin-4yl}carbonyl)amino]-4-(2,5-difluorophenyl)pentanoate (mixture diastereoisomers, 55 mg, 86.7 µmol, example 270A), the product was reacted and worked up as described for 5-[({6-bromo-2-[3-ethylpiperidin-1-yl]-3-methylquinolin-4-yl}carbonyl)amino ]-4-(2,5-difluorophenyl)valeric acid (Example 255). 43 mg (100% pure, 86% thor.) of the title compound were obtained.

LC-MS (method 1): Rt = 2.02 min; MS (ESIpos): m/z = 578/580 [M+H]+.

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: -0.149 (0.90), -0.008 (10.95), 0.008 (6.96), 0.017 (0.58), 0.146 (0.90), 1.643 (2.02), 1.806 (3.83), 1.899 (3.35), 1.948 (2.02), 1.983 (1.70), 2.003 (2.29), 2.016 (2.55) (7.44), 2.128 (14.41), 2.327 (1.54), 2.523 (3.88), 2.665 (1.38) (3.99), 3.401 (1.75), 3.434 (2.29), 3.460 (1.54), 3.540 (0.64) (1.70), 7.127 (2.92), 7.147 (1.97), 7.204 (2.76), 7.216 (2.92), 7.227 (4.36), 7.239 (4.25), 7.251 (2.07) (2.60), 7.295 (2.71), 7.304 (3.72), 7.313 (2.66), 7.319 (2.50), 7.327 (2.13) (9.51), 7.699 (1.97), 7.704 (2.13), 8.732 (2.71), 8.747 (4.73), 8.761 (2.50), 12.068 (2.29).

Example 265.

(-)-5-({[6-Bromo-2-(3,3-difluoropiperidin-1-yl)-3-methylquinolin-4-yl]carbonyl}amino)-4-(2,6dichlorophenyl)valeric acid ( enantiomer 1)

Mixture of (+/-)-5-{[(6-bromo-2-chloro-3-methylquinolin-4-yl)carbonyl]amino}-4-(2,6dichlorophenyl)valeric acid (racemate, 401mg, 72 % purity, 5 µmol, example 246A), 3,3difluoropiperidine hydrochloride (580 mg, 3.68 mmol), and DIPEA (1.5 ml, 8.8 mmol) in NMP (1.9 ml) were stirred for four days at 120°C. After cooling to RT, the reaction mixture was added to 1M hydrochloric acid and extracted with dichloromethane. The organic phase was dried over sodium sulfate and concentrated. The starting material was purified by column chromatography (Isolera, LiChroprep RP-18, eluent: water/acetonitrile, gradient: 20-100% acetonitrile). A fraction of the product (238 mg) was dissolved in dichloromethane/methanol (1:1, 5 ml) and separated into enantiomers by preparative HPLC on a chiral phase [column: Chiralpak IA, 5 μm, 250 mm x 30 mm; flow: 50 ml/min; detection: UV 254 nm; sample injection: 1.0 ml; eluent: 70% hexane + 0.1 vol% trifluoroacetic acid/30% isopropanol, isocratic]. The combined target fractions were respectively concentrated and the corresponding residue was lyophilized.

The title target compound (52 mg, 98% pure, >99% ee) was obtained as the previously eluted enantiomer.

[a] _D20 = -10.2°, 589 nm, c = 0.50 g/100 ml ^, chloroform;

LC-MS (method 25): Rt = 1.37 min; MS (ESIpos): m/z = 628/630/632 [M+H] ⁺ .

1H-NMR (400 MHz, chloroform-d) δ [ppm]: 0.888 (0.45), 0.894 (0.47), 1.215 (0.47), 1.226 (1.52), 1.241 (1.34), 1.263 (2.42), 1.286 (1.77) , 1.304 (0.89), 1.379 (4.12), 1.395 (4.07), 1.999 (2.53), 2.115 (1.08), 2.152 (2.73), 2.163 (3.07), 2.180 (2.45), 2.244 (0.69), 2.310 (16.00) . . . . , 7.790 (2.66), 7.859 (2.44), 7.881 (1.58), 8.350 (0.78).

Example 266.

(+)-5-({[6-Bromo-2-(3,3-difluoropiperidin-1-yl)-3-methylquinolin-4-yl]carbonyl}amino)-4-(2,6dichlorophenyl)valeric acid ( enantiomer 2).

Separation of the enantiomers as described in Example 265 gave 50 mg (95% pure, 98% ee) of the title compound as the later eluted enantiomer.

[a] _D20 = +14.8°, 589 nm, c = 0.50 g/100 ml ^, chloroform.

1H-NMR (400 MHz, chloroform-d) δ [ppm]: 0.861 (0.55), 0.876 (0.59), 0.888 (0.89), 0.894 (0.86), 0.901 (0.64), 0.913 (0.48), 1.199 (0.55) , 1.215 (0.70), 1.227 (1.84), 1.242 (1.70), 1.263 (4.61), 1.379 (3.69) . , 4.268 (0.91), 6.702

- 233 040220 (1.37) 7.154 (2.59) 7.174 (6.12) 7.194 (3.69) 7.322 (3.68) 7.326 (4.24) 7.343 (3.18) 7.345 (3.19) 7.367 (4.49) ), 7.386 (3.70), 7.390 (3.25), 7.529 (0.51), 7.767 (3.80), 7.791 (3.05), 7.863 (2.27), 7.884 (1.87), 7.947 (0.79).

Example 267.

(+)-5-[({6-Bromo-3-methyl-2-[( ² H ₁₀ )piperidin-1-yl]quinolin-4-yl}carbonyl)amino]-4-(2chlorophenyl)valeric acid ( enantiomer 1)

To a solution of (+)-tert-butyl-5-[({6-bromo-3-methyl-2-[( ² H ₁₀ )piperidin-1-yl]quinolin-4yl}carbonyl)amino]-4-( 2-chlorophenyl)pentanoate (262 mg, 419 µmol, enantiomer 7, example 278A) in dichloromethane (3.2 ml) was added with TFA (711 µl, 9.23 mmol) and the mixture was left for 24 h at RT. The mixture was then concentrated and mixed several times with dichloromethane and re-concentrated. The residue was purified by preparative HPLC (method 11). The combined target fractions were concentrated and the residue was lyophilized. 187 mg (100% pure, 79% theoretical) of the title compound were obtained.

[a] _D20 = +13.3°, 589 nm, c = 0.38 ^g /100 ml, methanol;

LC-MS (method 1): R _t = 2.15 min; MS (ESIpos): m/z = 568/570 [M+H] ⁺ .

1H-NMR (500 MHz, DMSO-d6) δ [ppm]: -0.021 (0.35), 1.232 (0.75), 1.540 (0.53), 1.613 (0.41), 1.792 (0.63), 1.800 (0.99), 1.818 (2.03 ), 1.835 (2.41), 1.853 (1.25), 1.873 (0.28), 2.024 (0.57), 2.036 (1.20), 2.041 (1.40), 2.052 (5.86), 2.074 (4.33), 2.081 (4.40), 2.097 (4.07 ), 2.127 (15.83), 2.154 (2.03), 2.196 (0.35), 2.363 (0.20), 2.636 (0.22), 3.078 (0.18), 3.086 (0.20), 3.593 (2.03), 3.674 (3.19), 7.258 (1.99 ), 7.261 (2.01), 7.274 (4.38), 7.288 (3.00), 7.291 (2.84), 7.359 (2.69), 7.374 (4.82), 7.388 (2.54), 7.443 (8.16), 7.446 (7.64), 7.459 (7.24 ), 7.462 (6.59), 7.480 (6.24), 7.482 (6.15), 7.496 (4.97), 7.623 (4.16), 7.640 (16.00), 7.650 (10.72), 7.654 (9.32), 7.667 (2.58), 7.671 (2.69 ), 8.710 (2.72), 8.721 (5.30), 8.733 (2.56), 12.042 (0.39).

Example 268.

(-)-5-[({6-Bromo-3-methyl-2-[( ² H ₁₀ )piperidin-1-yl]quinolin-4-yl}carbonyl)amino]-4-(2chlorophenyl)valeric acid ( enantiomer 2).

To a solution of (-)-tert-butyl-5-[({6-bromo-3-methyl-2-[( ² H ₁₀ )piperidin-1-yl]quinolin-4yl}carbonyl)amino]-4-( 2-Chlorophenyl)pentanoate (244 mg, 391 µmol, enantiomer 2, example 279A) in dichloromethane (3.0 ml) was added with TFA (662 µl, 8.59 mmol) and the mixture was left for 24 h at RT. The mixture was then concentrated and mixed several times with dichloromethane and re-concentrated. The residue was purified by preparative HPLC (method 11). The combined target fractions were concentrated and the residue was lyophilized. 180 mg (100% pure, 81% thor.) of the title compound were obtained.

[a] _D20 = -11.1°, 589 nm, c = ^0.40 g/100 ml, methanol;

LC-MS (method 1): R _t = 2.17 min; MS (ESIpos): m/z = 568/570 [M+H] ⁺ .

1H-NMR (600 MHz, DMSO-d6) δ [ppm]: 1.538 (0.58), 1.611 (0.46), 1.799 (1.21), 1.814 (2.79), 1.828 (3.08), 1.843 (1.64), 2.028 (0.83) , 2.043 (1.96), 2.053 (7.45), 2.071 (6.42), 2.076 (5.14), 2.087 (2.91) . , 7.363 (3.08) , 7.656 (8.85), 7.668 (3.13), 7.671 (3.26), 8.734 (3.59), 8.744 (7.01), 8.753 (3.50), 12.078 (1.77).

Example 269.

(-)-5-[({6-Bromo-3-methyl-2-[( ² H ₁₀ )piperidin-1-yl]quinolin-4-yl}carbonyl)amino]-4-[2(trifluoromethyl)phenyl ]valeric acid (enantiomer 1)

- 234 040220

To a solution of (-)-tert-butyl-5-[({6-bromo-3-methyl-2-[( ² H ₁₀ )piperidin-1-yl]quinolin-4yl}carbonyl)amino]-4-[ 2-(trifluoromethyl)phenyl]pentanoate (231 mg, 352 µmol, enantiomer 1, example 280A) in dichloromethane (2.7 ml) was added with TFA (596 µl, 7.74 mmol) and the mixture was left for 24 h at RT. The mixture was then concentrated and mixed several times with dichloromethane and re-concentrated. The residue was purified by preparative HPLC (method 11). The combined target fractions were concentrated and the residue was lyophilized. 166 mg (100% pure, 79% thor.) of the title compound were obtained.

[a] ^D20 = -19.1°, 589 nm, c = 0.31 g/100 ml, methanol;

LC-MS (method 1): Rt = 2.18 min; MS (ESIpos): m/z = 602/604 [M+H]+.

1H-NMR (600 MHz, DMSO-d6) δ [ppm]: 0.005 (0.22), 1.229 (0.23), 1.546 (0.54), 1.620 (0.59), 1.876 (0.59), 1.885 (0.81), 1.892 (1.34) , 1.900 (1.97), 1.907 (1.66), 1.915 (1.99), 1.923 (1.82), 1.939 (1.08), 1.953 (1.49), 1.962 (1.01), 1.969 (1.61), 1.980 (2.72), 1.989 (1.82) , 1.996 (2.72), 2.005 (2.10), 2.047 (2.24), 2.058 (3.02), 2.063 (2.06), 2.074 (3.61), 2.078 (1.32), 2.085 (1.93), 2.101 (1.97), 2.116 (1.74) . , 7.484 (4.85), 7.497 (2.90), 7.639 (4.67), 7.654 (16.00), 7.662 (9.66), 7.666 (8.77), 7.677 (2.62) , 7.724 (4.34), 7.729 (7.06), 7.741 (10.81), 7.753 (3.07), 8.793 (3.05), 8.803 (6.14), 8.813 (3.01), 12.085 (0.33).

Example 270.

(+)-5-[({6-Bromo-3-methyl-2-[( ² H ₁₀ )piperidin-1-yl]quinolin-4-yl}carbonyl)amino]-4-[2(trifluoromethyl)phenyl ]valeric acid (enantiomer 2).

To a solution of (+)-tert-butyl-5-[({6-bromo-3-methyl-2-[( ² H ₁₀ )piperidin-1-yl]quinolin-4yl}carbonyl)amino]-4-[ 2-(trifluoromethyl)phenyl]pentanoate (204 mg, 310 µmol, enantiomer 2, example 281A) in dichloromethane (2.4 ml) was added with TFA (525 µl, 6.82 mmol) and the mixture was left for 24 h at RT. The mixture was then concentrated and mixed several times with dichloromethane and re-concentrated. The residue was purified by preparative HPLC (method 11). The combined target fractions were concentrated and the residue was lyophilized. 157 mg (100% pure, 84% thor.) of the title compound were obtained.

[a] _D20 = +19.1°, 589 nm, c = 0.45 g/100 mL ^, methanol;

LC-MS (method 1): Rt = 2.23 min; MS (ESIpos): m/z = 602/604 [M+H] ⁺ .

1H-NMR (600 MHz, DMSO-d6) δ [ppm]: 1.546 (0.56), 1.620 (0.64), 1.877 (0.74), 1.892 (1.70), 1.900 (2.53), 1.907 (2.16), 1.915 (2.60) , 1.923 (2.32), 1.939 (1.35), 1.954 (1.73), 1.963 (1.23), 1.970 (1.91), 1.981 (3.42), 1.990 (2.23), 1.997 (3.23), 2.006 (2.55), 2.048 (2.67) , 2.059 (3.62), 2.074 (4.25), 2.086 (2.28), 2.101 (2.44), 2.117 (2.22), 2.126 (3.06), 2.162 (9.18), 2.387 (0.23), 2.614 (0.20), 3.096 (0.31) . , 7.711 (6.46), 7.729 (8.95), 7.742 (13.87), 7.753 (3.91), 8.792 (3.69), 8.802 (7.25), 8.812 (3.62), 12.063 (7.55).

Example 271.

