EA040284B1 - SUBSTITUTED N-ARYLETHYL-2-ARYLQUINOLINE-4-CARBOXAMIDES, METHOD FOR THEIR PRODUCTION AND DRUG CONTAINING THE SPECIFIED COMPOUND - Google Patents

Description

The invention relates to new substituted derivatives of N-arylethyl-2-arylquinoline-4-carboxamide, 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 L2-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 pains and childbirth. 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. 2010, 30, 383391]. 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 interleukin6 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 such as COX-2 [Sales et al., 2007, Endocrinology 148:3635-44], FGF-2 and VEGF [Sales et al., 2010 Am J Pathol 176:431] indicating that 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 (OPCs) 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 OPC 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. Thus, using FP receptor-deficient mice and FP agonist treatment, AL-8810 exerts 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 2010, 1, 1-7; Ding et al., Int. J Biochem. cell. Biol, 2012, 44, 1031-1039; Ding et al., J. Mol. Med., 2014, 6, 629-640].

Thus, the 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], as, for example, also with 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. 2010, 30, 383-391]. During the latter application, stimulation of hair growth, such as eyelashes, was observed as a side effect due to a chemically stable PGF2a analog, such as 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 (see Powell et al., Prostaglandins 1985, 29, 273-290; Dawood and Khan-Dawood, Am. J. Obstet. Gynecol. 2007, 196, 35. e1-35.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), lung diffusion capacity for carbon monoxide (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 through chronic inhalation and consequent pulmonary fibrosis, causes a strong upregulation of PGF2α synthesis [O'Reilly et al., Am. J Physiol. cell. Mol. Appl. 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, 15, 1426-1430]. In FP-/- mice, after bleomycin administration, 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 [Olman, Nat. Med. 2009, 15, 1360-1361]. The involvement of PGF2a in the induction of fibrotic 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 fibrotic 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 2.5-3.5 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, 13641370]. 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), 105-111]. The prevalence of pulmonary hypertension among interstitial lung diseases is 10-40% [Lettieri et al., Chest 2006, 129, 746-752; Behr et al., Eur. Respir. J. 2008, 31, 13571367]. 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 RA [Wells et al. Nat Rev Rheumatol 2014, 10, 728-739]. Approximately 10% of RA patients have clinically proven interstitial lung disease (RA-ILD), and another third show subclinical ILD on chest CT scans. The mortality rate in patients with RA-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 RAILD [Catrina et al. Nat. Rev. Rheumatol. 2014, 10(11), 645-653].

Pulmonary hypertension (PH) is a progressive lung disease that, if left untreated, leads to death approximately 2.8 years after 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-PAH 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

- 3 040284 pulmonary hypertension is classified according to the Dan Point classification, into different 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, through non-selective vasodilation, they result in arterial oxygen depletion (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, PAH also covers persistent pulmonary hypertension of the newborn and associated pulmonary arterial hypertension (APAH), 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, eg, proximal and distal pulmonary thromboembolic obstruction (CTEPH) or non-thrombotic emboli (eg, due to 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 an inflammatory event that is associated with changes in the lung tissue, primarily affecting the small airways. Damage and inflammatory changes in the epithelial cells and subepithelial structures of the smaller airways lead to excessive fibroproliferation due to inefficient epithelial regeneration and repair of aberrant tissue. 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 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 fibrotic 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. EP 2415755-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,3-diphenylnaphthalene-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.

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

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in which Ar means phenyl or pyridyl, and phenyl can be substituted up to four times and pyridyl once, 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 (C ₁ -C ₂ )alkoxy, or moreover, two substituents of the phenyl group, if connected to adjacent ring atoms, can be so linked to each other that together they form a methylenedioxy group,

Y means a bond or a group of formula # ¹ -X-(CR ^10A R ^10B ) _k -# ² or

--# 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, -CH2-, -O-, -S(=O) _m - or -N(R ¹¹ )-, where m is 0 or 2, and

R ¹¹ means hydrogen or methyl,

R ^10A and R ^10B are independently hydrogen, fluorine or methyl, k is 1, 2 or 3,

R ¹ means halogen or ethynyl,

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

R ⁵ means halogen or (C ₁ -C ₄ )alkyl,

R ⁶ means phenyl,

R ^7A and R ^7B are independently hydrogen or methyl,

R ⁸ means hydrogen, fluorine, methyl, ethyl or hydroxy,

R ⁹ means hydrogen, as well as their salts.

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 include, in particular, conventional salt base derivatives, such as, for example and preferably, alkali metal salts (eg sodium and potassium salts), alkaline earth metal salts (eg calcium salts and magnesium salts), salts zinc, as well as ammonium salts, ammonia derivatives of organic amines with 1 16 C-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 acids. , 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 040284 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 necessary, also in the form of conformational isomers (enantiomers and/or diastereoisomers, including atropical isomers). Therefore, this invention includes enantiomers and diastereoisomers and mixtures thereof. From such mixtures of enantiomers and/or diastereoisomers, stereoisomeric single components can be isolated in a manner known per se. To this end, 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 a diastereomeric salt with 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. The enantiomeric excess (ee-value) is calculated in this case by interpreting the HPLC analysis chromatogram in the chiral phase according to the following formula:

I Enantiomer 1 (Area Percentage) - Enantiomer 2 (Area Percentage) I ee ⁼ ΓΞ----------TTL --------------- _λ , _Q --- ------------D ^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; due to 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, the methods described below and further demonstrated in the described exemplary embodiments, while using 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 by metabolic or hydrolytic means, are converted 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 (C ₁ -C ₄ )alkyl ester of the 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 C ₁ -C ₄ -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 or 4 carbon atoms. A C ₃ -C ₄ -cycloalkyl group means for example a monocyclic hydrocarbon ring, for example a cyclopropyl or cyclobutyl group.

The term C ₁ -C ₂ -alkoxy means a straight chain or branched saturated monovalent group of the formula (C ₁ -C ₂ -alkyl)-O-, in which the term C ₁ -C ₂ -alkyl has the above meanings, for example means a methoxy or ethoxy group or an isomer thereof.

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

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

The term C1-C4 means, as, for example, in the context of this invention, for example in accordance with the definition of C ₁ -C ₄ -alkyl, an alkyl group with a limited number of carbon atoms 1-3, i.e. 1, 2, 3 or 4 carbon atoms.

If a range of defined values is specified, then it is each individual value and the subranges must lie within the defined range.

Ci-C ₄ , for example, must contain Ci, C ₂ , C ₃ , C ₄ , Ci-C ₄ , C1-C3, Ci-C ₂ , C ₂ -C ₄ , C ₂ -C ₃ and C ₃ -C ₄ .

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 invention are compounds of formula (I) in which

Ar is phenyl or 2-pyridyl, wherein the phenyl may be substituted up to four times with fluorine, or up to three times, equally or differently, with fluorine, chlorine, methyl, trifluoromethyl, methoxy, difluoromethoxy, trifluoromethoxy, or ethoxy, or where two substituents on the phenyl group, if they are connected to adjacent ring atoms, they can be so connected to each other that together they form a methylenedioxy group, and moreover, 2-pyridyl can be substituted once by chlorine or methoxy,

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 -CH2-, -O-, -S(=O) _m - or -N(R ¹¹ )-, where m is 0 or 2, and

R ¹¹ means hydrogen or methyl,

R ^10A and R ^10B are independently hydrogen, fluorine or methyl, k is 1, 2 or 3, R ¹ is bromine or ethynyl,

R ² means hydrogen,

R ³ and R ⁴ are hydrogen,

R ⁵ means chlorine or methyl, and

R ⁶ means phenyl,

R ^7A means hydrogen or methyl,

R ^7B means hydrogen,

R ⁸ means hydrogen, fluorine, methyl, ethyl or hydroxy,

R ⁹ means hydrogen, as well as their salts.

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

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

Y means a group of the formula # ¹ -(CH2)n-# 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, 2 or 3,

R ¹ means bromine or ethynyl,

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

R ⁵ means chlorine or methyl, and

R ⁶ means phenyl,

R ^7A and R ^7B are respectively hydrogen,

R ⁸ means hydrogen or methyl,

R ⁹ means hydrogen, as well as their salts.

Particularly preferred within the scope of the invention are compounds of formula (I) in which Ar is phenyl, where phenyl may be substituted up to four times with fluorine or up to three times, identically or differently, with fluorine, chlorine, methyl, trifluoromethyl or trifluoromethoxy,

Y means a group of formula # ¹ -CH2CH2 - # 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 or ethynyl,

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

R ⁵ means methyl or chlorine,

R ⁶ means phenyl, r7a, r7b, rS and R9 respectively mean hydrogen, as well as their salts.

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

R ¹ means ethynyl, and

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

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

R ⁵ means methyl or chlorine, as well as their salts.

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

R ⁵ means methyl, as well as their salts.

Another particular embodiment of the invention includes compounds of formula (I) in which R ⁶ is phenyl, as well as salts thereof.

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

Y means bond, as well as their salts.

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

Y means a group of the formula # ¹ -CH2 - # 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

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 their salts.

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

X stands for -O- as well as salts.

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

R ⁸ means hydrogen or methyl, as well as their salts.

Another particular embodiment of the invention includes compounds of formula (I), in which R ^7A means methyl, R ⁷ b means hydrogen, as well as their salts.

Another particular embodiment of the invention includes compounds of formula (I) in which Ar is phenyl, where phenyl may be substituted up to four times by fluorine or up to three times, equally or differently, by fluorine, chlorine, methyl, trifluoromethyl, methoxy, difluoromethoxy, trifluoromethoxy , or ethoxy, may be substituted, or moreover, two substituents of the phenyl group, if connected to adjacent ring atoms, may be so connected to each other that together they form a methylenedioxy group, as well as their salts.

- 9 040284

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

Ar is phenyl, where phenyl may be substituted up to four times with fluorine or up to three times, equally or differently, with fluorine, chlorine, methyl, trifluoromethyl, difluoromethoxy or trifluoromethoxy, and also their salts.

Another particular embodiment of the invention includes compounds of formula (I) in which Ar is 2-pyridyl, where 2-pyridyl may be substituted once with chlorine or methoxy, as well as their salts.

Another particular embodiment of the invention includes compounds of formula (I) in which R ² , R ³ and R ⁴ are independently hydrogen, as well as their salts.

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

R ¹ means bromine,

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

R ⁵ means methyl,

R ⁶ means phenyl, as well as their salts.

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

R ¹ means ethynyl,

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

R ⁵ means methyl,

R ⁶ means phenyl, 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 and R ⁶ have the above meanings, in the first step

[A] upon activation of the carboxylic acid function is reacted with an amine compound of formula (III-A) or (III-B)

Oh Oh

^HN r ⁹ (Ill-A) ^HN > ⁹ (Ill-B) wherein R ^7A , R ^7B , R ⁸ , R ⁹ and Ar are as defined above, and

T means the protective group of esters, which is (C ₁ -C ₄ )alkyl, and in the next step

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

- 10 040284 about

wherein 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 T is an ester protecting group which is (C ₁ -C ₄ )alkyl, and thus the 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 Ar have the above meanings, if necessary with the appropriate bases or acids are converted into their salts. The coupling reaction (II) + (III-A) ^ (I) and (II) + (III-B) ^ (IV) [formation of amides] can be carried out either directly with a condensing agent or activator, or with an intermediate step from (II) carboxylic acid chloride or carboxylic acid amidazolide.

Suitable condensing agents or activators are, for example, carbodiimides such as N,N'-diethyl-, N,N'-dipropyl-, N,N'-diisopropyl-, N,N'-dicyclohexylcarbodiimide (DCC) or N -(3dimethylaminopropyl)-N,N'-ethylcarbodiimide hydrochloride (EDC), phosgene derivatives such as N,N'carbonyldiimidazole (CDI) or isobutyl chloroformate, 1,2-oxazolium compounds such as 2-ethyl-5phenyl-1,2-oxazolium- 3-sulfate or 2-tert-butyl-5-methylisoxazolium perchlorate, acylamines like 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline, α-chlorenamines like 1-chloro-N,N,2-trimethylprop -1-en-1-amine, 1,3,5-triazine derivatives as 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride, phosphorus compounds as anhydride n-propanephosphonic acid (PPA), cyanophosphonic acid diethyl ester, diphenylphosphoryl azide (DPPA), bis-(2-oxo-3-oxazolidinyl)phosphoryl chloride, benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate, or benzotriazol-1-yloxy -tris(pyrrolidino)phosphonium hexafluorophosphate (PyBOP), and whether uronium compounds such as O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU), O-(1H-6-chlorobenzotriazol-1-yl)-1,1, 3,3-tetramethyluronium-tetrafluoroborate (TCTU), O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium-hexafluorophosphate (HBTU), O-(7-azabenzotriazol-1-yl)- N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) or 2-(2-oxo-1-(2H)-pyridyl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TPTU) as needed , in combination with other excipients, such as 1-hydroxybenzotriazole (HOBt) or N-hydroxysuccinimide (HOSu), and as a base to an alkali metal carbonate, such as sodium or potassium carbonate, or a tertiary amine base, such as triethylamine, Ν,Ν -diisopropylethylamine, N-methylmorpholine (NMM), N-methylpiperidine (NMP), DIPEA, pyridine, or 4-N,N-dimethylaminopyridine (DMAP). O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) is preferably used as a condensation agent or activator in combination with DIPEA.

In a two-step reaction with carboxylic acid chlorides or imidazolides derived from (II), a coupling reaction is carried out with the amine component (III-A)/(III-B) in the presence of a common base such as sodium or potassium carbonate, triethylamine, DIPEA , N-methylmorpholine (NMM), N-methylpiperidine (NMP), pyridine, 2,6-dimethylpyridine, 4-N,N-dimethylaminopyridine (DMAP), 1,8-diazabicyclo[5.4.0]undec-7-ene ( DBU), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), sodium or potassium ethoxide, sodium or potassium tert-butoxide, or sodium or potassium hydride. Preferably, triethylamine or DIPEA is used as the base.

A preferred coupling reaction is the direct conversion of (II) with the amine compound (III) using a condensing agent or an activator.

Inert solvents for said 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, such as carbon

- 11 040284 hydrogens such as benzene, toluene, xylene, pentane, hexane or cyclohexane, halocarbons such as dichloromethane, trichloroethane, carbon tetrachloride, 1,2-dichloroethane, trichloroethylene or chlorenzene, or polar aprotic solvents such as acetone, methyl ethyl ketone, ethyl acetate , acetonitrile, butyronitrile, pyridine, dimethyl sulfoxide (DMSO), N,N-dimethylformamide (DMF), N-dimethylpropyleneurea (DMPU), or N-methylpyrrolidinone (NMP). Mixtures of these solvents can also be used. Preferably, N,N-dimethylformamide is used. The coupling reaction is generally carried out at temperatures of 0-130°C, preferably 20-80°C.

The carboxylic acid imidazolides themselves are prepared in a known manner by the conversion of (II) N,N'-carbonyldiimidazole (CDI) at elevated temperatures (60-150°C) in an appropriate high-boiling solvent such as N,N-dimethylformamide (DMF) Preparation of carboxylic acid chlorides proceeds in the usual way by treating (II) with thionyl chloride or oxalic acid chloride in an inert solvent such as dichloromethane.

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-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 as ether protecting group T.

The elimination of the ester group T in the technological stage (IV) ^ (I) is carried out by conventional methods, by treating the ester in an inert solvent with an acid or base, and in the latter version, the carboxylic acid salt formed first is converted by subsequent treatment with acid into the 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, n-propanol, isopropanol, n-butanol or tert-butanol, ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane or 1,2-dimethoxyethane, or others. 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, for example, 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 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 salt base derivatives.

Salts of compounds of formula (I) derived from the usual bases 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

- 12 040284 isolation of free carboxylic acid. Preferred ester groups T with respect to base separation are methyl and ethyl groups.

Compounds of formula (II) can be obtained depending on the appropriate substituent reference in a similar way to known literature methods (see also WO 2016/146602 A1, pages 26-32), or during the conversion of the isatin derivative of formula (V) during acid-mediated or a condensation reaction base with a ketomethylene compound of formula (VI) to a compound of formula (VII) (Scheme 1) or with an o-aminophenylacetic acid ester of formula (VIII) during an acid-induced condensation reaction with a diketo compound of formula (IX) to a compound of formula ( VII-A) (scheme 2).

Scheme 1

Scheme 2

The condensation of an isatin derivative of formula (V) with a ketomethylene compound of formula (VI) to a quinoline-4-carboxylic acid of formula (VII) (Scheme 1) can be obtained by heating the reagents in the presence of an aqueous acid, such as, for example, sulfuric acid or concentrated hydrochloric acid, or in the presence of an aqueous base, such as sodium hydroxide or potassium liquor. When using an acid for the conversion, acetic acid is preferably used as a solvent; in an alkaline reaction, alcoholic solvents such as methanol or ethanol are preferably used. The condensation is generally carried out at temperatures of 70-120°C [see, for example, K. Lackey and D.D. Sternbach, Synthesis, 1993, 993-997; A.N. Boa et al., Bioorg. Med. Chem. 2005, 13 (6), 1945-1967].

The condensation reaction to quinoline-4-carboxylic acid of formula (VII-A) (Scheme 2) is carried out similarly by heating the ortho-aminophenylacetic acid ester of formula (VIII) and the deketone of formula (IX) with aqueous acid, in particular concentrated hydrochloric acid. Acetic acid is also preferably used here as inert solvents for the conversion.

The ortho-aminophenylacetic acid ester of formula (VIII) can, for its part, be converted following the base-mediated reaction of an α-chloroacetic acid ester of formula (XX) with a nitrophenyl derivative of formula (XXI) as described in the literature into an ortho-nitrophenylacetic acid ester of formula (XXII) (scheme 3). The subsequent reduction of the nitro group to the compound of formula (XXI) can be obtained, for example, using catalytic hydrogenation [see. P. Beier et al., J. Org. Chem. 2011, 76, 4781-4786].

Scheme 3

Compounds of formulas (III-A) and (III-B) can be obtained depending on the appropriate substituent reference, for example, according to the synthetic routes described in the following Schemes 4-10 and the experimental part of the corresponding examples and similarly to the synthesis methods known in the literature Scheme 4 (for Y=F-CCH,),,-# ² with n=0, 1, 2, 3 (III-B-1)).

[Alkyl - methyl, ethyl; Ar - substitute. phenyl, subst. pyridyl; T is a protecting group of esters, eg methyl, ethyl, tert-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

- 13 040284

LiHMDS, -78°C; or tert-butyl acrylate, potassium carbonate or sodium hydride; for n=3: tert-butyl-4-bromobutanoate, LDA, -78° C., b): H2, Raney nickel or PtO ₂ . LDA - lithium diisopropylamide; LiHMDS - lithium bis(trimethylsilyl)amide].

Scheme 5 (for R ⁸ = fluorine (III-B-2), hydroxy (III-B-3))

[Ar - substitute. phenyl, subst. pyridyl; T is a protecting group of esters, eg methyl, ethyl, tert-butyl; n = 0, 1, 2, 3; a): for example, KCN or TMSCN; b) DAST; c): H ₂ , catalyst, eg Raney nickel or PtO2. DAST = diethylaminosulfur trifluoride].

Scheme 6 (for R ^7A / R ^7B = H, Me (III-B-4))

[Ar- subst. phenyl, subst. pyridyl; T is a protecting group of esters, eg methyl, ethyl, tert-butyl; a): Nitroethane, base, eg 2-tert-butyl-1,1,3,3-tetramethylguanidine; b) zinc dust, hydrochloric acid].

Scheme 7 (for r ^10A / r ^10B = Me, Me (III-B-5) or F, F (III-B-6))

(XXIII) (lll-B-6)

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

Scheme 8 (for X = NH (III-B-7) or NMe (III-B-8))

[Ar - substitute. phenyl, subst. pyridyl; T is a protecting group of esters, eg methyl, ethyl, tert-butyl; a) TMS-CN; b) H2, Raney nickel].

Scheme 9 (for X = S (III-B-9) or SO ₂ (III-B-10))

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

- 14 040284

Scheme 10 (for X = O (III-B-11))

Ag Ag

^ΝΗ about NH ₂ O (XVIII) (XXIX) (III-B-11)

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

The separation of the compounds according to the invention into the respective enantiomers and/or diastereoisomers can optionally also take place, depending on the purpose, already at the stage of the individual intermediates (III-A), (III-B) or (IV), these intermediates being in 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.

Compounds of formulas (V), (VI), (VIII), (IX), (X), (XI), (XIII), (XV), (XVII), (XIX), (XX), (XXII), (XXIV), (XXV), (XXVII), (XVIII) and (XXIX) are commercially available or can be obtained according to 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 the formula (I) according to the invention can also be obtained, if appropriate, by converting the functional groups of individual residues and substituents, in particular those named among R ¹ and R ⁵ , starting from other compounds obtained by the aforementioned methods or in the appropriate steps. formulas. 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 a 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 (ALI), α-1-antitrypsin deficiency (AATD), pulmonary emphysema (eg, cigarette smoke-induced pulmonary emphysema), cystic fibrosis (CF), inflammatory and fibrotic kidney diseases, chronic inflammation bowel disease (IBD, Crohn's disease, ulcerative colitis), peritonitis, peritoneal fibrosis, rheumatoid diseases, multiple sclerosis, inflammatory and fibrotic skin diseases, drepanocytosis, and inflammatory and fibrotic 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 lungs and related diseases, coughs and colds (chronic inflammatory cough, iatrogenic cough), inflammation of the nasal mucosa (including drug-induced, vasomotor and seasonal, allergic rhinitis, e.g. 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, heart vascular disease, stable and unstable angina, renal hypertension, peripheral and cardiac angiopathy, arrhythmias, atrial and ventricular arrhythmias, 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 extrasystole and atrial , atrioventricular 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), boxer cardiomyopathy, 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 coronary and peripheral arteries, edema formation, such as pulmonary edema, cerebral edema, renal or heart failure edema, 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 the treatment of 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, for example, hypertension, pulmonary edema, heart failure, uremia, anemia, electrolyte disturbances (e.g., hyperkalemia, hyponatremia), disturbance of bone metabolism, and disturbance of carbohydrate exchange.

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 emptying disorder, lower urinary tract syndrome (LUTS), neurogenic overactive bladder (OAB), incontinence such as mixed, urge incontinence, stress or overflow incontinence (MUI, UUI, SUI, OUI), pelvic pain, as well as erectile dysfunction in men and sexual dysfunction in women.

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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 prophylaxis of inflammatory diseases of the internal organs, such as those of the lungs, heart, kidneys, 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, liver cirrhosis, pulmonary fibrosis, endomyocardial fibrosis, nephropathy, glomerulonephritis, renal interstitial fibrosis, fibrotic lesions due to diabetes, bone marrow fibrosis, peritoneal fibrosis, and similar fibrotic diseases. diseases, scleroderma, localized 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 glaumoma 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 gangraenose 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 d, 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's syndrome- Christian, scarring, wart formation, frostbite), inflammatory eye diseases (saccoidosis, blepharitis, conjunctivitis, iritis, choroiditis uveitis, ophthalmitis), viral diseases (caused by group viruses, adeno- and coronaviruses, such as HPV, HCMV, HIV , SARS), diseases of the bones of the skeleton, joints and skeletal muscles (different 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,

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Arthritis urica, Arthritis villonodularis pigmentosa, 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 ossificans progressiva multiplex, 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 a, rheumatoid arteritis, deforming arteritis, temporal arteritis, temporal arteritis, giant cell arteritis and granulomatous arteritis, as well as Horton's syndrome, Churg-Strauss syndrome and Takayasu's arteritis), Muckle-Wells syndrome, Kikuchi disease, polychondritis, scleroderma, as well as other diseases with inflammatory and immunological constituents 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.

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 fibrotic diseases of the skin and eyes; and fibrotic 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, ailment, 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 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 object 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 or prevention of previously named diseases. As these suitable combinations of biologically active substances, for example and preferably, 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), e.g. 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 activators of soluble guanylate cyclase (sGC), 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 ;

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NO-independent but also heme-dependent stimulators of soluble guanylate cyclase (sGC), such as those described in particular 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, for example 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 remodeling of the extracellular matrix, for example and preferably inhibitors of matrix metalloprotease (MMP), in particular inhibitors of stromelysin, collagenase, gelatinase and agrecanase (especially mmP-1, mmP-3, mmP-8, mmP-9, mmP-10, mmP-11 and mmP13), as well as metal elastase (MMP-12);

compounds which block the binding of serotonin to its receptors, for example and preferably 5-HT2 _B 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, inhibitors of Wnt signaling pathway or CCR2 antagonist;

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

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, a-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 for example and preferably inhibitors of 3-hydroxy-3-methylglutarylcoenzyme A reductase or squalene synthase, acyl-CoA-cholesterol acyltransferase inhibitors, transfer inhibitors cholesteryl ester inhibitors, microsomal triglyceride transfer protein inhibitors, peroxisome proliferator-activated PPAR-α-, PPAR-γ- and/or PPAR-δ receptor antagonists, cholesterol uptake blockers, lipase inhibitors, polymeric bile acid adsorbers, bile acid reabsorption blockers 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 agonists.

- 19 040284 receptors, as for example and preferably with 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, 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 may be administered in combination with a glycoprotein (GP) IIb-IIIa antagonist, such as, for example and preferably, with tirofiban or abciximab.

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, 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 finerenone.

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, trichlormethiazil, chlorthalidone, indapamide, metolazone, quinetazol, chlorthiazolamide, chlorthiazolamide, , glycerin, isosorbide, mannitol, amiloride or triamterene.

Substances affecting fat metabolism are preferably understood to mean compounds from the group of cholesterol ester transfer inhibitors, thyroid receptor antagonists, cholesterol synthesis inhibitors such as inhibitors of 3-hydroxy-3-methylglutarylcoenzyme A reductase or squalene synthase, inhibitors of acyl-KoA-cholesterol acyltransferase, inhibitors of microsomal triglyceride transfer protein, PPAR-α, PPAR-γ and/or PPAR-δ agonists, cholesterol uptake blockers,

- 20 040284 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).

The compounds of the invention may 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 statin class, such as, for example and preferably, 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-KoA cholesterol acyltransferase inhibitor, such as, for example and preferably, with avasimib, melinamide, pactimib, efflucimib or SMP-797.

The compounds of the invention may be administered in combination with a microsomal triglyceride transfer protein inhibitor such as, for example and preferably, implitapid, BMC-201038, R103757 or JTT-130.

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

The compounds of the invention may be administered in combination with a PPAR-δ 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, cholestyramine, colestyrol, colesolvam, cholestagel or colestimide.

The compounds according to the invention can be administered in combination with a bile acid reabsorption blocker, such as, for example and preferably, with ASBT (= IBAT) inhibitors, such as, for example, AZD7806, 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, gemcaben calcium (CI-1027) or nicotinic acid.

Particularly preferred are combinations of the compounds of the invention with one or more additional 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 are drug 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, by oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, vaginal, dermal, transdermal route, by instillation of drugs into the eyes, ear canal, or as implant or 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 (for example, hard or soft gelatin capsules), dragees, substance in granules, granules, powder, emulsions, suspensions, aerosols or solutions.

Parenteral administration may occur regardless of the stage of absorption (eg, intravenous, intraarterial, intracardiac, intravertebral, or intralumbar) or include the stage of absorption (eg, intramuscular, 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 fillers and excipients (e.g. cellulose, microcrystalline cellulose, such as Avicel®, lactose, mannitol, starch, calcium phosphates, such as Di-Cafos®), ointment bases (e.g. 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®, fatty polyoxyethylene sorbitan 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 (e.g. phosphates, carbonates, citric acid, acetic acid, hydrochloric acid, sodium hydroxide, ammonium carbonate, trometamol, triethanolamine), isotonizing agents (e.g. glucose, sodium chloride), adsorbents (e.g. , highly dispersed silica), viscosifiers, gelling agents, thickeners or binders (e.g. polyvinylpyrrolidone, me tilcellulose, hydroxypropylcellulose, hydroxypropyl methylcellulose, 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, lubricant, 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, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose phthalate, cellulose acetate , cellulose acetate phthalate, p oliacrylates, polymethacrylates, such as Eudragit®);

encapsulating materials (e.g. gelatins, hydroxypropyl methylcellulose), synthetic polymers (e.g. polylactides, polyglycolides, polyacrylates, polymethacrylates such as Eudragit®, polyvinylpyrrolidones such as Kollidon®, polyvinyl alcohol, polyvinyl acetate, polyethylene oxides, polyethylene glycols and their copolymers and block copolymers), emollients (e.g. polyethylene glycols, propylene glycol, glycol, triacetin, triacetyl citrate, dibutyl phthalate), penetration enhancers, stabilizers (e.g. antioxidants such as ascorbic acid, ascorbyl 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),

- 22 040284 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 of 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. If a larger amount is used, 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.

A. Examples.

Abbreviations and abbreviations.

[a] _D ²⁰ special angle of rotation (for polarometry) br. lat. (at NMR) ca. approximately d doublet (by NMR) dd doublet by doublet (by NMR)

DIPEA A/L%isopropylethylamine

DMF Ν,Ν-dimethylformamide

DMSO DMSO dimethyl sulfoxide

ΔΤ Heating, temperature increase (in the reaction scheme)

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

EI electron impact ionization (at MS)

ESI electrospray ionization (at MS)

Et ethyl h hour(s)

HATU O-(7-azabenzotriazol-1-yl)-7\/L/A",L-tetramethyluronium hexafluorophosphate (CASRN 148893-10-1)

HPLC HPLC high pressure liquid chromatography, high performance liquid chromatography:

iPr Isopropyl

LC liquid chromatography

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

- 23 040284

LDA lithium diisopropylamide

LiHMD S Lithium bis(trimethylsilyl)amide m multiplet (by NMR)

M molar

Me methyl min minute (minutes)

MS MS Mass Spectrometry

NMR NMR nuclear magnetic resonance spectroscopy 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

TosMIC para-toluenesulfonyl methyl isocyanide

UHPLC Ultra High Performance Liquid Chromatography

UV ultraviolet spectrometry

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, 2.1 x 75 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 contour 210-300 nm.

Method 2 (LC-MS).

Instrument: Waters ACQUITY SQD UPLC System; column: Waters Acquity UPLC HSS T3 1.8 µm 50 x 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 ^ 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 ACQUITY SQD UPLC System; column: Waters Acquity UPLC HSS T3 1.8 µm 50 x 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 95% A ^ 6.0 min 5% A ^ 7.5 min 5% A oven: 50°C; flow: 0.35 ml/min; UV detection: 210-400 nm.

Method 4 (LC-MS).