(+)-5-[({6-Bromo-3-methyl-2-[( ² H ₁₀ )piperidin-1-yl]quinolin-4-yl}carbonyl)amino]-4-[2(trifluoromethoxy)phenyl ]valeric acid (enantiomer 1)

To a solution of (+)-tert-butyl-5-[({6-bromo-3-methyl-2-[( ² H ₁₀ )piperidin-1-yl]quinolin-4yl}carbonyl)amino]-4-[ 2-(trifluoromethoxy)phenyl]pentanoate (181 mg, 268 µmol, enantiomer 1, example 282A) in dichloromethane (2.1 ml) was added with TFA (460 µl, 5.90 mmol) and the mixture was left for 24 h at RT. The mixture was then concentrated and mixed several times with dichloromethane and re-concentrated. The residue was purified by preparative HPLC (method 11). The combined target fractions were concentrated and the residue was lyophilized. 140 mg (100% pure, 84% th. y.) of the title compound were obtained.

[a] _D20 = +19.7°, 589 nm, c = 0.33 ^g /100 mL, methanol;

LC-MS (method 1): Rt = 2.28 min; MS (ESIpos): m/z = 618/620 [M+H] ⁺ .

1H-NMR (600 MHz, DMSO-d6) δ [ppm]: 1.231 (0.17), 1.543 (0.59), 1.615 (0.66), 1.788 (0.36), 1.799 (0.68), 1.812 (2.24), 1.819 (2.71) , 1.826 (2.26), 1.834 (3.75), 1.849 (2.42), 1.867 (0.57), 2.031 (0.65), 2.048 (1.50), 2.057 (4.09), 2.077 (16.00), 2.098 (4.42), 2.105 (3.31) . , 3.620 (3.25), 3.631

- 235 040220 (3.89), 3.641 (2.48), 3.664 (2.81), 3.674 (2.40), 7.282 (0.18), 7.352 (4.12), 7.364 (6.45), 7.394 (2.55), 7.408 (8.73), 7.414 (8.57) ), 7.421 (8.95), 7.433 (2.43), 7.559 (5.83), 7.569 (4.84), 7.573 (4.73), 7.634 (5.43), 7.649 (15.94), 7.661 (9.19), 7.664 (9.30), 7.679 (3.24 ), 8.756 (3.78), 8.765 (7.15), 8.775 (3.68), 12.083 (13.49).

Example 272.

(-)-5-[({6-Bromo-3-methyl-2-[( ² H ₁₀ )piperidin-1-yl]quinolin-4-yl}carbonyl)amino]-4-[2(trifluoromethoxy)phenyl ]valeric acid (enantiomer 2).

To a solution of (-)-tert-butyl-5-[({6-bromo-3-methyl-2-[( ² H ₁₀ )piperidin-1-yl]quinolin-4yl}carbonyl)amino]-4-[ 2-(trifluoromethoxy)phenyl]pentanoate (215 mg, 320 µmol, enantiomer 2, example 283A) in dichloromethane (2.5 ml) was added with TFA (540 µl, 7.03 mmol) and the mixture was left for 24 h at RT. The mixture was then concentrated and mixed several times with dichloromethane and re-concentrated. The residue was purified by preparative HPLC (method 11). The combined target fractions were concentrated and the residue was lyophilized. 166 mg (100% pure, 84% thor.) of the title compound were obtained.

[a]D ²⁰ = -17.5°, 589 nm, c = 0.36 g/100 ml, methanol;

LC-MS (method 1): Rt = 2.23 min; MS (ESIpos): m/z = 618/620 [M+H]+.

1H-NMR (600 MHz, DMSO-d ₆ ) δ [ppm]: 0.005 (0.31), 1.230 (0.24), 1.543 (0.56), 1.615 (0.58), 1.786 (0.29), 1.799 (0.52), 1.811 (1.78) ), 1.819 (2.11), 1.826 (1.75), 1.833 (2.88), 1.849 (2.02), 1.866 (0.46), 2.030 (0.51), 2.035 (0.44), 2.047 (1.22), 2.056 (3.38), 2.075 (11.92 ), 2.078 (11.58), 2.082 (10.29), 2.097 (3.39), 2.105 (2.47), 2.110 (2.68), 2.135 (4.84), 2.219 (0.43), 2.387 (0.17), 2.615 (0.17), 3.089 (0.30 ), 3.392 (2.55), 3.402 (2.34), 3.598 (0.88), 3.608 (1.48), 3.620 (2.50), 3.630 (2.95), 3.641 (1.87), 3.652 (1.45), 3.663 (2.07), 3.674 (1.76 ), 7.351 (3.20), 7.361 (4.27), 7.364 (5.30), 7.394 (2.04), 7.403 (5.07), 7.408 (6.93), 7.414 (7.35), 7.420 (7.47), 7.423 (5.23), 7.433 (1.99 ), 7.558 (4.77), 7.569 (3.85), 7.573 (3.74), 7.634 (5.48), 7.649 (16.00), 7.661 (8.72), 7.664 (8.01), 7.676 (2.81), 7.679 (2.85), 8.756 (3.09 ), 8.765 (5.88), 8.775 (3.00), 12.090 (0.88).

Example 273.

(+)-5-[({6-Bromo-3-methyl-2-[( ² H ₁₀ )piperidin-1-yl]quinolin-4-yl}carbonyl)amino]-4-(2-chloro-3 ,6difluorophenyl)valeric acid (enantiomer 1)

To a solution of (+)-tert-butyl-5-{[(6-bromo-2-chloro-3-methylquinolin-4-yl)carbonyl]amino}-4-(2-chloro3,6-difluorophenyl)pentanoate ( 241 mg, 400 µmol, enantiomer 1, example 48A) in NMP (1.6 ml) was added piperidine-D11 (120 µl, 1.20 mmol) and the mixture was stirred for 20 h at 110°C. After cooling to RT, the mixture was mixed with water (100 ml) and extracted twice with ethyl acetate (respectively 80 ml). The combined organic phases were dried over sodium sulfate, filtered and concentrated and the residue was purified by preparative HPLC (method 32). The combined target fractions were concentrated and the residue was lyophilized from acetonitrile/water. The title compound was obtained directly (without isolation of the corresponding tert-butyl ether). 32 mg (100% pure, 13% thor.) of the title compound were obtained.

[a] _D20 = +37.3°, 589 nm, c = 0.30 g/100 ml ^, methanol;

LC-MS (method 1): R _t = 2.12 min; MS (ESIpos): m/z = 604/606 [M+H] ⁺ .

1H-NMR (600 MHz, DMSO-d ₆ ) δ [ppm]: -0.022 (0.32), 0.070 (0.18), 1.095 (0.19), 1.106 (0.18), 1.228 (1.01), 1.312 (0.88), 1.343 ( 0.85), 1.353 (0.90), 1.377 (0.85), 1.402 (0.51), 1.539 (0.67), 1.612 (0.55), 1.950 (1.96), 2.069 (4.94), 2.084 (5.40), 2.135 (16.00), 0.38), 2.616 (0.42), 2.694 (0.48), 3.084 (0.84), 3.394 (4.23), 3.714 (4.00), 7.293 (3.51), 7.299 (3.54), 7.309 (2.55), 7.413 (3.39), 6.05), 7.646 (14.75), 7.661 (9.57), 7.665 (8.43), 7.676 (3.85), 7.679 (3.58), 8.842 (4.13).

Example 274.

(-)-5-[({6-Bromo-3-methyl-2-[( ² H ₁₀ )piperidin-1-yl]quinolin-4-yl}carbonyl)amino]-4-(2-chloro-3 ,6difluorophenyl)valeric acid (enantiomer 2).

To a solution of (-)-tert-butyl-5-{[(6-bromo-2-chloro-3-methylquinolin-4-yl)carbonyl]amino}-4-(2-chloro3,6-difluorophenyl)pentanoate ( 241 mg, 400 µmol, enantiomer 2, example 49A) in NMP (1.6 ml) was added piperidine-D11 (120 µl, 1.20 mmol) and the mixture was stirred for 20 h at 110°C. After cooling to RT, the mixture was mixed with water (100 ml) and extracted twice with ethyl acetate (respectively 80 ml). The combined organic phases were dried over sodium sulfate, filtered and concentrated and the residue was purified by preparative HPLC (method 32). Combined target scon fractions

- 236 040220 was centered and the residue was lyophilized from acetonitrile/water. The title compound was obtained directly (without isolation of the corresponding tert-butyl ether). 42 mg (100% pure, 17% thor.) of the title compound were obtained.

[a]D ²⁰ = -29.2°, 589 nm, c = 0.33 g/100 ml, methanol;

LC-MS (method 1): Rt = 2.12 min; MS (ESIpos): m/z = 604/606 [M+H] ⁺ .

1H-NMR (600 MHz, DMSO-d6) δ [ppm]: -0.022 (0.18), 0.072 (0.21), 1.228 (1.00), 1.343 (0.66), 1.354 (0.71), 1.361 (0.75), 1.402 (0.20 ), 1.540 (0.68), 1.613 (0.55), 1.954 (1.87), 2.071 (4.75), 2.088 (5.11), 2.135 (16.00), 2.388 (0.30), 2.616 (0.35), 2.695 (0.50), 3.085 (0.78 ), 3.394 (3.81), 7.294 (3.41), 7.300 (3.44), 7.310 (2.45), 7.413 (3.29), 7.632 (6.00), 7.647 (14.77), 7.662 (9.74), 7.665 (8.27), 7.677 (3.79 ), 7.680 (3.41), 8.842 (4.09).

Example 275.

(+)-5-[({6-Bromo-3-methyl-2-[( ² H ₈ )pyrrolidin-1-yl]quinolin-4-yl}carbonyl)amino]-4-(2chlorophenyl)valeric acid ( enantiomer 1)

To a solution of (+)-tert-butyl-5-[({6-bromo-3-methyl-2-[( ² H ₈ )pyrrolidin-1-yl]quinolin-4yl}carbonyl)amino]-4-( 2-Chlorophenyl)pentanoate (232 mg, 380 µmol, enantiomer 1, example 284A) in dichloromethane (2.9 ml) was added with TFA (645 µl, 8.37 mmol) and the mixture was left for 24 h at RT. The mixture was then concentrated and mixed several times with dichloromethane and re-concentrated. The residue was purified by preparative HPLC (method 11). The combined target fractions were concentrated and the residue was lyophilized. 170 mg (100% pure, 81% theoretical) of the title compound were obtained.

[a] _D20 = +12.8°, 589 nm, c = 0.38 g/100 ml ^, methanol;

LC-MS (method 1): Rt = 1.42 min; MS (ESIpos): m/z = 552/554 [M+H] ⁺ .

1H-NMR (500 MHz, DMSO-d6) δ [ppm]: 1.232 (0.37), 1.792 (0.70), 1.800 (1.02), 1.818 (2.38), 1.835 (2.71), 1.853 (1.37), 2.022 (0.70) . , 2.237 (0.36) . , 7.490 (5.16), 7.543 (7.85), 7.548 (7.12), 7.561 (4.96), 7.566 (4.68), 8.663 (2.87), 8.674 (5.45), 8.686 (2.67).

Example 276.

(-)-5-[({6-Bromo-3-methyl-2-[( ² H ₈ )pyrrolidin-1-yl]quinolin-4-yl}carbonyl)amino]-4-(2chlorophenyl)valeric acid ( enantiomer 2).

To a solution of (-)-tert-butyl-5-[({6-bromo-3-methyl-2-[( ² H ₈ )pyrrolidin-1-yl]quinolin-4yl}carbonyl)amino]-4-( 2-chlorophenyl)pentanoate (236 mg, 388 µmol, enantiomer 2, example 285A) in dichloromethane (3.0 ml) was added with TFA (657 µl, 8.53 mmol) and the mixture was left for 24 h at RT. The mixture was then concentrated and mixed several times with dichloromethane and re-concentrated. The residue was purified by preparative HPLC (method 11). The combined target fractions were concentrated and the residue was lyophilized. 177 mg (100% pure, 83% th. y.) of the title compound were obtained.

[a] _D20 = -11.5°, 589 nm, c = 0.48 ^g /100 ml, methanol;

LC-MS (method 1): Rt = 1.43 min; MS (ESIpos): m/z = 552/554 [M+H] ⁺ .

1H-NMR (600 MHz, DMSO-d ₆ ) δ [ppm]: 1.800 (1.03), 1.815 (2.52), 1.829 (2.74), 1.845 (1.38), 2.027 (0.69), 2.035 (1.39), 2.051 (6.12 ), 2.069 (5.24), 2.088 (2.40), 2.099 (2.00), 2.117 (3.32), 2.132 (5.50), 2.148 (5.66), 2.238 (0.37), 2.283 (0.33), 3.585 (2.21), 3.651 (2.02 ), 7.258 (1.88), 7.270 (3.56), 7.282 (2.45), 7.360 (2.37), 7.372 (3.84), 7.384 (2.29), 7.441 (8.20), 7.455 (7.11), 7.469 (8.21), 7.484 (16.00 ), 7.495 (4.67), 7.548 (5.71), 7.551 (5.48), 7.562 (4.01), 7.565 (3.91), 8.686 (3.02), 8.695 (5.74), 8.704 (2.88), 12.077 (1.33).

Example 277.

(-)-5-[({6-Bromo-3-methyl-2-[( ² H ₈ )pyrrolidin-1-yl]quinolin-4-yl}carbonyl)amino]-4-[2(trifluoromethyl)phenyl ]valeric acid (enantiomer 1)

- 237 040220

To a solution of (-)-tert-butyl-5-[({6-bromo-3-methyl-2-[( ² H ₈ )pyrrolidin-1-yl]quinolin-4yl}carbonyl)amino]-4-[ 2-(trifluoromethyl)phenyl]pentanoate (200 mg, 311 µmol, enantiomer 1, example 286A) in dichloromethane (2.4 ml) was added with TFA (528 µl, 6.85 mmol) and the mixture was left for 24 h at RT. The mixture was then concentrated and mixed several times with dichloromethane and re-concentrated. The residue was purified by preparative HPLC (method 11). The combined target fractions were concentrated and the residue was lyophilized. 151 mg (100% pure, 83% th. y.) of the title compound were obtained.

[a] ^D20 = -18.0°, 589 nm, c = 0.30 g/100 ml, methanol;

LC-MS (method 1): Rt = 1.51 min; MS (ESIpos): m/z = 586/588 [M+H]+.