Instrument: Waters Single Quad MS System; Waters UPLC Acquity; column: Waters BEH C18 1.7 µm 50 x 2.1 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;

- 24 040284

UV detection: 210 nm (208-400 nm).

Method 5 (LC-MS).

Instrument: Waters Acquity UPLCMS SingleQuad; column: Acquity UPLC BEH C18 1.7 µm, 50x2.1 mm;

eluent A: water + 0.1 vol.% formic acid (99%), eluent B: acetonitrile; gradient: 0.0 min 1% B^

1.6 min 99% B ^ 2.0 min 99% B; flow 0.8 ml/min; temperature: 60°C; DAD scan: 210-400 nm.

Method 6 (LC-MS).

Instrument: Waters Acquity UPLCMS SingleQuad; column: Acquity UPLC BEH C18 1.7 µm, 50x2.1 mm; eluent A: water + 0.2 vol% aqueous ammonia (32%), eluent B: acetonitrile; gradient: 0.0 min 1% B ^ 1.6 min 99% B ^ 2.0 min 99% B; flow 0.8 ml/min; temperature: 60°C; DAD scan: 210-400 nm.

Method 7 (LC-MS).

Instrument: Agilent MS Quad 6150; HPLC: Agilent 1290; column: Waters Acquity UPLC HSS T3 1.8 µm 50 x 2.1 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 min 5% A oven: 50°C; flow: 1.20 ml/min; UV detection: 205 - 305 nm.

Method 8 (LC-MS).

MS device type: ThermoFisherScientific LTQ-Orbitrap-XL; HPLC device type: Agilent 1200SL; column: Agilent, POROSHELL 120, 3 x 150 mm, SB - C18 2.7 µm; eluent A: 1 l water + 0.1% trifluoroacetic acid; eluent B: 1 L acetonitrile + 0.1% trifluoroacetic acid; gradient: 0.0 min 2% B ^ 0.3 min 2% B ^ 5.0 min 95% B ^ 10.0 min 95% B; oven: 40°C; flow: 0.75 ml/min; UV detection: 210 nm.

Method 9 (LC-MS).

Detection: MSD ESI positive/negative; column: Waters XSelect CSH C18, 30 x 2.1 mm, 3.5 µm; eluent A: 0.1% formic acid in acetonitrile; eluent B: 0.1% formic acid in water; gradient: 0.0 min 5% A ^ 1.6 min 98% A ^ 3.0 min 98% A; oven: 35°C; flow: 1.0 ml/min; UV detection: 220-320 nm.

Method 10 (LC-MS).

Detection: MSD ES posit; column: Waters XSelect CSH C18, 30 x 2.1 mm, 3.5 µm; eluent A: 95% acetonitrile + 5% 10 mM ammonium hydrogen carbonate in water; eluent B: 10 mM ammonium bicarbonate in water; gradient: 0.0 min 5% A ^ 1.6 min 98% A ^ 3.0 min 98% A; oven: 25°C; flow: 1.0 ml/min; UV detection: 220 nm.

Method 11 (LC-MS).

Detection: MSD ESI positive/negative; column: Waters XSelect CSH C18, 50 x 2.1 mm, 3.5 µm; eluent A: 0.1% formic acid in acetonitrile; eluent B: 0.1% formic acid in water; gradient: 0.0 min 5% A ^ 3.5 min 98% A ^ 6.0 min 98% A; oven: 35°C; flow: 0.8 ml/min; UV detection: 270 nm.

Method 12 (GC-MS).

Instrument: Thermo Scientific DSQII, Thermo Scientific Trace GC Ultra; column: Restek RTX-35MS, 15 m x 200 µm x 0.33 µm; constant flow with helium: 1.20 ml/min; oven: 60°C; inlet: 220°C; gradient: 60°C, 30°C/min ^ 300°C (3.33 min exposure).

Method 13 (GC-MS).

Instrument: Agilent 6890N; detection: MSD EI pos; column: RXi-5MS 20 m, ID 180 µm; df 0.18 µm; detection temperature: 280°C; weight range 50-550; carrier gas: helium; average speed: 50 cm/s; start temperature: 100°C, start time: 1.5 min; solvent delay: 1.0 min; end temperature: 250°C, end time: 250°C; sample injection volume 1 µl; split ratio 100:1.

Method 14 (preparative HPLC).

Column: Chromatorex C18, 10 µm, 250 x 40 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 15 (preparative HPLC).

Column: Chromatorex C18, 10 µm, 125 x 30 mm; eluent A: water + 0.1% TFA, 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 16 (preparative HPLC).

Column: Chromatorex C18, 10 µm, 250 x 40 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 17 (preparative HPLC).

Column: Chromatorex C18, 10 µm, 125 x 30 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

- 25 040284 min 30% B ^ 20.51 min 30% B; flow: 75 ml/min. UV detection: 210 nm.

Method 18 (preparative HPLC).

Column: Chromatorex C18, 10 µm, 125 x 30 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 19 (preparative HPLC).

Column: Chromatorex C18, 10 µm, 250 x 40 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 20 (preparative HPLC).

Column: Chromatorex C18, 10 µm, 250 x 40 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 21 (preparative HPLC).

Column: Reprosil C18, 10 µm, 250 x 40 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 22 (preparative HPLC).

Column: Reprosil C18, 10 µm, 125 x 30 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 23 (preparative HPLC).

Chromatorex C18, 10 µm, 125 x 30 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 24 (preparative HPLC).

Column: Reprosil C18, 10 µm, 125 x 30 mm; eluent A: water + 0.1% TFA, 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 25 (preparative HPLC).

Appliance: Waters Acquity SQD UPLC System; column: Waters Acquity UPLC HSS T3 1.8 µm, 50 x 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 ^ 1.2 min 5% A ^ 2.0 min 5% A; oven: 50°C; flow: 0.40 ml/min; UV detection: 208-400 nm.

Method 26 (preparative HPLC).

Instrument: Waters Prep LC/MS System, column: Phenomenex Kinetex C18, 5 µm 100 x 30 mm; injection of a sample 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: 210 nm.

Method 27 (preparative HPLC).

Column: Chromatorex, C18, 10 µm, 125 mm x 30 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 28 (preparative HPLC).

Column: Reprosil C18 10 µm, 250 mm x 40 mm; eluent A: water + 0.1% formic acid, eluent B: acetonitrile + 0.1% formic acid; 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 29 (preparative HPLC).

Column: Chromatorex C18, 10 µm, 250 mm x 40 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 30 (preparative HPLC).

Column: Chromatorex C18, 10 µm, 125 mm x 30 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 31 (preparative HPLC).

- 26 040284

Column: Chromatorex C18 10 µm, 250 mm x 40 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 32 (preparative HPLC).

Column: Reprosil C18 10 µm, 250 mm x 40 mm; eluent A: water + 0.1% formic acid, eluent B: methanol + formic acid; gradient: 0.0 min 5% B ^ 5.0 min 5% B ^ 5.5 min 20% B ^ 10.4 min 40% B ^ 10.9 min 100% B ^ 18.9 min 100% B ^ 19.2 min 5% B ^ 22.4 min 5% B; flow: 75 ml/min, UV detection: 210 nm.

Other data.

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

When the compounds according to the invention are purified by preparative HPLC using the methods described above, in which the eluents contain additives such as, for example, 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 necessarily 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 ¹ H-NMR signal combination pattern descriptions are in part 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 a ¹ H-NMR peak list. 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), δ ₂ (intensity^, ..., δ; (intensity;), ..., δ _n (intensity _n ).

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 of the target compounds and/or impurity peaks are typically of lower intensity than those of the desired compounds (eg >90% pure). 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 method. 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 1H-NMR interpretation.

- 27 040284

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, August 1, 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 that describes their preparation.

parent compounds and intermediate compounds.

Example 1A. 6-Bromo-3-methyl-2-phenylquinoline-4-carbonyl chloride

A suspension of 6-bromo-3-methyl-2-phenylquinoline-4-carboxylic acid (10.0 g, 29.2 mmol, prepared according to WO 2016 146602 A1, page 51, example 3A) in dichloromethane (100 ml) was mixed with a few drops of DMF . Then oxalyl chloride (5.1 ml, 58 mmol) was slowly added dropwise. The mixture was stirred until gas production ceased and then concentrated and dried in vacuo. The resulting residue was used directly (without further processing) for subsequent chemical processes.

Example 2A. (6-Chloro-2,3-difluorophenyl)methanol

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. The mixture was then mixed with dichloromethane (100 ml), water (100 ml) and saturated 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 a saturated aqueous sodium chloride solution, 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.

GC-MS (Method 12): R _t = 3.23 min, MS (EIpos): m/z = 178 [M] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 7.45 (dd, 1H), 7.36 (ddd, 1H), 5.36 (t, 1H), 4.59 (dd, 3H).

Example 3A. [2-(Difluoromethoxy)-6-fluorophenyl]methanol

A solution of 2-(difluoromethoxy)-6-fluorobenzaldehyde (10.0 g, 52.6 mmol) in ethanol (100 ml) was mixed portionwise with sodium borohydride (995 mg, 26.3 mmol) under ice-cooling, the internal temperature rising to approx. 20°C. The mixture was then stirred for an additional 2 hours without cooling. The mixture was then mixed with dichloromethane (100 ml), water (150 ml) and saturated ammonium chloride solution (50 ml) and shaken. The mixture was acidified with concentrated acetic acid (approx. 1 ml). After phase separation, the aqueous phase was extracted once with dichloromethane (100 ml) and the combined organic phases were washed once with saturated aqueous sodium chloride, dried over sodium sulfate, filtered and concentrated, and the residue was dried quickly in vacuo. 9.90 g (99% pure, 97% theoretical) of the title compound was obtained.

GC-MS (Method 12): R _t = 3.04 min, MS (EIpos): m/z = 192 [M] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (0.53), 0.008 (0.55), 0.918 (0.70), 1.909 (1.97), 4.488 (14.37), 4.492 (15.14), 4.501 (15.42) ), 4.505 (15.39), 5.105 (7.08), 5.119 (14.11), 5.133 (6.48), 7.017 (8.05), 7.035 (6.81), 7.056 (7.70), 7.099 (4.02), 7.121 (8.26), 7.142 (4.75 ), 7.202 (16.00), 7.386 (11.15), 7.403 (4.54), 7.407 (7.33), 7.423 (7.21), 7.428 (3.89), 7.444 (3.19).

- 28 040284

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 7.50-6.97 (m, 4H), 5.12 (t, 1H), 4.50 (dd, 2H).

Example 4A. 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 2A) 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 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 quickly dried in vacuo. 3.88 g (94% pure by GC-MS, 51% th. y.) of the title compound were obtained.

GC-MS (Method 12): Rt = 3.57 min, MS (EIpos): m/z = 240 [M] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 7.55 (dd, 1H), 7.45 (ddd, 1H), 4.71 (d, 3H).

Example 5A. (+/-)-2-(3-chloropyridin-2-yl)propanenitrile (racemate)

CI-M M ^ ^s

To a solution of 2,3-dichloropyridine (4.00 g, 27.0 mmol) and propionitrile (2.68 g, 48.7 mmol) in THF (50 mL) in argon was added dropwise at RT a 1M solution of LiHMDS in THF/ethylbenzene (100 mL, 100 mmol) and the mixture was stirred 20 h at RT. The mixture was then mixed with water and extracted with ethyl acetate. The organic phase was dried, filtered and concentrated and the residue was first prepurified by flash column chromatography (100 g Biotage Snap-Cartridge KP-Sil, dichloromethane/methanol 95:5, Isolera One) and then further purified by preparative HPLC (Method 15 ). 2.23 g (80% pure, 40% th. y.) of the title compound was obtained.

LC-MS (Method 1): R _t = 1.29 min; MS (ESIpos): m/z = 167 [M+H] ⁺ .

From an analogous experiment, the following H-NMR of the title compound was obtained: 1H-NMR (400 MHz, DMSO-d6): δ [ppm] = 8.59 (dd, 1H), 8.03 (dd, 1H), 7.48 (dd, 1H), 4.73 (q, 1H), 1.59 (d, 3H).

Example 6A. (+/-)-2-(5-Fluoro-2-methoxyphenyl)propanenitrile (racemate)

To a solution of diisopropylamine (3.3 ml, 23 mmol) in THF (110 ml) at -78°C was added 1.6M solution of butyllithium in hexane (15 ml, 23 mmol) in drops, and the mixture was stirred for 45 min at -78°C. Then a solution of (5-fluoro-2-methoxyphenyl)acetonitrile (3.50 g, 21.2 mmol, CAS-RN 501008-41-9, commercially available) in THF (110 ml) was added dropwise at -78°C and the mixture was stirred for another hour at -78°C. Then a solution of iodomethane (1.4 ml, 22 mmol) in THF (15 ml) was slowly added and the mixture was stirred for an additional 10 min at -78°C. Then the cold bath was removed and the mixture was stirred for 1.5 h at RT. The mixture was mixed with saturated ammonium chloride solution and shaken. After the addition of ethyl acetate, the phases were separated and the aqueous phase was extracted twice with ethyl acetate. 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 (120 g Reveleris silica gel, flow 80 ml/min, heptane/ethyl acetate gradient 1:0 ^ 6:4, duration actions 38 minutes). 2.40 g (97% pure, 61% theoretical) of the title compound was obtained.

GC-MS (Method 13): Rt = 2.99 min; MS (ESIpos): m/z = 179 [M] ⁺ .

1H-NMR (400 MHz, CDCl ₃ ): δ [ppm] = 7.20-7.10 (m, 1H), 7.05-6.96 (m, 1H), 6.85-6.81 (m, 1H), 2.22 (q, 1H), 3.84 (s, 3H), 1.57 (d, 3H).

Example 7A. (+/-)-2-(3,5-Difluoro-2-methoxyphenyl)propanenitrile (racemate)

- 29 040284

To a solution of diisopropylamine (1.9 ml, 14 mmol) in THF (25 ml) was added dropwise at -78°C a 1.6 M solution of butyllithium in hexane (8.2 ml, 13 mmol) and the mixture was stirred for 30 min at -78°C. Then a solution of (3,5-difluoro-2-methoxyphenyl)acetonitrile (2.00 g, 10.9 mmol, CAS-RN 886761-64-4, commercially available) in THF (5.5 ml) was added dropwise at -78°C and the mixture was stirred additional 30 min at -78°C. Then slowly added a solution of iodomethane (710 μl, 11 mmol) in THF (25 ml) and the mixture was stirred for an additional 30 min at -78°C. The mixture was then mixed with saturated ammonium chloride solution and shaken. The cooling bath was removed and the mixture was brought to RT. By adding 1M hydrochloric acid, the pH of the aqueous phase was adjusted to approx. 3. After adding a saturated sodium chloride solution, the mixture was extracted three times with ethyl acetate and the combined organic phases were dried over sodium sulfate, filtered and concentrated. The residue was purified by flash column chromatography (40 g silica gel, solvent dichloromethane). The combined desired fractions were concentrated and the residue was dried in vacuo. 1.99 g (88% pure, 81% th. y.) of the title compound was obtained.

GC-MS (Method 13): Rt = 2.97 min; MS (ESIpos): m/z = 179 [M] ⁺ .

Example 8A. (+/-)-2-(4-Fluoro-2-methoxyphenyl)propanenitrile (racemate)

F

To a solution of 1-(4-fluoro-2-methoxyphenyl)ethanone (5.00 g, 29.7 mmol, CAS-RN 51788-80-8, commercially available) in 1,2-dimethoxyethane (30 mL) under nitrogen was added TosMIC ( 6.39 g, 32.7 mmol) and the mixture was cooled to -10°C. Then a solution of potassium tert-butoxide (6.67 g, 59.5 mmol) in tert-butanol (75 ml) was added slowly while maintaining the temperature below 5°C. After 2 h stirring at 0° C. and 1 h at RT, the resulting suspension was concentrated to a precipitate and mixed with water (60 ml). After extraction three times with diethyl ether (respectively 50 ml), the combined organic phases were dried over sodium sulfate, filtered and concentrated. The residue was purified by flash column chromatography (120 g silica gel, solvent dichloromethane, flow 40 ml/min). The combined desired fractions were concentrated and the residue was dried in vacuo. 3.77 g (99% pure, 70% theoretical) of the title compound were obtained.

GC-MS (Method 13): Rt = 2.97 min; MS (ESIpos): m/z = 179 [M] ⁺ .

Example 9A. (+/-)-2-(2-Fluoro-6-methoxyphenyl)propanenitrile (racemate)

To a solution of Ν,N-diisopropylethylamine (5.8 ml, 33 mmol) in THF (75 ml) in argon at -78°C was slowly added a mixture of a 2.5 M solution of butyllithium in hexane (13 ml, 33 mmol) and THF (50 ml ). The reaction mixture was brought to 0°C, stirred for 5 min at 0°C and re-cooled to -78°C. Then a solution of (2-fluoro-6-methoxyphenyl)acetonitrile (5.00 g, 30.3 mmol, CAS-RN 500912-18-5, commercially available) in THF (25 ml) was slowly added. The reaction mixture was again brought to 0°C, stirred for 5 min at 0°C and re-cooled to -78°C. Then a solution of iodomethane (2.0 ml, 31.79 mmol) in THF (25 ml) was slowly added. The mixture was stirred overnight while the temperature was slowly brought to RT. The mixture was then slowly mixed at 0° C. with saturated ammonium chloride solution and water (corresponding to 50 ml), shaken and extracted twice with ethyl acetate (corresponding to 150 ml). The combined organic phases were washed once with saturated aqueous sodium chloride (200 ml), dried over sodium sulfate, filtered and concentrated, and the residue was adsorbed in dichloromethane and purified by flash column chromatography (400 g of Buchi Snap-Cartridge KP-Sil, cyclohexane/ ethyl acetate 9:1). The combined target fractions were concentrated and the residue was (quickly) dried in vacuo. 3.33 g (100% pure, 61% th. y.) of the title compound was obtained.

GC-MS (Method 12): Rt = 4.31 min; MS (ESIpos): m/z = 179 [M] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.492 (15.85), 1.509 (16.00), 3.314 (9.13), 3.887 (0.90), 4.452 (0.69), 4.455 (0.70), 4.470 (2.12) , 4.473 (2.10), 4.488 (2.11), 4.491 (2.05), 4.505 (0.69), 4.508 (0.65), 6.861 (1.62), 6.863 (1.60), 6.884 (2.45), 6.907 (1.81), 6.909 (1.81) , 6.943 (3.36), 6.964 (3.72), 7.353 (1.56), 7.370 (1.87), 7.374 (2.99), 7.391 (3.02), 7.395 (1.60), 7.412 (1.36).

1H-NMR (400 MHz, DMSO-d6): δ [ppm] = 7.44-7.30 (m, 1H), 6.95 (d, 1H), 6.92-6.85 (m, 1H), 4.48 (qd, 1H), 3.88 (s, 3H), 1.50 (d, 3H).

Example 10A. (+/-)-2-(2-Chloro-5-fluorophenyl)propanenitrile (racemate)

- 30 040284

To a solution of Ν,N-diisopropylethylamine (2.8 ml, 16 mmol) in THF (40 ml) in argon at -78°C was slowly added dropwise with stirring a 2.5 M solution of butyllithium in hexane (6.5 ml, 16 mmol) diluted with THF ( 20 ml). The mixture was then brought to 0°C with stirring and after 5 min cooled further to -78°C. Then a solution of (2-chloro-5-fluorophenyl)acetonitrile (2.50 g, 14.7 mmol, CAS-RN 395675-23-7, commercially available) in THF (20 ml) was added slowly dropwise. The mixture was then brought to 0°C with stirring and after 5 min cooled further to -78°C. Then a solution of iodomethane (960 μl, 15 mmol) in THF (20 ml) was slowly added dropwise. 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 0° C. with a saturated ammonium chloride solution and water (respectively 50 ml) and shaken. After phase separation, the aqueous phase was extracted twice with ethyl acetate (corresponding to 150 ml). The combined organic phases were washed once with saturated aqueous sodium chloride (200 ml), dried over sodium sulfate, filtered and concentrated, and the residue was adsorbed in dichloromethane and purified by flash column chromatography (100 g of 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. 2.54 g (97% pure, 91% th. y.) of the title compound were obtained.

LC-MS (Method 1): Rt = 1.78 min; MS (ESIpos): m/z = 184 [M+H]+.

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 7.60 (dd, 1H), 7.48 (dd, 1H), 7.31 (td, 1H), 4.52 (q, 1H), 1.59 (d, 3H) .

Example 11A. (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 sodium hydrogen carbonate solution, dried over sodium sulfate, filtered and concentrated, and the residue was quickly dried in vacuo. 3.80 g (94% pure, 96% th. y.) of the title compound were obtained.

LC-MS (Method 1): Rt = 1.59 min; MS (ESIneg): m/z = 186 [MH] ^- .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 7.57 (td, 1H), 7.44 (td, 1H), 4.15 (d, 2H).

Example 12A. (2-Chloro-3-fluorophenyl)acetonitrile

F CI^J^

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 sodium hydrogen carbonate solution, dried over sodium sulfate, filtered and concentrated, and the residue was quickly dried in vacuo. 4.98 g (100% pure, 94% th. y.) of the title compound was obtained.

GC-MS (Method 12): Rt = 4.03 min, MS (Elpos): 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 13A. (6-Chloro-2,3-difluorophenyl)acetonitrile

GT d^y^F

Trimethylsilyl cyanide (2.5 ml, 18 mmol) and a 1M solution of

- 31 040284 tetrabutylammonium fluoride in THF (19 ml, 19 mmol) 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 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 Biotage SnapCartridge KP-Sil, 93:7^7:3 cyclohexane/ethyl acetate gradient, Isolera One). The combined desired fractions were concentrated and the residue was dried in vacuo. 2.24 g (71% pure according to GCMS, 96% theoretical yield) of the title compound were obtained.

GC-MS (Method 12): Rt = 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-d6) δ [ppm]: 7.58 (dd, 1H), 7.49 (ddd, 1H), 4.16 (d, 2H).

Example 14A. (2,3,5,6-Tetrafluorophenyl)acetonitrile

Provided potassium cyanide (1.34 g, 20.6 mmol) in acetonitrile (64 ml) and water (13 ml) at RT. 3-(Bromomethyl)-1,2,4,5-tetrafluorobenzene (5.00 g, 20.6 mmol) was added and the mixture was then stirred 5 h at 40° C., then further stirred overnight at RT. For processing, the reaction mixture was diluted with 150 ml of water, approx. 10 ml of 1M sodium hydroxide solution was adjusted to pH 13 and extracted twice with tert-butyl methyl ether. The combined organic phases are washed twice with saturated sodium chloride solution, dried over sodium sulfate, concentrated and on a rotary evaporator at 80 mbar vacuum and a maximum of 40°C. The residue was taken up in a small amount of dichloromethane and purified by flash chromatography (Isolera, 100 g Ultra Snap Saule, cyclohexane/ethyl acetate gradient). The combined target fractions were concentrated on a rotary evaporator at 80 mbar vacuum and a maximum of 40°C. 2.47 g (100% pure, 63% th. y.) of the title compound were obtained.

LC-MS (Method 2): R _t = 0.77 min; weak ionization.

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (2.92), 0.008 (1.75), 2.524 (1.31), 4.221 (16.00), 7.924 (0.58), 7.943 (1.16), 7.951 (1.18) ), 7.963 (0.79), 7.970 (2.15), 7.977 (0.73), 7.989 (1.16), 7.997 (1.11), 8.016 (0.53).

Example 15A. (+/-)-Ethyl-(2-chlorophenyl)(cyano)acetate (racemate)

To a solution of (2-chlorophenyl)acetonitrile (75.0 g, 495 mmol) in toluene (2.0 1) in argon was added sodium hydride (21.8 g, 544 mmol, 60% in mineral oil) and diethyl carbonate (60 ml, 490 mmol) and the mixture was stirred overnight at 80°C. After cooling to RT, the mixture was mixed with 1 L of 1M hydrochloric acid, stirred for 5 minutes, and extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered, concentrated and the residue was purified by flash column chromatography (silica gel, cyclohexane/ethyl acetate 10:1). The combined desired fractions were concentrated and the residue was dried in vacuo. 100 g (90% th. y.) of the title compound were obtained. An alternative preparation is described in Journal of the American Chemical Society 1965, 87 (5), 1115-1120.

Example 16A. (+/-)-tert-Butyl-2-(3-chloropyridin-2-yl)-2-cyanopropanoate (racemate)

To a solution of (+/-)-2-(3-chloropyridin-2-yl)propanenitrile (1.00 g, 6.00 mmol, example 5A) in THF (8.8 ml) in argon at -78°C was slowly added a 2M solution of LDA in THF (4.5 ml, 9.0 mmol) and the mixture was brought to 0°C and additionally cooled to -78°C after 15 min. Then) di-tert-butyl dicarbonate (1.96 ml, 9.00 mmol) was slowly added dropwise at -78°C, the cooling bath was removed and the reaction mixture was stirred at RT overnight. The mixture was then slowly mixed with water with stirring, shaken and extracted twice with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride, dried over sodium sulfate, filtered and concentrated and the residue was purified by preparative HPLC (Method 22).

- 32 040284 target fractions were concentrated and the residue was dried in vacuum. Received 921 mg (86% pure,

49% theor. out) specified in the connection header.

LC-MS (Method 1): Rt= 1.95 min.

Example 17A. (+/-)-tert-Butyl-2-cyano-2-(2,6-difluorophenyl) propanoate (racemate)

To a solution of (+/-)-2-(2,6-difluorophenyl)propanenitrile (5.00 g, 29.91 mmol, obtained according to Russian Journal of Organic Chemistry 2009, 45, 1531-1534) in THF (38 ml) in argon at -78°C was slowly added 2M solution of LDA in THF (24 ml, 49 mmol) and the mixture was brought to 0°C and after 15 min further cooled to -78°C. Di-tert-butyl dicarbonate (10.7 g, 49.0 mmol) was then slowly added dropwise at -78°C and the mixture was then stirred for 3 h at 0°C. The mixture was then slowly mixed with water with stirring, shaken and extracted twice with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride, dried over sodium sulfate, filtered and concentrated, and the residue was dried in vacuo. 6.80 g (79% pure, 66% theoretical yield) of the title compound were obtained.

LC-MS (Method 1): Rt = 2.08 min; MS (ESIpos): m/z = 268 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.116 (2.15), 1.132 (2.17), 1.385 (1.30), 1.403 (13.17), 1.437 (16.00), 1.468 (5.97), 1.945 (1.50) , 1.949 (2.52), 1.953 (1.48), 7.223 (0.50), 7.245 (0.67), 7.248 (0.58), 7.269 (0.62), 7.563 (0.41).

Example 18A (+/-)-tert-Butylcyano(3-methoxyphenyl)acetate (racemate)

To a solution of (3-methoxyphenyl)acetonitrile (3.00 g, 20.4 mmol) in THF (16 ml) in argon at -78°C was slowly added a 2M solution of LDA in THF (15 ml, 31 mmol) and the mixture was brought to 0° C and after 15 min additionally cooled to -78°C. Di-tert-butyl dicarbonate (6.67 g, 30.6 mmol) dissolved in THF (15 ml) was then slowly added dropwise at -78°C and the mixture was brought to RT and stirred overnight at RT. The mixture was then slowly mixed with water with stirring, shaken and extracted twice with ethyl acetate (60 ml and 45 ml). The combined organic phases were washed with saturated aqueous sodium chloride, dried over sodium sulfate, filtered and concentrated, and the residue was dried in vacuo. The residue was purified by flash column chromatography (100 g Biotage Snap-Cartridge KP-Sil, cyclohexane/ethyl acetate 100:0^9:1). The combined desired fractions were concentrated and the residue was dried in vacuo. 4.00 g (78% pure, 62% th. y.) of the title compound was obtained.

LC-MS (Method 2): Rt = 1.01 min; MS (ESIpos): m/z = 248 [M+H] ⁺ .

Example 19A. (+/-)-tert-Butyl-(3-chlorophenyl)(cyano)acetate (racemate)

To a solution of (3-chlorophenyl)acetonitrile (3.00 g, 19.8 mmol) in THF (16 ml) in argon at -78°C was slowly added a 2M solution of LDA in THF (15 ml, 30 mmol) and the mixture was brought to 0° C and after 15 min additionally cooled to -78°C. Di-tert-butyl dicarbonate (6.48 g, 29.7 mmol) dissolved in THF (15 ml) was then slowly added dropwise at -78°C and the mixture was brought to RT and stirred overnight at RT. The mixture was then slowly mixed with water with stirring, shaken and extracted twice with ethyl acetate (60 ml and 40 ml). The combined organic phases were washed with saturated aqueous sodium chloride, dried over sodium sulfate, filtered and concentrated, and the residue was dried in vacuo. The residue was purified by flash column chromatography (120 g Biotage Snap-Cartridge KP-Sil, cyclohexane/ethyl acetate 100:0^9:1). The combined desired fractions were concentrated and the residue was dried in vacuo. Yields 400 mg (55% pure, 4% th. y.) of the first batch of the title compound, 2.6 g (80% pure, 42% th. y., see Analysis) of the second batch of the title compound, and 2.5 g (70% pure, 35% th. y.) third batch of the title compound. Three batches were purified and used in the following reactions (see example 86A).

- 33 040284

LC-MS (Method 1): Rt = 2.07 min; MS (ESIneg): m/z = 250 [M-H]-.

Example 20A. (+/-)-tert-Butylcyano(3-methylphenyl)acetate (racemate)

To a solution of (3-methylphenyl)acetonitrile (3.00 g, 22.9 mmol) in THF (35 ml) in argon at -78°C was slowly added a 2M solution of LDA in THF (17 ml, 34 mmol) and the mixture was brought to 0° C and after 15 min additionally cooled to -78°C. Then di-tert-butyl dicarbonate (7.49 g, 34.3 mmol) was slowly added dropwise at -78°C and the mixture was stirred for 3 h at 0°C. The mixture was then slowly mixed with water (50 ml) with stirring, shaken and extracted twice with ethyl acetate (70 ml and 50 ml). The combined organic phases were washed with saturated aqueous sodium chloride, dried over sodium sulfate, filtered and concentrated, and the residue was dried in vacuo. The residue was purified by flash column chromatography (100 g Biotage Snap-Cartridge KP-Sil, cyclohexane/ethyl acetate 100:0^9:1). The combined desired fractions were concentrated and the residue was dried in vacuo. 3.20 g (82% pure, 50% th. y.) of the title compound was obtained.

LC-MS (Method 2): R _t = 1.07 min; MS (ESIneg): m/z = 230 [MH]-.

Example 21A. (+/-)-tert-Butyl-cyano(2-fluoro-6-methoxyphenyl)acetate (racemate)

To a solution of (2-fluoro-6-methoxyphenyl)acetonitrile (5.00 g, 30.3 mmol, CAS-RN 500912-18-5) in THF (25 ml) in argon at -65°C was slowly added a 2M solution of LDA in THF (23 ml, 45 mmol) and the mixture was brought to 0°C and after 15 min additionally cooled to -65°C. Then a solution of di-tert-butyl dicarbonate (10 ml, 45 mmol) in THF (11 ml) was slowly added dropwise, the internal temperature being kept below -40°C. The mixture was stirred overnight while the temperature was slowly brought to RT. The mixture was then slowly mixed with 1 M hydrochloric acid (45.4 ml, 45.4 mmol) under ice-cooling, and then with water (30 ml) and ethyl acetate (80 ml). After shaking and phase separation, the aqueous phase was extracted once with ethyl acetate (80 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 (500 g silica gel, cyclohexane/ethyl acetate 10:1). The combined desired fractions were concentrated and the residue was dried in vacuo. 10.4 g (62% pure, 80% th. y.) of the title compound were obtained.

LC-MS (Method 1): R _t = 1.89 min; MS (ESIpos): m/z = 266 [M+H] ⁺ .

Example 22A. (+/-)-tert-Butyl-2-cyano-2-(2-methoxyphenyl)propanoate (racemate)

To a solution of 2-(2-methoxyphenyl)propanenitrile (2.00 g, 12.4 mmol, CAS-RN 62115-71-3, commercially available) in THF (18 ml) in argon at THF (9.3 ml, 19 mmol) and the mixture was brought to 0°C and additionally cooled to -78°C after 15 min. Di-tert-butyl dicarbonate (4.06 g, 18.6 mmol) was then slowly added. The mixture was stirred overnight while the temperature was slowly brought to RT. The mixture was then slowly mixed with water with stirring and extracted twice with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride, dried over sodium sulfate, filtered and concentrated, and the residue was adsorbed in dichloromethane and previously purified by flash column chromatography (100 g silica gel, cyclohexane/ethyl acetate 85:15). The combined target fractions were concentrated and the residue was lyophilized in acetonitrile/water. The prepurified product was then further purified by preparative HPLC (column: XBridge C18, 5 µm, 100 mm x 30 mm; flow: 75 ml/min; detection: 210 nm; temperature: 40°C; sampling: 0.30 ml; eluent: 40% acetonitrile/55% water/5% (water + 1% ammonia) → 70% acetonitrile/25% water/5% (water + 1% ammonia; duration 5 min) The pooled target fractions were concentrated and the residue was lyophilized in acetonitrile /water to give 1.44 g (100% pure, 44% th. y.) of the title compound.

- 34 040284

LC-MS (Method 1): R _t = 1.97 min; MS (ESIpos): m/z = 262 [M+H]+.

Example 23A. (+/-)-tert-Butyl-2-(2-chloro-6-fluorophenyl)-2-cyanopropanoate (racemate)

2M a solution of LDA in THF (20 ml, 41 mmol) and the mixture was brought to 0°C and after 15 min additionally cooled to -78°C. Di-tert-butyl dicarbonate (9.4 ml, 41 mmol) was then slowly added. The mixture was stirred overnight while the temperature was slowly brought to RT. The mixture was then slowly mixed with water with stirring and extracted twice with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride, dried over sodium sulfate, filtered and concentrated, and the residue was purified twice by preparative HPLC (Method 14). The combined target fractions were concentrated and the residue was lyophilized in acetonitrile/water. 1.33 g (98% pure, 17% th. y.) of the title compound was obtained.

LC-MS (Method 3): Rt = 3.49 min; MS (ESIpos): m/z = 284 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 7.59-7.43 (m, 2H), 7.37 (ddd, 1H), 2.04 (d, 3H), 1.44 (s, 9H).

Example 24A. (+/-)-tert-Butyl-3-(2-chlorophenyl)-3-cyanopropanoate (racemate)

To a solution of (2-chlorophenyl)acetonitrile (5.00 g, 33.0 mmol) in THF (50 ml) under argon at -78°C was added a 2M solution of LDA in THF (25 ml, 49 mmol) slowly with stirring. The mixture was brought to 0°C and after 15 min further cooled to -78°C. Then, tert-butyl bromoacetate (5.8 ml, 40 mmol) was slowly added dropwise with stirring. The cooling bath was removed and the mixture was brought to RT with stirring overnight. The mixture was then slowly mixed with water and extracted twice with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride, dried over magnesium sulfate, filtered and concentrated and the residue was purified by preparative HPLC [column: Kinetix C18, 5 μm, 100 x 21.2 mm; flow: 30 ml/min; detection: 210 nm; sample injection volume: 0.4 ml; eluent: 50% water/45% acetonitrile/5% formic acid (1% in water) ^ 5% water/90% acetonitrile/5% formic acid (1% in water), duration: 6.0 min]. 6.98 g (purity 100%, 78% of theor. yield) of the title compound were obtained.

LC-MS (Method 1): Rt = 2.10 min; MS (ESIpos): m/z = 266 [M+H] ⁺ .

Example 25A. (+/-)-tert-Butyl-3-(3-chlorophenyl)-3-cyanopropanoate (racemate)

To a solution of (3-chlorophenyl)acetonitrile (1.00 g, 6.60 mmol) in THF (10 ml) in argon at -78°C was added a 2M solution of LDA in THF (4.9 ml, 9.9 mmol) slowly with stirring. The mixture was brought to 0°C and after 15 min further cooled to -78°C. Then, tert-butyl bromoacetate (1.5 ml, 9.9 mmol) was slowly added dropwise with stirring. The cooling bath was removed and the mixture was brought to RT with stirring overnight. The mixture was then slowly mixed with water and extracted twice with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride, dried over magnesium sulfate, filtered and concentrated. The crude product was combined with the crude product obtained from the analog preliminary test (amount of (3-chlorophenyl)acetonitrile used: 100 mg (0.66 mmol)) adsorbed in dichloromethane and purified by flash column chromatography (100 g Biotage Snap-Cartridge KP-silica gel). Sil, cyclohexane/ethyl acetate 97:3 and 8:2, Isolera One). 710 mg (95% purity, 35% thor.) of the title compound were obtained.

LC-MS (Method 1): R _t = 2.10 min; MS (ESIpos): m/z = 266 [M+H] ⁺ .

1H-NMR (500 MHz, DMSO-d6) δ [ppm]: 1.215 (0.55), 1.365 (16.00), 1.399 (0.56), 1.418 (1.40), 1.430 (0.66), 2.927 (0.56), 2.940 (0.56) , 3.024 (0.54), 3.040 (0.55), 4.538 (0.40), 7.430 (0.56), 7.434 (0.78), 7.440 (1.60), 7.451 (0.49), 7.556 (0.75).

Example 26A. (+/-)-tert-Butyl-3-cyano-3-(2-methylphenyl)propanoate (racemate)

- 35 040284

To a solution of (2-methylphenyl)acetonitrile (1.00 g, 7.62 mmol) in THF (11 mL) in argon at -78°C was added a 2M solution of LDA in THF (5.7 mL, 11 mmol) slowly with stirring. The mixture was brought to 0°C and after 15 min further cooled to -78°C. Then, tert-butyl bromoacetate (1.7 ml, 11 mmol) was slowly added dropwise with stirring. The cooling bath was removed and the mixture was brought to RT with stirring overnight. The mixture was then slowly mixed with water and extracted twice with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride, dried over magnesium sulfate, filtered and concentrated. The residue was adsorbed into dichloromethane and purified by flash column chromatography (100 g Biotage Snap-Cartridge KP-Sil, cyclohexane/ethyl acetate 97:3^8:2, Isolera One). Received 880 mg (purity 98%, 47% theoretical. out.) specified in the title compound.

LC-MS (Method 1): Rt = 2.10 min; MS (ESIpos): m/z = 246 [M+H]+.

1H-NMR (400 MHz, DMSO-d6): δ [ppm] = 7.47-7.39 (m, 1H), 7.29-7.20 (m, 3H), 4.50 (dd, 1H), 3.012.81 (m, 2H) , 2.36 (s, 3H), 1.37 (s, 9H).

Example 27A. (+/-)-tert-Butyl-3-cyano-3-(2,6-dichlorophenyl)propanoate (racemate)

To a solution of (2,6-dichlorophenyl)acetonitrile (1.00 g, 5.38 mmol) in THF (8 ml) in argon at -78°C was added a 2M solution of LDA in THF (4.0 ml, 8.1 mmol) slowly with stirring. The mixture was brought to 0°C and after 15 min further cooled to -78°C. Then, tert-butyl bromoacetate (1.2 ml, 8.1 mmol) was slowly added dropwise with stirring. The cooling bath was removed and the mixture was brought to RT with stirring overnight. The mixture was then slowly mixed with water and extracted twice with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride, dried over magnesium sulfate, filtered and concentrated. The residue was adsorbed into dichloromethane and purified by flash column chromatography (100 g Biotage silica gel

Snap-Cartridge KP-Sil, cyclohexane/ethyl acetate 97:3 ^ 8:2, Isolera One). 682 mg (98% pure, 41% thor.) of the title compound were obtained.

LC-MS (Method 1): R _t = 2.17 min; MS (ESIpos): m/z = 300 [M+H] ⁺ .

1H-NMR (500 MHz, DMSO-d6) δ [ppm]: 0.933 (1.68), 0.946 (1.79), 1.363 (16.00), 1.392 (2.64), 1.401 (1.37), 3.025 (0.58), 3.038 (0.57) , 3.181 (0.57), 3.198 (0.58), 3.315 (0.99), 7.461 (0.61), 7.463 (0.68), 7.478 (0.76), 7.582 (2.03), 7.598 (1.35).

Example 28A. (+/-)-tert-Butyl-3-cyano-3-(3-methoxyphenyl)propanoate (racemate)

To a solution of (3-methoxyphenyl)acetonitrile (1.00 g, 6.79 mmol) in THF (10 ml) in argon at -78°C was added a 2M solution of LDA in THF (5.1 ml, 10 mmol) slowly with stirring. The mixture was brought to 0°C and after 15 min further cooled to -78°C. Then, tert-butyl bromoacetate (1.5 ml, 10 mmol) was slowly added dropwise with stirring. The cooling bath was removed and the mixture was brought to RT with stirring overnight. The mixture was then slowly mixed with water and extracted twice with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride, dried over magnesium sulfate, filtered and concentrated. The residue was adsorbed into dichloromethane and purified by flash column chromatography (100 g Biotage Snap-Cartridge KP-Sil, cyclohexane/ethyl acetate 97:3^8:2, Isolera One). 389 mg (90% pure, 20% thor.) of the title compound were obtained.

LC-MS (Method 1): Rt = 1.96 min; MS (ESIpos): m/z = 262 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6): δ [ppm] = 7.36-7.27 (m, 1H), 7.05-6.98 (m, 2H), 6.94-6.87 (m, 1H), 4.43 (dd, 1H) , 3.76 (s, 3H), 3.00 (dd, 1H), 2.87 (dd, 1H), 1.38 (s, 9H).

Example 29A. (+/-)-tert-Butyl-3-(3-chloropyridin-2-yl)-3-cyanobutanoate (racemate)

- 36 040284

A 2M solution of from LDA to THF (5.4 ml, 11 mmol). The mixture was brought to 0°C and after 15 min further cooled to -78°C. Then, tert-butyl bromoacetate (1.3 ml, 8.6 mmol) was slowly added dropwise with stirring. The cooling bath was removed and the mixture was brought to RT with stirring overnight. The mixture was then slowly mixed with water and extracted twice with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride, dried over magnesium sulfate, filtered and concentrated. The residue was purified by preparative HPLC (Method 22). 1.08 g (100% pure, 53% th. y.) of the title compound was obtained.

LC-MS (Method 1): Rt = 1.93 min; MS (ESIpos): m/z = 225 [M-tBu+H] ⁺ .

Example 30A. (+/-)-tert-Butyl-3-(2-chloro-6-fluorophenyl)-3-cyanopropanoate (racemate) o CH ₃

CH ₃

To a solution of (2-chloro-6-fluorophenyl)acetonitrile (1.00 g, 5.90 mmol) in THF (8.7 mL) in argon at 78°C was slowly added a 2M solution of LDA in THF (4.4 mL, 8.8 mmol) with stirring. The mixture was brought to 0°C and after 15 min further cooled to -78°C. Then, tert-butyl bromoacetate (1.3 ml, 8.8 mmol) was slowly added dropwise with stirring. The cooling bath was removed and the mixture was brought to RT with stirring overnight. The mixture was then slowly mixed with water and extracted twice with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride, dried over magnesium sulfate, filtered and concentrated. The residue was adsorbed into dichloromethane and purified by flash column chromatography (100 g Biotage Snap-Cartridge KP-Sil, cyclohexane/ethyl acetate 97:3^8:2, Isolera One). Received 878 mg (98% pure, 51% theoretical. out.) specified in the title compound.

LC-MS (Method 1): Rt = 2.07 min; MS (ESIpos): m/z = 284 [M+H] ⁺ .

1H-NMR (500 MHz, DMSO-d ₆ ): δ [ppm] = 7.54-7.47 (m, 1H), 7.47-7.42 (m, 1H), 7.37 (ddd, 1H), 4.884.82 (m, 1H ), 3.14-3.07 (m, 1H), 3.02-2.93 (m, 1H), 1.34 (s, 9H).

Example 31A. (+/-)-tert-Butyl-3-cyano-3-(4-methylphenyl)propanoate (racemate)

To a solution of (4-methylphenyl)acetonitrile (1.00 g, 7.62 mmol) in THF (11 mL) in argon at -78°C was added a 2M solution of LDA in THF (5.7 mL, 11 mmol) slowly with stirring. The mixture was brought to 0°C and after 15 min further cooled to -78°C. Then, tert-butyl bromoacetate (1.7 ml, 11 mmol) was slowly added dropwise with stirring. The cooling bath was removed and the mixture was brought to RT with stirring overnight. The mixture was then slowly mixed with water and extracted twice with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride, dried over magnesium sulfate, filtered and concentrated. The residue was adsorbed into dichloromethane and purified by flash column chromatography (100 g Biotage Snap-Cartridge KP-Sil, cyclohexane/ethyl acetate 97:3^8:2, Isolera One). 288 mg (90% pure, 14% thor.) of the title compound were obtained.

LC-MS (Method 1): Rt = 2.09 min; MS (ESIpos): m/z = 246 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6): δ [ppm] = 7.32 (d, 2H), 7.21 (d, 2H), 4.40 (dd, 1H), 2.95 (dd, 1H), 2.83 (dd, 1H ), 2.29 (s, 3H), 1.37 (s, 9H).

Example 32A. (+/-)-tert-Butyl-3-cyano-3-(3-methylphenyl)propanoate (racemate)

L D about CH.

sn ₃

To a solution of (3-methylphenyl)acetonitrile (1.00 g, 7.62 mmol) in THF (11 ml) in argon at -78°C was added a 2M solution of LDA in THF (5.7 ml, 11 mmol) slowly with stirring. The mixture was brought to

- 37 040284

0°C and after 15 min additionally cooled to -78°C. Then, tert-butyl bromoacetate (1.7 ml, 11 mmol) was slowly added dropwise with stirring. The cooling bath was removed and the mixture was brought to RT with stirring overnight. The mixture was then slowly mixed with water and extracted twice with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride, dried over magnesium sulfate, filtered and concentrated. The residue was adsorbed into dichloromethane and purified by flash column chromatography (100 g Biotage Snap-Cartridge KP-Sil, cyclohexane/ethyl acetate 97:3^8:2, Isolera One). 174 mg (90% pure, 8% thor.) of the title compound were obtained.

LC-MS (Method 1): Rt = 2.09 min; MS (ESIpos): m/z = 246 [M+H]+.

1H-NMR (400 MHz, DMSO-d6): δ [ppm] = 7.34-7.08 (m, 4H), 4.41 (dd, 1H), 2.96 (dd, 1H), 2.85 (dd, 1H), 2.31 (s , 3H), 1.37 (s, 9H).

Example 33A. (+/-)-tert-Butyl-3-cyano-3-(2-methoxyphenyl)propanoate (racemate)

To a solution of (2-methoxyphenyl)acetonitrile (5.00 g, 34.0 mmol) in THF (50 ml) in argon at -78°C was added a 2M solution of LDA in THF (25 ml, 51 mmol) slowly with stirring. The mixture was brought to 0°C and after 15 min further cooled to -78°C. Then, tert-butyl bromoacetate (7.5 ml, 51 mmol) was slowly added dropwise with stirring. The cooling bath was removed and the mixture was brought to RT with stirring overnight. The mixture was then slowly mixed with water and extracted twice with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride, dried over magnesium sulfate, filtered and concentrated. The residue was dissolved in a mixture of acetonitrile and methanol (64 ml) and purified by preparative HPLC [column: Kinetix C18, 5 μm, 150 x 21.2 mm; flow: 30 ml/min; detection: 210 nm; sample injection volume: 0.5 ml; eluent: 65% water/30% acetonitrile/5% formic acid (1% in water) ^ 15% water/80% acetonitrile/5% formic acid (1% in water), duration: 6.0 min]. 4.90 g (96% pure, 53% th. y.) of the title compound were obtained.

LC-MS (Method 1): R _t = 2.00 min; MS (ESIpos): m/z = 262 [M+H] ⁺ .

Example 34A. (+/-)-tert-Butyl-3-cyano-3-[2-(trifluoromethoxy)phenyl]propanoate (racemate)

To a solution of [2-(trifluoromethoxy)phenyl]acetonitrile (5.00 g, 24.9 mmol) in THF (37 ml) in argon at -78°C was added a 2M solution of LDA in THF (19 ml, 37 mmol) slowly with stirring. The mixture was brought to 0°C and after 15 min further cooled to -78°C. Then, tert-butyl bromoacetate (5.5 ml, 37 mmol) was slowly added dropwise with stirring. The cooling bath was removed and the mixture was brought to RT with stirring overnight. The mixture was then slowly mixed with water and extracted twice with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride, dried over magnesium sulfate, filtered and concentrated. The residue was purified by flash column chromatography (150 g silica gel, cyclohexane ^ cyclohexane/ethyl acetate 95:5). 6.70 g (65% pure, 56% th. y.) of the title compound were obtained.

LC-MS (Method 1): Rt = 2.19 min; MS (ESIpos): m/z = 316 [M+H] ⁺ .

Example 35A. (+/-)-tert-Butyl-3-cyano-3-(pyridin-2-yl)propanoate (racemate)

To a solution of pyridin-2-ylacetonitrile (5.00 g, 42.3 mmol) in THF (62 ml) in argon at -78°C was added a 2M solution of LDA in THF (32 ml, 63 mmol) slowly with stirring. The mixture was brought to 0°C and after 15 min further cooled to -78°C. Then, tert-butyl bromoacetate (9.4 ml, 63 mmol) was slowly added dropwise with stirring. The cooling bath was removed and the mixture was brought to RT with stirring overnight. The mixture was then slowly mixed with water and extracted twice with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride, dried over magnesium sulfate, filtered and concentrated. The residue was purified by preparative HPLC [column: Kinetix C18, 5 µm, 150 x 21.2 mm; flow: 30 ml/min; detection: 210 nm; sample injection volume: 0.75 ml; eluent: 65% water/30% acetonitrile/5% formic acid (1% in water) ^ 15% water/80% acetonitrile/5% formic acid (1% in water), duration

- 38 040284 steps: 6.0 min]. 1.94 g (98% pure, 19% th. y.) of the title compound was obtained.

LC-MS (Method 1): R _t = 1.59 min; MS (ESIpos): m/z = 231 [MH] ^- .

Example 36A. (+/-)-tert-Butyl-3-cyano-3-[2-(trifluoromethyl)phenyl]propanoate (racemate)

To a solution of [(trifluoromethyl)phenyl]acetonitrile (2.50 g, 13.5 mmol) in THF (22 ml) in argon at -78 was added slowly with stirring a 2M solution of LDA in THF (10 ml, 20 mmol). The mixture was brought to 0°C and after 15 min further cooled to -78°C. Then, tert-butyl bromoacetate (3.0 ml, 20 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 mixed at 0° C. with water and ethyl acetate (respectively 50 ml), shaken and brought to RT. 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 (100 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 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. 2.7 g (98% pure, 66% theoretical) of the title compound were obtained.

LC-MS (Method 2): Rt = 1.14 min; MS (ESIpos): m/z = 300 [M+H]+.

Example 37A. (+/-)-tert-Butyl-3-cyano-3-(3-methoxypyridin-2-yl)propanoate (racemate)

2M solution from LDA in THF (10 ml, 20 mmol). The mixture was brought to 0°C and after 15 min further cooled to -78°C. Then, tert-butyl bromoacetate (3.0 ml, 20 mmol) was slowly added dropwise with stirring. The cooling bath was removed and the mixture was brought to RT with stirring overnight. The mixture was then slowly mixed with water and extracted twice with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride, dried over magnesium sulfate, filtered and concentrated. The residue was purified by preparative HPLC [column: Chromatorex C18, 10 μm, 290 x 100 mm; flow: 250 ml/min; detection: 210 nm; sample injection volume: 18 ml; eluent: 70% water/30% acetonitrile ^ 10% water/90% acetonitrile; duration of action: 40 min]. 2.32 g (99% pure, 65% th. y.) of the title compound were obtained.

LC-MS (Method 1): R _t = 1.69 min; MS (ESIneg): m/z = 261 [MH] ^- .

Example 38A. (+/-)-tert-Butyl-3-(2-chlorophenyl)-3-cyanobutanoate (racemate)

To a solution of (+/-)-2-(2-chlorophenyl)propanenitrile (5.00 g, 30.2 mmol, obtained according to ChemCatChem 2014, 6 (8), 2425-2431) in THF (42 ml) in argon at -78° A 2M solution of LDA in THF (23 mL, 45 mmol) was added slowly with stirring. The mixture was brought to 0°C and after 15 min further cooled to -78°C. Then, tert-butyl bromoacetate (5.3 ml, 36 mmol) was slowly added dropwise with stirring. The cooling bath was removed and the mixture was brought to RT with stirring overnight. The mixture was then slowly mixed with water and extracted twice with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride, dried over magnesium sulfate, filtered and concentrated. The residue was adsorbed into dichloromethane and purified by flash column chromatography (100 g Biotage Snap-Cartridge KP-Sil, cyclohexane/ethyl acetate 8:2). 6.30 g (97% pure, 72% th. y.) of the title compound was obtained.

LC-MS (Method 1): R _t = 2.11 min; MS (ESIpos): m/z = 280 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 1.256 (16.00), 1.390 (0.79), 1.397 (4.13), 1.889 (4.42), 3.116 (0.68), 3.155 (1.02), 3.297 (1.02 ), 3.313 (0.96), 3.336 (0.68), 7.406 (0.44), 7.410 (0.66), 7.420 (0.95), 7.429 (0.88), 7.434 (0.57), 7.525 (0.55), 7.564 (0.55).

Example 39A. (+/-)-tert-Butyl-3-(2-chloro-6-fluorophenyl)-3-cyanobutanoate (racemate)

- 39 040284

To a solution of (+/-)-2-(2-chloro-6-fluorophenyl)propanenitrile (5.00 g, 27.2 mmol) obtained from (2chloro-6-fluorophenyl)acetonitrile by methylation with tetrabutylammonium iodide and potassium carbonate in toluene, at 80°C (similar to ChemCatChem 2014, 6 (8), 2425-2431) in THF (38 ml) in argon at -78°C, a 2M solution of LDA in THF (20 ml, 41 mmol) was added slowly with stirring . The mixture was brought to 0°C and after 15 min further cooled to -78°C. Then, tert-butyl bromoacetate (4.8 ml, 33 mmol) was slowly added dropwise with stirring. The cooling bath was removed and the mixture was brought to RT with stirring overnight. The mixture was then slowly mixed with water and extracted twice with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride, dried over magnesium sulfate, filtered and concentrated. The residue was adsorbed into dichloromethane and purified by flash column chromatography (100 g Biotage Snap-Cartridge KP-Sil, cyclohexane/ethyl acetate 8:2). 5.26 g (98% pure, 64% th. y.) of the title compound were obtained.

LC-MS (Method 2): Rt = 1.12 min; MS (ESIpos): m/z = 298 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.298 (16.00), 1.862 (2.46), 1.868 (2.44), 3.246 (0.50), 3.259 (0.51), 3.311 (0.83), 3.406 (0.53) , 3.415 (0.52), 7.412 (1.35), 7.419 (0.70), 7.422 (0.55), 7.429 (0.41).

Example 40A. (+/-)-tert-Butyl-3-cyano-3-(2-methoxyphenyl)butanoate (racemate)

To a solution of 2-(2-methoxyphenyl)propanenitrile (8.00 g, 49.6 mmol, obtained according to Organic Letters 2008, 10 (20), 4573-4576) in THF (73 ml) in argon at -78°C was added slowly with stirring 2M solution from LDA in THF (37 ml, 74 mmol). The mixture was brought to 0° C. and after 15 minutes further cooled to -78° C., then tert-butyl bromoacetate (11 ml, 74 mmol) was added dropwise slowly with stirring. The cooling bath was removed and the mixture was brought to RT with stirring overnight. The mixture was then slowly mixed with water and extracted twice with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride, dried over magnesium sulfate, filtered and concentrated. The residue was purified by preparative HPLC [column: Chromatorex C18, 10 μm, 370 x 100 mm; flow: 250 ml/min; detection: 210 nm; temperature: 22°C; sample injection volume: 18 ml; eluent: 30% water/70% acetonitrile ^ 10% water/90% acetonitrile; duration of action: 31 min]. 7.93 g (95% pure, 55% theoretical) of the title compound were obtained.

LC-MS (Method 1): R _t = 2.05 min; MS (ESIpos): m/z = 276 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.215 (16.00), 1.782 (4.55), 2.949 (0.80), 2.987 (1.16), 3.131 (1.14), 3.169 (0.78), 3.312 (0.57) , 6.989 (0.56), 6.992 (0.59), 7.098 (0.52), 7.117 (0.61), 7.360 (0.49), 7.370 (0.67), 7.375 (0.63), 7.390 (0.59), 7.394 (0.43).

1H-NMR (400 MHz, DMSO-d6): δ [ppm] = 7.41-7.31 (m, 2H), 7.11 (d, 1H), 6.99 (td, 1H), 3.86 (s, 3H), 3.15 (d , 1H), 2.97 (d, 1H), 1.78 (s, 3H), 1.21 (s, 9H).

Example 41A. (+/-)-tert-Butyl-3-cyano-3-(5-fluoro-2-methoxyphenyl)propanoate (racemate)

To a solution of lithium bis(trimethylsilyl)amide (6.36 ml, 1M, 6.36 mmol) in THF (22 ml) under nitrogen at -78°C was added dropwise a solution of (5-fluoro-2-methoxyphenyl)acetonitrile (1.00 g, 6.05 mmol) in THF (22 ml). After 45 min stirring at -78°C, the reaction mixture was mixed with a solution of tert-butyl bromoacetate (1.18 g, 6.05 mmol) in THF (22 ml) and stirred for another hour at -78°C and then 2 h at RT. The mixture was then mixed with ethyl acetate and water, shaken and the phases were separated. The aqueous phase was extracted twice with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride, dried over sodium sulfate, filtered and concentrated, and the residue was previously purified by flash column chromatography (40 g Reveleris silica gel, heptane/ethyl acetate gradient). The prepurified product was then further purified by flash column chromatography (40 g Reversed Phase C18 Reveleris, stream 40

- 40 040284 ml/min, (water + 0.1% formic acid)/(acetonitrile + 0.1% formic acid) gradient). 941 mg (98% purity, 55% thor.) of the title compound were obtained.

LC-MS (Method 10): R _t = 2.28 min; MS (ESpos): m/z = 297 [M] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 7.15 (d, 1H), 7.02 (dd, 1H), 6.84 (dd, 1H), 4.47 (dd, 1H), 3.86 (s, 3H), 2.90-2.70 (m, 2H), 1.45 (s, 9H).

Example 42A. (+/-)-tert-Butyl-3-cyano-3-(2-fluoro-6-methoxyphenyl)propanoate (racemate)

A 2M solution of LDA in THF (23 ml, 45 mmol). The mixture was brought to 0°C and after 15 min further cooled to -78°C. Then, tert-butyl bromoacetate (6.7 ml, 45 mmol) was added dropwise slowly with stirring at -78 to -60°C. The cooling bath was removed and the mixture was slowly brought to RT with stirring. After 4 hours the mixture was mixed at 0° C. with water and ethyl acetate (respectively 50 ml), shaken and the phases were separated. The aqueous phase was extracted once with ethyl acetate (50 ml). The combined organic phases were washed once with saturated aqueous sodium chloride solution (100 ml), dried over sodium sulfate, filtered and concentrated, and the residue was dried in vacuo. 11.4 g (93% pure, >100% th. yield, containing additional impurities) of the title compound were obtained.

LC-MS (Method 1): R _t = 2.00 min; MS (ESIpos): m/z = 280 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.334 (16.00), 1.397 (0.78), 1.425 (3.42), 2.844 (0.47), 2.862 (0.47), 2.999 (0.42), 3.020 (0.42) , 3.309 (3.17), 4.017 (0.76), 4.635 (0.44), 6.894 (0.43), 6.958 (0.53), 6.980 (0.58), 7.402 (0.46), 7.419 (0.45).

1H-NMR (400 MHz, DMSO-d6): δ [ppm] = 7.41 (dd, 1H), 6.97 (d, 1H), 6.89 (t, 1H), 4.63 (dd, 1H), 3.89 (s, 3H ), 3.03 (dd, 1H), 2.83 (dd, 1H), 1.33 (s, 9H).

Example 43A. (+/-)-tert-Butyl-3-cyano-3-(2-ethoxyphenyl)propanoate (racemate)

To a solution of diisopropylamine (2.9 ml, 20 mmol) in THF (110 ml) at -78°C was added a solution of 1.6 M butyllithium in hexane (13 ml, 20 mmol) in drops, and the mixture was stirred for 45 min at -78°C. A solution of (2-ethoxyphenyl)acetonitrile (3.00 g, 18.6 mmol) in THF (110 mL) was then added dropwise. After one hour of stirring at -78°C, the mixture was mixed with a solution of tert-butyl bromoacetate (2.8 ml, 20 mmol) in THF (15 ml) and stirred for an additional 45 min at -78°C. The cold bath was then removed and the mixture was stirred for an additional 2 hours at RT. After re-cooling to -78° C., the mixture was mixed with saturated ammonium chloride solution, brought to RT and mixed with ethyl acetate and shaken. After phase separation, the aqueous phase was extracted twice with ethyl acetate. 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 (40 g Reversed Phase C18 Reveleris, flow 100 ml/min, (water + 0.1% formic acid) / (Acetonitrile + 0.1% formic acid)-gradient). The combined desired fractions were concentrated and the residue was dried in vacuo. 1.96 g (99% pure, 38% th. y.) of the title compound was obtained.