1H-NMR (600 MHz, DMSO-d ₆ ) δ [ppm]: 1.829 (0.40), 1.874 (0.82), 1.883 (1.18), 1.890 (1.90), 1.898 (2.80), 1.905 (2.37), 1.913 (2.80 ), 1.920 (2.63), 1.937 (1.64), 1.946 (2.11), 1.955 (1.34), 1.962 (2.15), 1.972 (3.71), 1.981 (2.35), 1.989 (3.43), 1.997 (2.66), 2.049 (2.83 ), 2.059 (3.89), 2.075 (4.72), 2.086 (2.77), 2.102 (3.03), 2.113 (2.77), 2.121 (3.45), 2.135 (4.67), 2.145 (4.69), 2.159 (4.40), 2.169 (3.85 ), 2.178 (3.42), 2.278 (0.75), 2.387 (0.30), 2.615 (0.24), 3.598 (2.01), 3.722 (2.08), 7.247 (0.41), 7.394 (0.44), 7.467 (3.00), 7.480 (14.90 ), 7.495 (16.00), 7.555 (7.51), 7.558 (7.44), 7.570 (5.29), 7.573 (5.31), 7.696 (2.72), 7.709 (6.63), 7.722 (12.22), 7.736 (13.62), 7.751 (4.23 ), 8.737 (3.79), 8.746 (7.33), 8.756 (3.77), 12.063 (3.78).

Example 278.

(+)-5-[({6-Bromo-3-methyl-2-[( ² H ₈ )pyrrolidin-1-yl]quinolin-4-yl}carbonyl)amino]-4-[2(trifluoromethyl)phenyl ]valeric acid (enantiomer 2).

To a solution of (+)-tert-butyl-5-[({6-bromo-3-methyl-2-[( ² H ₈ )pyrrolidin-1-yl]quinolin-4yl}carbonyl)amino]-4-[ 2-(trifluoromethyl)phenyl]pentanoate (184 mg, 287 µmol, enantiomer 2, example 287A) in dichloromethane (2.2 ml) TFA (486 µl, 6.32 mmol) was added and the mixture was left for 24 h at RT. The mixture was then concentrated and mixed several times with dichloromethane and re-concentrated. The residue was purified by preparative HPLC (method 11). The combined target fractions were concentrated and the residue was lyophilized. 139 mg (100% pure, 82% thor.) of the title compound were obtained.

[a] _D20 = +19.2°, 589 nm, c = 0.30 g/100 mL ^, methanol;

LC-MS (method 1): Rt = 1.47 min; MS (ESIpos): m/z = 586/588 [M+H]+.

1H-NMR (600 MHz, DMSO-d ₆ ) δ [ppm]: 0.005 (0.36), 1.232 (0.17), 1.830 (0.45), 1.876 (0.97), 1.884 (1.37), 1.891 (2.25), 1.899 (3.28) ), 1.907 (2.78), 1.914 (3.26), 1.922 (3.14), 1.938 (1.95), 1.948 (2.59), 1.957 (1.61), 1.964 (2.69), 1.975 (4.42), 1.983 (2.89), 1.991 (4.33 ), 1.999 (3.30), 2.050 (3.56), 2.061 (4.90), 2.066 (3.43), 2.077 (6.09), 2.088 (3.47), 2.104 (3.78), 2.114 (3.37), 2.122 (4.01), 2.136 (5.33 ), 2.147 (5.35), 2.152 (5.03), 2.161 (5.04), 2.170 (4.40), 2.180 (3.85), 2.281 (0.77), 2.387 (0.31), 2.616 (0.25), 3.325 (4.10), 3.601 (2.25 ), 3.724 (2.31), 7.118 (0.19), 7.247 (0.51), 7.396 (0.52), 7.467 (3.62), 7.483 (11.19), 7.498 (11.31), 7.557 (7.64), 7.561 (7.43), 7.572 (5.45 ), 7.575 (5.28), 7.696 (3.26), 7.709 (7.80), 7.722 (14.33), 7.737 (16.00), 7.751 (4.94), 8.739 (4.26), 8.748 (8.09), 8.758 (4.19), 12.062 (8.04 ).

Example 279.

(+)-5-[({6-Bromo-3-methyl-2-[( ² H ₈ )pyrrolidin-1-yl]quinolin-4-yl}carbonyl)amino]-4-[2(trifluoromethyl)phenyl ]valeric acid (enantiomer 1)

To a solution of (+)-tert-butyl-5-[({6-bromo-3-methyl-2-[( ² H ₈ )pyrrolidin-1-yl]quinolin-4-yl}carbonyl)amino]-4 -[2-(trifluoromethoxy)phenyl]pentanoate (221 mg, 335 µmol, enantiomer 7, example 288A) in dichloromethane (2.6 ml) was added with TFA (569 µl, 7.38 mmol) and the mixture was left for 24 h at RT. The mixture was then concentrated and mixed several times with dichloromethane and re-concentrated. The residue was purified by preparative HPLC (method 11). Combined Target Sconcen Fractions

- 238 040220 were triturated and the residue was lyophilized. 173 mg (100% pure, 86% thor.) of the title compound were obtained.

[a] ^D20 = +17.6°, 589 nm, c = 0.44 g/100 mL, methanol;

LC-MS (method 1): R _t = 1.52 min; MS (ESIpos): m/z = 602/604 [M+H] ⁺ .

1H-NMR (600 MHz, DMSO-d6) δ [ppm]: 0.005 (0.45), 1.232 (0.18), 1.371 (0.16), 1.785 (0.41), 1.797 (0.70), 1.809 (2.46), 1.817 (2.57) , 1.824 (2.21), 1.832 (4.22), 1.847 (2.31), 1.863 (0.70), 2.025 (0.79), 2.043 (1.94), 2.052 (4.74), 2.057 (2.57), 2.062 (4.02), 2.070 (16.00) , 2.077 (11.82), 2.080 (12.48), 2.095 (4.14), 2.099 (3.35), 2.110 (3.35), 2.128 (2.33), 2.154 (2.44), 2.299 (0.39), 2.387 (0.29) , 2.615 (0.27), 3.388 (2.82), 3.539 (0.29), 3.576 (1.26), 3.586 (1.99), 3.597 (2.89), 3.608 (3.17), 3.618 (1.85), 3.665 (2.28) , 7.279 (0.39), 7.342 (3.44), 7.345 (4.50), 7.355 (5.69), 7.357 (7.09), 7.360 (5.29), 7.389 (2.33) . .

Example 280.

(-)-5-[({6-Bromo-3-methyl-2-[(H ₈ )pyrrolidin-1-yl]quinolin-4-yl}carbonyl)amino]-4-[2(trifluoromethyl)phenyl] valeric acid (enantiomer 2).

To a solution of (-)-tert-butyl-5-[({6-bromo-3-methyl-2-[( ² H ₈ )pyrrolidin-1-yl]quinolin-4yl}carbonyl)amino]-4-[ 2-(trifluoromethoxy)phenyl]pentanoate (188 mg, 286 µmol, enantiomer 2, example 289A) in dichloromethane (2.2 ml) was added with TFA (484 µl, 6.28 mmol) and the mixture was left for 24 h at RT. The mixture was then concentrated and mixed several times with dichloromethane and re-concentrated. The residue was purified by preparative HPLC (method 11). The combined target fractions were concentrated and the residue was lyophilized. 140 mg (100% pure, 81% thor.) of the title compound were obtained.

[a] _D20 = -14.4°, 589 nm, c = ^0.36 g/100 ml, methanol;

LC-MS (method 1): Rt = 1.57 min; MS (ESIpos): m/z = 602/604 [M+H] ⁺ .

1H-NMR (600 MHz, DMSO-d6) δ [ppm]: 1.786 (0.41), 1.799 (0.79), 1.811 (2.56), 1.819 (2.97), 1.833 (4.47), 1.848 (2.43), 1.865 (0.72) , 2.026 (0.76), 2.044 (1.92), 2.053 (4.55), 2.071 (16.00), 2.081 (13.66), 2.096 (4.73), 2.111 (3.63), 2.130 (2.70), 2.156 (2.87) , 2.386 (0.22), 2.614 (0.20), 3.391 (3.10), 3.539 (0.31), 3.577 (1.37), 3.587 (2.26), 3.598 (3.23), 3.609 (3.59), 3.619 (2.09) , 3.676 (2.45), 7.278 (0.44), 7.345 (4.72), 7.357 (7.31), 7.389 (2.62), 7.405 (7.34), 7.409 (8.25), 7.417 (7.84), 7.429 (2.59) , 7.492 (11.72), 7.556 (12.90), 7.570 (9.71), 8.707 (3.63), 8.717 (6.58), 8.726 (3.55), 12.080 (13.05).

Example 281.

(+)-5-[({6-Bromo-3-methyl-2-[( ² H ₈ )pyrrolidin-1-yl]quinolin-4-yl}carbonyl)amino]-4-(2-chloro-3 ,6difluorophenyl)valeric acid (enantiomer 1)

Method A.

To a solution of tert-butyl-5-[({6-bromo-3-methyl-2-[(H ₈ )pyrrolidin-1-yl]quinolin-4yl}carbonyl)amino]-4-(2-chloro-3 ,6-Difluorophenyl)pentanoate (38 mg, 59 µmol, enantiomer 7, example 290A) in dichloromethane (1.0 ml) was added with TFA (100 µl, 1.30 mmol) and the mixture was left for 24 h at RT. The mixture was then concentrated and mixed several times with dichloromethane and re-concentrated. The residue was purified by preparative HPLC (method 11). The combined target fractions were concentrated and the residue was lyophilized. 9 mg (100% pure, 25% thor.) of the title compound were obtained.

LC-MS (method 1): R _t = 1.43 min; MS (ESIpos): m/z = 588/560 [M+H] ⁺ .

1H-NMR (600 MHz, DMSO-d6) δ [ppm]: -0.022 (0.55), 1.232 (1.37), 1.825 (0.38), 1.966 (2.96), 2.072 (4.00), 2.079 (4.99), 2.092 (5.37 ), 2.105 (8.11), 2.128 (11.23), 2.139 (14.79), 2.151 (15.29), 2.160 (16.00), 2.171 (11.89), 2.341 (0.60), 2.387 (0.49), 2.616 (0.55), 3.440 (0.93 ), 3.536 (0.44), 3.708 (6.36), 7.301 (5.26), 7.415 (4.77), 7.478 (9.92), 7.493 (13.42), 7.560 (10.14), 7.562 (9.70), 7.574 (7.34), 7.577 (7.07 ), 7.649 (0.55), 8.792 (7.56), 12.132 (4.16).

Method B.

As described in Example 290A below, starting from (+)-tert-butyl-5-{[(6-bromo-2-chloro-3-methylquinolin-4yl)carbonyl]amino}-4-(2-chloro-3, 6-difluorophenyl)pentanoate (241 mg, 400 µmol, Example 48A) gave the title compound as fraction 1 directly (without isolating the corresponding

- 239 040220 tert-butyl ether) (34 mg, 100% pure, 14% theoretical).

[a] ^D20 = +41.9°, 589 nm, c = 0.32 g/100 mL, methanol;

LC-MS (method 1): R _t = 1.43 min; MS (ESIpos): m/z = 588/560 [M+H] ⁺ .

1H-NMR (600 MHz, DMSO-d ₆ ) δ [ppm]: 0.071 (0.24), 1.085 (0.75), 1.232 (0.38), 1.357 (0.72), 1.368 (0.31), 1.825 (0.35), 1.956 (1.60 ), 2.081 (4.26), 2.098 (4.30), 2.157 (7.33), 2.338 (0.36), 2.387 (0.36), 2.615 (0.42), 3.703 (3.89), 7.297 (3.26), 7.410 (2.92), 7.473 (11.97 ), 7.488 (16.00), 7.555 (7.89), 7.559 (7.36), 7.570 (5.57), 7.573 (5.29), 8.792 (4.04).

Example 282.

(-)-5-[({ 6-Bromo-3 -methyl-2-[( ² H ₈ )pyrrolidin-1 -yl] quinolin-4-yl} carbonyl)amino] -4-(2-chloro-3 ,6difluorophenyl)valeric acid (enantiomer 2)

Method A.

To a solution of tert-butyl-5-[({6-bromo-3-methyl-2-[( ² H ₈ )pyrrolidin-1-yl]quinolin-4yl}carbonyl)amino]-4-(2-chloro- 3,6-difluorophenyl)pentanoate (20 mg, 31 µmol, enantiomer 2, example 291A) in dichloromethane (1.0 ml) was added with TFA (52 µl, 682 µmol) and the mixture was left for 24 h at RT. The mixture was then concentrated and mixed several times with dichloromethane and re-concentrated. The residue was purified by preparative HPLC (method 11). The combined target fractions were concentrated and the residue was lyophilized. 7 mg (100% pure, 40% thor.) of the title compound were obtained.

LC-MS (method 1): Rt = 1.43 min; MS (ESIpos): m/z = 588/590 [M+H] ⁺ .

1H-NMR (600 MHz, DMSO-d ₆ ) δ [ppm]: -0.023 (0.78), 0.841 (0.28), 0.853 (0.58), 0.864 (0.25), 1.232 (2.98), 1.824 (0.24), 1.965 ( 1.80), 2.078 (2.77), 2.090 (3.00), 2.104 (4.61), 2.126 (5.66), 2.136 (7.73), 2.149 (8.42), 2.158 (9.21), 2.338 (0.40), 2.387 (0.34), 0.43), 2.478 (0.57), 2.615 (0.40), 2.655 (0.45),3.507 (0.69), 3.709 (3.84), 6.739 (0.25), 7.302 (3.16), 7.410 (2.83), 7.474 (11.76), 16.00), 7.556 (7.66), 7.560 (7.21), 7.571 (5.50), 7.575 (5.26), 8.791 (4.57), 12.136 (0.40).

Method B.

As described in Example 291A below, starting from (-)-tert-butyl-5-{[(6-bromo-2-chloro-3-methylquinolin-4yl)carbonyl]amino}-4-(2-chloro-3, 6-Difluorophenyl)pentanoate (241 mg, 400 µmol, Example 49A) gave the title compound as Fraction 1 directly (without isolation of the corresponding tert-butyl ether) (55 mg, 100% pure, 23% theoretical).

[a] _D20 = -35.2°, 589 nm, c = ^0.34 g/100 ml, methanol;

LC-MS (method 1): R _t = 1.40 min; MS (ESIpos): m/z = 588/590 [M+H] ⁺ .

1H-NMR (600 MHz, DMSO-d ₆ ) δ [ppm]: 0.071 (0.17), 1.231 (0.19), 1.357 (0.26), 1.825 (0.27), 1.964 (1.63), 2.076 (2.62), 2.099 (4.96 ), 2.118 (4.75), 2.130 (5.92), 2.153 (8.09), 2.339 (0.43), 2.387 (0.35), 2.615 (0.33), 3.708 (3.65), 7.300 (3.01), 7.414 (2.67), 7.474 (11.71 ), 7.489 (16.00), 7.556 (7.50), 7.560 (7.17), 7.571 (5.41), 7.574 (5.25), 8.790 (4.30).

Example 283.

(-)-5-({[6-Bromo-3-methyl-2-(pyrrolidin-1-yl)quinolin-4-yl]carbonyl}amino)-4-(2chlorophenyl)valeric acid hydrochloride (enantiomer 1)

To prepare the study, three different batches of (-)-5-({[6-bromo-3-methyl-2-(pyrrolidin-1yl)quinolin-4-yl]carbonyl}amino)-4-(2-chlorophenyl)valeric acid (enantiomer 1, 1.386 g total, 2.54 mmol, Example 34) were each dissolved in a few milliliters of methanol, the solutions were combined, and most of the methanol was re-removed on a rotary evaporator. The residue was then dissolved in dioxane (14 ml) and mixed with drops at RT with a 4 M solution of hydrogen chloride in dioxane (3.2 ml, 12.72 mmol). The mixture was left for 1 h at RT. The resulting solid was then filtered off and dried in vacuo. Since, according to LC-MS, the methyl ester corresponding to the title compound was also formed from the methanol used to prepare the assay, the residue was first purified by preparative HPLC (method 32). The combined desired fractions were concentrated and the residue was dried in vacuo. The residue (960 mg) was then dissolved in dioxane (10 ml) and at RT slowly mixed with a 4 M solution of hydrogen chloride in dioxane (3.2 ml, 12.72 mmol) and the mixture was left for 2 h at RT. The solid formed was then filtered off and the residue was lyophilized from acetonitrile/water. 603 mg (100% pure, 41% thor.) of the title compound were obtained.

- 240 040220

[a] _D20 = -17.0°, 589 nm, c = 0.42 g ^/ 100 ml, methanol;

LC-MS (method 1): Rt = 1.42 min; MS (ESIpos): m/z = 544/546 [M+H]+.

1H-NMR (500 MHz, DMSO-d6) δ [ppm]: 0.006 (0.51), 1.699 (0.22), 1.797 (0.88), 1.808 (1.38), 1.825 (2.64), 1.842 (2.97), 1.859 (1.76) , 1.875 (0.81), 1.971 (16.00), 2.016 (1.20), 2.054 (6.83), 2.075 (5.25), 2.084 (4.69), 2.092 (3.14), 2.099 (3.96), 2.123 (3.41), 2.136 (3.36) . , 7.278 (3.55) , 7.804 (2.56), 7.821 (2.63), 8.192 (0.78), 8.921 (3.10).

Example 284.

(+)-5-({[6-Bromo-3-methyl-2-(pyrrolidin-1-yl)quinolin-4-yl]carbonyl}amino)-4-(2chlorophenyl)valeric acid hydrochloride (enantiomer 2) .

Method A.

To a solution of (+)-5-({[6-bromo-3-methyl-2-(pyrrolidin-1-yl)quinolin-4-yl]carbonyl}amino)-4-(2chlorophenyl)valeric acid (200 mg , 367 µmol, enantiomer 2, example 35) in dioxane (2 ml) in argon at RT was slowly added dropwise with 4 M solution of hydrogen chloride in dioxane (460 µl, 1.89 mmol) and the mixture was stirred for 16 h at RT. The solid formed was then filtered off and dried in vacuo. 195 mg (100% pure, 89% thor.) of the title compound were obtained.

Ion chromatography (method 34): wt.% chloride: 9.9 wt.% (1.7 eq.) LC-MS (method 1): Rt = 1.49 min; MS (ESIpos): m/z = 544/546 [M+H] ⁺ .

1H-NMR (500 MHz, DMSO-d6) δ [ppm]: -0.061 (0.36), -0.007 (1.38), 0.007 (0.75), 1.085 (0.25), 1.368 (1.02), 1.799 (0.66), 1.809 ( 1.07), 1.827 (2.10), 1.843 (2.36), 1.861 (1.33), 1.877 (0.54), 1.911 (0.37) 2.67), 2.099 (2.82), 2.123 (2.59), 2.136 (2.33), 2.155 (1.09), 2.167 (0.49), 2.256 (2.66), 2.347 (2.35) 16.00) 3.99), 7.510 (3.54), 7.850 (3.33), 7.868 (3.51), 8.371 (2.22), 8.387 (2.08), 8.972 (2.46), 8.984 (4.49), 8.995 (2.33).

One part of the title compound was then lyophilized from acetonitrile/water and analyzed again:

Ion chromatography (method 34): wt.% chloride: 4.6 wt.% (0.8 eq.) LC-MS (method 1): Rt = 1.47 min; MS (ESIpos): m/z = 544/546 [M+H] ⁺ .

1H-NMR (500 MHz, DMSO-d6) δ [ppm]: -0.061 (0.46), -0.007 (0.68), 0.007 (0.49), 1.086 (0.47), 1.143 (0.19), 1.368 (1.75), 1.795 ( 0.91), 1.806 (1.50), 1.824 (2.91), 1.840 (3.33), 1.858 (1.93), 1.874 (0.82), 1.962 (16.00), 2.015 (1.18), 2.053 (7.92), 2.074 (5.96), 5.25), 2.091 (3.40), 2.098 (4.54), 2.118 (3.35), 2.123 (3.80), 2.135 (3.95), 2.153 (2.00), 2.165 (1.04), 2.248 (3.53), 2.363 (0.78), 0.43), 3.679 (5.00), 3.839 (5.70), 7.277 (4.13), 7.292 (3.05), 7.361 (2.86), 7.375 (4.27), 7.389 (2.53) 9.93), 7.461 (8.79), 7.491 (6.84), 7.506 (5.46), 7.786 (2.10), 8.063 (0.54), 8.875 (2.69).

Method B.

To a solution of (+)-5-({[6-bromo-3-methyl-2-(pyrrolidin-1-yl)quinolin-4-yl]carbonyl}amino)-4-(2chlorophenyl)valeric acid (3.31 g , 6.08 mmol, enantiomer 2, example 35) in dioxane (33 ml) at RT was slowly added 4 M solution of hydrogen chloride in dioxane (7.6 ml, 30.37 mmol) in drops, and the mixture was left for 4 h at RT. The resulting solid was then filtered off, adsorbed in water/acetonitrile and lyophilized to give the first lyophilisate. The filtrate was left overnight at RT and the precipitate formed overnight was filtered off. The resulting precipitate was combined with the lyophilisate described above, and the mixture was adsorbed in water/acetonitrile and lyophilized to obtain a second lyophilisate. 3.21 g (100% pure, 91% th. ee, 99% ee) of the title compound were obtained.

Ion chromatography (method 34): chloride mass fraction: 4.8 wt.% (0.9 eq.) LC-MS (method 1): Rt = 1.47 min; MS (ESIpos): m/z = 544/546 [M+H] ⁺ .

1H-NMR (600 MHz, DMSO-d6) δ [ppm]: 0.005 (0.73), 1.799 (0.90), 1.808 (1.47), 1.823 (3.13), 1.837 (3.31), 1.851 (1.89), 1.865 (0.77) , 1.974 (16.00), 2.021 (1.18), 2.045 (3.16), 2.056 (7.95), 2.074 (5.59) . , 7.448 (10.89) .

Method C.

To a solution of (+)-tert-butyl-5-({[6-bromo-3-methyl-2-(pyrrolidin-1-yl)quinolin-4yl]carbonyl}amino)-4-(2-chlorophenyl)pentanoate (6.50 g, 10.82 mmol, enantiomer 7, example 292A) in dioxane (70 ml) at RT was added slowly dropwise 4 M solution of hydrogen chloride in dioxane (100 ml, 400 mmol) and the mixture was stirred for 6 h at RT. Again, a 4 M solution of hydrogen chloride in dioxane (40 ml, 40 mmol) was added dropwise and the mixture was stirred for an additional 16 hours at RT. Since according to

- 241 040220

HPLC still had 1-2% educt, the mixture was sonicated for 1 hour. Diisopropyl ether (300 ml) was then slowly added to the mixture and the solid present was filtered off and washed successively with three portions of diisopropyl ether (respectively 50 ml) and then dried at 60° C. in vacuo. 6.18 g (100% pure, 89% th. y.) of the title compound was obtained.

LC-MS (method 1): R _t = 1.42 min; MS (ESIpos): m/z = 544/546 [M+H]+.

1H-NMR (500 MHz, DMSO-d ₆ ) δ [ppm]: -0.007 (1.43), 0.007 (0.81), 1.030 (1.11), 1.042 (1.11), 1.086 (0.20), 1.368 (1.75), 1.595 ( 0.60), 1.797 (0.87), 1.808 (1.42), 1.825 (2.76), 1.842 (3.11), 1.859 (1.78),1.877 (0.74), 1.971 (16.00), 2.016 (1.24), 2.047 (3.15), 7.39), 2.076 (5.65), 2.084 (5.03), 2.093 (3.33), 2.099 (4.13), 2.120 (3.19), 2.124 (3.52), 2.136 (3.47), 2.155 (1.73), 2.167 (0.87), 3.11) 9.79), 7.459 (9.09), 7.462 (7.90), 7.493 (6.15), 7.508 (5.00), 7.821 (2.31), 8.219 (0.58), 8.924 (2.84).

Example 285.

(-)-sodium-5-({[6-bromo-3-methyl-2-(pyrrolidin-1-yl)quinolin-4-yl]carbonyl}amino)-4-(2chlorophenyl)pentanoate (enantiomer 1)

To a suspension of (-)-5-({[6-bromo-3-methyl-2-(pyrrolidin-1-yl)quinolin-4-yl]-carbonyl}amino)-4-(2chlorophenyl)valeric acid (125 mg, 229 µmol, enantiomer 7, example 34) in water (10 ml) 1 M aqueous sodium hydroxide solution (229 µl, 229 µmol) was added at RT. The mixture was sonicated and mixed with THF (2 ml) whereupon a solution formed. After 1 hour stirring at RT, the mixture was concentrated and the residue was lyophilized from acetonitrile/water. 110 mg (98% pure, 83% thor.) of the title compound were obtained.

Ion chromatography (method 34): mass fraction of sodium: 3.5 wt.% (0.9 eq.).

[a] _D20 = -10.6°, 589 nm, c = 0.36 g ^/ 100 ml, methanol;

LC-MS (method 1): R _t = 1.45 min; MS (ESIpos): m/z = 544/546 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 1.355 (2.06), 1.695 (1.15), 1.707 (2.06), 1.729 (4.57), 1.738 (3.79), 1.753 (5.65), 1.768 (3.60 ), 1.782 (2.15), 1.807 (3.30), 1.833 (4.04), 1.872 (16.00), 1.916 (2.99), 1.933 (3.03), 2.178 (13.86), 2.256 (0.54), 2.267 (0.63), 2.710 (0.42 ), 3.465 (2.14), 3.480 (3.21), 3.497 (2.73), 3.514 (1.48), 3.572 (12.27), 3.618 (3.97), 7.215 (2.22), 7.233 (5.04), 7.251 (3.56), 7.325 (2.98 ), 7.343 (5.56), 7.361 (3.60), 7.407 (8.57), 7.426 (8.75), 7.438 (4.80), 7.462 (6.70), 7.484 (11.36), 7.536 (6.50), 7.541 (5.90), 7.558 (3.81 ), 7.564 (3.51), 9.051 (2.89).

Example 286.

(+)-sodium-5-({[6-bromo-3-methyl-2-(pyrrolidin-1-yl)quinolin-4-yl]carbonyl}amino)-4-(2chlorophenyl)pentanoate (enantiomer 2).

To a suspension of (+)-5-({[6-bromo-3-methyl-2-(pyrrolidin-1-yl)quinolin-4-yl]-carbonyl}amino)-4-(2chlorophenyl)valeric acid (125 mg, 229 µmol, enantiomer 2, example 35) in water (10 ml) 1 M aqueous sodium hydroxide solution (229 µl, 229 µmol) was added at RT. The mixture was sonicated and mixed with THF (2 ml) whereupon a solution formed. After 1 hour stirring at RT, the mixture was concentrated and the residue was lyophilized from acetonitrile/water. 129 mg (100% pure, 99% thor., ee >99%) of the title compound were obtained.

Ion chromatography (method 34): mass fraction of sodium: 4.7 wt.% (1.2 eq.).

[a] _D20 = +11.4°, 589 nm, c = 0.31 ^g /100 mL, methanol;

LC-MS (method 1): R _t = 1.41 min; MS (ESIpos): m/z = 544/546 [M+H] ⁺ .

1H-NMR (600 MHz, DMSO-d ₆ ) δ [ppm]: 1.354 (3.55), 1.366 (1.65), 1.701 (1.24), 1.710 (2.34), 1.731 (5.80), 1.743 (5.24), 1.748 (5.40 ), 1.758 (4.03), 1.770 (2.04), 1.823 (4.25), 1.832 (3.64), 1.841 (6.72), 1.867 (15.69), 1.907 (3.02), 1.925 (3.71), 1.940 (2.01), 2.163 (6.98 ), 2.245 (0.69), 2.268 (0.64), 3.489 (4.06), 3.567 (10.12), 3.600 (5.64), 3.611 (4.58), 7.223 (2.64), 7.236 (5.49), 7.248 (3.68), 7.332 (3.31 ), 7.345 (5.80), 7.357 (3.71), 7.413 (10.88), 7.426 (16.00), 7.439 (6.16), 7.466 (11.09), 7.481 (15.50), 7.542 (7.81), 7.545 (7.58), 7.556 (5.65 ), 7.560 (5.53), 8.942 (3.81), 8.952 (7.12), 8.961 (3.87).

Example 287.

(-)-potassium-5-({[6-bromo-3-methyl-2-(pyrrolidin-1-yl)quinolin-4-yl]carbonyl}amino)-4-(2chlorophenyl)pentanoate (enantiomer 1)

- 242 040220

To a suspension of (-)-5-({[6-bromo-3-methyl-2-(pyrrolidin-1-yl)quinolin-4-yl]-carbonyl}amino)-4-(2chlorophenyl)valeric acid (125 mg, 229 µmol, enantiomer 1, example 34) in water (10 ml) at RT was added 1 M potassium tert-butoxide in THF (229 µl, 229 µmol). The mixture was sonicated and mixed with THF (2 ml) whereupon a solution formed. After 1 hour stirring at RT, the mixture was concentrated and the residue was lyophilized from acetonitrile/water. 110 mg (98% pure, 81% thor.) of the title compound were obtained.