LC-MS (Method 10): R _t = 2.22 min; MS (ESpos): m/z = 293 [M+18] ⁺ .

1H-NMR (400 MHz, CDCl ₃ ): δ [ppm] = 7.39 (d, 1H), 7.38-7.25 (m, partially hidden, 1H), 7.00-6.90 (m, 1H), 6.88 (d, 1H) , 4.50 (dd, 1H), 4.10 (dd, 2H), 2.90–2.70 (m, 2H), 1.50–1.43 (m, 12H).

Example 44A. (+/-)-tert-Butyl-3-cyano-3-(5-fluoro-2-methoxyphenyl)butanoate (racemate)

To a solution of diisopropylamine (2.3 ml, 16 mmol) in THF (80 ml) under nitrogen at -78°C was added a solution of 1.6 M butyllithium in hexane (10 ml, 16 mmol) in drops, and the mixture was stirred for 45 min at -78°C . A solution of (+/-)-2-(5-fluoro-2-methoxyphenyl)propanenitrile (2.40 g, 13.4 mmol, example 6A) in THF (80 ml) was then added dropwise. After 50 min stirring at -78°C, the mixture was mixed with a solution of tert-butyl bromoacetate (2.3 ml, 16 mmol) in THF (10 ml) and stirred an additional 30 min at 78°C. The cold bath was then removed and the mixture was stirred for an additional 2 hours at RT. mix mix

- 41 040284 with saturated ammonium chloride solution and shaken. After the addition of ethyl acetate, the phases were separated and the aqueous phase was extracted twice with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride, dried over sodium sulfate, filtered and concentrated, and the residue was previously purified by flash column chromatography (120 g Reveleris silica gel, flow 80 ml/min, heptane/dichloromethane gradient 1:0^0: 1, duration of action 38 min). Two pre-purified product fractions were obtained, which were further purified by flash column chromatography (40 g resp. 80 g Reveleris silica gel, flow 40 ml/min resp. 55 ml/min, heptane/ethyl acetate gradient 1:0^7: resp. 31:0 ^ 6:4, duration of action 32 min resp. 25 min). Received 486 mg (97% pure, 12% th. y., see section Analytics) of the first batch and 890 mg (96% pure, 22% th. y.) of the second batch of the title compound.

LC-MS (Method 10): Rt = 2.27 min; MS (ESpos): m/z = 294 [M+1] + GC-MS (Method 13): Rt = 3.84 min; MS (ESIpos): m/z = 293 [M] ⁺

1H-NMR (400 MHz, CDCl3): δ [ppm] = 7.24 (d, 1H), 7.05-6.93 (m 1H), 7.90-7.81 (m, 1H), 3.89 (s, 3H), 3.18 (d, 1H), 2.96 (d, 1H), 1.86 (s, 3H), 1.31 (s, 9H).

Example 45A. (+/-)-tert-Butyl-3-cyano-3-(3,5-difluoro-2-methoxyphenyl)butanoate (racemate)

To a solution of diisopropylamine (1.8 ml, 13 mmol) in THF (25 ml) under nitrogen at -78°C was added a solution of 1.6 M butyllithium in hexane (7.6 ml, 12 mmol) in drops, and the mixture was stirred for 30 min at -78°C . A solution of (+/-)-2-(3,5-difluoro-2-methoxyphenyl)propanenitrile (1.99 g, 10.1 mmol, example 7A) in THF (10 mL) was then added dropwise. After 30 min stirring at -78°C, the mixture was mixed with a solution of tert-butyl bromoacetate (2.56 g, 13.1 mmol) in THF (25 ml) and stirred an additional 30 min at -78°C. The mixture was then mixed with saturated ammonium chloride solution, shaken and brought to RT. By adding 1M hydrochloric acid, the pH of the aqueous phase was adjusted to approx. 3. After adding a saturated sodium chloride solution, the mixture was extracted three times with ethyl acetate and the combined organic phases were dried over sodium sulfate, filtered and concentrated. The residue was purified by flash column chromatography (120 g Reveleris silica gel, flow 40 ml/min, solvent dichloromethane). The combined desired fractions were concentrated and the residue was dried in vacuo. 1.54 g (99% pure, 49% tho.) of the title compound was obtained.

LC-MS (Method 9): Rt = 2.26 min; MS (ESpos): m/z = 312 [M+1] ⁺ GC-MS (Method 13): Rt = 3.64 min; MS (ESIpos): m/z = 311 [M] ⁺ .

Example 46A. (+/-)-tert-Butyl-3-cyano-3-(4-fluoro-2-methoxyphenyl)butanoate (racemate)

F

To a solution of diisopropylamine (3.7 ml, 27 mmol) in THF (50 ml) under nitrogen at -78°C was added a solution of 1.6 M butyllithium in hexane (16 ml, 25 mmol) in drops, and the mixture was stirred for 30 min at -78°C . A solution of (+/-)-2-(4-fluoro-2-methoxyphenyl)propanenitrile (3.77 g, 21.0 mmol, example 8A) in THF (20 ml) was then added dropwise. After 30 min stirring at -78°C, the mixture was mixed with a solution of tert-butyl bromoacetate (5.33 g, 27.3 mmol) in THF (50 ml) and stirred an additional 30 min at 78°C. The mixture was then mixed with water, shaken and brought to RT. By adding 1M hydrochloric acid, the pH of the aqueous phase was adjusted to approx. 3. After adding a saturated sodium chloride solution, the mixture was extracted three times with ethyl acetate and the combined organic phases were dried over sodium sulfate, filtered and concentrated. The residue was purified by flash column chromatography (220 g silica gel, solvent dichloromethane, flow 80 ml/min). The combined desired fractions were concentrated and the residue was dried in vacuo. 3.02 g (99% pure, 49% th. y.) of the title compound was obtained.

GC-MS (Method 13): Rt = 3.81 min; MS (ESIpos): m/z = 293 [M] ⁺ .

1H-NMR (400 MHz, CDCl3): δ [ppm] = 7.50-7.40 (m, 1H), 6.70-6.65 (m, 2H), 3.89 (s, 3H), 3.14 (d, 1H), 2.95 (d , 1H), 1.86 (s, 3H), 1.30 (s, 9H).

Example 47A. (+/-)-tert-Butyl-3-cyano-3-(2-fluoro-6-methoxyphenyl)butanoate (racemate)

- 42 040284

To a solution of (+/-)-2-(2-fluoro-6-methoxyphenyl)propanenitrile (578 mg, 3.22 mmol, example 9A) in THF (6.0 ml) in argon at -78 was added slowly with stirring a 2M solution of LDA in THF (2.4 ml, 4.8 mmol). The mixture was brought to 0°C and after 15 min further cooled to -78°C. Then, tert-butyl bromoacetate (943 mg, 4.84 mmol) was slowly added dropwise with stirring at -78°C. After 3 hours of stirring at -78°C, the mixture was mixed with water and ethyl acetate (respectively 50 ml), shaken and brought to RT. 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 (100 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 SnapCartridge KP-Sil, cyclohexane/ethyl acetate gradient 93:7 x 7:3, Isolera One). The combined desired fractions were concentrated and the residue was dried in vacuo. 809 mg (80% pure, 68% thor.) of the title compound were obtained.

LC-MS (Method 1): R _t = 2.01 min; MS (ESIpos): m/z = 294 [M+H] ⁺ .

¹ H-NMR (400 MHz, DMSO-d ₈ ): δ [ppm] = 7.39-7.30 (m, 1H), 6.98-6.93 (m, 1H), 6.85-6.74 (m, 1H), 3.85 (s, 3H), 3.27 (dd, 1H), 3.05 (dd, 1H), 1.76 (d, 3H), 1.27 (s, 9H).

Example 48A. tert-Butyl-3-(2-chlorophenyl)-4-nitropentanoate (mixture of diastereoisomers)

To a solution of tert-butyl-(2E)-3-(2-chlorophenyl)acrylate (1.00 g, 4.19 mmol, obtained according to Beilstein Journal of Organic Chemistry 2012, 8, 1747-1752) in nitroethane (8.0 ml, 92 mmol) added 2tert-butyl-1,1,3,3-tetramethylguanidine (210 μl, 1.0 mmol) and the mixture was stirred over night under reflux. After cooling to RT, the mixture was filtered and purified by preparative HPLC (Method 16). 1.10 g (purity approx. 90% according to 1H-NMR, 75% theoretical yield) of the title compound was obtained.

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 1.153 (16.00), 1.180 (12.81), 1.266 (2.26), 1.283 (2.28), 1.302 (0.50), 1.308 (1.93), 1.504 (1.82 ), 1.520 (1.84), 2.030 (0.60), 2.644 (0.50), 2.656 (0.49), 2.720 (0.45), 2.745 (0.52), 2.751 (0.51), 2.766 (0.56), 2.771 (0.51), 2.798 (0.47 ), 7.290 (0.42), 7.294 (0.44), 7.309 (0.44), 7.314 (0.59), 7.328 (0.52), 7.333 (0.73), 7.338 (0.64), 7.344 (0.43), 7.358 (0.50), 7.362 (0.50 ), 7.410 (0.42), 7.414 (0.41), 7.480 (0.56), 7.483 (0.59), 7.492 (0.82), 7.498 (0.86), 7.502 (0.47), 7.511 (0.49), 7.516 (0.41).

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 7.70-6.93 (m, 4H), 5.22-4.81 (m, 1H), 4.27-3.94 (m, 1H), 2.872.57 (m, 2H ), 1.51 & 1.27 (2x d, 3H), 1.18 & 1.15 (2x d, 9H).

Example 49A. (+/-)-tert-Butyl-4-(2-chlorophenyl)-4-cyanobutanoate (racemate)

o sn ₃

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 2M solution of LDA in THF (25 ml, 49 mmol) slowly with stirring. The mixture was brought to 0°C and after 15 min further 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 19). 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 50A. (+/-)-tert-Butyl-4-(2-chlorophenyl)-4-cyanopentanoate (racemate)

- 43 040284

To a solution of 2-(2-chlorophenyl)propanenitrile (5.00 g, 30.2 mmol, obtained by methylation of 2-(2-chlorophenyl)acetonitrile according to WO 2011/123419 A1, pp. 386-387) in THF (42 ml) in argon at -78°C, a 2M solution of LDA in THF (23 ml, 45 mmol) was added slowly with stirring. The mixture was brought to 0°C and after 15 min further cooled to -78°C. Then, tert-butyl-3-bromopropanoate (7.57 g, 36.2 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 16). The combined desired fractions were concentrated and the residue was dried in vacuo. 2.21 g (81% pure, 20% th. y.) of the title compound was obtained.

LC-MS (Method 1): R _t = 2.27 min; MS (ESIpos): m/z = 294 [M+H]+.

Example 51A. (+/-)-tert-Butyl-4-(2-chloro-6-fluorophenyl)-4-cyanobutanoate (racemate)

o sn ₃

To a solution of (2-chloro-6-fluorophenyl)acetonitrile (2.00 g, 11.8 mmol) in THF (15 mL) in argon at 78°C was added a 2M solution of LDA in THF (8.8 mL, 18 mmol) slowly with stirring. The mixture was brought to 0°C and after 15 min further cooled to -78°C. Then, tert-butyl-3-bromopropanoate (2.2 ml, 14 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 previously purified by flash column chromatography (50 g Biotage Snap-Cartridge KP-Sil, cyclohexane/ethyl acetate gradient 93:7^6 :4, Isolera One). Then further purified by preparative HPLC (Method 16). The combined desired fractions were concentrated and the residue was dried in vacuo. 1.45 g (100% pure, 41% th. y.) of the title compound was obtained.

LC-MS (Method 1): R _t = 2.16 min; MS (ESIpos): m/z = 298 [M+H] ⁺ .

Example 52A. (+/-)-tert-Butyl-4-cyano-4-(2-methylphenyl)butanoate (racemate)

To a solution of (2-methylphenyl)acetonitrile (2.00 g, 15.2 mmol) in THF (17 ml) in argon at -78°C was added a 2M solution of LDA in THF (11 ml, 23 mmol) slowly with stirring. The mixture was brought to 0°C and after 15 min further cooled to -78°C. Then, tert-butyl-3-bromopropanoate (2.9 ml, 18 mmol) was added dropwise slowly 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 previously purified by flash column chromatography (100 g Biotage Snap-Cartridge KP-Sil, cyclohexane/ethyl acetate 85:15, Isolera One ). Then further purified by preparative HPLC (Method 16). The combined desired fractions were concentrated and the residue was dried in vacuo. 534 mg (98% pure, 13% thor.) of the title compound were obtained.

LC-MS (Method 1): R _t = 2.17 min; MS (ESIpos): m/z = 260 [M+H] ⁺ .

Example 53A. (+/-)-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

- 44 040284

-78°C slowly with stirring was added a 2M solution of LDA in THF (44 ml, 88 mmol). The mixture was brought to 0°C and after 15 min further cooled to -78°C. Then, tert-butyl-3-bromopropanoate (11 ml, 71 mmol) was added dropwise slowly 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 54A. (+/-)-tert-Butyl-4-cyano-4-(2-methoxyphenyl)butanoate (racemate)

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 2M solution of LDA in THF (10 ml, 20 mmol) slowly with stirring. The mixture was brought to 0°C and after 15 min further 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 aqueous sodium chloride, dried over sodium sulfate, filtered and concentrated, and the residue was previously purified by flash column chromatography (100 g Biotage Snap-Cartridge KP-Sil silica gel, 93:7 cyclohexane/ethyl acetate gradient). 6:4, Isolera One). Then further purified by preparative HPLC (Method 16). 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): Rt = 2.13 min; MS (ESIpos): m/z = 276 [M+H]+.

Example 55A. (+/-)-tert-Butyl-4-(2-chloro-5-fluorophenyl)-4-cyanopentanoate (racemate)

A 2M solution of from LDA to THF (10 ml, 20 mmol). The mixture was brought to 0°C and after 15 min further 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 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. 1.20 g (75% pure, 21% th. y.) of the title compound was obtained.

LC-MS (Method 1): R _t = 2.29 min; MS (ESIpos): m/z = 312 [M+H]+.

Example 56A. (+/-)-tert-Butyl-4-(2-chloro-3,6-difluorophenyl)-4-cyanobutanoate (racemate)

A 2M solution of LDA in THF (12 ml, 25 mmol). The mixture was brought to 0°C and after 15 min further cooled to -78°C. A solution of tert-butyl-3-bromopropanoate (2.6 ml, 16 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. Then the mixture at approx. 0°C was slowly mixed with water and ethyl acetate (respectively 100 ml) and shaken. After phase separation, the aqueous phase was extracted

- 45 040284 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 into 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]+.

'H-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 57A.

(+/-)-tert-Butyl-4-cyano-4-(2-fluorophenyl)butanoate (racemate)

To a solution of (2-fluorophenyl)acetonitrile (5.00 g, 37.0 mmol) in THF (35 ml) in argon at -78°C was added a 2M solution of LDA in THF (22 ml, 44 mmol) slowly with stirring. The mixture was brought to 0°C and after 15 min further cooled to -78°C. A solution of tert-butyl-3-bromopropanoate (7.0 ml, 44 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. Then the mixture at approx. 0°C was slowly mixed 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 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 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. 4.22 g (69% pure, 29% th. y.) of the title compound was obtained.

LC-MS (Method 1): R _t = 2.08 min; MS (ESIpos): m/z = 264 [M+H] ⁺ .

Example 58A. (+/-)-tert-Butyl-4-cyano-4-[2-(difluoromethoxy)phenyl]butanoate (racemate)

To a solution of [2-(difluoromethoxy)phenyl]acetonitrile (5.00 g, 27.3 mmol) in THF (25 ml) in argon at -78°C was added a 2M solution of LDA in THF (16 ml, 33 mmol) slowly with stirring. The mixture was brought to 0°C and after 15 min further cooled to -78°C. A solution of tert-butyl-3-bromopropanoate (5.2 ml, 33 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. Then the mixture at approx. 0°C was slowly mixed 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 into 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. 3.85 g (83% pure, 38% th. y.) of the title compound was obtained.

LC-MS (Method 1): R _t = 2.10 min; MS (ESIpos): m/z = 312 [M+H] ⁺ .

Example 59A. (+/-)-tert-Butyl-4-cyano-4-(2,6-difluorophenyl)butanoate (racemate)

To a solution of (2,6-difluorophenyl)acetonitrile (5.00 g, 32.7 mmol) in THF (30 ml) in argon at -78°C was added a 2M solution of LDA in THF (20 ml, 39 mmol) slowly with stirring. The mixture was brought to 0°C and after 15 min further 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. Then the mixture at approx. 0°C was slowly mixed 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 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. 4.87 g (76% pure, 40% th. y.) of the title compound was obtained.

LC-MS (Method 1): Rt = 2.06 min; MS (ESIpos): m/z = 282 [M+H]+.

Example 60A. (+/-)-tert-Butyl-4-(2-chloro-3-fluorophenyl)-4-cyanobutanoate (racemate)

To a solution of (2-chloro-3-fluorophenyl)acetonitrile (4.00 g, 23.6 mmol, example 12A) in THF (30 ml) in argon at -78°C was added a 2M solution of LDA in THF (14 ml, 28 mmol). The mixture was brought to 0°C and after 15 min further 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. Then the mixture at approx. 0°C was slowly mixed 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 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. Got

4.36 g (95% pure, 59% theoretical) of the title compound.

LC-MS (Method 1): R _t = 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) . . , 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).

1H-NMR (400 MHz, DMSO-d6) 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 61A. (+/-)-tert-Butyl-N-[(2-chlorophenyl)(cyano)methyl]-N-methylglycinate (racemate)

A solution of tert-butyl-N-methylglycinate hydrochloride (1.03 g, 7.11 mmol) in ethyl acetate (10 ml) was mixed with saturated sodium carbonate solution and shaken. After phase separation, the organic phase was dried over sodium sulfate, filtered and concentrated. The residue was dissolved in dichloromethane (50 ml) and mixed with 2-chlorobenzaldehyde (1.00 g, 7.11 mmol) dropwise at RT. After 15 min stirring at RT, trimethylsilanecarbonitrile (706 mg, 7.11 mmol) was added dropwise and the mixture was stirred overnight at RT. The mixture was then concentrated, and the residue was adsorbed into ethyl acetate and washed with a saturated aqueous sodium chloride solution. The organic phase was dried, filtered and concentrated and the residue was purified by preparative HPLC (Method 16). The combined desired fractions were concentrated and the residue was dried in vacuo. 1.47 g (90% pure, 63% th. y.) of the title compound was obtained.

LC-MS (Method 1): R _t = 2.19 min; MS (ESIpos): m/z = 295 [M+H] ⁺ .

Example 62A. (+/-)-tert-Butyl-N-[(2-chlorophenyl)(cyano)methyl]glycinate (racemate)

To a solution of tert-butylglycinate (933 mg, 7.11 mmol) in dichloromethane (50 mL) was added 2-chlorobenzaldehyde (1.00 g, 7.11 mmol) dropwise at RT. After 15 min stirring at RT, trimethylsilanecarbonitrile (706 mg, 7.11 mmol) was added dropwise and the mixture was stirred overnight at RT.

- 47 040284

The mixture was then concentrated, and the residue was adsorbed into ethyl acetate and washed with a saturated aqueous sodium chloride solution. The organic phase was dried, filtered and concentrated and the residue was purified by preparative HPLC (Method 16). The combined desired fractions were concentrated and the residue was dried in vacuo. 1.47 g (33% purity, 24% th. y.) of the title compound was obtained.

LC-MS (Method 1): Rt = 2.01 min; MS (ESIpos): m/z = 225 [MC ₄ H ₈ +H]+.

Example 63A. (+/-)-Methyl-{[1-(2-chlorophenyl)-2-nitroethyl]sulfanyl}acetate (racemate)

A solution of 1-chloro-2-[(B)-2-nitrovinyl]benzene (1.00 g, 5.45 mmol) in dichloromethane (50 ml) in argon at -30°C was mixed dropwise with a solution of methylsulfanyl acetate (578 mg, 5.45 mmol ) in dichloromethane (25 ml) and the mixture was stirred 2 h at -30°C and 16 h at RT. The mixture was then concentrated and the residue was dissolved in acetonitrile and purified by preparative HPLC (Method 16). The combined desired fractions were concentrated and the residue was dried in vacuo. 1.52 g (100% pure, 97% th. y.) of the title compound was obtained.

LC-MS (Method 2): R _t = 0.96 min; MS (ESIpos): m/z = 307.

'H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 7.62-7.59 (m, 1H), 7.52-7.48 (m, 1H), 7.40-7.32 (m, 2H), 5.35 (dd, 1H ), 5.29 (dd, 1H), 5.13 (dd, 1H), 3.60 (s, 3H), 3.59 (d, 1H), 3.43 (d, 1H).

Example 64A. (+/-)-tert-Butyl-4-(6-chloro-2,3-difluorophenyl)-4-cyanobutanoate (racemate)

To a solution of (6-chloro-2,3-difluorophenyl)acetonitrile (2.23 g, 11.9 mmol, uncorrected purity, Example 13A) in THF (15 ml) in argon at -78°C was added a 2M solution of LDA slowly with stirring in THF (7.1 ml, 14 mmol). The mixture was brought to 0°C and after 15 min further cooled to -78°C. A solution of tert-butyl-3-bromopropanoate (4.5 ml, 28 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. Then the mixture at approx. 0°C was slowly mixed with water (50 ml) and ethyl acetate (100 ml) 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 65A. (+/-)-Methyl-4-cyano-4-[2-(trifluoromethyl)phenyl]butanoate (racemate)

To a solution of [2-(trifluoromethyl)phenyl]acetonitrile (5.00 g, 27.0 mmol) in THF (15 mL) in argon at -78°C was slowly added a 2M solution of LDA in THF (16 mL, 32 mmol) with stirring. The mixture was brought to 0°C and after 15 min further cooled to -78°C. A solution of methyl 3-bromopropanoate (5.41 g, 32.4 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. Then the mixture at approx. 0°C was slowly mixed 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 (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. 48 040284 4.97 g (98% pure, 66% theoretical yield) of the title compound was obtained.

LC-MS (Method 1): R _t = 1.82 min.

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 7.92-7.75 (m, 3H), 7.67-7.56 (m, 1H), 4.39 (dd, 1H), 3.59 (s, 3H), 2.57 -2.43 (m, 2H, partially hidden), 2.37-2.23 (m, 1H), 2.22-2.09 (m, 1H).

Example 66A. (+/-)-tert-Butyl-4-cyano-4-(5-fluoro-2-methylphenyl)butanoate (racemate)

To a solution of (5-fluoro-2-methylphenyl)acetonitrile (4.00 g, 26.8 mmol) in THF (30 ml) in argon at -78°C was added slowly with stirring a 2M solution of LDA in THF (16 ml, 32 mmol) . The mixture was brought to 0°C and after 15 min further cooled to -78°C. A solution of tert-butyl-3-bromopropanoate (5.1 ml, 32 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. Then the mixture at approx. 0°C was slowly mixed 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 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. 4.94 g (100% pure, 66% th. y.) of the title compound was obtained.

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

1H-NMR (400 MHz, DMSO-d6) 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 67A. (+/-)-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 a 2M solution of LDA in THF (15 ml, 30 mmol) slowly with stirring. The mixture was brought to 0°C and after 15 min further 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. Then the mixture at approx. 0°C was slowly mixed 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 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. 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 68A. (+/-)-tert-Butyl-4-cyano-4-(pyridin-2-yl)butanoate (racemate)

Starting mixture A: pyridin-2-ylacetonitrile (27 mg, 229 µmol), tert-butyl acrylate (50 µL, 340 µmol) and potassium carbonate (63 mg, 457 µmol) were adsorbed in DMF (0.3 ml) and heated in a microwave oven for 1 h. oven (100°C). The reaction mixture was concentrated in vacuo. The LC-MS spectrum of the crude product showed up to approx. 10% (UV) product with the desired weight.

Starting mixture B: pyridin-2-ylacetonitrile (988 mg, 8.36 mmol) was adsorbed in DMF (10 ml) and mixed slowly with sodium hydride (401 mg, 60% pure, 10.0 mmol) (gas formation). After 10 min at RT, tert-butyl acrylate (1.2 mL, 8.4 mmol) was slowly added and the reaction mixture was stirred for 3 h at RT. The reaction mixture was added to water, extracted with dichloromethane, dried (sodium sulfate) and concentrated. The LC-MS spectrum of the crude product showed up to approx. 8% (UV)

- 49 040284 products with the desired weight.

Starting mixture C: tetrahydrofuran (10 ml) was provided in an unheated flask under nitrogen atmosphere, pyridin-2-ylacetonitrile (1.09 g, 9.23 mmol) was added and at -78°C a 2M solution of LDA in THF (6.9 ml, 14 mmol) was added slowly dropwise ). The mixture was further stirred for 10 min at -78°C and 20 min at 0°C and then cooled further to -78°C. Then, tert-butyl-3-bromopropanoate (2.32 g, 11.1 mmol) was slowly added dropwise and after complete addition was stirred for an additional 1 h at -78°C. the cooling bath was removed and the reaction mixture was stirred an additional 20 hours while warming to RT. The mixture was added to water, extracted with ethyl acetate, the organic phase was washed with saturated sodium chloride solution, dried (sodium sulfate) and concentrated. The LC-MS spectrum of the crude product showed up to approx. 17% (UV) product with the desired weight.

The combined crude products from feed A, feed B, and feed C were purified by chromatography (Biotage Isolera Four, LiChroprep RP-18 (40-63 µm); gradient 5%^45% acetonitrile in 0.1% aqueous ammonia). 799 mg (48% pure, 9% thor.) of the title compound were obtained.

LC-MS (Method 6): R _t = 1.09 min; MS (ESIpos): m/z = 247 [M+H]+.

Example 69A. (+/-)-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 (1.6M solution in hexane, 27 ml, 43 mmol) and the mixture was further stirred for 10 min at 0°C. 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 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. 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 1M 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 70A. (+/-)-tert-Butyl-4-cyano-4-(2,3,5,6-tetrafluorophenyl)butanoate (racemate)

o sn ₃

The reaction was carried out in argon. To obtain an LDA solution, a solution of diisopropylamine (2.1 ml, 15 mmol) in THF (9 ml) at -15°C was slowly mixed with butyllithium (1.6M solution in hexane, 9 ml, 14 mmol) and the mixture was additionally stirred for 10 min at 0°C. C. This solution was slowly added dropwise to a -78° C. cooled solution of (2,3,5,6-tetrafluorophenyl)acetonitrile (2.47 g, 13.1 mmol, example 14A) in THF (25 ml). 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 (2.5 ml, 16 mmol) in THF (9 ml) 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 100 ml water) was added, 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 1M hydrochloric acid, saturated sodium hydrogen carbonate solution and saturated sodium chloride solution, then dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel flash chromatography (Isolera, 50 g Ultra

Snap Saule, cyclohexane/ethyl acetate gradient). The combined desired fractions were concentrated and the residue was dried in vacuo. 3.43 g (100% pure, 83% th. y.) of the title compound was obtained.

LC-MS (Method 1): Rt = 2.11 min; MS (ESIpos): m/z = 318 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 1.211 (0.06), 1.347 (1.57), 1.370 (16.00), 1.397 (0.08), 1.527 (0.06), 2.058 (0.05), 2.076 (0.15 ), 2.095 (0.19), 2.111 (0.29), 2.129 (0.28), 2.148 (0.11), 2.167 (0.08), 2.185 (0.27), 2.202 (0.33), 2.220 (0.25), 2.236 (0.15), 2.254 (0.08 ), 2.283 (0.02), 2.311 (0.06), 2.356 (0.68), 2.374 (1.21), 2.392 (0.47), 2.419 (0.03), 2.444 (0.04), 2.669 (0.03), 2.709 (0.03), 4.612 (0.25 ), 4.631 (0.50), 4.650 (0.24), 7.944 (0.06), 7.963 (0.13), 7.970 (0.14), 7.989 (0.27), 8.009 (0.15), 8.016 (0.15), 8.035 (0.08). Example 71A. (+/-)-tert-Butyl-4-cyano-4-(2,3,5-trifluorophenyl)butanoate (racemate)

To a solution of (2,3,5-trifluorophenyl)acetonitrile (2.50 g, 97% pure, 14.2 mmol, CAS-RN 24366614-0, commercially available) in THF (15 ml) in argon at -78°C was slowly added with stirring LDA solution (2M in THF, 7.8 ml, 16 mmol). The mixture was brought to 0°C and after 15 min further cooled to -78°C. A solution of tert-butyl-3-bromopropanoate (3.36 g, 97% pure, 15.6 mmol) in 5 ml THF was then added dropwise slowly with stirring at -78°C. The mixture was further stirred overnight while the cooling bath (dry ice/acetone) was slowly brought to RT. Then the mixture was slowly mixed with ethyl acetate and water (respectively 100 ml). The phases are separated. The aqueous phase was extracted twice with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride, dried over sodium sulfate and concentrated. The residue was adsorbed into dichloromethane and purified by flash column chromatography (Biotage 100 g KieselgelKartusche, cyclohexane/ethyl acetate gradient 97:3 - 90:10). Two fractions were obtained, which were separately concentrated in vacuo. After drying in vacuo, 600 mg (100% pure, 14% theoretical) of the first batch of the title compound was obtained from the second fraction. The contaminated first fraction was further purified by preparative HPLC (Method 28). The combined desired fractions were concentrated and the residue was dried in vacuo. 1.30 g (100% pure, 31% th. y., see Analysis section) of the second batch of the title compound was obtained.

LC-MS (Method 1): R _t = 2.15 min; MS (ESIpos): m/z = 300 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 1.220 (0.06), 1.379 (16.00), 1.536 (0.06), 2.051 (0.05), 2.070 (0.16), 2.088 (0.22), 2.104 (0.34 ), 2.122 (0.34), 2.141 (0.15), 2.165 (0.26), (0.13), 2.235 (0.08), 2.329 (0.77), 2.348 (1.15), 2.366 (0.40), 2.671 (0.02), (0.61), 4.526 (0.31), 7.253 (0.16), 7.259 (0.21), 7.267 (0.22), 7.272 (0.21), (0.11), 7.576 (0.08), 7.583 (0.09), 7.592 (0.10), 7.599 (0.16), 7.603 (0.16), (0.16), 7.632 (0.10), 7.639 (0.09), 7.647 (0.09).