Ion chromatography (method 34): mass fraction of Kalium: 6.9 wt.% (1.0 eq.).

[a]D ²⁰ = -11.1°, 589 nm, c = 0.50 g/100 ml, methanol;

LC-MS (method 1): R _t = 1.45 min; MS (ESIpos): m/z = 544/546 [M+H]+.

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 1.299 (0.67), 1.612 (0.45), 1.694 (2.98), 1.717 (3.05), 1.730 (2.65), 1.758 (2.16), 1.782 (2.10) ), 1.794 (1.32), 1.863 (12.88), 1.947 (0.70), 2.184 (16.00), 2.227 (1.36), 2.237 (1.34), 2.709 (0.40), 3.552 (11.72), 3.597 (2.67), 3.617 (2.06 ), 3.650 (0.84), 7.054 (0.49), 7.137 (0.50), 7.181 (2.23), 7.200 (1.66), 7.223 (0.61), 7.289 (1.71), 7.307 (3.07), 7.325 (1.86), 7.361 (2.90 ), 7.381 (2.64), 7.403 (4.69), 7.420 (5.12), 7.442 (3.90), 7.482 (2.93), 7.503 (2.19).

Example 288.

(+)-potassium-5-({[6-bromo-3-methyl-2-(pyrrolidin-1-yl)quinolin-4-yl]carbonyl}amino)-4-(2chlorophenyl)pentanoate (enantiomer 2).

To a suspension of (+)-5-({[6-bromo-3-methyl-2-(pyrrolidin-1-yl)quinolin-4-yl]-carbonyl}amino)-4-(2chlorophenyl)valeric acid (125 mg, 229 µmol, enantiomer 2, example 35) in water (10 ml) at RT was added 1 M potassium tert-butoxide in THF (229 µl, 229 µmol). The mixture was sonicated and mixed with THF (2 ml) whereupon a solution formed. After 1 hour stirring at RT, the mixture was concentrated and the residue was lyophilized from acetonitrile/water. 137 mg (100% pure, 102% thor., ee >99%) of the title compound were obtained.

Ion chromatography (method 34): mass fraction of Kalium: 5.8 wt.% (0.9 eq.).

[a] _D20 = +11.3°, 589 nm, c = 0.31 ^g /100 mL, methanol;

LC-MS (method 1): Rt = 1.41 min; MS (ESIpos): m/z = 544/546 [M+H]+.

1H-NMR (600 MHz, DMSO-d6) δ [ppm]: 1.109 (1.62), 1.354 (3.30), 1.366 (1.60), 1.683 (1.38), 1.692 (2.50), 1.707 (5.61), 1.712 (5.58) , 1.724 (5.74), 1.733 (3.59), 1.748 (1.84), 1.758 (1.21), 1.764 (1.24), 1.781 (4.21), 1.790 (2.78), 1.798 (5.09), 1.808 (3.45), 1.825 (2.13) . , 7.233 (5.99) , 7.543 (7.97), 7.546 (7.69), 7.557 (5.73), 7.561 (5.54), 9.146 (3.89), 9.155 (7.29), 9.164 (3.93).

Example 289.

(+)-5-({[6-Bromo-2-(3,3-difluoropiperidin-1-yl)-3-methylquinolin-4-yl]carbonyl}amino)-4-(2methoxyphenyl)valeric acid (enantiomer 1 )

H ₃ C ^ A. JJ ³ oy

O^NH O

N s

XX L

5-{[(6-bromo-2-chloro-3-methylquinolin-4-yl)carbonyl]amino}-4-(2-methoxyphenyl)valeric acid (enantiomer 1, 200 mg, 85% pure, 336 µmol, example 241A), 3,3-difluoropiperidine hydrochloride (312 mg, 1.98 mmol), and DIPEA (830 μl, 4.7 mmol) in NMP (1.0 ml) were stirred for four days at 120°C. After cooling to RT, the reaction mixture was added to 1M hydrochloric acid and extracted with dichloromethane. The organic phase was dried over sodium sulfate and concentrated. The starting material was previously purified by column chromatography (Isolera, KP-Sil, eluent: dichloromethane/methanol, gradient: 0-40% methanol) and further purified by preparative HPLC (method 27). Received 54 mg (99% purity, 27% theoretical. output.).

[a] _D20 = +6.7°, 589 nm, c = 0.50 g/100 ml ^, chloroform.

- 243 040220

LC-MS (method 26): Rt = 0.80 min; MS (ESIpos): m/z = 590/592 [M+H]+.

1H-NMR (400 MHz, chloroform-d) δ [ppm]: 1.262 (0.43), 1.953 (1.11), 1.965 (0.97), 1.981 (0.52), 2.025 (0.71), 2.038 (0.82), 2.057 (1.02) . , 2.108 (0.48) . , 3.989 (0.59), 5.786 (0.50), 5.800 (1.00), 5.814 (0.52), 6.853 (1.55), 6.873 (1.58) , 7.001 (0.96), 7.216 (1.85), 7.220 (1.39), 7.224 (0.68), 7.235 (1.67),7.238 (1.56), 7.259 (0.89), 7.263 (0.94), 7.602 (0.82), 7.607 (0.89) , 7.624 (1.77), 7.630 (2.19), 7.649 (0.42), 7.659 (3.62), 7.671 (2.06), 7.676 (1.81), 7.680 (1.92).

B. Analysis of pharmacological efficacy

The pharmacological activity of the compounds according to the invention can be demonstrated by in vitro and in vivo studies, which are known to the skilled person. The following application examples describe the biological action of the compounds according to the invention without limiting the invention to these examples.

Abbreviations and abbreviations:

CRTH2 - chemoattractant homologous receptor molecule expressed on 2 Helper cells;

DMEM - medium needle in Dulbecco's modification;

DMSO, DMSO - dimethyl sulfoxide;

DP - PGD2 receptor (prostaglandin D2 receptor, type 2);

EC5 ₀ - half maximum effective concentration;

Em - emission;

EP - PGE2 receptor (prostaglandin E2 receptor);

Ex - excitement;

Fa. - company (supplier company);

FCS - fetal calf serum;

FP - PGF2α receptor;

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

IC ₅₀ - half maximum inhibitory concentration;

IP - PGI2 receptor (prostacyclin receptor);

Lit. - literary source;

MES - 2-(N-morpholino)ethanesulfonic acid;

Pen/Strep - penicillin/streptomycin;

PGD2 - prostaglandin D2;

PGE2 - prostaglandin E2;

PGF2a - prostaglandin F2a;

PGI2 - prostaglandin I2;

TC - tissue culture;

TR - thromboxane A2 receptor;

Tris - tris-(hydroxymethyl)aminomethane;

vol./rev. - volume to the ratio of volume (solution);

wt./wt. - mass to the ratio of mass (solution).

IN 1. Test in vitro-Test for blocking the activity of the human FP receptor.

PGF2a-induced calcium flux in FP-expressed CHEM1 cells (millipores, HTS093C) was used to characterize the test substance for FP incompatibility.

3000 cells in 30 µl of complete medium (DMEM F12, 10% FCS, 1.35 mM Na-pyruvate, 20 mM HEPES, 4 mM GlutaMAX™, 2% sodium bicarbonate, 1% Pen/Strep, 1% 100x non-essential amino acids) were seeded into wells 384-microtiter plate (Greiner, TC Platte, black with clear bottom) and incubated at 33°C, 5% CO ₂ for 24 h. Before measurement, the medium was replaced with 30 µl of measurement medium (Optimem) and incubated at 33° , 5% CO2 for 24 h. Before measurement, the medium was replaced with 30 µl of Fluo-8 AM-loading buffer solution [calcium-free Tyrode solution (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 , 6.3 mM probenecid, 5 µm Fluo-8 AM, 0.0112% Pluronic®] and incubated at 37°C, 5% CO ₂ for 30 min. The test substance was pre-prepared in DMSO at different concentrations (initial concentration 10 mM, dilution factor 3.16) as a dose-effect curve and pre-diluted 1:50 with calcium-free Tyrode's solution, 2 mM CaCl ₂ , 0.002% SmartBlock (Ltd. CANDOR). 10 µl of the pre-diluted substance solution was added to the Fluo-8-loaded cells and incubated at 37°C, 5% CO ₂ for 10 min. The FP receptor was activated by adding 40 μl of 2 nm (final concentration) PGF2a in calcium-free Tyrode solution, 2 mM CaCl ₂ , 0.002% SmartBlock, and the calcium flux was determined by measuring fluorescence at Ex. 470

- 244 040220 nm/Em. 525 nm for 120 s in a fluorescence instrument (FLIPR Tetra®, Molecular Devices).

In the next table. 1 shows the IC ₅₀ values obtained on the basis of individual embodiments of the invention from this test (partially as averages of multiple independent individual values).

Note. No. FPreceptor activity IC50 [µmol/l] 1 0.026 2 0.023 3 0.092 4 0.17 5 0.0094 6 0.0078 7 0.0066 8 0.058 9 0.29 10 0.036 eleven 0.025 12 0.22 13 0.018 14 0.07 15 0.048 16 0.29 17 0.0041 18 0.08 19 0.13 20 0.49 21 0.23 22 0.0066 23 0.0053 24 0.0049 25 0.022 26 0.021 27 0.014 28 0.031

Note. No. FPreceptor activity IC50 [µmol/l] 29 0.022 thirty 0.0087 31 0.029 32 0.048 33 0.032 34 0.0072 35 0.01 36 0.022 37 0.022 38 oh and 39 0.024 40 0.062 41 0.43 42 0.13 43 0.09 44 0.12 45 0.0047 46 0.0013 47 0.014 48 0.0012 49 0.014 50 0.003 51 0.013 52 0.0071 53 0.0057 54 0.85 55 oh and 56 0.33

Table 1

Note. No. FPreceptor activity IC50 [µmol/l] 57 0.00084 58 0.00052 59 0.011 60 0.0075 61 0.00083 62 oh and 63 0.0073 64 0.0098 65 oh and 66 0.012 67 0.0065 68 0.014 69 0.042 70 0.016 71 oh and 72 0.08 73 0.048 74 0.17 75 0.12 76 0.67 77 0.066 78 0.0044 79 0.0078 80 0.098 81 0.18 82 0.0039 83 0.0064 84 0.028

- 245 040220

85 0.59 115 0.029 145 0.0015 86 0.33 116 0.0046 146 0.022 87 0.55 117 0.016 147 0.008 88 0.88 118 0.0085 148 0.0045 89 0.35 119 0.014 149 0.013 90 0.059 120 0.011 150 0.022 91 0.0099 121 0.0041 151 0.0013 92 0.39 122 0.0067 152 0.00063 93 0.08 123 0.013 153 0.027 94 0.015 124 0.0028 154 0.0034 95 0.065 125 0.0052 155 0.003 96 0.95 126 0.0017 156 0.0025 97 0.53 127 0.00079 157 0.0017 98 0.53 128 0.0038 158 0.0016 99 0.5 129 0.0061 159 0.0031 100 0.34 130 0.0026 160 0.0053 101 0.45 131 0.0098 161 0.0014 102 0.25 132 0.0031 162 0.042 103 0.34 133 0.002 163 0.011 104 0.41 134 0.0049 164 0.08 105 0.0054 135 0.003 165 0.0029 106 0.004 136 0.0011 166 0.0095 107 0.005 137 0.0038 167 0.0037 108 0.36 138 0.003 168 0.09 109 0.86 139 0.0015 169 0.0091 BY 0.024 140 0.0023 170 0.0027 111 0.0064 141 0.0058 171 0.0094 112 0.003 142 0.0043 172 0.041 FROM 0.0099 143 0.0093 173 0.0022 114 0.014 144 0.0022 174 0.011 175 0.16 205 0.00041 235 0.0014 176 0.0078 206 0.0095 236 0.011 177 0.01 207 0.022 237 0.0043 178 0.056 208 0.0014 238 0.044 179 0.0023 209 0.007 239 0.0014 180 0.014 210 0.00068 240 0.016 181 0.0066 211 0.017 241 0.012 182 0.0029 212 0.0019 242 0.0071 183 0.0016 213 0.01 243 0.011 184 0.013 214 0.021 244 0.012 185 0.004 215 0.0039 245 0.027 186 0.0086 216 0.0029 246 0.0031 187 0.024 217 0.05 247 0.055 188 0.0061 218 0.0012 248 0.12 189 0.025 219 0.029 249 0.0094

- 246 040220

190 0.011 191 0.0041 192 0.0056 193 0.00062 194 0.011 195 0.077 196 0.0026 197 0.021 198 0.0037 199 0.0016 200 0.017 201 0.0027 202 0.0017 203 0.011 204 0.0026 265 0.013 266 0.037 267 0.0056 268 0.0031 269 0.0028 270 0.0033 271 0.0063 272 0.00085 273 0.03 274 0.00073

220 0.00076 221 0.0084 222 0.003 223 0.14 224 0.038 225 0.0032 226 0.0018 227 0.057 228 0.0011 229 0.013 230 0.012 231 0.039 232 0.018 233 0.084 234 0.0089 275 0.015 276 0.0097 277 0.034 278 0.034 279 0.011 280 0.0024 281 0.08 282 0.0019 283 0.0066 284 0.011

250 0.02 251 0.072 252 0.0094 253 0.025 254 0.0028 255 0.02 256 0.0084 257 0.015 258 0.08 259 0.055 260 0.029 261 0.028 262 0.018 263 0.028 264 0.03 285 0.0053 286 0.013 287 0.0047 288 0.014 289 0.0024

AT 2. In vitro test inhibition of FP receptor binding.

For testing for FP receptor coupling, human recombinant prostanoid FP receptors were used, which were expressed in HEK293 cells, in a modified MES buffer solution, pH 6.0. This test has already been proposed (Eurofins Panlabs, catalog #268510). 80 μg of the membrane was incubated with 1 nm [ ³ H]-PGF2a for 60 min at 25°C. The amount of membrane protein may vary lot by lot and is negotiable if necessary. Non-specific communication is determined in the presence of 1 μm cloprostenol. The membranes were filtered, washed and then measured to determine the specific relationship of [ ³ H]-PGF2a. Substances were tested for inhibitory activity at a concentration of 10 μm or in various concentrations [Lit.: Abramovitz et al., J. Biol. Chem. 1994, 269 (4): 2632].