2.182

2.711

7.281

7.612 (0.30), 2.200 (0.23), 2.216 (0.02), 4.489 (0.33), 4.508 (0.22), 7.287 (0.16), 7.293 (0.15), 7.620 (0.16), 7.625

Example 72A. (+/-)-tert-Butyl-4-cyano-4-(2,3,6-trichlorophenyl)butanoate (racemate)

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 (1.6M solution in hexane, 30 ml, 48 mmol) and the mixture was additionally stirred for 10 min at 0°C. 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 after 15 min was further cooled to -78°C. 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. For work-up, ammonium chloride solution (10% in 300 ml water) was added, the mixture was stirred vigorously for 5 minutes and then extracted twice with ethyl acetate. The combined organic phases were washed twice each successively with 1M hydrochloric acid, saturated sodium hydrogen carbonate solution and saturated sodium chloride solution and then dried over sodium sulfate and concentrated in vacuo. The residue was purified by preparative HPLC (Method 27). 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]+.

'H-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 73A. (+/-)-tert-Butyl-5-(2-chlorophenyl)-5-cyanopentanoate (racemate)

To a solution of (2-chlorophenyl)acetonitrile (2.12 g, 14.0 mmol) in THF (20 ml) in argon at -78°C was added a 2M solution of LDA in THF (8.4 ml, 17 mmol) slowly with stirring. The mixture was brought to 0°C and after 15 min further cooled to -78°C. A solution of tert-butyl-4-bromobutanoate (3.75 g, 16.8 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. Then the mixture at approx. 0°C was slowly mixed with water and ethyl acetate (respectively 70 ml) and shaken. After phase separation, the aqueous phase was extracted once with ethyl acetate (70 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 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. 2.70 g (96% pure, 63% th. y.) of the title compound were obtained.

LC-MS (Method 1): Rt = 2.31 min; MS (ESIpos): m/z = 294 [M+H]+.

'H-NMR (400 MHz, DMSO-d6) δ [ppm]: 7.62-7.50 (m, 2H), 7.49-7.37 (m, 2H), 4.49 (dd, 1H), 2.28 (td, 2H), 1.99 -1.78 (m, 2H), 1.72-1.51 (m, 2H), 1.38 (s, 9H).

Example 74A. (+/-)-tert-Butyl-5-(2-chlorophenyl)-5-cyanohexanoate (racemate)

To a solution of 2-(2-chlorophenyl)propanenitrile (2.32 g, 14.0 mmol, CAS-RN 75920-46-6, commercially available) in THF (20 ml) in argon at LDA in THF (11 ml, 21 mmol). The mixture was brought to 0°C and after 15 min further cooled to -78°C. A solution of tert-butyl-4-bromobutanoate (3.75 g, 16.8 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. Then the mixture at approx. 0°C was slowly mixed 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 of 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. 2.47 g (98% pure, 56% th. y.) of the title compound were obtained.

LC-MS (Method 1): R _t = 2.34 min; MS (ESIpos): m/z = 308 [M+H]+.

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.217 (0.06), 1.377 (16.00), 1.429 (0.19), 1.454 (0.11), 1.476 (0.30), 1.494 (0.46), 1.514 (0.33) , 1.533 (0.21), 1.808 (3.89), 1.939 (0.15), 1.960 (0.23), 1.973 (0.21), 1.982 (0.16), 1.989 (0.18), 2.000 (0.20), 2.015 (0.16), 2.212 (0.19) . , 7.429 (0.53) , 7.582 (0.35), 7.588 (0.37).

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 7.61-7.51 (m, 2H), 7.48-7.36 (m, 2H), 2.31-2.18 (m, 3H), 2.041.92 (m, 1H), 1.81 (s, 3H), 1.57–1.44 (m, 2H), 1.38 (s, 9H).

Example 75A. (+/-)-Methyl-3-amino-2-phenylpropanoate hydrochloride (racemate) nh ₂ o

Oxalyl chloride (740 µl, 8.5 mmol) was slowly added dropwise to a suspension of (+/-)-3-amino-2-phenylpropionic acid (700 mg, 4.24 mmol) in methanol (10 ml) at RT and the mixture was stirred for 5 days

- 52 040284 at CT. The mixture was then concentrated. The residue was mixed successively with dichloromethane several times and re-concentrated. The residue was then dried in vacuo. Received 933 mg (95% pure,

97% theory out) specified in the connection header.

LC-MS (Method 4): R _t = 0.93 min; MS (ESIpos): m/z = 180 [M+H]+.

'H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 8.20 (br. s, 3H), 7.63-7.10 (m, 5H), 4.11 (dd, 1H), 3.64 (s, 3H) , 3.46 (dd, 1H), 3.07 (dd, 1H).

Example 76A. (+/-)-Ethyl-3-amino-2-(2-chlorophenyl)propanoate (racemate)

A

D^O^CH3 nh ₂ o

A solution of (+/-)-ethyl-(2-chlorophenyl)(cyano)acetate (8.60 g, 38.5 mmol, example 15A) in ethanol (140 ml) was mixed with Raney nickel (1.13 g, 19.2 mmol) and hydrogenated for 20 h at 3 bar. The catalyst was then filtered through silica gel, washed with ethanol, and the mother liquor was concentrated. The residue was adsorbed into dichloromethane and purified by flash column chromatography (200 g Biotage Snap-Cartridge KP-Sil, dichloromethane/methanol 40:1). The combined desired fractions were concentrated and the residue was dried in vacuo. 869 mg (87% pure, 9% th. y.) of the title compound were obtained.

LC-MS (Method 4): Rt = 1.19 min; MS (ESIpos): m/z = 228 [M+H]+.

'H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 7.50-7.44 (m, 1H), 7.43-7.26 (m, 3H), 4.15-4.03 (m, 3H), 3.10 (dd, 'H), 2.83 (dd, 1H), 1.54 (br. s, 2H), 1.14 (t, 3H).

Example 77A. (+/-)-Methyl-3-amino-2-(2-methoxyphenyl) propanoate hydrochloride (racemate)

To a solution of (+/-)-3-amino-2-(2-methoxyphenyl)propionic acid-hydrochloride (1.39 g, 6.00 mmol, CAS-RN 91012-74-7, commercially available) in methanol (14 ml, 350 mmol) while cooling with an ice-acetone bath, oxalyl chloride (1.0 mL, 12 mmol) was slowly added dropwise, and the mixture was stirred for 24 h at RT. The mixture was then concentrated. The residue was mixed successively with dichloromethane several times and re-concentrated. The residue was then dried in vacuo. Received 1.83 g (89% purity, >100% theory. yield. containing solvent) indicated in the title compound.

LC-MS (Method 4): Rt = 0.94 min; MS (ESIpos): m/z = 210 [M+H]+.

'H-NMR (400 MHz, DMSO-d6) δ [ppm]: 3.373 (1.52), 3.394 (1.49), 3.425 (1.14), 3.716 (5.40), 3.766 (1.44), 3.780 (16.00), 3.805 (5.37 ), 6.936 (0.77), 6.939 (0.84), 6.955 (1.68), 6.958 (1.78), 6.974 (0.96), 6.976 (0.99), 7.042 (1.55), 7.063 (1.84), 7.182 (1.39), 7.187 (1.54 ), 7.201 (1.21), 7.205 (1.25), 7.306 (0.96), 7.311 (0.89), 7.325 (1.25), 7.345 (0.73), 7.350 (0.64), 8.079 (0.97).

'H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 8.08 (br. s, 2H), 7.36-7.29 (m, 1H), 7.19 (dd, 1H), 7.05 (d, 1H) , 6.99-6.92 (m, 1H), 4.30-4.22 (m, 1H), 3.81 (s, 1H), 3.78 (s, 3H), 3.72 (s, 1H), 3.62 (s, 3H), 3.45-3.35 (m, 1H, hidden), 3.02-2.93 (m, 1H).

Example 78A. (+/-)-Methyl-3-amino-2-(4-fluorophenyl) propanoate hydrochloride (racemate)

To a solution of (+/-)-3-amino-2-(4-fluorophenyl)propionic acid-hydrochloride (500 mg, 2.28 mmol, CAS-Nr. 15032-53-8) in methanol (5.4 ml, 130 mmol) while cooling with an ice-acetone bath, oxalyl chloride (400 µl, 4.6 mmol) was slowly added dropwise and the mixture was stirred for 24 h at RT. The mixture was then concentrated. The residue was mixed successively with dichloromethane several times and re-concentrated. The residue was then dried in vacuo. Received 570 mg (100% purity, >100% theory. yield. containing solvent) specified in the title compound.

LC-MS (Method 4): Rt = 0.99 min; MS (ESIpos): m/z = 198 [M+H]+.

'H-NMR (400 MHz, DMSO-d6) δ [ppm]: 3.428 (0.95), 3.449 (0.95), 3.639 (16.00), 3.680 (1.34), 7.204 (1.44), 7.226 (3.36), 7.248 (1.99 ), 7.342 (2.08), 7.348 (0.90), 7.355 (2.25), 7.364 (1.75), 7.377 (1.52), 8.125 (1.09).

Example 79A. (+/-)-Methyl-3-amino-2-hydroxy-2-phenylpropanoate hydrochloride (racemate)

- 53 040284

Via a suspension of (+/-)-3-amino-2-hydroxy-2-phenylpropionic acid (4.0 g, 22.10 mmol, prepared according to Justus Liebigs Annalen der Chemie 1961, 639, 166-180) in methanol (600 ml) 15 min passed hydrogen chloride. In this case, the suspension passed into the solution. Then the reaction mixture was stirred for 2.5 h under reflux. After cooling to RT, the mixture was concentrated and the residue was stirred in t-butyl methyl ether. The solid present was filtered off and dried in vacuo. 2.81 g (55% th. y.) of the title compound was obtained.

Example 80A. (+/-)-Ethyl-3-amino-2-[3-(trifluoromethyl)phenyl]propanoate (racemate)

A solution of (+/-)-ethylcyano[3-(trifluoromethyl)phenyl]acetate (1.26 g, 4.90 mmol, prepared according to US 4909830, 1990 and European Journal of Organic Chemistry 2014, 27, 6025-6029) in tert-butanol ( 20 ml) was mixed with Raney nickel (288 mg, 4.90 mmol) and hydrogenated at normal pressure for two days. The catalyst was then filtered through silica gel, the mother liquor was concentrated and the residue was dried in vacuo. The residue was purified by preparative HPLC (Method 22). The combined desired fractions were concentrated and the residue was dried in vacuo. 63 mg (100% pure, 5% thor.) of the title compound were obtained.

LC-MS (Method 4): Rt = 1.43 min; MS (ESIpos): m/z = 262 [M+H] ⁺ .

Example 81A. (+/-)-Ethyl-3-amino-2-(1,3-benzodioxol-5-yl) propanoate (racemate)

A solution of (+/-)-ethyl-1,3-benzodioxol-5-yl(cyano)acetate (750 mg, 3.22 mmol, prepared according to Beilstein Journal of Organic Chemistry 2015, 11, 875-883) in tert-butanol ( 13 ml) was mixed with Raney nickel (189 mg, 3.22 mmol) and hydrogenated at normal pressure for two days. The catalyst was then filtered through silica gel, the mother liquor was concentrated and the residue was dried in vacuo. 150 mg (100% pure, 20% thor.) of the title compound were obtained.

LC-MS (Method 1): R _t = 0.71 min; MS (ESIpos): m/z = 238 [M+H] ⁺ .

Example 82A. (+/-)-tert-Butyl-3-amino-2-(3-chloropyridin-2-yl)-2-methylpropanoate (racemate)

A solution of (+/-)-tert-butyl-2-(3-chloropyridin-2-yl)-2-cyanopropanoate (900 mg, uncorrected purity, 3.37 mmol, Example 16A) in tert-butanol (20 mL) was mixed with Raney nickel (198 mg, 3.37 mmol) and hydrogenated overnight at normal pressure. The catalyst was then filtered through silica gel and the mother liquor was concentrated. The residue was dried in vacuo and then purified by preparative HPLC (Method 16). The combined desired fractions were concentrated and the residue was dried in vacuo. 255 mg (100% pure, 28% thor.) of the title compound were obtained.

LC-MS (Method 1): R _t = 1.04 min; MS (ESIpos): m/z = 271 [M+H] ⁺ .

Example 83A. (+/-)-tert-Butyl-3-amino-2-(2,6-difluorophenyl)-2-methylpropanoate (racemate)

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A solution of (+/-)-tert-butyl-2-cyano-2-(2,6-difluorophenyl)propanoate (6.80 g, 79% pure, 20.1 mmol, Example 17A) in tert-butanol (22 ml) was mixed with Raney nickel (1.03 g, 17.5 mmol) and hydrogenated for three days at normal pressure. The catalyst was then filtered through silica gel and the mother liquor was concentrated. The residue was adsorbed into ethyl acetate and extracted twice with 1M hydrochloric acid. The combined aqueous phases were made basic with 20% sodium hydroxide solution and then extracted twice with ethyl acetate. The combined organic phases were dried over magnesium sulfate, filtered and concentrated, and the residue was dried in vacuo. 1.40 g (99% pure, 25% th. y.) of the title compound was obtained.

LC-MS (Method 2): R _t = 0.57 min; MS (ESIpos): m/z = 216 [M-tBu+H]+.

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 1.368 (16.00), 1.497 (1.28), 1.502 (2.25), 1.508 (1.24), 2.990 (0.85), 2.998 (0.74), 7.005 (0.55 ), 7.026 (0.72), 7.031 (0.61), 7.052 (0.67), 7.332 (0.44).

1H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 7.39-7.28 (m, 1H), 7.08-6.98 (m, 2H), 3.05-2.94 (m, 2H), 1.50 (t, 3H ), 1.37 (s, 9H).

Example 84A. (+/-)-ethyl-3-Amino-2-methyl-2-[3-(trifluoromethyl)phenyl]propanoate (racemate)

A solution of (+/-)-ethyl-2-cyano-2-[3-(trifluoromethyl)phenyl]propanoate (1.80 g, 6.64 mmol, obtained according to WO 2016/94260 A1, page 82, by analogy with obtaining (+ /-)-ethyl-2-cyano-2-(4-fluorophenyl)propanoate) in tert-butanol (39 ml) was mixed with Raney nickel (390 mg, 6.64 mmol) and hydrogenated overnight at normal pressure. The catalyst was then filtered through silica gel, the mother liquor was concentrated and the residue was dried in vacuo. The residue was purified by preparative HPLC (Method 16). The combined desired fractions were concentrated and the residue was dried in vacuo. 615 mg (96% pure, 32% thor.) of the title compound were obtained.

LC-MS (Method 2): R _t = 0.55 min; MS (ESIpos): m/z = 276 [M+H] ⁺ .

Example 85A. (+/-)-tert-Butyl-3-amino-2- (3-methoxyphenyl) propanoate (racemate) nh ₂ o ch ₃

A solution of (+/-)-tert-butylcyano(3-methoxyphenyl)acetate (4.00 g, 16.2 mmol, example 18A) in tert-butanol (75 ml) was mixed with Raney nickel (1.00 g, 17.03 mmol) and hydrogenated for 5 days at normal pressure. The catalyst was then filtered through silica gel, the mother liquor was concentrated and the residue was dried in vacuo. The residue was then adsorbed into ethyl acetate and extracted with 1M hydrochloric acid. The aqueous phase was then alkalized with concentrated sodium hydroxide solution and extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and concentrated, and the residue was dried in vacuo. 750 mg (89% pure, 16% thor.) of the title compound were obtained.

LC-MS (Method 2): Rt = 0.59 min; MS (ESIpos): m/z = 252 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 7.24 (t, 1H), 6.86-6.76 (m, 3H), 3.73 (s, 3H), 3.48 (dd, 1H), 3.01 ( dd, 1H), 2.73 (dd, 1H), 1.37 (s, 9H).

Example 86A. (+/-)-tert-Butyl-3-amino-2-(3-chlorophenyl)propanoate (racemate)

A solution of (+/-)-tert-butyl-(3-chlorophenyl)(cyano)acetate (5.50 g, 21.9 mmol, uncorrected purity, example 19A) in tert-butanol (95 ml) was mixed with Raney nickel (1.28 g , 21.9 mmol) and hydrogenated for 5 days at normal pressure. The catalyst was then filtered through silica gel, the mother liquor was concentrated and the residue was dried in vacuo. The residue was then adsorbed into ethyl acetate (50 ml) and extracted with 1M hydrochloric acid (80 ml). The aqueous phase was then alkalized with concentrated sodium hydroxide solution and extracted with ethyl acetate (70 ml). The combined organic phases were dried over sodium sulfate, filtered and concentrated, and the residue was dried in vacuo. 500 mg (95% pure, 9% thor.) of the title compound were obtained.

LC-MS (Method 1): R _t = 1.11 min; MS (ESIpos): m/z = 200 [M- ^t Bu+H] ⁺ .

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1H-NMR (400 MHz, DMSO-d6): δ [ppm] = 7.42-7.29 (m, 3H), 7.26-7.20 (m, 1H), 3.60 (t, 1H), 3.08 (dd,

1H), 2.81 (dd, 1H), 1.37 (s, 9H).

Example 87A. (+/-)-tert-Butyl-3-amino-2-(3-methylphenyl)propanoate (racemate)

A solution of (+/-)-tert-butylcyano(3-methylphenyl)acetate (3.20 g, 13.8 mmol, example 20A) in tert-butanol (60 ml) was mixed with Raney nickel (812 mg, 13.8 mmol) and hydrogenated for 5 days at normal pressure. The catalyst was then filtered through silica gel, the mother liquor was concentrated and the residue was dried in vacuo. The residue was then adsorbed into ethyl acetate (50 ml) and extracted with 1M hydrochloric acid (80 ml). The aqueous phase was then alkalized with concentrated sodium hydroxide solution and extracted with ethyl acetate (70 ml). The combined organic phases were dried over sodium sulfate, filtered and concentrated, and the residue was dried in vacuo. 700 mg (90% pure, 19% thor.) of the title compound were obtained.

LC-MS (Method 2): Rt = 0.63 min; MS (ESIpos): m/z = 236 [M+H]+.

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.366 (16.00), 1.384 (0.46), 1.399 (0.45), 2.282 (4.17), 3.451 (0.41), 7.019 (0.47), 7.049 (1.41) , 7.068 (0.54), 7.185 (0.44), 7.203 (0.64).

1H-NMR (400 MHz, DMSO-d6): δ [ppm] = 7.25-7.15 (m, 1H), 7.09-6.99 (m, 3H), 3.45 (dd, 1H), 3.02 (dd, 1H), 2.71 (dd, 1H), 2.28 (s, 3H), 1.37 (s, 9H).

Example 88A. (+/-)-tert-Butyl-3-amino-2-(2-fluoro-6-methoxyphenyl)propanoate (racemate)

A solution of (+/-)-tert-butylcyano(2-fluoro-6-methoxyphenyl)acetate (1.04 g, 62% pure, 2.43 mmol, Example 21A) in acetic acid (10 ml) was mixed with palladium on charcoal (26 mg , 10% purity, 24.3 µmol) and hydrogenated for 24 h at normal pressure. The catalyst was then filtered through silica gel and washed twice with acetic acid (corresponding to 2 ml). The filtrate was diluted with water (100 ml) and extracted twice with ethyl acetate (respectively 50 ml). The aqueous phase was then adjusted to pH 8 with sodium hydroxide solution 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 was dried in vacuo. 222 mg (71% pure, 24% thor.) of the title compound were obtained.

LC-MS (Method 1): Rt = 0.96 min; MS (ESIpos): m/z = 270 [M+H]+.

Example 89A. (+/-)-tert-Butyl-3-amino-2-(2-methoxyphenyl)-2-methylpropanoate (racemate)

A solution of (+/-)-tert-butyl-2-cyano-2-(2-methoxyphenyl)propanoate (1.30 g, 4.97 mmol, example 22A) in tert-butanol (25 ml) was mixed with Raney nickel (292 mg, 4.97 mmol) and hydrogenated overnight at normal pressure. The catalyst was then filtered through silica gel and the mother liquor was concentrated. The residue was dried in vacuo. 1.31 g (70% pure, 69% th. y.) of the title compound was obtained.

LC-MS (Method 1): Rt = 1.02 min; MS (ESIpos): m/z = 266 [M+H]+.

Example 90A. (+/-)-tert-Butyl-3-amino-2-(2-chloro-6-fluorophenyl)-2-methylpropanoate (racemate)

A solution of (+/-)-tert-butyl-2-(2-chloro-6-fluorophenyl)-2-cyanopropanoate (1.30 g, 4.58 mmol, example 23A) in tert-butanol (26 ml) was mixed with Raney nickel ( 269 mg, 4.58 mmol) and hydrogenated overnight at normal pressure. The catalyst was then filtered through silica gel and the mother liquor was concentrated. The residue was dried in vacuo. 1.25 g (70% pure, 67% th. y.) of the title compound was obtained.

LC-MS (Method 1): Rt = 1.08 min; MS (ESIpos): m/z = 288 [M+H]+.

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Example 91A. (+/-)-tert-Butyl-4-amino-3-(2-chlorophenyl)butanoate (racemate)

A solution of (+/-)-tert-butyl-3-(2-chlorophenyl)-3-cyanopropanoate (100 mg, 376 µmol, Example 24A) in tert-butanol (10 ml) was mixed with Raney nickel (22 mg, 376 µmol) and hydrogenated overnight at normal pressure. The catalyst was then filtered through silica gel and the mother liquor was purified by preparative HPLC (Method 22). Received 87 mg (purity 100%, 86% theoretical. out.) specified in the title compound.

LC-MS (Method 1): Rt = 0.99 min; MS (ESIpos): m/z = 270 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 1.200 (16.00), 1.212 (0.81), 2.683 (0.47), 2.708 (0.49), 2.811 (0.49), 2.825 (0.51), 3.053 (0.47 ), 7.305 (0.48), 7.308 (0.50), 7.365 (0.52), 7.460 (1.19), 7.480 (0.88), 7.483 (0.77), 7.939 (0.44).

Example 92A. (+/-)-tert-Butyl-4-amino-3-(3-chlorophenyl)butanoate (racemate)

A solution of (+/-)-tert-butyl-3-(3-chlorophenyl)-3-cyanopropanoate (710 mg, 2.67 mmol, Example 25A) in tert-butanol (11.6 ml) was mixed with Raney nickel (157 mg, 2.67 mmol) and hydrogenated overnight at normal pressure. The catalyst was then filtered through silica gel and the mother liquor was concentrated. The residue was dried in vacuo. 294 mg (40% purity, 16% thor.) of the title compound were obtained.

LC-MS (Method 1): R _t = 1.39 min; MS (ESIpos): m/z = 270 [M+H] ⁺ .

Example 93A. (+/-)-tert-Butyl-4-amino-3-(2-methylphenyl)butanoate (racemate)

A solution of (+/-)-tert-butyl-3-cyano-3-(2-methylphenyl)propanoate (850 mg, 3.46 mmol, example 26A) in tert-butanol (15 ml) was mixed with Raney nickel (203 mg, 3.46 mmol) and hydrogenated overnight at normal pressure. The catalyst was then filtered through silica gel and the mother liquor was concentrated. 724 mg (95% pure, 80% thor.) of the title compound were obtained.

LC-MS (Method 4): Rt = 1.32 min; MS (ESIpos): m/z = 250 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6): δ [ppm] = 7.18-7.02 (m, 4H), 3.31-3.22 (m, 1H), 2.76 (dd, 1H), 2.70-2.55 (m, 2H) , 2.40 (dd, 1H), 2.32 (s, 3H), 1.18 (s, 9H).

Example 94A. (+/-)-tert-Butyl-4-amino-3-(2,6-dichlorophenyl)butanoate (racemate)

A solution of (+/-)-tert-butyl-3-cyano-3-(2,6-dichlorophenyl)propanoate (680 mg, 2.27 mmol, Example 27A) in tert-butanol (10 ml) was mixed with Raney nickel (133 mg, 2.27 mmol) and hydrogenated overnight at normal pressure. The catalyst was then filtered through silica gel and the mother liquor was concentrated. The residue was purified by preparative HPLC (Method 25). 255 mg (94% pure, 35% thor.) of the title compound were obtained.

LC-MS (Method 4): Rt = 1.46 min; MS (ESIpos): m/z = 304 [M+H] ⁺ .

Example 95A. (+/-)-tert-Butyl-4-amino-3-(3-methoxyphenyl)butanoate (racemate)

A solution of (+/-)-tert-butyl-3-cyano-3-(3-methoxyphenyl)propanoate (389 mg, 1.49 mmol, example 28A) in tert-butanol (6.5 ml) was mixed with Raney nickel (88 mg, 1.49 mmol) and hydrogenated overnight at normal pressure. The catalyst was then filtered through silica gel and the mother liquor was concentrated and dried in vacuo. Received 500 mg (90% purity, >100% theory. yield. containing solvent) indicated in the title compound.

LC-MS (Method 4): R _t = 1.26 min; MS (ESIpos): m/z = 266 [M+H]+.

Example 96A (+/-)-tert-Butyl-4-amino-3-(3-chloropyridin-2-yl)-3-methylbutanoate (racemate)

A solution of (+/-)-tert-butyl-3-(3-chloropyridin-2-yl)-3-cyanobutanoate (1.00 g, 3.56 mmol, example 29A) in tert-butanol (21 ml) was mixed with Raney nickel ( 209 mg, 3.56 mmol) and hydrogenated overnight at normal pressure. The catalyst was then filtered through silica gel and the mother liquor was purified by preparative HPLC (Method 16). 616 mg (100% pure, 61% thor.) of the title compound were obtained.

LC-MS (Method 2): R _t = 0.62 min; MS (ESIpos): m/z = 285 [M+H]+.

Example 97A. (+/-)-tert-Butyl-4-amino-3-(2-chloro-6-fluorophenyl)butanoate (racemate)

Method A

A solution of (+/-)-tert-butyl-3-(2-chloro-6-fluorophenyl)-3-cyanopropanoate (870 mg, 3.07 mmol, example 30A) in tert-butanol (13.4 ml) was mixed with Raney nickel ( 180 mg, 3.07 mmol) and hydrogenated for three days at normal pressure. The catalyst was then filtered through silica gel and the mother liquor was concentrated. 551 mg (30% pure, 19% thor.) of the title compound were obtained.

LC-MS (Method 1): R _t = 1.02 min; MS (ESIpos): m/z = 288 [M+H]+.

Method B

A solution of (+/-)-tert-butyl-3-(2-chloro-6-fluorophenyl)-3-cyanopropanoate (43.9 g, 79% pure, 122 mmol, Example 30A) in tert-butanol (500 ml) was mixed with Raney nickel (7.15 g, 122 mmol) and hydrogenated for four days at normal pressure. Raney nickel (7.15 g, 122 mmol) was then added again and the mixture was hydrogenated for another day at normal pressure. The catalyst was then filtered through silica gel and washed twice with t-butanol (15 ml). The filtrate was concentrated and the residue was adsorbed into ethyl acetate (300 ml) and extracted twice with 1M hydrochloric acid (250 ml). The combined aqueous phases were adjusted to pH 8-9 with saturated sodium carbonate solution and extracted twice with ethyl acetate (200 ml). The combined organic phases were dried over sodium sulfate, filtered and concentrated. 20.11 g (98% 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]+.

1H-NMR (400 MHz, DMSO-d^): δ [ppm] = 7.36-7.22 (m, 2H), 7.21-7.07 (m, 1H), 3.73-3.54 (m, 1H), 2.872.72 (m , 3H), 2.70-2.56 (m, 1H), 1.20 (s, 9H).

Example 98A. (+/-)-tert-Butyl-4-amino-3-(4-methylphenyl)butanoate (racemate)

A solution of (+/-)-tert-butyl-3-cyano-3-(4-methylphenyl)propanoate (280 mg, 90% pure, 1.03 mmol, Example 31A) in tert-butanol (4.5 ml) was mixed with Raney nickel (60 mg, 1.03 mmol) and hydrogenated overnight at normal pressure. The catalyst was then filtered through silica gel and the mother liquor was concentrated. 106 mg (97% pure, 40% theoretical) of the title compound were obtained.

LC-MS (Method 2): Rt = 0.66 min; MS (ESIpos): m/z = 250 [M+H]+.

Example 99A. (+/-)-tert-Butyl-4-amino-3-(3-methylphenyl)butanoate (racemate)

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A solution of (+/-)-tert-butyl-3-cyano-3-(3-methylphenyl)propanoate (174 mg, 709 µmol, example 32A) in tert-butanol (3.1 ml) was mixed with Raney nickel (42 mg, 709 µmol) and hydrogenated overnight at normal pressure. The catalyst was then filtered through silica gel and the mother liquor was concentrated. 171 mg (77% pure, 74% thor.) of the title compound were obtained.

LC-MS (Method 1): Rt = 1.02 min; MS (ESIpos): m/z = 250 [M+H] ⁺ .

Example 100A. (+/-)-tert-Butyl-4-amino-3-(2-methoxyphenyl)butanoate (racemate)

A solution of (+/-)-tert-butyl-3-cyano-3-(2-methoxyphenyl)propanoate (4.80 g, 18.4 mmol, example 33A) in tert-butanol (80 ml) was mixed with Raney nickel (1.08 g, 18.4 mmol) and hydrogenated overnight at normal pressure. The catalyst was then filtered through silica gel and the mother liquor was concentrated. 4.23 g (92% pure, 80% th. y.) of the title compound were obtained.

LC-MS (Method 2): Rt = 0.57 min; MS (ESIpos): m/z = 266 [M+H] ⁺ .

'H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 7.21-7.14 (m, 1H), 7.11 (dd, 1H), 6.94 (d, 1H), 6.87 (td, 1H), 3.76 (s, 3H), 3.45-3.33 (m, 1H), 2.75-2.65 (m, 2H), 2.61 (dd, 1H), 2.43 (dd, 1H), 1.22 (s, 9H).

Example 101A. (+/-)-tert-Butyl-4-amino-3-[2-(trifluoromethoxy)phenyl]butanoate (racemate)

A solution of (+/-)-tert-butyl-3-cyano-3-[2-(trifluoromethoxy)phenyl]propanoate (6.70 g, 65% pure, 13.8 mmol, Example 34A) in tert-butanol (14 ml) was mixed with Raney nickel (669 mg, 11.4 mmol) and hydrogenated for 24 h at normal pressure. The catalyst was then filtered through silica gel and the mother liquor was concentrated. The residue was adsorbed into ethyl acetate and extracted twice with 1M hydrochloric acid. The combined aqueous phases were made basic with 20% sodium hydroxide solution and then extracted twice with ethyl acetate. The combined organic phases were dried over magnesium sulfate, filtered and concentrated, and the residue was dried in vacuo. 700 mg (100% pure, 16% thor.) of the title compound were obtained.