B-3. In vitro test inhibition of CRTH2 receptor binding.

For this test, human recombinant prostanoid FP receptors were used, which were expressed in CHO-K1 cells, in a modified Tris-HCl buffer solution, pH 7.4. This test has already been proposed (Eurofins Panlabs, catalog #268030). 4 μg of the membrane was incubated with 1 nm [ ³ H]-PGF2 for 120 min at 25°C. The amount of membrane protein may vary lot by lot and is negotiable if necessary. Non-specific communication is determined in the presence of 1 μm PGD2. The membranes were filtered, washed and then measured to determine the specific relationship of [ ³ H]-PGF2. Substances were tested for inhibitory activity at a concentration of 10 μm or in various concentrations [Lit.: Sugimoto et al., J. Pharmacol. Exp. Ther. 2003, 305 (1): 347].

B-4. In vitro test inhibition of DP-receptor binding.

For this test, human recombinant prostanoid DP receptors were used, which were expressed in Chem-1 cells, in a modified HEPES buffer solution, pH 7.4. This test has already been proposed (Eurofins Panlabs, catalog #268060). 10 μg of the membrane was incubated with 2 nm [ ³ H]-PGF2 for 120 min at 25°C. The amount of membrane protein may vary lot by lot and is negotiable if necessary. Non-specific communication is determined in the presence of 1 μm PGD2. The membranes were filtered, washed and then measured to determine the specific relationship of [ ³ H]-PGF2. Substances were tested for inhibitory activity at a concentration of 10 μm or in various concentrations [Lit.: Wright et al., Br. J Pharmacol. 1998, 123 (7): 1317; Sharif et al., Br. J Pharmacol. 2000, 131 (6): 1025].

B-5. In vitro test inhibition of EPl-receptor binding.

For this test, human recombinant prostanoid EP1 receptors were used,

- 247 040220 which were expressed in HEK293 cells, in a modified MES buffer solution, pH 6.0. This test has already been proposed (Eurofins Panlabs, catalog #268110). 14 µg of the membrane were incubated with 1 nm [ ³ H]-PGF2 for 60 min at 25°C. The amount of membrane protein may vary lot by lot and is negotiable if necessary. Non-specific communication is determined in the presence of 10 μm PGE2. The membranes were filtered, washed and then measured to determine the specific relationship of [ ³ H]-PGF2. Substances were tested for inhibitory activity at a concentration of 10 μm or in various concentrations [Lit.: Abramovitz et al., Biochim. Biophys. Acta 2000, 1483 (2): 285; Funk et al., J. Biol. Chem. 1993, 268 (35): 26767].

AT 6. In vitro test inhibition of EP2 receptor binding.

For this test, human recombinant prostanoid EP2 receptors were used, which were expressed in HEK293 cells, in a modified MES/KOH buffer solution, pH 6.0. This test has already been proposed (Eurofins Panlabs, catalog #268200). 25 mg/ml membranes were incubated with 4 nm [ ³ H]-PGF2 for 120 min at 25°C. The amount of membrane protein may vary lot by lot and is negotiable if necessary. Non-specific communication is determined in the presence of 10 μm PGE2. The membranes were filtered, washed and then measured to determine the specific relationship of [ ³ H]-PGF2. Substances were tested for inhibitory activity at a concentration of 10 μm or in various concentrations [Lit.: Bastien et al., J. Biol. Chem. 1994, 269 (16): 11873; Boie et al., Eur. J Pharmacol. 1997, 340 (2-3): 227].

B-7. In vitro test inhibition of EP3 receptor binding.

For this test, human recombinant prostanoid EP3 receptors were used, which were expressed in HEK293 cells, in a modified MES buffer solution, pH 6.0. This test has already been proposed (Eurofins Panlabs, catalog #268310). 3 µg of the membrane was incubated with 0.5 nm [ ³ H]-PGF2 for 120 min at 25°С. The amount of membrane protein may vary lot by lot and is negotiable if necessary. Non-specific communication is determined in the presence of 10 μm PGE2. The membranes were filtered, washed and then measured to determine the specific relationship of [ ³ H]-PGF2. Substances were tested for inhibitory activity at a concentration of 10 μm or in various concentrations [Lit.: Schmidt et al., Eur. J Biochem. 1995, 228(1):23].

B-8. In vitro test inhibition of EP4 receptor binding.

For this test, human recombinant prostanoid EP4 receptors were used, which were expressed in Chem-1 cells, in a modified MES buffer solution, pH 6.0. This test has already been proposed (Eurofins Panlabs, catalog #268420). 3 μg of the membrane was incubated with 1 nm [ ³ H]-PGF2 for 120 min at 25°C. The amount of membrane protein may vary lot by lot and is negotiable if necessary. Non-specific communication is determined in the presence of 10 μm PGE2. The membranes were filtered, washed and then measured to determine the specific relationship of [ ³ H]-PGF2. Substances were tested for inhibitory activity at a concentration of 10 μm or in various concentrations [Lit.: Davis et al., Br. J Pharmacol. 2000, 130 (8): 1919].

B-9. In vitro test for IP receptor binding inhibition.

For this test, human recombinant prostanoid IP receptors were used, which were expressed in HEK293 cells, in a modified HEPES buffer solution, pH 6.0. This test has already been proposed (Eurofins Panlabs, catalog #268600). 15 µg of the membrane were incubated with 5 nm [ ³ H]-iloprost for 60 min at 25°C. The amount of membrane protein may vary lot by lot and is negotiable if necessary. Non-specific communication is determined in the presence of 10 μm iloprost. The membranes were filtered, washed and then measured to determine the specific relationship of [ ³ H]-iloprost. Substances were tested for inhibitory activity at a concentration of 10 μm or in various concentrations [Lit.: Armstrong et al., Br. J Pharmacol. 1989, 97 (3): 657; Boie et al., J. Biol. Chem. 1994, 269 (16): 12173].

B-10. In vitro test inhibition of TP receptor binding.

For this test, human recombinant prostanoid TP receptors were used, which were expressed in HEK-293 EBNA cells, in modified Tris-HCl buffer, pH 7.4. This test has already been proposed (Eurofins Panlabs, catalog #285510). 18.4 μg of the membrane were incubated with 5 nm [ ³ H]-SQ-29,548 for 30 min at 25°C. The amount of membrane protein may vary lot by lot and is negotiable if necessary. Non-specific binding is determined in the presence of 1 μm SQ-29,548. The membranes were filtered, washed and then measured to determine the specific relationship of [ ³ H]-SQ-29,548. Substances were tested for inhibitory activity at a concentration of 10 μm or in various concentrations [Lit.: Saussy Jr. et al., J. Biol. Chem. 1986, 261: 3025; Hedberg et al., J. Pharmacol. Exp. Ther. 1988, 245: 786].

AT 11. In vitro test for DP agonism and α-incompatibility.

PGD2 induced calcium flux in DP-expressed CHEM1 cells (millipores, HTS091C) was used to characterize the test substance for DP agonism and α-incompatibility: 3000

- 248 040220 cells in 25 µl 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 v/ml penicillin and streptomycin] were inoculated into the wells of a 384-microtiter plate (Greiner, TC Platte, black with a transparent bottom) and incubated at 37°C, 5% CO ₂ for 24 hours. dye (FLIPR Calcium Assay, Molecular Devices) and incubated at 37°C, 5% CO ₂ for 60 min. The test substance was pre-prepared in DMSO at various concentrations (initial concentration 10 mM, dilution factor 3.16) as a dose-response curve and pre-diluted 1:50 s with e.g. calcium-free Tyrode's solution (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 . To determine DP agonism in a fluorescence measuring device (FLIPR Tetra®, Molecular Devices), 10 μl of a pre-diluted substance solution was added to calcium-dye-loaded cells and the calcium flux was determined by measuring fluorescence at Ex. 470 nm/Em. 525 nm in 120 s. The cells were then incubated at 37°C/5% CO ₂ for 10 min. To determine DP incompatibility, activate the DP receptor in FLIPR Tetra® by adding 20 μl ~76 nm (2xEC ₅₀ , final concentration) of PGD2 in e.g. calcium-free Tyrode/2 mM CaCl ₂ solution and determine calcium flux by measuring fluorescence at Ex. 470 nm/Em. 525 nm in 120 s [Ref.: T. Matsuoka et al. (2000) Science 287: 2013-2017; S. Narumiya and GA Fitzgerald (2001) J. Clin. Invest. 108:25-30].

B-12. In vitro test for EP1 agonism and α-incompatibility.

To characterize the test substance for EP1 agonism and -incompatibility, PGD2 induced calcium flux in EP1-expressed CHEM1 cells (millipores, HTS099C) was used: 3000 cells in 25 µl of complete medium [DMEM, 4.5 g/l glucose, 10% non-activated at elevated temperature FCS, 1% 100x non-essential amino acids, 10 mM FLEPES, 0.25 mg/mL geneticin (G418), 100 v/mL penicillin and streptomycin] were plated in the wells of a 384 microtitre plate (Greiner, TC Platte, black with clear bottom) and incubated at 37°C, 5% CO ₂ for 24 h. Before measurement, the medium was replaced with 30 μl of calcium dye loading buffer solution (FLIPR Calcium Assay, Molecular Devices) and incubated at 37°C, 5% CO ₂ for 60 min . The test substance was pre-prepared in DMSO at various concentrations (initial concentration 10 mM, dilution factor 3.16) as a dose-response curve and pre-diluted 1:50 s with e.g. calcium-free Tyrode's solution (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 . To determine EP1 agonism in a fluorescence measuring device (FLIPR Tetra®, Molecular Devices), 10 μl of a pre-diluted substance solution was added to calcium-dye-loaded cells and the calcium flux was determined by measuring fluorescence at Ex. 470 nm/Em. 525 nm in 120 s. The cells were then incubated at 37°C/5% CO ₂ for 10 min. To determine EP1 incompatibility, activate the EP1 receptor in FLIPR Tetra® by adding 20 μl ~6 nm (2xEC ₅₀ , final concentration) of PGE2 in e.g. calcium-free Tyrode/2 mM CaCl ₂ solution and determine calcium flux by measuring fluorescence at Ex. 470 nm/Em. 525 nm in 120 s [Ref.: Y. Matsuoka et al. (2005) Proc. Natl. Acad. sci. USA 102: 16066-16071; S. Narumiya and GA Fitzgerald (2001) J. Clin. Invest. 108:25-30; K. Watanabe et al. (1999) Cancer Res. 59: 50935096].

B-13. In vitro test for EP2 agonism and α-incompatibility.

To characterize the test substance for EP2 agonism and α-incompatibility, PGE2-induced calcium flux in EP2-expressed CHEM9 cells (millipores, HTS185C) was used: 3000 cells in 25 µl of diluted media [DMEM, 4.5 g/l glucose, 4% glutamine, 10% non-heat-activated FCS, 1% 100x non-essential amino acids, 10 mM HEPES, 100 v/ml penicillin and streptomycin] were plated in the wells of a 384 microtiter plate (Greiner, TC Platte, black with clear bottom) and incubated at 37°C /5% CO 2 for 24 hours. Before measurement, the medium was replaced with 30 μl of calcium dye loading buffer solution (FLIPR Calcium Assay, Molecular Devices) and incubated at 37° C., 5% CO ₂ for 60 min. The test substance was pre-prepared in DMSO at various concentrations (initial concentration 10 mM, dilution factor 3.16) as a dose-response curve and pre-diluted 1:50 s with e.g. calcium-free Tyrode's solution (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 . To determine EP2 agonism in a fluorescence measuring device (FLIPR Tetra®, Molecular Devices), 10 μl of a pre-diluted substance solution was added to calcium-dye loaded cells and calcium flux was determined by measuring fluorescence at Ex. 470 nm/Em. 525 nm in 120 s. The cells were then incubated at 37°C/5% CO ₂ for 10 min. To determine EP2 incompatibility, activate the EP2 receptor in FLIPR Tetra® by adding 20 μl ~22 nm (2xEC ₅₀ , final concentration) of PGE2 in e.g. calcium-free Tyrode/2 mM CaCl ₂ solution and determine calcium flux by measuring fluorescence at Ex. 470 nm/Em. 525 nm in 120 s [Ref.: C. R. Kennedy et al. (1999) Nat. Med. 5:217-220; S. Narumiya and GA Fitzgerald (2001) J.

- 249 040220

Clin. Invest. 108:25-30; N. Yang et al. (2003) J. Clin. Invest. 111:727-735].

B-14. In vitro test for EP3 agonism and α-incompatibility.

To characterize the test substance for EP3 agonism and α-incompatibility, PGE22 induced calcium flux in EP3 (splicing option 6)-expressed CHEM1 cells (millipores, HTS092C) was used: 3000 cells in 25 µl of diluted medium [DMEM, 4.5 g/l glucose, 4 % glutamine, 10% heat-inactivated FCS, 1% 100x non-essential amino acids, 10 mM HEPES, 100 v/ml penicillin, and streptomycin] were seeded into the wells of a 384 microtiter plate (Greiner, TC Platte, black with clear bottom) and incubated at 37° C./5% CO ₂ for 24 h. Before measurement, the medium was replaced with 30 μl of calcium dye loading buffer solution (FLIPR Calcium Assay, Molecular Devices) and incubated at 37° C., 5% CO 2 for 60 min. The test substance was pre-prepared in DMSO at various concentrations (initial concentration 10 mM, dilution factor 3.16) as a dose-response curve and pre-diluted 1:50 s with e.g. calcium-free Tyrode's solution (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 . To determine EP3 agonism in a fluorescence measuring device (FLIPR Tetra®, Molecular Devices), 10 μl of a pre-diluted substance solution was added to calcium-dye-loaded cells and the calcium flux was determined by measuring fluorescence at Ex. 470 nm/Em. 525 nm in 120 s. The cells were then incubated at 37°C/5% CO ₂ for 10 min. To determine EP3 incompatibility, activate the EP3 receptor in FLIPR Tetra® by adding 20 μl ~2 nm (2xEC ₅₀ , final concentration) of PGE2 in e.g. calcium-free Tyrode/2 mM CaCl2 solution and determine calcium flux by measuring fluorescence at Ex . 470 nm/Em. 525 nm in 120 s [Ref.: M. Kotani et al. (1995) Mol. Pharmacol. 48:869879; 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 agonism and α-incompatibility.