LC-MS (Method 2): Rt = 0.71 min; MS (ESIpos): m/z = 320 [M+H] ⁺ .

'H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 7.46-7.39 (m, 1H), 7.38-7.26 (m, 3H), 3.43-3.33 (m, 1H), 2.80 (dd, 1H), 2.75-2.59 (m, 2H), 2.42 (dd, 1H), 1.22 (s, 9H).

Example 102A. (+/-)-tert-Butyl-4-amino-3-(pyridin-2-yl)butanoate (racemate)

A solution of (+/-)-tert-butyl-3-cyano-3-(pyridin-2-yl)propanoate (1.90 g, 8.18 mmol, example 35A) in tert-butanol (35 ml) was mixed with Raney nickel (480 mg, 8.18 mmol) and hydrogenated overnight at normal pressure. The catalyst was then filtered through silica gel and the mother liquor was concentrated. The residue was purified by preparative HPLC [column: XBridge C18, 5 µm, 100 mm x 30 mm; flow: 75 ml/min; detection: 210 nm; temperature: 40°C; sample injection: 0.60 ml; eluent: 90% water/5% (acetonitrile/water 8:2) + 1% ammonia/5% acetonitrile x 0% water/5% (acetonitrile/water 8:2) + 1% ammonia/95% acetonitrile; duration of action 8.5 min]. 559 mg of the first batch of the title compound (80% pure, 23% of theory, siehe LC-MS) and 383 mg of the second batch of the title compound (27% pure, 5% of theory) were obtained.

LC-MS (Method 4): R _t = 1.06 min; MS (ESIpos): m/z = 237 [M+H] ⁺ .

Example 103A. (+/-)-tert-Butyl-4-amino-3-[2-(trifluoromethyl)phenyl]butanoate (racemate)

A solution of (+/-)-tert-butyl-3-cyano-3-[2-(trifluoromethyl)phenyl]propanoate (2.00 g, 6.68 mmol, example 36A) in tert-butanol (39 ml) was mixed with Raney nickel ( 392 mg, 6.68 mmol) and hydrogenated overnight at normal pressure. Raney nickel (392 mg, 6.68 mmol) was then added again and the mixture was hydrogenated for an additional 24 hours at normal pressure. The catalyst was then filtered off through silica gel, the filtrate was concentrated and the residue was dried in vacuo. 1.90 g (purity 60%, 56% th. y.) of the title compound was obtained.

LC-MS (Method 1): Rt = 1.16 min; MS (ESIpos): m/z = 304 [M+H]+.

Example 104A. (+/-)-tert-Butyl-4-amino-3-(3-methoxypyridin-2-yl)butanoate (racemate)

A solution of (+/-)-tert-butyl-3-cyano-3-(3-methoxypyridin-2-yl)propanoate (2.20 g, 8.39 mmol, example 37A) in tert-butanol (37 ml) was mixed with Raney nickel (492 mg, 8.39 mmol) and hydrogenated overnight at normal pressure. The catalyst was then filtered through silica gel and the mother liquor was concentrated and dried in vacuo. 2.02 g (95% pure, 86% th. y.) of the title compound was obtained.

LC-MS (Method 4): Rt = 1.12 min; MS (ESIpos): m/z = 267 [M+H] ⁺ .

Example 105A. (+/-)-tert-Butyl-3-(2-chlorophenyl)-2,2-dimethyl-4-nitrobutanoate (racemate)

Cl-

About CH ₃

O H ₃ C SN ₃ ^SNz

To a 2M solution of LDA in THF/heptane/ethylbenzene in argon at -78°C was added slowly dropwise a solution of tert-butyl-2-methylpropanoate (511 mg, 3.54 mmol) in THF (2 ml) and the mixture was stirred for 30 min at - 78°C. Then a solution of 1-chloro-2-(2-nitrovinyl)benzene (500 mg, 2.72 mmol, CAS-Nummer 3156-34-1) in THF (2 ml) was added dropwise and the mixture was further stirred for 30 min at -78°C . The mixture was then mixed with anhydrous acetic acid and then with water, brought to RT and then extracted several times with ethyl acetate. The combined organic phases were washed once with brine, dried over magnesium sulfate, filtered and concentrated, and the residue was purified by flash column chromatography (50 g Biotage Snap-Cartridge KP-Sil, 80:20 cyclohexane/ethyl acetate). 590 mg (88% pure, 58% thor.) of the title compound were obtained.

LC-MS (Method 7): Rt = 1.61 min; MS (ESIneg): m/z = 326 [M-H]-.

1H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 7.54 (dd, 1H), 7.47 (dd, 1H), 7.40-7.28 (m, 2H), 5.14 (dd, 1H), 4.91 ( dd, 1H), 4.49 (dd, 1H), 1.42 (s, 9H), 1.08 (s, 3H), 1.06 (s, 3H).

Example 106A. (+/-)-tert-Butyl-4-amino-3-(2-chlorophenyl)-2,2-dimethylbutanoate (racemate) /Ώ сг'ц- ^х о сн3 ^H 2N^LA.O^) -CH ₃ H ₃ C CH ₃ ^CH 3

A solution of (+/-)-tert-butyl-3-(2-chlorophenyl)-2,2-dimethyl-4-nitrobutanoate (595 mg, 1.82 mmol, example 105A) in methanol (10 mL) was mixed with Raney nickel ( ca 200 mg, 3.4 mmol) and hydrogenated for 3 hours at normal pressure. The catalyst was then filtered through silica gel, washed with methanol and the mother liquor was purified by preparative HPLC (Method: Chromatorex C18, 10 µm, 30 x 125 mm, acetonitrile/(water + 0.005% ammonia)-gradient: acetonitrile 10%^90%). 320 mg (purity 100%, 86% of theory) of the title compound were obtained.

LC-MS (Method 8): R _t = 5.00 min; MS (ESIpos): m/z = 298 [M+H] + LC-MS (Method 7): R _t = 0.86 min; MS (ESIpos): m/z = 242 [M-tBu+H]+.

1H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 7.45 (dd, 1H), 7.39-7.30 (m, 2H), 7.28-7.22 (m, 1H), 3.72 (dd, 1H), 2.98-2.89 (m, 1H), 2.85-2.79 (m, 1H), 1.40 (s, 9H), 1.01 (s, 3H), 0.97 (s, 3H).

Example 107A. (+/-)-tert-Butyl-4-amino-3-(2-chlorophenyl)-3-methylbutanoate (racemate)

A solution of (+/-)-tert-butyl-3-(2-chlorophenyl)-3-cyanobutanoate (5.00 g, 17.9 mmol, example 38A) in tert-butanol (100 ml) was mixed with Raney nickel (1.05 g, 17.9 mmol) and hydrogenated for 24 h at normal pressure. The catalyst was then filtered through silica gel, the mother liquor was concentrated and the residue was dried in vacuo. 3.58 g (70% pure, 49% th. y.) of the title compound were obtained.

- 60 040284

LC-MS (Method 1): Rt = 1.05 min; MS (ESIpos): m/z = 284 [M+H]+.

Example 108A. (+/-)-tert-Butyl-4-amino-3-(2-fluorophenyl)-3-methylbutanoate (racemate)

A solution of (+/-)-tert-butyl-3-(2-chloro-6-fluorophenyl)-3-cyanobutanoate (4.00 g, 13.4 mmol, example 39A) in tert-butanol (76 ml) was mixed with Raney nickel ( 789 mg, 13.4 mmol) and hydrogenated overnight at normal pressure. The catalyst was then filtered through silica gel, the mother liquor was concentrated and the residue was flash column chromatographed (100 g Biotage Snap-Cartridge KP-Sil, cyclohexane/ethyl acetate 85:15). The combined desired fractions were concentrated and the residue was dried in vacuo. 2.51 g (75% pure, 51% theoretical) of the title compound was obtained in a mixture with tert-butyl-4-amino-3-(2-chloro-6-fluorophenyl)-3-methylbutanoate (containing up to 10% according to LC-MS).

LC-MS (Method 1): Rt = 0.90 min; MS (ESIpos): m/z = 268 [M+H]+.

Example 109A. (+/-)-tert-Butyl-4-amino-3-methyl-3-(pyridin-2-yl)butanoate (racemate)

A solution of (+/-)-tert-butyl-3-(3-chloropyridin-2-yl)-3-cyanobutanoate (14.8 g, 52.7 mmol), example 29A) in tert-butanol (300 ml) was mixed with Raney nickel (3.09 g, 52.7 mmol) and hydrogenated overnight at normal pressure. The catalyst was then filtered through silica gel, the mother liquor was concentrated and the residue was purified by preparative HPLC (Method 16). 5.55 g of a fraction were isolated, in which the predominantly unreacted educt (+/-)-tert-butyl-3-(3-chloropyridin-2-yl)-3-cyanobutanoate was obtained. This fraction was redissolved in tert-butanol (200 ml), mixed with Raney nickel (3.09 g, 52.7 mmol) and hydrogenated overnight at normal pressure. The catalyst was then filtered through silica gel. The mother liquor was concentrated and the residue was dried in vacuo. 4.0 g of the title compound (11% pure, ca. 3% tho.) was obtained in admixture with tert-butyl 4-amino-3-(3-chloropyridin-2-yl)-3-methylbutanoate (containing up to 10% according to LCMS). This mixture was used directly (without further purification) in the appropriate subsequent reactions (see example 203A).

LC-MS (Method 2): Rt = 0.54 min; MS (ESIpos): m/z = 251 [M+H]+.

Example 110A. (+/-)-tert-Butyl-4-amino-3-(2-methoxyphenyl)-3-methylbutanoate (racemate)

A solution of (+/-)-tert-butyl-3-cyano-3-(2-methoxyphenyl)butanoate (7.00 g, 25.4 mmol, example 40A) in tert-butanol (140 ml) was mixed with Raney nickel (1.49 g, 25.4 mmol) and hydrogenated overnight at normal pressure. The catalyst was then filtered through silica gel, the mother liquor was concentrated and the residue was dried in vacuo. 5.52 g (92% pure, 72% th. y.) of the title compound were obtained.

LC-MS (Method 2): Rt = 0.63 min; MS (ESIpos): m/z = 280 [M+H]+.

Example 111A. (+/-)-tert-Butyl-4-amino-3-(5-fluoro-2-methoxyphenyl)butanoate hydrochloride

A solution of (+/-)-tert-butyl-3-cyano-3-(5-fluoro-2-methoxyphenyl)propanoate (150 mg, 537 µmol, Example 41A) in methanol (10 ml) under nitrogen was mixed with concentrated hydrochloric acid (150 µl, 12 M, 1.8 mmol), then with platinum dioxide (29 mg, 83% purity, 107 µmol) and then hydrogenated for 1 h at normal pressure. The catalyst was then filtered through silica gel, the mother liquor was concentrated and the residue was dried in vacuo. In a repeat experiment, a solution of (+/-)-tert-butyl-3-cyano-3-(5-fluoro-2-methoxyphenyl)propanoate (775 mg, 2.78 mmol, example 41A) in methanol (50 ml) was mixed with concentrated hydrochloric acid (0.55 ml, 12 M, 6.58 mmol), then with platinum dioxide (106 mg, 83% purity, 387 µmol) and hydrogenated for 2 h at normal pressure. The catalyst was then filtered through silica gel, the mother liquor was concentrated and the residue was dried in vacuo.

- 61 040284

The residues from both experiments were combined and partitioned between dichloromethane and saturated sodium bicarbonate. After phase separation, the aqueous phase was extracted twice with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated and the residue was purified by flash column chromatography (40 g Reveleris silica gel, dichloromethane/(10% methanol in dichloromethane) 100:0^16:84). The combined target fractions were concentrated and mixed successively with t-butyl methyl ether three times and re-concentrated. The residue was dissolved in tert-butyl methyl ether and mixed with 1M hydrochloric acid in diethyl ether (1.94 ml, 1.94 mmol) and stirred for 30 min at RT. The suspension was then concentrated, then admixed twice successively with tert-butyl methyl ether and re-concentrated and the residue dried in vacuo. Received 541 mg (purity 98%, 50% theoretical. yield, based on the amount of (+/-)-tert-butyl-3-cyano-3-(5-fluoro-2-methoxyphenyl)-propanoate used) specified in connection header.

LC-MS (Method 9): R, = 2.35 min; MS (ESIpos): m/z = 284 [M-HCl+H] ⁺ .

'H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.98 (br. s, 3H), 7.15-6.95 (m, 3H), 3.79 (s, 3H), 3.70-3.60 (m, 1H ), 3.01 (br. s, 2H), 2.76 (dd, 1H), 2.62 (dd, H), 1.22 (s, 9H).

Example 112A. (+/-)-tert-Butyl-4-amino-3-(2-fluoro-6-methoxyphenyl)butanoate (racemate)

A solution of (+/-)-tert-butyl-3-cyano-3-(2-fluoro-6-methoxyphenyl)propanoate (1.00 g, 93% pure, 3.34 mmol, Example 42A) in methanol (30 mL) was mixed with platinum dioxide (152 mg, 667 µmol) and hydrogenated for 3 h at normal pressure. The mixture was then mixed with 1M hydrochloric acid (3.3 ml, 3.3 mmol) and hydrogenated for an additional 17 hours at normal pressure. The catalyst was then filtered through silica gel and the filtrate was mixed with saturated sodium hydrogen carbonate solution and water (respectively 30 ml) and extracted twice with dichloromethane (respectively 50 ml). The combined organic phases were dried over magnesium sulfate, filtered and concentrated, and the residue was dried in vacuo. 799 mg (82% pure, 69% thor.) of the title compound were obtained.

LC-MS (Method 1): R = 1.02 min; MS (ESIpos): m/z = 284 [M+H] ⁺ .

Example 113A. (+/-)-tert-Butyl-4-amino-3-(2-ethoxyphenyl)butanoate hydrochloride (racemate)

A solution of (+/-)-tert-butyl-3-cyano-3-(2-ethoxyphenyl)propanoate (150 mg, 537 µmol, Example 43A) in methanol (140 ml) under nitrogen was mixed with platinum dioxide (384 mg , 83% pure, 1.40 mmol) and concentrated hydrochloric acid (580 μl, 12M, 7.0 mmol) and then hydrogenated for 4 h at normal pressure. The catalyst was then filtered off and the filtrate partitioned between dichloromethane and saturated sodium hydrogen carbonate solution. After phase separation, the aqueous phase was extracted twice with dichloromethane. The combined organic phases were dried over sodium sulfate and filtered. The filtrate was mixed with a 2M solution of hydrogen chloride in diethyl ether (3.5 ml, 7.0 mmol), concentrated and then mixed with dichloromethane and re-concentrated. The residue was taken up in acetonitrile, the solution was concentrated again and the residue was dried in vacuo.

After removal of 200 mg of residue for purification tests, 1.80 g (90% pure, 73% thor.) of the title compound was then obtained.

LC-MS (Method 10): Rt = 2.08 min; MS (ESpos): m/z = 280 [M-HCl+H]+.

'H-NMR (400 MHz, DMSO-d6) δ [ppm]: 8.89 (br. s, 3H), 7.24 (dd, 1H), 7.18 (d, 1H), 6.95 (d, 1H), 6.91 (dd , 1H), 4.05 (q, 2H), 3.62-3.53 (m, 1H), 3.04 (d, 2H), 2.75 (dd, 1H), 2.66 (dd, 1H), 1.38 (t, 3H, partially hidden) , 1.20 (s, 9H).

Example 114A. (+/-)-tert-Butyl-4-amino-3-(5-fluoro-2-methoxyphenyl)-3-methylbutanoate hydrochloride (racemate)

A solution of (+/-)-tert-butyl-3-cyano-3-(5-fluoro-2-methoxyphenyl)butanoate (1.38 g, 4.69 mmol, Example 44A) in methanol (95 ml) under nitrogen was mixed with concentrated hydrochloric acid (390 μl, 12 M, 4.7 mmol), then with platinum dioxide (257 mg, 83% purity, 938 μmol) and then hydrogenated for 2.5 h at normal pressure. The catalyst was then filtered off and the filtrate partitioned between dichloromethane and saturated sodium hydrogen carbonate solution. After phase separation, the aqueous phase was extracted twice with dichloromethane. The combined organic phases were dried over sodium sulfate and filtered. The filtrate was then mixed with a 2M solution of hydrogen chloride in diethyl ether (2.3 ml, 4.7 mmol), concentrated and mixed twice successively with dichloromethane and re-concentrated. The residue was dried in vacuo. 1.33 g (95% pure, 81% th. y.) of the title compound was obtained.

LC-MS (Method 11): Rt = 2.39 min; MS (ESpos): m/z = 298 [M-HCl+H] ⁺ .

1H-NMR (400 MHz, CDCl ₃ ): δ [ppm] = 7.96 (br. s, 3H), 7.10-6.90 (m, 2H), 6.88-6.80 (m, 1H), 3.86 (s, 3H), 3.48 (d, 1H), 3.14 (d, 1H), 3.03 (d, 1H), 2.58 (d, 1H), 1.62 (s, 3H), 1.22 (s, 9H).

Example 115A. (+/-)-tert-Butyl-4-amino-3-(3,5-difluoro-2-methoxyphenyl)-3-methylbutanoate hydrochloride (racemate)

JL JI ³ O CH ₃ xHCI

NzS-L^1 ₀ ^sn ₃

H sn ₃ nh ₂ ³

A solution of (+/-)-tert-butyl-3-cyano-3-(3,5-difluoro-2-methoxyphenyl)butanoate (1.54 g, 4.95 mmol, Example 45A) in methanol (100 mL) under nitrogen was mixed with platinum dioxide hydrate (242 mg, 989 µmol), then with a solution of concentrated hydrochloric acid (410 µl, 12 M, 4.9 mmol) in water (4.5 ml) and then hydrogenated for 4 h at normal pressure. The catalyst was then filtered off and the filtrate was divided into two portions and washed in succession with saturated sodium hydrogen carbonate solution and extracted twice with dichloromethane. The combined organic phases were suitably dried over sodium sulfate and filtered. After addition of a 1M solution of hydrogen chloride in diethyl ether (total 5 ml, proportionally divided into two portions), the resulting mixture was suitably concentrated and the residue was suitably dried in vacuo. Both resulting residues were combined. 1.50 g (96% pure, 83% th. y.) of the title compound was obtained.

LC-MS (Method 11): Rt = 2.43 min; MS (ESpos): m/z = 316 [M-HCl+H] ⁺ .

1H-NMR (400 MHz, CDCl ₃ ): δ [ppm] = 8.11 (br. s, 3H), 6.90-6.70 (m, 2H), 4.00 (s, 3H), 3.42 (dd, 1H), 3.17 ( dd, 1H), 3.00 (d, 1H), 2.60 (d, 1H), 1.62 (s, 3H), 1.27 (s, 9H).

Example 116A. (+/-)-tert-Butyl-4-amino-3-(4-fluoro-2-methoxyphenyl)-3-methylbutanoate hydrochloride (racemate)

F

About CH ₃ xHCI

Ν ^Γ Η ₂ ^SNz

A solution of (+/-)-tert-butyl-3-cyano-3-(4-fluoro-2-methoxyphenyl)butanoate (3.02 g, 10.3 mmol, example 46A) in methanol (200 ml) under nitrogen atmosphere was mixed with the hydrate platinum dioxide (563 mg, 83% purity, 2.06 mmol), then with concentrated hydrochloric acid (860 μl, 12M, 10 mmol) and then hydrogenated for 4 h at normal pressure. The catalyst was then filtered off and the filtrate was washed with saturated sodium hydrogen carbonate solution and extracted twice with dichloromethane. The combined organic phases were dried over sodium sulfate and filtered. After adding a 2M solution of hydrogen chloride in diethyl ether (5.2 ml), the resulting mixture was concentrated and the residue was dried in vacuo. 3.02 g (99% pure, 87% th. y.) of the title compound was obtained.

LC-MS (Method 11): Rt = 3.01 min; MS (ESpos): m/z = 298 [M-HCl+H] ⁺ .

1H-NMR (400 MHz, CDCl3): δ [ppm] = 7.90 (br. s, 3H), 7.20-7.15 (m, 1H), 6.65-6.55 (m, 2H), 3.87 (s, 3H), 3.40 (m, 1H), 3.13 (m, 1H), 2.96 (d, 1H), 2.58 (d, 1H), 1.62 (s, 3H), 1.22 (s, 9H).

Example 117A. (+/-)-Ethyl-2,2-difluoro-3-(2-methoxyphenyl)-4-nitrobutanoate (racemate)

H ₃ C _X J^JI ³ ο ο

Ο=Ν ⁺ FF δ ^-

In a heated flask under argon, a swollen suspension of Riquet's zinc (ca. 5 ml, ca. 500 mg, ca. 7.7 mmol) was heated to 80°C and mixed dropwise with ethyl bromo(difluoro)acetate (740 μl, 5.6 mmol). After an additional 5 min at 80°C, 1-methoxy-2-[(E)-2-nitrovinyl]benzene (500 mg, 2.79 mmol) was added and stirred for an additional 15 min at 80°C. The mixture was then brought to RT and mixed with 1M hydrochloric acid (approx. 20 ml). After the zinc residues were dissolved, the mixture was extracted with ethyl acetate. The organic phase was washed with saturated aqueous sodium chloride solution, dried

- 63 040284 over sodium sulfate, filtered and concentrated. The residue was purified by flash column chromatography (50 g Biotage Snap-Cartridge KP-Sil, cyclohexane/ethyl acetate gradient

1:0 ^ 10:1). The combined target fractions were concentrated and the residue was lyophilized. Got

105 mg (47% pure, 3% theoretical) of the title compound.

LC-MS (Method 7): R _t = 1.31 min; MS (ESIneg): m/z = 302 [MH] ^- .

Example 118A. (+/-)-Ethyl-4-amino-2,2-difluoro-3-(2-methoxyphenyl)butanoate hydrochloride (racemate) |n ₃ s.

³ O x HCl

NH ₂ F ^F

A mixture of (+/-)-ethyl-2,2-difluoro-3-(2-methoxyphenyl)-4-nitrobutanoate (95 mg, 313 µmol, uncorrected purity, Example 117A) in a mixture of methanol (3 ml) and 1M hydrochloric acid (630 µl) was mixed with platinum dioxide (30 mg, 132 µmol) and hydrogenated overnight. Platinum dioxide (30 mg, 132 µmol) and 1M hydrochloric acid (1 ml) were then added again and the mixture was hydrogenated for an additional 3 days at RT. The mixture was then filtered through silica gel and concentrated. The residue was mixed successively with dichloromethane several times and re-concentrated. After drying in vacuo, 80 mg (35% pure, 33% theoretical) of the title compound were obtained.

LC-MS (Method 7): Rt = 0.72 min; MS (ESIpos): m/z = 274 [M+H] ⁺ .

Example 119A. (+/-)-tert-Butyl-4-amino-3-(2-fluoro-6-methoxyphenyl)-3-methylbutanoate (racemate) o ch ₃ ⁿ 3C-D% O- ^ch z G ch3 nh ₂ ³

A solution of (+/-)-tert-butyl-3-cyano-3-(2-fluoro-6-methoxyphenyl)butanoate (798 mg, 79% pure, 2.14 mmol, Example 47A) in methanol (19 mL) was mixed with platinum dioxide (97.0 mg, 427 µmol) and then with 1 M hydrochloric acid (2.1 ml, 2.1 mmol) and then hydrogenated for 17 h at normal pressure. The catalyst was then filtered off and the filtrate with saturated sodium hydrogen carbonate solution and water (respectively 30 ml) was mixed and extracted twice with dichloromethane (respectively 50 ml). The combined organic phases were dried over sodium sulfate, filtered and concentrated, and the residue was dried in vacuo. 714 mg (82% pure, 92% th. y.) of the title compound were obtained.

LC-MS (Method 2): R _t = 0.66 min; MS (ESIpos): m/z = 298 [M+H] ⁺ .

Example 120A. tert-Butyl 4-amino-3-(2-chlorophenyl)pentanoate (mixture of diastereoisomers)

A solution of tert-butyl 3-(2-chlorophenyl)-4-nitropentanoate (602 mg, 1.92 mmol, example 48A) in ethanol (30 ml) was mixed at RT with 1 M hydrochloric acid (26.1 ml, 26.1 mmol) and zinc dust (5.01 g, 76.74 mmol) and stirred for one day at RT. The mixture was then adjusted to pH 9 with saturated sodium hydrogen carbonate solution (approx. 50 ml), mixed with water (50 ml) and ethyl acetate (100 ml) and shaken. The present solid was filtered through silica gel. The filtrate was separated into an organic and an aqueous phase and the aqueous phase was extracted once with ethyl acetate (50 ml). The combined organic phases were washed once with saturated aqueous sodium chloride solution (100 ml) and dried over sodium sulfate, filtered and concentrated. The residue was quickly dried in vacuo. 493 mg (74% pure, 67% thor.) of the title compound were obtained.

LC-MS (Method 2): R _t = 0.61 & 0.63 min; MS (ESIpos): respectively m/z = 284 [M+H] ⁺ .

Example 121A. (+/-)-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 49A) in tert-butanol (90 ml) was mixed with Raney nickel (944 mg, 16.1 mmol) and hydrogenated overnight at normal pressure. The mixture was then mixed again with Raney nickel (944 mg, 16.1 mmol) and hydrogenated for an additional 24 hours at normal pressure. 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 KP-Sil 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 4): R _t = 1.70 min; MS (ESIpos): m/z = 284 [M+H] ⁺ .

Example 122A. (+/-)-tert-Butyl-5-amino-4-(2-chlorophenyl)-4-methylpentanoate (racemate)

A solution of (+/-)-tert-butyl-4-(2-chlorophenyl)-4-cyanopentanoate (1.50 g, 5.11 mmol, example 50A) in tert-butanol (30 ml) was mixed with Raney nickel (300 mg, 5.11 mmol) and hydrogenated overnight at normal pressure. The mixture was then mixed again with Raney nickel (944 mg, 16.1 mmol) and hydrogenated for an additional 24 hours at normal pressure. The mixture was then mixed once more with Raney nickel (944 mg, 16.1 mmol) and hydrogenated for an additional 24 hours at normal pressure. Thereafter, the catalyst was filtered through silica gel and the mother liquor was concentrated. The residue was purified by preparative HPLC (Method 16). The combined desired fractions were concentrated and the residue was dried in vacuo. 840 mg (73% pure, 40% thor.) of the title compound were obtained.

LC-MS (Method 1): R _t = 1.22 min; MS (ESIpos): m/z = 298 [M+H] ⁺ .

Example 123A. (+/-)-tert-Butyl-5-amino-4-(2-chloro-6-fluorophenyl)pentanoate (racemate)

A solution of (+/-)-tert-butyl-4-(2-chloro-6-fluorophenyl)-4-cyanobutanoate (1.45 g, 4.87 mmol, example 51A) in tert-butanol (30 ml) was mixed with Raney nickel ( 286 mg, 4.87 mmol) and hydrogenated overnight at normal pressure. The mixture was then mixed again with Raney nickel (286 mg, 4.87 mmol) and hydrogenated for an additional 24 hours at normal pressure. Thereafter, the catalyst was filtered through silica gel and the mother liquor was concentrated. 1.28 g (67% pure, 58% th. y.) of the title compound was obtained.

LC-MS (Method 1): Rt = 1.19 min; MS (ESIpos): m/z = 302 [M+H] ⁺ .

Example 124A. (+/-)-tert-Butyl-5-amino-4-(2-methylphenyl)pentanoate (racemate)

A solution of (+/-)-tert-butyl-4-cyano-4-(2-methylphenyl)butanoate (534 mg, 2.06 mmol, example 52A) in tert-butanol (13 ml) was mixed with Raney nickel (121 mg, 2.06 mmol) and hydrogenated overnight at normal pressure. The catalyst was then filtered through silica gel and the mother liquor was concentrated. 505 mg (95% pure, 89% thor.) of the title compound were obtained.

LC-MS (Method 1): Rt = 1.18 min; MS (ESIpos): m/z = 264 [M+H] ⁺ .

Example 125A. (+/-)-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 53A) in tert-butanol (260 mL) was mixed with Raney nickel (2.57 g, 43.7 mmol) and hydrogenated overnight at normal pressure. The mixture was then mixed again with Raney nickel (2.57 g, 43.7 mmol) and hydrogenated for an additional 24 hours at normal pressure. 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. 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): Rt = 1.14 min; MS (ESIpos): m/z = 302 [M+H] ⁺ .

Example 126A. (+/-)-tert-Butyl-5-amino-4-(2-methoxyphenyl)pentanoate (racemate)

- 65 040284

A solution of (+/-)-tert-butyl-4-cyano-4-(2-methoxyphenyl)butanoate (495 mg, 1.80 mmol, Example 54A) 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 silica gel 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].

Example 127A. (+/-)-tert-Butyl-5-amino-4-(2-chloro-5-fluorophenyl)-4-methylpentanoate (racemate)

A solution of (+/-)-tert-butyl-4-(2-chloro-5-fluorophenyl)-4-cyanopentanoate (1.20 g, 3.85 mmol, example 55A) in tert-butanol (25 ml) was mixed with Raney nickel ( 226 mg, 3.85 mmol) and hydrogenated overnight at normal pressure. The catalyst was then filtered through silica gel and the mother liquor was concentrated. 1.54 g (66% pure, 84% th. y.) of the title compound was obtained.

LC-MS (Method 1): Rt = 1.24 min; MS (ESIpos): m/z = 316 [M+H] ⁺ .

Example 128A. (+/-)-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 56A) in tert-butanol (75 ml) was mixed with nickel Raney (762 mg, 13.0 mmol) and hydrogenated for 24 h at normal pressure. The catalyst was then filtered through silica gel, washed additionally 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 1M hydrochloric acid and water (respectively 80 ml). The combined aqueous phases were adjusted to pH 8-9 with saturated sodium hydrogen carbonate solution 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 was 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 129A. (+/-)-tert-Butyl-5-amino-4-(2-fluorophenyl)pentanoate (racemate)

A solution of (+/-)-tert-butyl-4-cyano-4-(2-fluorophenyl)butanoate (4.22 g, 16.0 mmol, uncorrected purity, example 57A) in tert-butanol (100 ml) was mixed with Raney nickel (941 mg, 16.0 mmol) and hydrogenated overnight at normal pressure. Then again mixed with Raney Nickel (941 mg, 16.0 mmol) and hydrogenated one more night at normal pressure. The catalyst was then filtered through silica gel and the mother liquor was concentrated. 3.02 g (60% pure, 42% th. y.) of the title compound was obtained.

LC-MS (Method 2): R _t = 0.61 min; MS (ESIpos): m/z = 268 [M+H] ⁺ .

Example 130A. (+/-)-tert-Butyl-5-amino-4-[2-(difluoromethoxy)phenyl]pentanoate (racemate)

A solution of (+/-)-tert-butyl-4-cyano-4-[2-(difluoromethoxy)phenyl]butanoate (3.85 g, 12.4 mmol, Example 58A) in tert-butanol (75 ml) was mixed with Raney nickel ( 726 mg, 12.4 mmol) and hydrogenated overnight at normal pressure. The catalyst was then filtered through silica gel and the mother liquor was concentrated. Yielded 2.92 g (80% pure, 60% th. y.) of the title

- 66 040284 connections.

LC-MS (Method 2): R _t = 0.68 min; MS (ESIpos): m/z = 316 [M+H]+.

Example 131A (+/-)-tert-Butyl-5-amino-4-(2,6-difluorophenyl)pentanoate (racemate)

A solution of (+/-)-tert-butyl-4-cyano-4-(2,6-difluorophenyl)butanoate (4.80 g, 17.1 mmol, example 59A) in tert-butanol (100 ml) was mixed with Raney nickel (1.00 g, 17.1 mmol) and hydrogenated overnight at normal pressure. The catalyst was then filtered through silica gel and the mother liquor was concentrated. 4.06 g (81% pure, 67% th. y.) of the title compound was obtained.

LC-MS (Method 2): R _t = 0.64 min; MS (ESIpos): m/z = 286 [M+H] ⁺ .

Example 132A. (+/-)-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 60A) in tert-butanol (85 ml) was mixed with Raney nickel ( 852 mg, 14.5 mmol) and hydrogenated overnight at normal pressure. The catalyst was then filtered through silica gel, washed additionally twice with t-butanol (15 ml) and the mother liquor was concentrated. The residue was adsorbed into ethyl acetate (80 ml) and extracted successively with 1M hydrochloric acid and water (respectively 80 ml). The pH of the combined aqueous phases was adjusted to 8-9 with saturated sodium hydrogen carbonate solution and extracted twice with ethyl acetate (80 ml). The combined organic phases were dried over sodium sulfate, filtered and concentrated, and the residue was 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 133A. (+/-)-tert-Butyl-N-[2-amino-1-(2-chlorophenyl)ethyl]-N-methylglycinate (racemate)

A solution of (+/-)-tert-butyl-N-[(2-chlorophenyl)(cyano)methyl]-N-methylglycinate (1.40 g, 4.75 mmol, example 61A) in tert-butanol (28 ml) was mixed with nickel Raney (279 mg, 4.75 mmol) and hydrogenated overnight at normal pressure. Raney nickel (279 mg, 4.75 mmol) was then added again and the mixture was hydrogenated for an additional 24 hours at normal pressure. The catalyst was then filtered through silica gel and the mother liquor was concentrated and the residue was dried in vacuo. 800 mg (41% pure, 23% thor.) of the title compound were obtained.

LC-MS (Method 1): R _t = 1.21 min; MS (ESIpos): m/z = 299 [M+H] ⁺ .

Example 134A. (+/-)-tert-Butyl-N-[2-amino-1-(2-chlorophenyl)ethyl]glycinate (racemate)

A solution of (+/-)-tert-butyl-K-[(2-chlorophenyl)(cyano)methyl]glycinate (1.40 g, 4.99 mmol, uncorrected purity, example 62A) in tert-butanol (29 ml) was mixed with Raney nickel (293 mg, 4.99 mmol) and hydrogenated overnight at normal pressure. The catalyst was then filtered through silica gel and the mother liquor was concentrated and the residue was dried in vacuo. 1.25 g (approx. 50% pure, 44% theoretical yield) of the title compound was obtained.

LC-MS (Method 2): R _t = 0.66 min; MS (ESIpos): m/z = 285 [M+H] ⁺ .

Example 135A. (+/-)-tert-Butyl-[2-(2-chlorophenyl)-2-hydroxyethyl]carbamate (racemate)

- 67 040284

Triethylamine (3.6 ml, 26 mmol) and di-tert- butyl dicarbonate (5.67 g, 26.0 mmol) (gas formation) and the mixture was stirred 18 h at RT. The mixture was then diluted with dichloromethane (100 ml), washed with dilute sodium hydrogen carbonate solution and saturated sodium chloride solution (respectively 100 ml), dried over sodium sulfate, filtered and concentrated, and the residue was dried in vacuo. 7.50 g (53% pure by GC-MS, 63% th. y.) of the title compound were obtained.

GC-MS (Method 12): Rt = 6.53 min, MS (EIpos): m/z = 215 [M-CHs]*.

Example 136A. (+/-)-Ethyl-[2-[(tert-butoxycarbonyl)amino]-1-(2-chlorophenyl)ethoxy]acetate (racemate)

O. NH o ⁿ ₃ s o n ₃ s-T sn ₃

To a solution of (+/-)-tert-butyl-[2-(2-chlorophenyl)-2-hydroxyethyl]carbamate (7.41 g, 85% pure, 23.2 mmol, Example 135A), in dichloroethane (50 ml) in argon ethyl diazoacetate (4.6 ml, 44 mmol) and rhodium(II) acetate-dimer were added at RT (gas formation) and the mixture was stirred 17 h at RT. Ethyl diazoacetate (4.6 ml, 44 mmol) was then added again and the mixture was stirred an additional four days at RT and then concentrated when a residue (residue 1) formed. One part of this residue 1 (ca. 1.4 g) was dissolved in dichloromethane (50 ml) and the solution was washed with water (50 ml) and dilute sodium hydrogen carbonate solution, dried over sodium sulfate, filtered and concentrated. The residue was adsorbed into dichloromethane and purified by flash column chromatography (50 g Biotage Snap-Cartridge Ultra silica gel, cyclohexane/ethyl acetate 97:3^7:3, Isolera One). Concentration and drying of the combined target fractions gave 300 mg (75% pure, 3% thor. y.) of the first batch of the title compound. The residual residue 1 (approx. 12 g) was adsorbed in dichloromethane and purified in two portions by flash column chromatography (corresponding to 100 g of Biotage Snap-Cartridge Ultra silica gel, cyclohexane/ethyl acetate 97:3 ^ 7:3, Isolera One). Concentration and drying of the combined target fractions yielded 2.89 g (86% pure, 31% th. y.) of a second batch of the title compound. 500 mg were taken from this second batch, dissolved in acetonitrile and further purified by preparative HPLC (Method 16). Target fractions were pooled and adjusted to pH 7-8 with saturated sodium bicarbonate solution. The acetonitrile phase was removed on a rotary evaporator and 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 dried in vacuo. 234 mg (100% pure) of additionally purified title compound was obtained (see Analysis section).

LC-MS (Method 1): R _t = 2.13 min; MS (ESIpos): m/z = 358 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.150 (0.11), 0.007 (0.79), 1.150 (3.98), 1.168 (8.32), 1.186 (4.12), 1.254 (1.35), 1.332 (16.00 ), 1.987 (1.08), 2.327 (0.14), 2.365 (0.15), 2.669 (0.14), 2.709 (0.15), 3.213 (1.08), 3.223 (1.17), 3.238 (0.75), 3.911 (1.58), 3.952 (2.73 ), 4.020 (0.28), 4.043 (1.39), 4.067 (1.23), 4.085 (3.99), 4.102 (3.21), 4.120 (1.04), 4.905 (0.64), 4.920 (0.93), 4.934 (0.49), 6.774 (0.68 ), 7.310 (0.28), 7.329 (0.82), 7.348 (0.84), 7.361 (0.83), 7.379 (1.24), 7.395 (0.57), 7.418 (1.21), 7.444 (1.55), 7.463 (0.85).

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 7.51-7.24 (m, 4H), 6.78 (t, 1H), 4.92 (t, 1H), 4.09 (q, 2H), 4.063.86 (m, 2H), 3.28-3.16 (m, 2H), 1.33 (s, 7H), 1.26 (br. s, 2H), 1.17 (t, 3H).

Example 137A. (+/-)-Ethyl-[2-amino-1-(2-chlorophenyl)ethoxy]acetate hydrochloride (racemate)

nh ₂ o (+/-)-Ethyl-[2-[(tert-butoxycarbonyl)amino]-1-(2-chlorophenyl)ethoxy]acetate (1.91 g, 5.34 mmol, Example 136A) was dissolved in a 4M solution of hydrogen chloride in dioxane and left for 2.5 h at RT. The mixture was then concentrated and mixed several times with dichloromethane and re-concentrated. The residue was dried in vacuo. 1.90 g (72% pure, 87% th. y.) of the title compound was obtained.

LC-MS (Method 2): R _t = 0.52 min; MS (ESIpos): m/z = 258 [M+H] ⁺ .

Example 138A. (+/-)-Methyl-{[2-amino-1-(2-chlorophenyl)ethyl]sulfanyl}acetate (racemate)

- 68 040284 nh ₂ o

Solution of (+/-)-methyl-{[1-(2-chlorophenyl)-2-nitroethyl]sulfanyl}acetate (1.40 g, 4.83 mmol, Example 63A) in methanol (28 ml) and acetic acid (14 ml) at RT was mixed with tin(II) chloride and the mixture was stirred for 3 h under reflux. After cooling to RT, the mixture was concentrated and the residue was taken up in acetonitrile and purified by preparative HPLC (Method 16). The combined desired fractions were concentrated and the residue was dried in vacuo. 3.80 g (50% pure HPLC-MS, >100% th. w/ solvent) of the title compound was obtained.

LC-MS (Method 1): R _t = 0.79 min; MS (ESIpos): m/z = 260 [M+H] ⁺ .

Example 139A. (+/-)-Methyl-({2-[(tert-butoxycarbonyl)amino]-1-(2-chlorophenyl)ethyl}sulfanyl)acetate (racemate)

Ο^ΝΗ O h ₃ cJ

H ₃ SP SN ₃

Solution of (+/-)-methyl-{[2-amino-1-(2-chlorophenyl)ethyl]sulfanyl}acetate (1.56 g, 45% pure, 2.70 mmol, Example 138A) in dichloromethane (5.8 ml) at RT mixed successively with triethylamine (420 μl, 3.0 mmol) and di-tert-butyl dicarbonate (661 mg, 3.03 mmol) (gas formation) and the mixture was stirred overnight at RT. The mixture was then diluted with dichloromethane to a volume of 100 ml and washed once with half concentrated sodium hydrogen carbonate solution. The precipitate thus formed was filtered off and discarded. The mixture was then washed with saturated aqueous sodium chloride, dried over sodium sulfate, filtered and concentrated, and the residue was purified twice successively by preparative HPLC (Method 16). The combined desired fractions were concentrated and the residue was dried in vacuo. 100 mg (98% pure, 10% th. y.) of the title compound were obtained.

LC-MS (Method 1): R _t = 2.00 min; MS (ESIpos): m/z = 382 [M+Na] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 7.50-7.41 (m, 2H), 7.40-7.23 (m, 2H), 6.99 (t, 1H), 4.60 (t, 1H), 3.55 (s, 3H), 3.50-3.28 (m, 3H), 3.23-3.13 (m, 1H), 1.33 (s, 9H).

Example 140A. (+/-)-Methyl-{[2-[(tert-butoxycarbonyl)amino]-1-(2-chlorophenyl)ethyl]sulfonyl}acetate (racemate)

A .

'cn ₃

O^NH O O ^Η 3θΧ

CH ₃

Solution of (+/-)-methyl-({2-[(tert-butoxycarbonyl)amino]-1-(2-chlorophenyl)ethyl}sulfanyl)acetate (100 mg, 278 µmol, Example 139A) in dichloromethane (5 ml ) at RT was mixed with metachloroperbenzoic acid (103 mg, 70% pure, 417 µmol) and the mixture was stirred overnight at RT. The mixture was then mixed with saturated sodium hydrogen carbonate solution (5 ml), stirred vigorously and then mixed with dichloromethane and water and shaken. After phase separation, the aqueous phase was extracted once with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated and the residue was taken up in acetonitrile and purified by preparative HPLC (Method 17). The combined desired fractions were concentrated and the residue was dried in vacuo. 75 mg (100% pure, 69% thor.) of the title compound were obtained.

LC-MS (Method 1): R _t = 1.77 min; MS (ESIneg): m/z = 390 [MH] ^- .

Example 141A. (+/-)-Methyl-{[2-amino-1-(2-chlorophenyl)ethyl]sulfonyl}acetate hydrochloride | _c ,xs ^{henna s} nh ₂ o o (+/-)-Methyl-{[2-[(tert-butoxycarbonyl)amino]-1-(2-chlorophenyl)ethyl]sulfonyl}acetate (75 mg, 191 µmol, example 140A) was dissolved in a 4M solution of hydrogen chloride in dioxane (720 μl, 2.9 mmol) and left for 3 h at RT. The mixture was then concentrated and mixed several times with dichloromethane and re-concentrated. 60 mg (97% pure, 93% thor.) of the title compound were obtained.

LC-MS (Method 4): R _t = 1.03 min; MS (ESIpos): m/z = 292 [M-HCl+H] ⁺ .

Example 142A. (+/-)-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 64A) in tert-butanol (35 ml ) was mixed with Raney nickel (349 mg, 5.95 mmol) and hydrogenated overnight at normal pressure. The catalyst was then filtered through silica gel, washed additionally twice with t-butanol (10 ml) and the filtrate was concentrated. The residue was adsorbed into ethyl acetate (50 ml) and extracted successively with 1M hydrochloric acid and water (respectively 50 ml). The pH of the combined aqueous phases was adjusted to 8-9 with saturated sodium bicarbonate solution and extracted twice with ethyl acetate (50 ml). The combined organic phases were dried over sodium sulfate, filtered and concentrated, and the residue was 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 143A. (+/-)-Methyl-5-amino-4-[2-(trifluoromethyl)phenyl]pentanoate (racemate)

A solution of (+/-)-methyl-4-cyano-4-[2-(trifluoromethyl)phenyl]butanoate (4.40 g, 16.2 mmol, example 65A) in methanol (150 ml) was mixed with platinum dioxide (737 mg, 3.24 mmol) and concentrated hydrochloric acid (1.4 ml, 12M, 16 mmol) and hydrogenated overnight at normal pressure. The catalyst was then filtered through silica gel, washed further with methanol, and the filtrate was concentrated. The residue was combined with the residue similarly obtained from the preliminary test (amount of (+/-)-methyl-4-cyano-4-[2-(trifluoromethyl)phenyl]butanoate used: 200 mg, 737 µmol). 5.50 g (77% pure, 91% theoretical yield, based on a total of 16.94 mmol of (+/-)-methyl-4-cyano-4-[2-(trifluoromethyl)phenyl]butanoate used) of the indicated in the connection header.

LC-MS (Method 2): R _t = 0.52 min; MS (ESIpos): m/z = 276 [M+H] ⁺ .

Example 144A. (+/-)-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 66A) in tert-butanol (100 ml) was mixed with Raney nickel (1.04 g, 17.7 mmol) and hydrogenated for 24 h at normal pressure. The catalyst was then filtered through silica gel, 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 1M hydrochloric acid and water (respectively 80 ml). The pH of the combined aqueous phases was adjusted to 8-9 with saturated sodium bicarbonate solution and extracted twice with ethyl acetate (80 ml). The combined organic phases were dried over sodium sulfate, filtered and concentrated, and the residue was 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 (0.06), 1.927 (0.05), 1.943 (0.10), 1.950 (0.13), 1.964 (0.28), 1.986 (1.50) . . , 6.909 (0.20), 6.916 (0.23), 6.968 (0.14), 1.709 (0.26), 2.018 (0.57), 2.681 (0.05), 3.312 (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 145A. (+/-)-tert-Butyl-5-amino-4-[2-(trifluoromethoxy)phenyl]pentanoate (racemate)

- 70 040284

A solution of (+/-)-tert-butyl-4-cyano-4-[2-(trifluoromethoxy)phenyl]butanoate (3.13 g, 80% pure, 7.59 mmol, Example 67A) in tert-butanol (45 mL) was mixed with Raney nickel (446 mg, 7.59 mmol) and hydrogenated overnight at normal pressure. Then again Raney nickel (446 mg, 7.59 mmol) was added and the mixture was further hydrogenated for 24 hours at normal pressure. 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 146A. (+/-)-tert-Butyl-5-amino-4-(pyridin-2-yl)pentanoate (racemate)

(+/-)-tert-Butyl-4-cyano-4-(pyridin-2-yl)butanoate (799 mg, 3.24 mm, example 68A) was dissolved in tert-butanol (10 ml), with Raney nickel (228 mg, 3.89 mmol) were mixed and the reaction mixture was stirred at normal pressure with hydrogen overnight. The reaction mixture was filtered and concentrated. 678 mg of the title compound was obtained as a crude product. The crude product was used directly (without further purification) in the subsequent reaction.

LC-MS (Method 6): R _t = 1.08 min; MS (ESIpos): m/z = 251 [M+H] ⁺ .

Example 147A. (+/-)-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 69A) 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. The reaction mixture was once more mixed with Raney nickel (2 g, 34.0 mmol) and vigorously stirred for 40 h at normal pressure with hydrogen. The catalyst was then filtered through silica gel, 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. This organic phase was 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 (0.16), 2.129 (0.11), 2.150 (0.24) , 2.828 (0.25), 2.872 (0.03), 4.019 (0.05), 4.037 (0.45), (0.04), (0.18), (0.05),

2.006

2.310

2.876

7.476 (0.19), 2.034 (0.07), 2.365 (0.18), 2.890 (0.66), 7.485 (0.10), (0.02), (0.29), (0.49),

2.055

2.669

2.895

7.489 (0.30), 2.074 (0.35), 2.093 (0.31), 2.118 (0.02), 2.782 (0.10), 2.799 (0.17), 2.812 (0.30), 2.920 (0.37), 3.494 (0.02), 3.522 (0.49), 7.501 (0.31), 7.509 (0.87), 7.521 (0.09), 7.550 (0.51), 7.557 (0.32), 7.564 (0.37), 7.573 (0.26), 7.614 (0.04), 7.637 (0.04).

Example 148A. (+/-)-tert-Butyl-5-amino-4-(2,3,5,6-tetrafluorophenyl)pentanoate (racemate)

A solution of (+/-)-tert-butyl-4-cyano-4-(2,3,5,6-tetrafluorophenyl)butanoate (850 mg, 2.68 mmol, example 70A) in tert-butanol (20 ml) and methanol ( 2.1 ml) was mixed with Raney nickel (157 mg, 2.68 mmol) and the mixture was hydrogenated overnight with stirring at normal pressure. The catalyst was then filtered through silica gel, washed additionally twice with t-butanol (10 ml) and methanol (10 ml) and the filtrate was concentrated in vacuo. The residue was adsorbed in ethyl acetate (100 ml). This organic phase was extracted twice with 1M hydrochloric acid (100 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 (corresponding to 100 ml). The combined organic phases were dried over sodium sulfate and concentrated on a rotary evaporator. Received 586 mg (95% purity, 65% theoretical.

out) specified in the connection header.

LC-MS (Method 1): R _t = 1.15 min; MS (ESIpos): m/z = 322 [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 149A. (+/-)-tert-Butyl-5-amino-4-(2,3,5-trifluorophenyl)pentanoate (racemate)

A solution of (+/-)-tert-butyl-4-cyano-4-(2,3,5-trifluorophenyl)butanoate (600 mg, 2.00 mmol, example 71A) in tert-butanol (15 ml) was mixed with Raney nickel (118 mg, 2.00 mmol) and hydrogenated overnight at normal pressure. The catalyst was then filtered through silica gel, washed additionally twice with t-butanol (5 ml each) and the filtrate was concentrated in vacuo. The residue was adsorbed in ethyl acetate (50 ml). This organic phase was extracted twice with 1M hydrochloric acid (corresponding to 50 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 50 ml). The combined organic phases were dried over sodium sulfate and concentrated on a rotary evaporator. 200 mg (96% pure, 32% thor.) of the title compound were obtained.

LC-MS (Method 3): R _t = 1.81 min; MS (ESIpos): m/z = 304 [M+H]+.

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 1.110 (0.34), 1.193 (0.08), 1.234 (0.08), 1.353 (16.00), 1.509 (0.17), 1.639 (0.07), 1.673 (0.16 ), 1.689 (0.20), 1.698 (0.17), 1.714 (0.17), 1.729 (0.09), 1.865 (0.06), 1.934 (0.06), 1.955 (0.13), 1.968 (0.17), 1.984 (0.18), 2.003 (0.18 ), 2.025 (0.88), 2.041 (0.91), 2.059 (0.29), 2.328 (0.05), 2.367 (0.04), 2.691 (0.14), 2.710 (0.21), 2.723 (0.39), 2.742 (0.46), 2.755 (0.40 ), 2.771 (0.46), 2.787 (0.14), 2.802 (0.16), 2.944 (0.18), 7.039 (0.22), 7.051 (0.22), 7.063 (0.22), 7.301 (0.08), 7.309 (0.09), 7.329 (0.18 ), 7.337 (0.17), 7.345 (0.17), 7.365 (0.10), 7.373 (0.09).

Example 150A. (+/-)-tert-Butyl-5-amino-4-(2,3,6-trichlorophenyl)pentanoate (racemate)

A solution of (+/-)-tert-butyl-4-cyano-4-(2,3,6-trichlorophenyl)butanoate (10.2 g, 95% pure, 27.9 mmol, Example 72A) 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. Additional Raney nickel (2.0 g, 34.0 mmol) was added and the mixture was hydrogenated for three additional days with stirring at normal pressure. The catalyst was then filtered through silica gel, washed additionally three times with methanol (corresponding to 30 ml) and the filtrate was concentrated. The residue was adsorbed in ethyl acetate (400 ml). This organic phase was extracted twice with 1M 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 (300 ml, respectively). The combined organic phases were dried over sodium sulfate and concentrated on a rotary evaporator. After drying in vacuo, 2.54 g (89% pure, 23% theoretical) of the title compound were obtained.

LC-MS (Method 1): R _t = 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 151A. (+/-)-tert-Butyl-6-amino-5-(2-chlorophenyl)hexanoate (racemate)

A solution of (+/-)-tert-butyl-5-(2-chlorophenyl)-5-cyanopentanoate (2.70 g, 9.19 mmol, example 73A) in tert-butanol (54 ml) was mixed with Raney nickel (540 mg, 9.19 mmol) and hydrogenated for 24 h at normal

- 72 040284 pressure. The catalyst was then filtered through silica gel, washed additionally twice with t-butanol (15 ml) and the filtrate was concentrated. The residue was adsorbed into ethyl acetate (60 ml) and extracted successively with 1M hydrochloric acid and water. The pH of the combined aqueous phases was adjusted to 8-9 with saturated sodium hydrogen carbonate solution 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 dried in vacuo. 1.32 g (95% pure, 46% th. y.) of the title compound was obtained.

LC-MS (Method 1): Rt = 1.33 min; MS (ESIpos): m/z = 298 [M+H]+.

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 1.111 (0.02), 1.195 (0.08), 1.271 (0.23), 1.290 (0.45), 1.315 (0.77), 1.334 (1.17), 1.356 (16.00 ), 1.462 (0.15), 1.477 (0.17), 1.485 (0.23), 1.496 (0.24), 1.509 (0.29), 1.519 (0.27), 1.532 (0.20), 1.542 (0.12), 1.556 (0.09), 1.697 (0.17 ), 1.710 (0.26), 1.724 (0.27), 1.736 (0.26), 1.744 (0.21), 1.769 (0.14), 1.784 (0.08), 1.876 (0.06), 2.074 (0.13), 2.093 (0.77), 2.162 (0.39 ), 2.183 (0.14), 2.201 (0.09), 2.367 (0.06), 2.739 (0.32), 3.140 (0.35), 3.150 (0.32), 3.163 (0.27), 3.180 (0.13), 7.171 (0.31), 7.217 (0.44 ), 7.227 (0.35), 7.238 (0.29), 7.248 (0.07), 7.293 (0.67), 7.425 (0.53).

2.113 (0.58), 2.131 (0.90), 2.144 (1.29), 2.756 (1.29), 3.110 (0.18), 3.127 (0.12), 7.196 (0.28), 7.206 (0.32), 7.211 (0.22), 7.315 (1.26), 7.326 (1.32), 7.405

Example 152A. (+/-)-tert-Butyl-6-amino-5-(2-chlorophenyl)-5-methylhexanoate (racemate)

A solution of (+/-)-tert-butyl-5-(2-chlorophenyl)-5-cyanohexanoate (2.38 g, 7.73 mmol, example 74A) in tert-butanol (45 ml) was mixed with Raney nickel (454 mg, 7.73 mmol) and hydrogenated for 24 h at normal pressure. Then mixed again with Raney nickel (454 mg, 7.73 mmol) and hydrogenated for an additional 24 hours at normal pressure. It was then mixed once more with Raney nickel (454 mg, 7.73 mmol) and hydrogenated for an additional 24 h at normal pressure. The catalyst was then filtered through silica gel, 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 1M hydrochloric acid and water (respectively 80 ml). The pH of the combined aqueous phases was adjusted to 8-9 with saturated sodium hydrogen carbonate solution 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 was dried in vacuo. 820 mg (61% pure, 21% thor.) of the title compound was obtained in admixture with the dechlorinated product ((+/-)-tert-butyl-6-amino-5-methyl-5-phenylhexanoate).

LC-MS (Method 1): R _t = 1.24 min; MS (ESIpos): m/z = 312 [M+H]+.

Example 153A. (+/-)-Methyl-3 - {[(6-bromo-3 -methyl-2-phenylquinolin-4-yl) carbonyl] amino} hydrotropate (racemate)

HATU (428 mg , 1.13 mmol) and DIPEA (390 μl, 2.3 mmol) and the mixture was stirred for 30 min at RT. Then (+/-)methyl-3-amino-2-phenylpropanoate hydrochloride (178 mg, 825 µmol, example 75A) was added and the mixture was stirred for 1.5 h at 60°C. After cooling to RT, the mixture was mixed with 10% citric acid (50 ml) and the precipitate formed was filtered off, washed twice with water (5 ml) and dried in vacuo. The precipitate was then adsorbed into dichloromethane and purified by flash column chromatography (50 g Biotage Snap-Cartridge KP-Sil, cyclohexane/ethyl acetate 97:3^8:2, Isolera One). 175 mg (90% pure, 42% thor.) of the title compound were obtained.

LC-MS (Method 1): R _t = 2.16 min; MS (ESIpos): m/z = 547/549 [M+H]+.

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (1.64), 0.008 (1.20), 2.167 (2.67), 3.287 (1.39), 3.647 (16.00), 4.106 (0.90), 4.126 (1.46) ), 7.325 (1.12), 7.336 (1.15), 7.347 (0.78), 7.387 (12.53), 7.398 (7.56), 7.493 (0.93), 7.507 (2.84), 7.514 (2.14), 7.526 (5.17), 7.537 (5.83 ), 7.543 (3.52), 7.555 (1.01), 7.851 (1.24), 7.856 (1.07), 7.873 (1.92), 7.879 (1.75), 7.945 (3.66), 7.968 (2.29), 9.024 (1.33).

Example 154A. (+/-)-Ethyl-3-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-2-(2-chlorophenyl)propanoate (racemate)

- 73 040284

To a solution of (+/-)-ethyl-3-amino-2-(2-chlorophenyl)propanoate (1.25 g, 5.50 mmol, example 76A) in dichloromethane (25 ml) was added triethylamine (1.4 ml, 10 mmol) in succession and a mixture of 6-bromo-3methyl-2-phenylquinoline-4-carbonyl chloride (1.80 g, 5.00 mmol, example 1A) in dichloromethane (25 ml) and the reaction mixture was stirred for 2 h at RT. The mixture was then mixed with dichloromethane (50 ml) and water (100 ml) and shaken. The aqueous phase was extracted twice with dichloromethane (corresponding to 100 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 (200 g Biotage Snap-Cartridge KP-Sil, cyclohexane/ethyl acetate 9:1). 2.36 g (100% pure, 86% th. y.) of the title compound was obtained.

LC-MS (Method 1): Rt = 2.37 min; MS (ESIpos): m/z = 551/553 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (1.26), 0.008 (1.20), 0.890 (2.24), 1.131 (7.34), 1.149 (16.00), 1.157 (1.41), 1.166 (7.62) ), 1.175 (1.72), 1.193 (0.77), 1.398 (7.12), 1.988 (2.67), 2.184 (11.70), 4.021 (1.07), 4.039 (1.23), 4.111 (1.87), 4.128 (5.28), 4.146 (5.04 ), 4.164 (1.63), 4.558 (1.60), 4.577 (3.41), 4.596 (1.41), 7.354 (1.78), 7.358 (1.84), 7.372 (1.87), 7.378 (2.92), 7.382 (1.97), 7.397 (2.15 ), 7.401 (2.27), 7.416 (0.98), 7.419 (0.83), 7.492 (1.87), 7.496 (3.72), 7.502 (3.99), 7.508 (6.94), 7.513 (7.28), 7.519 (4.27), 7.525 (7.98 ), 7.527 (9.43), 7.531 (6.54), 7.535 (8.60), 7.538 (8.48), 7.542 (5.71), 7.545 (4.27), 7.555 (1.57), 7.849 (2.18), 7.854 (1.90), 7.871 (3.29 ), 7.876 (3.13), 7.944 (5.62), 7.966 (3.53), 9.014 (1.17), 9.029 (2.36), 9.043 (1.14).

Example 155A. (+/-)-Methyl-3-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-2-(2-methoxyphenyl)propanoate (racemate) ^h 3% AJ / γ%Η ₃ CH ΝΗ Ο

Η 3 χτ ^Ν

Triethylamine (1.4 ml, 10 mmol) and a suspension of 6-bromo-3-methyl-2-phenylquinoline-4-carbonyl chloride (902 mg, 2.50 mmol, example 1A) in dichloromethane (10 ml) and the mixture was stirred for 24 h at RT. The mixture was then mixed with dichloromethane and water (respectively 100 ml) and shaken. 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 into dichloromethane and purified by flash column chromatography (200 g Biotage Snap-Cartridge KP-Sil, 8:2 cyclohexane/ethyl acetate). The combined desired fractions were concentrated and the residue was dried in vacuo. 1.14 g (100% pure, 85% th. y.) of the title compound was obtained.