PGE2-induced calcium flux in EP4-expressed CHEM1 cells (millipores, HTS142C) was used to characterize the test substance for EP4 agonism and α-incompatibility: 3000 cells in 25 µl of diluted media [DMEM, 4.5 g/l glucose, 4% glutamine, 10% non-heat-activated FCS, 1% 100x non-essential amino acids, 10 mM HEPES, 100 v/ml penicillin and streptomycin] were plated in the wells of a 384 microtiter plate (Greiner, TC Platte, black with clear bottom) and incubated at 37°C /5% CO ₂ for 24 h. Before measurement, the medium was replaced with 30 μl of calcium dye loading buffer solution (FLIPR Calcium Assay, Molecular Devices) and incubated at 37° C., 5% CO ₂ for 60 min. The test substance was pre-prepared in DMSO at various concentrations (initial concentration 10 mM, dilution factor 3.16) as a dose-response curve and pre-diluted 1:50 s with e.g. calcium-free Tyrode's solution (130 mM NaCl, 5 mM KCl, 20 mm HEPES, 1 mm MgCl2, 4.8 mm NaHCO3, pH 7.4)/2 mm CaCl ₂ . To determine EP4 agonism in a fluorescence measuring device (FLIPR Tetra®, Molecular Devices), 10 μl of a pre-diluted substance solution was added to calcium-dye-loaded cells and the calcium flux was determined by measuring fluorescence at Ex. 470 im/em. 525 im in 120 s. The cells were then incubated at 37°C/5% CO ₂ for 10 min. To determine EP4 incompatibility, activate the EP4 receptor in FLIPR Tetra® by adding 20 μl ~26 nm (2xEC ₅₀ , final concentration) of PGE2 in, for example, calcium-free Tyrode/2 mM CaCl ₂ solution and determine calcium flux by measuring fluorescence at Ex. 470 nm/Em. 525 nm in 120 s [Ref.: S. Narumiya und 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. sci. USA 99: 4580-4585].

B-16. In vitro test for IP agonism and α-incompatibility.

Iloprost-induced calcium flux in IP-expressed CHEM1 cells (millipores, HTS131C) was used to characterize the test substance for IP agonism and α-incompatibility: 3000 cells in 25 µl of diluted media [DMEM, 4.5 g/l glucose, 4% glutamine, 10 % heat-inactivated FCS, 1% 100x non-essential amino acids, 10 mM HEPES, 100 v/ml penicillin and streptomycin] were plated in the wells of a 384 microtiter plate (Greiner, TC Platte, black with clear bottom) and incubated at 37°C. C/5% CO ₂ for 24 h. Before measurement, the medium was replaced with 30 μl of calcium dye loading buffer (FLIPR Calcium Assay, Molecular Devices) and incubated at 37° C., 5% CO ₂ for 60 min. The test substance was pre-prepared in DMSO at various concentrations (initial concentration 10 mM, dilution factor 3.16) as a dose-response curve and pre-diluted 1:50 s with e.g. calcium-free Tyrode's solution (130 mM NaCl, 5 mM KCl, 20 mm HEPES, 1 mm MgCl2, 4.8 mm NaHCO3, pH 7.4)/2 mm CaCl ₂ . To determine IP agonism in a fluorescence measuring device (FLIPR Tetra®, Molecular Devices), 10 μl of a pre-diluted substance solution was added to calcium-dye-loaded cells and the calcium flux was determined by measuring fluorescence at Ex. 470 nm/Em. 525 nm in 120 s. The cells were then incubated at 37°C/5% CO ₂ for 10 min. To determine IP incompatibility, the IP receptor was activated in FLIPR Tetra® by adding 20 µl ~106 nm

- 250 040220 (2xEC ₅₀ , final concentration) of iloprost in eg calcium-free Tyrode/2 mm CaCl ₂ solution and the calcium flux was determined by measuring fluorescence at Ex. 470 nm/Em. 525 nm in 120 s [Ref.: S. Narumiya et al. (1999) Physiol. Rev. 79:1193-1226; T. Murata et al. (1997) Nature 388: 678-682; Y Cheng et al. (2002) Science 296: 539-541; C. H. Xiao et al. (2001) Circulation 104: 2210-2215; G. A. Fitzgerald (2004) N. Engl. J. Med. 351: 1709-1711].

B-17. In vitro test for TP-agonism and -incompatibility.

U46619 induced calcium flux in TP-expressed CHEM1 cells (millipores, HTS081C) was used to characterize test substance for TP agonism and β-incompatibility: 3000 cells in 25 µl of diluted media [DMEM, 10% heat-inactivated FCS, 1% 100x non-essential amino acids, 10 mM HEPES, 0.25 mg/mL geneticin (G418), 100 v/mL penicillin and streptomycin] were seeded into the wells of a 384 microtiter plate (Greiner, TC Platte, black with clear bottom) and incubated at 37°C, 5% CO ₂ for 24 h. Before measurement, the medium was replaced with 30 μl of calcium dye loading buffer (FLIPR Calcium Assay, Molecular Devices) and incubated at 37° C., 5% CO ₂ for 60 min. The test substance was pre-prepared in DMSO at various concentrations (initial concentration 10 mM, dilution factor 3.16) as a dose-response curve and pre-diluted 1:50 s with e.g. calcium-free Tyrode's solution (130 mM NaCl, 5 mM KCl, 20 mm HEPES, 1 mm MgCl ₂ , 4.8 mm NaHCO3, pH 7.4)/2 mm CaCl ₂ . To determine TP agonism in a fluorescence measuring device (FLIPR Tetra®, Molecular Devices), 10 μl of a pre-diluted substance solution was added to calcium-dye-loaded cells and the calcium flux was determined by measuring fluorescence at Ex. 470 nm/Em. 525 nm in 120 s. Cells were then incubated at 37°C/5% CO2 for 10 min. To determine TP incompatibility, the TP receptor was activated in FLIPR Tetra® by the addition of 20 μl ~88 nm (2xEC ₅₀ , final concentration) U46619 in, for example, calcium-free Tyrode/2 mM CaCl ₂ solution and the calcium flux was determined by measuring fluorescence at Ex. 470 nm/Em. 525 nm in 120 s [Ref.: 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-18. An animal model of bleomycin-induced pulmonary fibrosis.

Bleomycin-induced pulmonary fibrosis in mice or rats is a widely accepted animal model for pulmonary fibrosis. Bleomycin is a glycopeptide antibiotic that is used in oncology for the treatment of testicular tumors, Hodgkin tumors, and non-Hodgkin tumors. It is eliminated renally, has a half-life of approximately 3 hours, and acts as a cytostatic in various phases of the division cycle [Lazo et al., Cancer Chemother. Biol. response modif. 15, 44-50 (1994)]. Its antineoplastic effect is based on the oxidative-damaging effect on DNA [Hay et al., Arch. Toxicol. 65, 81-94 (1991)]. The lung tissue is particularly susceptible to the effects of bleomycin, since the so-called cysteine hydrolase, which in other tissues leads to the deactivation of bleomycin, is present in it only in limited quantities. After the introduction of bleomycin in animals, acute respiratory distress syndrome (ARDS) sets in, followed by the development of pulmonary fibrosis.

The administration of bleomycin can take place with a single or multiple administration intratracheally, inhalation, intravenous or intraperitoneal. Treatment of animals with the test substance (by force-feeding, addition to food or drinking water, using an osmotic minipump, by subcutaneous or intraperitoneal injection or by inhalation) begins on the day of the first administration of bleomycin or therapeutically after 3-14 days and continues for 2- 6 weeks. At the end of the study, bronchoalveolar lavage is performed to determine the content of cells and pro-inflammatory and pre-fibrosing markers, as well as a measurement of lung function and a histological assessment of pulmonary fibrosis.

B-19. Animal model of DQ12-silica-induced pulmonary fibrosis.

DQ12-silica-induced pulmonary fibrosis in mice and rats is a widely accepted animal model for pulmonary fibrosis. [Shimbori et al., Exp. Lung Res. 36, 292-301 (2010)]. DQ12-quartz is a highly active crushed or ground quartz. Intratracheal or inhalation administration of DQ12-quartz to mice and rats with alveolar proteinaceous dystrophy leads to interstitial pulmonary fibrosis. Animals receive single or multiple intratracheal or inhalation instillations of DQ12-quartz. Treatment of animals with the test substance (by force-feeding, adding to food or drinking water, using an osmotic mini-pump, by subcutaneous or intraperitoneal injection or by inhalation) begins on the day of the first silicate instillation or therapeutically after 3-14 days and continues for 3-12 weeks. At the end of the study, bronchoalveolar lavage is performed to determine the content of cells and pro-inflammatory and pre-fibrosing markers, as well as a measurement of lung function and a histological assessment of pulmonary fibrosis.

IN 20. Animal model of DQ12-silica-induced pulmonary inflammation.

Intratracheal administration of DQ12-quartz in mice and rats leads to inflammation in the lungs [Shimbori et al., Exp. Lung Res. 36, 292-301 (2010)]. Treatment of animals with the test substance (forcible

- 251 040220 feeding, adding to food or drinking water, using an osmotic mini-pump, by subcutaneous or intraperitoneal injection or by inhalation) start on the day of the first instillation of DQ12-quartz or one day later and continue from 24 hours to 7 days. At the end of the test, bronchoalveolar lavage is performed to determine the content of cells and pro-inflammatory and pre-fibrosing markers.

AT 21. Tetrachlorohydrocarbon (CCl ₄ ) induced liver fibrosis in mice.

Sixty C57BL/6J mice (Charles River lab, male, 8 weeks old) were divided randomly into 4 equal groups (15 mice per group). Group 1 was a healthy, untreated control group, while groups 2-4 were mice with liver fibrosis disease, liver fibrosis was induced by intraperitoneal injections of 50 μl of a suspension of CCl ₄ olive oil (CCl ₄ + olive oil, 1+9 v/v) three times a week (Monday, Wednesday and Friday) throughout the study period. CCl ₄ is the oldest substance used to induce toxic-induced liver fibrosis (Starkel and Leclercq, Best Pract. Res. Clin. Gastroenterol. 2011, 25, 319-333). Group 2 CCl ₄ treated mice served as a disease control group and received no other treatment, while Group 3 CCl ₄ treated mice additionally received drug vehicle treatment and thus served as a drug vehicle control group. Group ₄ mice receiving CCl 4 served as the group receiving compounds of formula (I). Treatment of group 3 with oral drug solution and group 4 with oral compound of formula (I) started on the first day and continued 2 times a day (morning and evening) throughout the study period for two weeks. All animals were sacrificed at the end of the study under anesthesia, the liver was removed and placed in 4% formaldehyde buffer solution for subsequent histological processing and study. To do this, all liver samples of all animals were covered with a layer of paraffin and received a layer of paraffin with a thickness of 3 μm. Then, the paraffin layer was removed from all liver samples and stained with picrosirius red (Waldeck, Germany) to determine liver fibrosis. Picrosirius red staining is a histological technique for staining collagen in tissue and thus fibrosis. A Carl Zeiss (Axio Observer) microscope, which is connected to a computer, was used to scan areas of the liver stained with Picro-Sirius Red to create corresponding photographs. The areas were scanned at 20x magnification and a light intensity of 4.8 V. The photographs thus obtained were then converted to JPG format and the red-stained area was quantified using ImageJ software (National Institute of Health, USA). Results are presented as % Sirius red per liver area.

Treatment with Example 284 resulted in significant reductions in fibrosis progression (p < 0.01; two-way statistical ANOVA by Dunnett's post hoc test, mean ± SD) during a 2-week study in mice with liver fibrosis (see Table 2). ).

table 2

Group Sirius red [% liver area] 1 healthy control group 1.64±0.34 2 non-treated control group (CC14) 4.37 ± 0.68

3 Control group treated with drug base (CC14 + drug base) 4.29±0.87 4 Treatment group (CC14 + 100 mg/kg Example 284) 3.51±0.65

B-22. Animal model of unilateral ureteral obstruction (OOM) V mice (renal fibrosis).

Unilateral ureteral obstruction in mice and rats is a widely accepted animal model of interstitial renal fibrosis (Chevalier et al., Kidney Int. 2009, 75, 1145-1152). Prolonged blockage of the ureter due to persistent urinary stagnation leads to increased inflammatory cell infiltration into the interstitium, tubular cell death, and irreversible loss of renal parenchyma. After 5-7 days, due to the large amount of deposits of extracellular matrix protein, interstitial fibrosis occurs. Adult male C57B16J mice (Charles River Labore, Sulzfeld, Germany) weighing 20-22 g were euthanized with isoflurane, then after opening the abdominal cavity, the ureter was ligated and divided below the ligature. In mice in the control group (SHAM)

- 252 040220 with a visible operation, only the abdominal cavity was opened, the ureter was not ligated. Postoperatively, treatment of the substance treated animals with the compound of Example 284 (10 and 30 mg/kg po twice daily (bid)) was started and continued for a further 10 days. Ten days after OOM, the animals were euthanized and euthanized by exsanguination. The kidneys were then removed and assessed for renal fibrosis based on the expression of pro-inflammatory and pro-fibrotic markers, as well as histological evaluation of renal tissues. The results are presented in table. 3 and 4.

Table 3

Expression of pro-inflammatory and profibrotic marker genes in treated and untreated animal models

Marker SHAM placebo Example 284 30 [mg/kg] Example 284 60 [mg/kg] aSMA 18.71±2.91 100.00±38.62 72.97 ± 39.94 51.72 ± 21.33 Col lai 5.04±0.83 100.00±26.21 76.70 ± 36.22 38.90 ± 13.11 Col3al 4.82±0.91 100.00±18.34 103.74±37.60 126.15±46.51 Col4al 24.66 ± 1.56 100.00 ± 19.04 71.15±20.20 45.97 ± 8.44 CTGF 16.43 ± 14.32 100.00±27.67 105.67±52.33 102.07±26.99 TGF-β 21.68 ± 1.48 100.00±23.90 67.57±32.67 31.79±9.06 KC 1.97±0.31 100.00±24.38 65.02 ± 15.98 50.69 ± 22.02 MCP-1 3.40±0.75 100.00±35.65 93.98±26.32 117.41±38.15 IL-6 0.52±0.17 100.00 ± 141.69 207.04 ± 389.13 494.83 ± 850.76 ILl-β 8.62 ± 1.23 100.00±51.64 81.91±31.93 112.05±71.38 n = 10 animals/group. Mean ± SD. The gene expression value of the placebo group was set to 100%, the expression of the other groups was calculated as a percentage compared to the placebo group. aSMA = alpha smooth muscle actin; Collal = alpha-1-type-1-collagen; Col3al = alpha-1-type-III-collagen; Col4al = alpha-1-type-1Y-collagen; CTGF = connective tissue growth factor; TGF-β = transforming growth factor-β; KS = keratinocyte chemoattractant; MCP-1 = monocytic chemoattractant protein 1; IL-6 = interleukin-6; ILl-β = interleukin-1β; SHAM = control group with visible operation

Table 4

Immunohistologically confirmed aSMA staining and histochemical staining of collagens (SR/FG)

Marker SHAM placebo Example 284 30 [mg/kg] Example 284 60 [mg/kg] aSMA positive area [%] 3.63±0.62 29.03 ± 3.90 25.19±3.23 22.28 ± 4.04 SR/FG positive square [%] 16.34±3.64 40.01±4.90 38.74±9.12 34.66±7.59 η = 10 animals/group. Mean ± SD. aSMA = alpha smooth muscle actin; SR/FG = Sirius Red/Fast Green; SHAM = control group with visible operation

OOM leads to increased gene expression of proinflammatory and profibrosing genes (eg, aSMA, collagen, TGF-b, KC, MCP-1) in obstructive kidneys. Treatment with the substance resulted in a dose-dependent reduction in the expression of aSMA, Col1a1, Col4a1, TGF-β and KC. The gene expression of Col3a1, CTGF, MCP-1, IL-6 and ILt-β was not affected by treatment.

Histological staining showed increased aSMA and collagen (SR/FG) in

- 253 040220

OOM kidneys compared with SHAM-operated mice. Treatment with 60 [mg/kg] of the substance resulted in a significant reduction in the aSMA-positive surface. Treatment had no effect on the collagen content of obstructive kidneys.

B-23. Silica-induced pulmonary fibrosis in mice: a therapeutic chronic 30 day study with an FP antagonist.

Adult female C57B16J mice (Charles River Laboratories, Sulzfeld, Germany) weighing 18-20 g were euthanized in a chamber with isoflurane (3% v/v) and intratracheally injected with 2.5 mg of crystalline DQ12 silica, which was dissolved in 70 µl of sterile phosphate buffered saline solution. An untreated control group of mice received the same volume of phosphate buffered saline. On the 10th day after the administration of silica, the animals of the groups receiving the substance were treated with the compound of Example 35 (10 and 30 mg/kg orally twice a day (bid)) for 20 days. Thirty days after silica instillation, animals were euthanized by intraperitoneal injection of ketamine/medetomidine (50 mg/kg and 0.33 mg/kg) combined with subcutaneous injection of temgesic (0.06 mg/kg) and euthanized by exsanguination. Then the trachea was cannulated and the lungs of the animals were washed three times with 0.5 ml of very cold phosphate-buffered saline. Then the lungs were removed, weighed and instantly frozen on dry ice. After lung tissue homogenization, hydroxyproline was determined by HPLC [Paroni et al., Clin. Chem. 1992, 38, 407-411; column: Phenomenex Synergi Hydro RP 4 µm 80A, 75x4.6 mm; gradient: solvent A: water (6 ml/l triethylamine, 3 ml/l acetic acid) pH 4.3; solvent B: acetonitrile; flow: 1.3 ml/min). Data are mean±SEM of 8-12 animals per group. Statistical analysis was performed using an unpaired Student's t-test. P-value with <0.05 was considered significant. The results are presented in table. 5.

Table 5

Group hydroxyproline [ng/lung] Healthy control group 1678 + 60.49 (n=8) Silica control group 2631 + 85.31 (n=12) silicon dioxide +10 mg/kg orally, twice a day, Example 284 2341 ± 54.99 (n=12) Silica +30mg/kg po twice daily, Example 284 2185 + 86.79 (n=12)

Silicon dioxide supplementation, compared with the untreated control group, resulted in a significant increase in hydroxyproline, a marker of collagen accumulation, and fibrosis in the lungs of the silica-treated animals. Treatment with the compound of Example 35 (10 and 30 mg/kg orally twice daily) resulted in a significant reduction in hydroxyproline formation and fibrosis in the treated groups compared to the silica control group.

B-24. Effect of an FP antagonist on mechanical sensitivity (peripherally, mice).

Mechanical allodynia was studied using Frey's test on the hind legs, treated and not treated with injections, after injections.

Mechanical allodynia was measured using 8 Semmes-Weinstein filaments (Stolting ©; Wood Dale, IL, USA) with different hardnesses (0.04; 0.07; 0.16; 0.4; 1.0; 4.0 and 8 0 g) according to the Up-Down method (Chaplan et al., J. Neurosci. Meth. 1994, 53, 56-63). Intact male ND4 mice (~30 g, 10 animals per group) were placed in individual actyl chambers on a surface with a metal grid, for at least 15 min before testing, the animals got used to the environment. Each thread was pressed perpendicularly to the underside of the paw with sufficient force to cause a slight bend in the paw, held for approximately 6 s or until a positive response was recorded (the paw abruptly returns back). Trials started with 0.4-g filament. If the paw did not come back, then the subsequent stimulus was stronger. When the paw returned back, the next stimulus was weaker. This process is repeated until 4 responses are received after the initial change in response (no response for positive response or positive response for no response). If the animal does not respond after using the strongest thread, or the animal responds after using the weakest thread, then the test is terminated at that point. The 50% Paw Response Threshold was calculated using the following formula:

50% Paw Response Threshold = ——

Xf = value (in logarithmic units) of the last applied Frey filaments;

k = table value for the yes/no response sample (see Chaplan et al., J. Neu

- 254 040220 rosci. Meth. 1994, 53, 56-63, appendix 1, p. 62);

δ = mean difference (in log units) between stimuli.

The mean and normalized error of the mean (SEM) are determined for each paw for each treatment group at any given time.

group model.

No. treatment Doziro in to and (mg/kg) Dosing volume drug base Note. Day of treatment/ Frequency 1 Fluprostenol -0.15 20 µl 10%DMSObPBS IPL day 0, T = 0 Medicinal base / 5 ml/kg DMSO/PEG400/H2O (10/60/30) PO Zx, T = -2, 8, 22 h 2 Fluprostenol -0.15 20 µl 10%DMSObPBS IPL day 0, T = 0 Test substance tbd 5 ml/kg DMSO/PEG400/H2O (10/60/30) PO Zx, T = -2, 8, 22 h 3 Fluprostenol - 1.5 20 µl 10%DMSObPBS IPL day 0, T = 0 Medicinal the basis / 5 ml/kg DMSO/PEG400/H2O (10/60/30) PO Zx, T = -2, 8, 22 h 4 Fluprostenol - 1.5 20 µl 10%DMSObPBS IPL day 0, T = 0 Test substance tbd 5 ml/kg DMSO/PEG400/H2O (10/60/30) PO Zx, T = -2, 8, 22 h

IPL: intraplantar injection; RO: orally.

To evaluate the analgesic effect of an FP antagonist on fluprostenol-induced mechanical sensitivity, the test substance is taken 2 hours before and 8 hours, and 22 hours after fluprostenol injection. Ipsilateral and contralateral 50% hindlimb response thresholds are measured before fluprostenol administration and 0.5, 2, 6 and 24 hours after administration.

C. Examples of pharmaceutical compositions.

Compounds according to the invention can be converted in the following way into pharmaceutical preparations.

Pills.

Compound.

100 mg of a compound according to the invention, 50 mg of lactose (monohydrate), 50 mg of cornstarch (natural), 10 mg of polyvinylpyrrolidone (PVP 25) (BASF, Ludwigshafen, Germany) and 2 mg of magnesium stearate.

Tablet weight 212 mg, diameter 8 mm, arch radius 12 mm.

Manufacturing.

A mixture of a compound according to the invention, lactose and starch is granulated with a 5% w/w solution of PVP in water. After drying, the granulate is mixed with magnesium stearate for 5 minutes. This mixture is compressed with a conventional tablet press (see above for tablet size). A press force of 15 kN is used as a guide value for pressing.

Orally administered suspensions.

Compound.

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

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

Manufacturing.

Rhodigel is made into a suspension in ethanol, the compound according to the invention is added to the suspension. Water is added while stirring. Finally, the swollen Rhodigel is stirred for about 6 hours.

Orally administered solutions.

Compound.

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

Manufacturing.

The compound according to the invention is made into a suspension in a mixture of polyethylene glycol and polysorbate with stirring. The mixing process is continued until the compound according to the invention is completely dissolved.

- 255 040220

intravenous solution.

The compound according to the invention at a concentration less than the saturated solubility is dissolved in a physiologically compatible solvent (for example, isotonic saline solution, glucose solution 5% and/or PEG 400 solution 30%). The solution is filtered under sterile conditions and dispensed into sterile and non-pyrogenic injection vessels.

Claims (7)

CLAIM 1. Compound of formula (I) in which Ar means phenyl, and phenyl can be substituted up to three times, in each case equally or differently, by fluorine, chlorine, up to three times substituted by fluorine (C ₁ -C ₄ )alkyl, up to three times substituted by fluorine (C1C ₂ )alkoxy , Y means a bond or a group of the formula # ¹ -X-(CR ^10A R ^10B ) _k -# ² where #1 means the place of attachment to the carbon atom, # ² means the place of attachment to the carboxy group, X is a bond or -CH2-, where R ^10A and R ^10B are independently hydrogen, k is 1 or 2, R ¹ means bromine, R ² , R ³ and R ⁴ are independently hydrogen, R ⁵ means (C1-C ₄ )alkyl, R ⁶ means -NR ¹² R ¹³ , and R ¹² is hydrogen or (C1-C ₃ )alkyl, and R ¹³ means (C 1 -C ₄ )alkyl or (C ₃ -C ₇ )cycloalkyl, and (C 1 -C ₄ ) alkyl can be substituted up to three times with fluorine or once with (C ₃ -C ₆ ) cycloalkyl, methoxy or phenyl , or means a saturated or partially unsaturated 4-8-membered monocyclic or 6-10-membered bicyclic heterocycle linked to a nitrogen atom, which may contain an additional, identical or different heteroatom from the series N, O, S, SO or SO2 as a ring member , and the 4-8-membered monocyclic and 6-10-membered bicyclic heterocycle, respectively, can be substituted with 1-2 substituents independently selected from the group (C _r C ₄ )alkyl, hydroxy, oxo, (C1-C ₃ ) alkoxy, cyano, amino, aminocarbonyl, and further up to four times by fluorine, and (C 1 -C ₄ ) alkyl can be substituted up to three times by fluorine or once by hydroxy or methoxy, R ^7A and R ^7B are independently hydrogen, R ⁸ means hydrogen, R ⁹ means hydrogen, as well as their salts. 2. The compound of formula (I) according to claim 1, in which Ar is phenyl, where phenyl may be substituted up to three times, equally or differently, with fluorine, chlorine, methyl, trifluoromethyl, methoxy, difluoromethoxy or trifluoromethoxy, Y means a bond or a group of the formula # ¹ -(CH ₂ ) _p - # ² , where # ¹ means the place of attachment to the carbon atom, # ² means the place of attachment to the carboxy group, n means 1 or 2, R ¹ means bromine, R ² , R ³ and R ⁴ are respectively hydrogen, R ⁵ means methyl and R ⁶ is -NR12R ¹³ , where R ¹² is hydrogen or methyl, and R ¹³ means (C1-C ₄ )alkyl, and (C1-C ₄ )alkyl may be substituted up to three times with fluorine or once with phenyl, or - 256 040220 means a nitrogen-linked, saturated or partially unsaturated, 5-7-membered monocyclic or 7-10-membered bicyclic heterocycle, which may contain an additional, identical or different heteroatom from the series N, O or S as a ring member, moreover, the 5-7-membered monocyclic and 7-10-membered bicyclic heterocycle, respectively, can be substituted with 1-2 substituents independently selected from the group of methyl, difluoromethyl, trifluoromethyl, ethyl, isopropyl, and further up to four times with fluorine, R ^7A , R ^7B , R ⁸ and R ⁹ are respectively hydrogen and their salts. 3. The compound of formula (I) according to one of claims 1, 2, in which Ar is phenyl, where phenyl may be substituted up to three times, equally or differently, with fluorine, chlorine, methyl, trifluoromethyl, difluoromethoxy or trifluoromethoxy, Y means a group of the formula #1-CH ₂ CH ₂ -# ² where #1 means the place of attachment to the carbon atom, # ² means the place of attachment to the carboxy group, R ¹ means bromine, R ² , R ³ , R ⁴ are respectively hydrogen, R ⁵ means methyl, R ⁶ means a group of formula where # ³ means the place of attachment to the rest of the molecule, R ¹⁴ means fluorine or methyl, R ¹⁵ means fluorine, methyl or ethyl, R ^7A , R ^7B , R ⁸ and R ⁹ are respectively hydrogen and their salts. 4. A process for the preparation of a compound of formula (I) as defined in one of claims 1 to 3, characterized in that the compound of formula (II) in which R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ^7A , R ^7B , R ⁸ , R ⁹ and Ar have the above meanings, T means the protective group of esters, which is (C1-C ₄ )alkyl, in the first stage [A] is reacted with an amine compound of formula (III) ^{R —H} (III) in which R ⁶ has the above meanings, and in the next step [B] isolate the ester residue of the compound of formula (IV) obtained in step [A] after reaction with the amine compound (III) R R R in which R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ^7A , R ^7B , R ⁸ , R ⁹ and Ar are as defined above, and (iv) - 257 040220 T is an ester protecting group which is (C _g C ₄ )alkyl and thus compounds of formula (I) are obtained in which R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ^7A , R ^7B , R ⁸ , R ⁹ and Ag have the above meanings. 5. The method according to claim 4, characterized in that, in addition, the compounds of formula (I) with the corresponding bases or acids are converted into their salts. 6. An active substance having FP receptor antagonist properties, which is a compound of formula (I) as defined in one of claims 1 to 3. 7. A drug for the treatment and/or prevention of diseases in which an FP receptor is involved in the course of an inflammatory process and/or remodeling of tissues or vessels, containing a compound as defined in one of claims 1 to 3, in combination with one or more inert, non-toxic, pharmaceutically acceptable excipients. Eurasian Patent Organization, EAPO Russia, 109012, Moscow, Maly Cherkassky per., 2 -258 -