LC-MS (Method 1): Rt = 2.14 min; MS (ESIpos): m/z = 533/535 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.988 (0.57), 2.194 (6.26), 3.303 (2.46), 3.324 (1.41), 3.622 (14.45), 3.799 (16.00), 4.364 (0.82) , 4.383 (1.55), 4.402 (0.71), 6.945 (0.84), 6.947 (0.81), 6.964 (1.83), 6.966 (1.71), 6.983 (1.08), 7.034 (1.46), 7.053 (1.84), 7.279 (3.27) . , 7.541 (5.04),7.546 (3.03), 7.549 (1.98), 7.558 (0.93), 7.850 (1.24), 7.855 (1.01), 7.872 (1.86), 7.878 (1.67), 7.943 (3.32),7.966 (2.06) , 8.929 (1.40).

Example 156A. (+/-)-Methyl-3-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-2-(4-fluorophenyl)propanoate (racemate)

- 74 040284 ^ ^{O'CH 3}

SK Ν Η O

Br.^1 CH ₃ XX ⁿ Xq

To a suspension of (+/-)-methyl-3-amino-2-(4-fluorophenyl)propanoate hydrochloride (129 mg, 550 µmol, Example 78A) in dichloromethane (3 mL) was added triethylamine (140 µL, 1.0 mmol) in succession and a suspension of 6-bromo-3-methyl-2-phenylquinoline-4-carbonyl chloride (180 mg, 500 μmol, example 1A) in dichloromethane (2 ml) and the mixture was stirred for 18 h at RT. Then (+/-)-methyl-3-amino-2-(4fluorophenyl)propanoate hydrochloride (129 mg, 550 µmol, example 78A) in dichloromethane (2 ml) and triethylamine (140 µl, 1.0 mmol) were added again and the reaction mixture was stirred additional 4 days at CT. The mixture was then mixed with dichloromethane and water (respectively 50 ml) and shaken. 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 (50 g Biotage Snap-Cartridge KP-Sil, 8:2 cyclohexane/ethyl acetate). The combined desired fractions were concentrated and the residue was dried in vacuo. 213 mg (90% pure, 74% thor.) of the title compound were obtained.

LC-MS (Method 1): Rt = 2.19 min; MS (ESIpos): m/z = 521/523 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 9.01 (t, 1H), 7.95 (d, 1H), 7.86 (dd, 1H), 7.71 (br. s, 1H), 7.577. 49 (m, 5H), 7.47-7.38 (m, 2H), 7.25-7.18 (m, 2H), 4.14 (t, 1H), 4.02-3.78 (br. m, 2H), 3.65 (s, 3H), 2.18 (br. s, 3H).

Example 157A. (+/-)-Ethyl-3-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-2-methylhydrotropate (racemate)

To a suspension of (+/-)-ethyl-3-amino-2-methyl-2-phenylpropanoate hydrochloride (146 mg, 600 µmol, prepared according to Archiv der Pharmazie 1985, 318 (7), 593-600) in dichloromethane (3 ml ) N,N-diisopropylethylamine (260 µl, 1.5 mmol) and a suspension of 6-bromo-3-methyl-2-phenylquinoline-4-carbonyl chloride (180 mg, 500 µmol, example 1A) in dichloromethane (2 ml) were added successively and the mixture was stirred 16 h at CT. The mixture was then mixed with dichloromethane and water (respectively 30 ml) and shaken. 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 SnapCartridge KP-Sil, cyclohexane/ethyl acetate 93:7^7:3, Isolera One). The combined desired fractions were concentrated and the residue was dried in vacuo. 225 mg (100% pure, 85% theoretical) of the title compound were obtained.

LC-MS (Method 1): Rt = 2.39 min; MS (ESIpos): m/z = 531/533 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 0.890 (0.83), 1.123 (6.66), 1.141 (13.96), 1.158 (7.14), 1.175 (1.38), 1.192 (0.72), 1.397 (2.24 ), 1.646 (16.00), 1.988 (2.56), 2.156 (2.64), 3.980 (0.77), 4.020 (0.70), 4.038 (0.69), 4.068 (0.78), 4.077 (0.77), 4.087 (1.02), 4.095 (2.44 ), 4.105 (1.73), 4.113 (2.67), 4.124 (2.66), 4.142 (2.42), 4.150 (1.36), 4.168 (0.87), 7.303 (1.56), 7.318 (1.50), 7.366 (1.45), 7.387 (5.68 ), 7.399 (7.92), 7.403 (13.69), 7.419 (1.37), 7.480 (0.44), 7.492 (1.60), 7.507 (4.84), 7.512 (3.61), 7.525 (6.69), 7.541 (8.34), 7.560 (1.72 ), 7.720 (0.61), 7.841 (1.93), 7.846 (1.67), 7.864 (2.87), 7.869 (2.68), 7.941 (5.55), 7.963 (3.54), 8.721 (1.12), 8.735 (2.00), 8.751 (1.09 ).

Example 158A. (+/-)-Methyl-2-({[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}methyl)-2phenylbutanoate (racemate)

- 75 040284

HATU (833 mg , 2.19 mmol) and DIPEA (760 µl, 4.4 mmol) and the mixture was stirred for 30 min at RT. Then (+/-)methyl-2-(aminomethyl)-2-phenylbutanoate-hydrochloride (562 mg, 95% pure, 2.19 mmol, obtained according to Archiv der Pharmazie 1985, 318 (7), 593-600) was added, dissolved in DMF (3 ml) and the mixture was stirred overnight at 60°C. After cooling to RT, the mixture was mixed with ethyl acetate and water (respectively 20 ml) and shaken. 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 was adsorbed into dichloromethane and purified by flash column chromatography (100 g Biotage Snap-Cartridge KP-Sil, cyclohexane/ethyl acetate 9:1). 567 mg (98% pure, 72% thor.) of the title compound were obtained.

LC-MS (Method 2): R _t = 1.24 min; MS (ESIpos): m/z = 531/533 [M+H]+.

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (0.63), 0.008 (0.56), 0.793 (2.77), 0.811 (6.44), 0.830 (2.94), 1.398 (0.51), 2.109 (1.08 ), 2.127 (3.11), 2.146 (4.00), 2.163 (2.40), 3.625 (16.00), 4.039 (0.43), 4.052 (0.47), 4.074 (0.65), 4.085 (0.60), 4.202 (0.58), 4.219 (0.62 ), 4.235 (0.46), 7.271 (0.56), 7.288 (1.55), 7.306 (1.12), 7.325 (2.20), 7.342 (5.33), 7.361 (3.46), 7.379 (2.92), 7.399 (0.99), 7.492 (1.16 ), 7.507 (3.59), 7.512 (2.64), 7.525 (4.86), 7.540 (5.95), 7.560 (1.26), 7.842 (1.41), 7.847 (1.26), 7.864 (2.14), 7.869 (2.02), 7.939 (4.01 ), 7.962 (2.55), 8.639 (0.83), 8.654 (1.55), 8.669 (0.80).

Example 159A. (+/-)-Ethyl 3-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-2-[3-(trifluoromethyl)phenyl]propanoate (racemate) ^F T ^F iQ

NH O ^Br ^^ UcH ₃ XIX^ ^N XQ

HATU (87 mg , 230 µmol) and DIPEA (80 µl, 460 µmol) and the mixture was stirred for 30 min at RT. Then (+/-)-ethyl-3-amino2-[3-(trifluoromethyl)phenyl]propanoate (60 mg, 230 µmol, example 80A) dissolved in DMF (1.5 ml) was added and the mixture was stirred overnight at 60° C. After cooling to RT, the mixture was purified by preparative HPLC (Method 22). The combined target fractions were concentrated and dried in vacuo. 43 mg (98% pure, 47% theoretical) of the title compound were obtained.

LC-MS (Method 1): Rt = 2.41 min; MS (ESIpos): m/z = 585/587 [M+H]+.

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.137 (5.86), 1.154 (11.79), 1.172 (5.88), 1.195 (3.38), 1.212 (3.46), 1.426 (11.61), 1.459 (1.63) , 2.011 (3.91), 2.111 (2.10), 2.189 (0.44), 2.321 (0.63), 3.656 (0.73), 3.721 (1.10), 3.736 (1.02), 3.898 (0.66), 3.918 (0.84) , 3.952 (2.40), 3.968 (2.49), 3.986 (1.38), 4.099 (0.63), 4.109 (1.09), 4.117 (1.61), 4.126 (2.89), 4.135 (3.04), 4.144 (3.09), 4.153 (2.68) 4.161 (1.51), 4.170 (0.92), 4.179 (0.53), 4.223 (1.36), 4.242 (2.35), 4.261 (1.04), 7.506 (3.76), 7.523 (16.00), 7.565 (0.63), 7.577 (0.56) , 7.585 (0.56), 7.597 (0.53), 7.625 (1.00), 7.644 (2.61), 7.664 (2.44), 7.699 (3.02), 7.741 (5.52), 7.847 (1.72), 7.852 (1.65), 7.870 (2.67) , 7.874 (2.58), 7.941 (4.43), 7.963 (2.81), 8.106 (0.43), 8.124 (0.41), 8.617 (0.41), 8.997 (1.32), 9.010 (2.41), 9.023 (1.25).

Example 160A. (+/-)-Ethyl-2-(1,3-benzodioxol-5-yl)-3-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}propanoate (racemate )

- 76 040284

HATU (240 mg , 632 µmol) and DIPEA (220 µl, 1.3 mmol) and the mixture was stirred for 30 min at RT. Then (+/-)ethyl-3-amino-2-(1,3-benzodioxol-5-yl)propanoate (150 mg, 632 µmol, Example 81A) dissolved in DMF (4 ml) was added and the mixture was stirred for nights at 60°C. After cooling to RT, the mixture was purified by preparative HPLC (Method 22). The combined target fractions were concentrated and dried in vacuo.

126 mg (98% pure, 52% thor.) of the title compound were obtained.

LC-MS (Method 2): R _t = 1.22 min; MS (ESIpos): m/z = 561/563 [M+H]+.

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.132 (7.84), 1.150 (16.00), 1.168 (7.82), 2.203 (8.18), 3.788 (0.91), 3.889 (0.95), 3.993 (2.51) 4.012 (4.07), 4.032 (1.55), 4.043 (0.47), 4.061 (1.04), 4.071 (1.16), 4.079 (1.28), 4.088 (3.86), 4.107 (5.28), 4.125 (3.40), 4.135 (1.13) . , 6.949 (6.20), 7.485 (0.65), 7.498 (1.98), 7.513 (5.89), 7.518 (4.93), 7.532 (9.29), 7.544 (12.04), 7.562 (2.49), 7.748 (0.84), 7.852 (2.40) , 7.857 (2.28), 7.874 (3.60), 7.879 (3.55), 7.948 (6.49), 7.970 (4.10), 8.979 (1.64), 8.992 (3.19), 9.006 (1.64).

Example 161A. (+/-)-tert-Butyl-3-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-2-(3chloropyridin-2-yl)-2-methylpropanoate ( racemate) ^nz ^ ° ^ n ₃

O ^ NH O CH ₃

Br/^lc H s XX x^ ^N [0

HATU (358 mg , 942 µmol) and DIPEA (330 µl, 1.9 mmol) and the mixture was stirred for 30 min at RT. Then (+/-) tert-butyl-3-amino-2-(3-chloropyridin-2-yl)-2-methylpropanoate (255 mg, 942 µmol, example 82A) dissolved in DMF (2 ml) was added and the mixture stirred overnight at 60°C. After cooling to RT, the mixture was purified by preparative HPLC (Method 15). The combined target fractions were concentrated and dried in vacuo. 230 mg (98% pure, 60% theoretical) of the title compound were obtained.

LC-MS (Method 2): Rt = 1.36 min; MS (ESIpos): m/z = 594/596 [M+H]+.

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.405 (16.00), 1.677 (4.42), 2.174 (1.39), 7.369 (0.45), 7.380 (0.48), 7.388 (0.50), 7.400 (0.48) , 7.504 (1.05), 7.511 (0.83), 7.522 (2.01), 7.531 (2.12), 7.839 (0.57),7.844 (0.42), 7.861 (0.83), 7.866 (0.71), 7.906 (0.70), 7.909 (0.69) , 7.926 (2.00), 7.948 (0.81), 8.519 (0.64), 8.521 (0.63), 8.530 (0.63), 8.671 (0.59).

1H-NMR (400 MHz, DMSO-d6): δ [ppm] = 8.67 (t, 1H), 8.53 (d, 1H), 7.98-7.89 (m, 2H), 7.85 (dd, 1H), 7.81 (br . s, 1H), 7.57-7.46 (m, 5H), 7.38 (dd, 1H), 4.48 (br. dd, 1H), 3.92 (br. d, 1H), 2.17 (br. s, 3H), 1.68 (s, 3H), 1.40 (s, 9H).

Example 162A. (+/-)-Methyl-3-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-2-(2-fluorophenyl)-2-methylpropanoate (racemate)

- 77 040284

To a suspension of (+/-)-methyl-3-amino-2-(2-fluorophenyl)-2-methylpropanoate (127 mg, 600 µmol, CASRN 1803580-97-3, commercially available) in dichloromethane (3 ml) successively N,N-diisopropylethylamine (260 µl, 1.5 mmol) and a suspension of 6-bromo-3-methyl-2-phenylquinoline-4-carbonyl chloride (180 mg, 500 µmol, example 1A) in dichloromethane (2 ml) were 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. 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 93:7^7:3, Isolera One) . The combined desired fractions were concentrated and the residue was dried in vacuo. 208 mg (100% pure, 78% thor.) of the title compound were obtained.

LC-MS (Method 1): Rt = 2.25 min; MS (ESIpos): m/z = 535/537 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 1.157 (0.91), 1.174 (1.83), 1.192 (0.94), 1.397 (0.91), 1.614 (8.25), 1.988 (3.41), 2.149 (0.77 ), 3.311 (16.00), 3.931 (0.42), 4.020 (0.84), 4.038 (0.83), 4.199 (0.51), 4.216 (0.55), 4.231 (0.46), 4.250 (0.42), 7.171 (0.61), 7.192 (0.83 ), 7.201 (0.75), 7.209 (0.64), 7.222 (1.09), 7.227 (1.32), 7.247 (0.77), 7.371 (0.64), 7.387 (0.59), 7.447 (0.69), 7.467 (1.23), 7.492 (1.21 ), 7.507 (2.39), 7.513 (1.85), 7.525 (3.88), 7.538 (4.70), 7.556 (0.86), 7.840 (0.91), 7.845 (0.86), 7.863 (1.41), 7.868 (1.37), 7.934 (2.68 ), 7.956 (1.66), 8.762 (0.58), 8.778 (1.03), 8.793 (0.57).

Example 163A. (+/-)-tert-Butyl-3-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-2-(2,6difluorophenyl)-2-methylpropanoate (racemate)

HATU (917 mg , 2.41 mmol) and DIPEA (840 µl, 4.8 mmol) and the mixture was stirred for 30 min at RT. Then (+/-)-tert-butyl-3-amino-2-(2,6-difluorophenyl)-2-methylpropanoate (689 mg, 95% pure, 2.41 mmol, example 83A) dissolved in DMF (3.5 ml) was added and the mixture was stirred overnight at 60°C. After cooling to RT, the mixture was mixed with ethyl acetate and water (respectively 20 ml) and shaken. The aqueous phase was extracted twice with ethyl acetate (corresponding to 20 ml). The combined organic phases were washed once with saturated aqueous sodium chloride, dried over sodium sulfate, filtered and concentrated, and the residue was adsorbed into dichloromethane and purified by flash column chromatography (100 g Biotage Snap-Cartridge KP-Sil, cyclohexane/ethyl acetate 85:15). 645 mg (98% pure, 66% th. y.) of the title compound were obtained.

LC-MS (Method 1): Rt = 2.59 min; MS (ESIpos): m/z = 595/597 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 1.401 (16.00), 1.744 (1.68), 7.072 (0.64), 7.096 (0.43), 7.506 (1.02), 7.512 (0.83), 7.524 (1.97) ), 7.533 (1.98), 7.838 (0.43), 7.860 (0.67), 7.865 (0.64), 7.930 (1.26), 7.953 (0.79), 8.791 (0.50).

1H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 8.79 (t, 1H), 7.94 (d, 1H), 7.85 (dd, 1H), 7.80-7.47 (m, 6H), 7.457. 34 (m, 1H), 7.07 (br. t, 2H), 4.18 (br. dd, 1H), 3.78 (br. d, 1H), 2.16 (br. s, 3H), 1.74 (br. s, 3H ), 1.40 (s, 9H).

Example 164A. (+/-)-Methyl-3-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-2-(2chlorophenyl)-2-methylpropanoate (racemate)

HATU (833 mg , 2.19 mmol) and DIPEA (760 µl, 4.4 mmol) and the mixture was stirred for 30 min at RT. Then added (+/-)methyl-3-amino-2-(2-chlorophenyl)-2-methylpropanoate (525 mg, 95% pure, 2.19 mmol, available from Santai Labs) dissolved in DMF (3 ml) and a mixture stirred overnight at 60°C. After cooling to RT, the mixture was mixed with ethyl acetate and water (respectively 20 ml) and shaken. water phase

- 78 040284 was extracted twice with ethyl acetate (corresponding to 20 ml). The combined organic phases were washed once with saturated aqueous sodium chloride, dried over sodium sulfate, filtered and concentrated, and the residue was adsorbed into dichloromethane and purified by flash column chromatography (100 g Biotage Snap-Cartridge KP-Sil, cyclohexane/ethyl acetate

85:15). 554 mg (98% pure, 67% thor.) of the title compound were obtained.

LC-MS (Method 1): Rt = 2.30 min; MS (ESIpos): m/z = 551/553 [M+H]+.

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 1.397 (1.34), 1.662 (9.58), 1.988 (0.59), 2.072 (0.62), 2.152 (0.72), 3.640 (16.00), 3.930 (0.48 ), 3.953 (0.55), 4.405 (0.60), 4.423 (0.64), 4.438 (0.58), 4.457 (0.52), 7.344 (0.97), 7.362 (1.87), 7.377 (1.41), 7.398 (0.76), 7.453 (1.58 ), 7.472 (1.30), 7.491 (1.10), 7.506 (3.18), 7.512 (2.71), 7.524 (6.80), 7.536 (6.85), 7.838 (1.13), 7.843 (1.11), 7.861 (1.78), 7.866 (1.77 ), 7.930 (3.34), 7.952 (2.02), 8.712 (0.72), 8.729 (1.22), 8.744 (0.69).

Example 165A. (+/-)-Ethyl-3 - {[(6-bromo-3-methyl-2-phenylquinolin-4-yl) carbonyl] amino} -2 -fluorohydrotropate (racemate) £ ^f A> v ^h 3

Ο^ΝΗ On z Xa ⁿ Xq

To a mixture of 6-bromo-3-methyl-2-phenylquinoline-4-carboxylic acid (171 mg, 500 µmol, prepared according to WO 2016146602 A1, page 51, example 3A) in DMF (5 ml) was added HATU (150 µl , 750 µmol) and DIPEA (260 µl, 1.5 mmol) and the mixture was stirred for 5 min at RT. Then (+/-)-ethyl 3-amino-2-fluoro-2-phenylpropanoate hydrochloride (186 mg, 750 µmol, CAS-RN 1909308-68-4, commercially available) was added and the mixture was stirred for 2.5 h at 60°C. After cooling to RT, the mixture was mixed with ethyl acetate and water (respectively 50 ml) and shaken. 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 KP-Sil, cyclohexane/ ethyl acetate 93:7 ^ 7:3). The combined desired fractions were concentrated and the residue was dried in vacuo. 222 mg (100% pure, 83% th. y.) of the title compound were obtained.

LC-MS (Method 2): R _t = 1.20 min; MS (ESIpos): m/z = 535/537 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: -0.008 (1.50), 0.008 (1.61), 1.143 (0.70), 1.179 (7.74), 1.197 (16.00), 1.215 (8.00), 1.233 ( 0.88), 1.397 (1.11), 2.168 (1.34), 2.327 (0.57), 4.217 (3.02), 4.233 (3.04), 5.754 (1.29), 7.387 (0.85), 7.398 (0.54), 7.478 (5.24), 7.07), 7.509 (9.52), 7.514 (8.51), 7.528 (12.06), 7.542 (13.27), 7.581 (9.10), 7.599 (6.45) 4.46), 9.179 (1.98), 9.194 (3.94), 9.209 (1.91).

Example 166A. (+/-)-Ethyl-3-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-2-methyl-2[3-(trifluoromethyl)phenyl]propanoate (racemate )

HATU (843 mg , 2.22 mmol) and DIPEA (770 μl, 4.4 mmol) and the mixture was stirred for 30 min at RT. Then (+/-)-ethyl 3-amino-2-methyl-2-[3-(trifluoromethyl)phenyl]propanoate (610 mg, 2.22 mmol, example 84A) dissolved in DMF (3 ml) was added and the mixture was stirred for nights at 60°C. After cooling to RT, the mixture was purified by preparative HPLC (Method 15). The combined desired fractions were concentrated and the residue was dried in vacuo. Received 577 mg (98% pure, 64% theoretical. yield.) specified in the title compound.

LC-MS (Method 1): Rt = 2.50 min; MS (ESIpos): m/z = 599/601 [M+H] ⁺ .

'H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 1.124 (6.68), 1.142 (14.17), 1.160 (6.91), 1.398 (0.94), 1.694

- 79 040284 (16.00), 2.074 (1.16), 3.939 (1.13), 3.952 (1.23), 3.973 (1.51), 3.986 (1.41), 4.100 (0.67), 4.109 (0.82), 4.118 (0.87), 4.127 (3.00) ), 4.144 (4.39), 4.162 (2.88), 4.170 (0.82), 4.179 (0.79), 4.188 (0.64), 4.219 (1.62), 4.237 (1.71), 4.253 (1.39), 4.271 (1.30), 7.478 (0.48 ), 7.493 (1.25), 7.503 (4.16), 7.510 (3.72), 7.521 (10.32), 7.525 (9.36), 7.621 (0.97), 7.641 (2.45), 7.660 (2.39), 7.686 (2.87), 7.706 (5.92 ), 7.732 (2.76), 7.751 (1.95), 7.837 (1.69), 7.842 (1.63), 7.859 (2.60), 7.864 (2.57), 7.935 (5.22), 7.957 (3.35), 8.766 (1.12), 8.782 (1.97 ),8.796 (1.16).

Example 167A. (+/-)-tert-Butyl-3-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-2-(3methoxyphenyl)propanoate (racemate)

HATU (1.14 g , 2.99 mmol) and DIPEA (1.4 ml, 8.0 mmol) and the mixture was stirred for 30 min at RT. Then (+/-)-tert-butyl-3-amino-2-(3-methoxyphenyl)propanoate (750 mg, 2.99 mmol, example 85A) dissolved in DMF (4.6 ml) was added and the mixture was stirred overnight at 60°C . After cooling to RT, the mixture was mixed with water (60 ml) and shaken. The aqueous phase was extracted twice with ethyl acetate (100 ml and 80 ml). 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 (50 g Biotage Snap-Cartridge KP-Sil, cyclohexane/ethyl acetate 100:0 ^ 7:3 , Isolera). 940 mg (92% pure, 76% thor.) of the title compound were obtained.

LC-MS (Method 2): Rt = 1.28 min; MS (ESIpos): m/z = 575/577 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (0.84), 0.008 (0.62), 1.375 (16.00), 1.398 (7.07), 2.184 (1.00), 2.523 (0.41), 3.749 (6.57 ), 3.960 (0.51), 6.879 (0.43), 6.898 (1.61), 6.923 (0.54), 6.943 (0.62), 7.304 (0.59), 7.509 (0.84), 7.516 (0.75), 7.529 (1.92), 7.535 (1.86 ), 7.542 (1.36), 7.849 (0.46), 7.871 (0.69), 7.876 (0.65), 7.945 (1.19), 7.967 (0.76), 8.992 (0.54).

Example 168A. (+/-)-tert-Butyl-3 - {[(6-bromo-3 -methyl-2-phenylquinolin-4-yl)carbonyl] amino } -2-(3 chlorophenyl) propanoate (racemate)

HATU (743 mg , 1.95 mmol) and DIPEA (910 µl, 5.2 mmol) and the mixture was stirred for 30 min at RT. Then (+/-)-tert-butyl-3-amino-2-(3-chlorophenyl)propanoate (500 mg, 1.95 mmol, example 86A) dissolved in DMF (3.0 ml) was added and the mixture was stirred overnight at 60°C . After cooling to RT, the mixture was mixed with water (40 ml) and shaken. The aqueous phase was extracted twice with ethyl acetate (70 ml and 50 ml). 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 (50 g Biotage Snap-Cartridge KP-Sil, cyclohexane/ethyl acetate 100:0 ^ 7:3 , Isolera). 430 mg (88% pure, 50% thor.) of the title compound were obtained.

LC-MS (Method 2): R _t = 1.36 min; MS (ESIpos): m/z = 579/581 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 8.98 (t, 1H), 7.95 (d, 1H), 7.86 (dd, 1H), 7.68 (br. s, 1H), 7.567. 47 (m, 5H), 7.46-7.32 (m, 4H), 4.01 (t, 1H), 3.93-3.76 (m, 2H), 2.15 (br. s, 3H), 1.38 (s, 9H).

Example 169A. (+/-)-tert-Butyl-3- {[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino} -2-(3methylphenyl)propanoate (racemate)

- 80 040284

HATU (1.13 g , 2.97 mmol) and DIPEA (1.4 ml, 7.9 mmol) and the mixture was stirred for 30 min at RT. Then (+/-)-tert-butyl-3-amino-2-(3-methylphenyl)propanoate (699 mg, 2.97 mmol, example 87A) dissolved in DMF (4.6 ml) was added and the mixture was stirred overnight at 60°C . After cooling to RT, the mixture was mixed with water (60 ml) and shaken. The aqueous phase was extracted twice with ethyl acetate (110 ml and 80 ml). The combined organic phases were washed once with saturated aqueous sodium chloride (60 ml), dried over sodium sulfate, filtered and concentrated, and the residue was purified by flash column chromatography (50 g of Biotage Snap-Cartridge KP-Sil, cyclohexane/ethyl acetate 100:0 ^ 7:3, Isolera). 830 mg (95% pure, 71% thor.) of the title compound were obtained.

C-MS (Method 1): Rt = 2.56 min; MS (ESIpos): m/z = 559/561 [M+H]+.

1H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 8.99 (t, 1H), 7.95 (d, 1H), 7.87 (dd, 1H), 7.76 (br. s, 1H), 7.597. 44 (m, 5H), 7.27 (t, 1H), 7.19-7.07 (m, 3H), 3.99-3.90 (m, 1H), 3.89-3.80 (m, 1H), 3.78-3.66 (m, 1H), 2.31 (s, 3H), 2.19 (br. s, 2H), 1.37 (s, 9H).

Example 170A. (+/-)-Methyl-3 - {[(6-bromo-3 -methyl-2-phenylquinolin-4-yl)carbonyl]amino} -2-hydroxy-2-(2-methoxyphenyl)propanoate (racemate)

To a mixture of 6-bromo-3-methyl-2-phenylquinoline-4-carboxylic acid (506 mg, 1.48 mmol, obtained according to WO 2016146602 A1, page 51, example 3A) in DMF (7.5 ml) was added HATU (150 μl , 2.2 mmol) and DIPEA (770 µl, 4.4 mmol) and the mixture was stirred for 5 min at RT. Then (+/-)-methyl 3-amino-2-hydroxy-2-(2-methoxyphenyl)propanoate (500 mg, 2.22 mmol, available from Santai Labs, Art Nr. ADH-GM-15173) was added and the mixture was stirred for 8.5 h at 60°C. After cooling to RT, the mixture was mixed with ethyl acetate and water (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 (80 ml), dried over sodium sulfate, filtered and concentrated, and the residue was adsorbed in dichloromethane and purified by flash column chromatography (100 g of Biotage Snap-Cartridge KP-Sil, cyclohexane/ethyl acetate 93 :7 ^ 4:6, Isolera). 586 mg (100% pure, 72% thor.) of the title compound were obtained.

LC-MS (Method 1): Rt = 1.98 min; MS (ESIpos): m/z = 549/551 [M+H]+.

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: -0.008 (0.91), 0.008 (0.93), 1.988 (0.67), 2.092 (1.03), 2.522 (0.43), 3.310 (16.00), 3.635 ( 12.16), 6.293 (3.96), 6.939 (0.57), 6.958 (1.16), 6.977 (0.66), 6.997 (1.00), 7.017 (1.16) 0.55), 7.494 (1.81), 7.501 (1.68), 7.514 (4.48), 7.518 (4.24), 7.526 (2.88), 7.538 (0.56), 7.590 (0.79), 7.609 (0.74), 7.813 (0.84), 7.818 0.78), 7.835 (1.31), 7.840 (1.30), 7.899 (2.67), 7.921 (1.57), 8.478 (0.46), 8.493 (0.78), 8.508 (0.45).

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.49 (t, 1H), 7.91 (d, 1H), 7.83 (dd, 1H), 7.71 (br. s, 1H), 7.60 (d , 1H), 7.55-7.46 (m, 5H), 7.30 (t, 1H), 7.05-6.92 (m, 2H), 6.29 (s, 1H), 4.35-4.11 (m, 1H), 4.09-3.93 (m , 1H), 3.76 (s, 3H), 3.64 (s, 3H), 2.09 (br. s, 3H).

Separation of enantiomers.

The title title compound (309 mg) was dissolved in a mixture of ethanol (2 ml) and dichloromethane (3 ml) and separated into enantiomers by chiral phase preparative HPLC (see Examples 171A and 172A) [column: Daicel Chiralpak IA, 5 µm, 250 mm x 20 mm; flow: 15 ml/min; detection: 220 nm; temperature: 50°C; sample injection: 0.15 ml; eluent: 100% ethanol; duration of action 18 min, isocratic]. The combined target fractions were concentrated and the residue was lyophilized in acetonitrile/water.

Example 171A. (-)-Methyl-3- {[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino} -2-hydroxy- 81 040284

2-(2-methoxyphenyl)propanoate (enantiomer 1).

The separation of enantiomers described in Example 170A gave 145 mg (100% pure, ee value 99%) of the title compound as the previously eluted enantiomer.

[a] _D20 = -68.6°, 589 nm, c = 0.34 ^g /100 ml, methanol.

LC-MS (Method 1): R _t = 2.00 min; MS (ESIpos): m/z = 549/551 [M+H]+.

1H-NMR (500 MHz, DMSO-d ₆ ) δ [ppm]: 2.095 (0.99), 3.465 (0.46), 3.473 (0.45), 3.487 (0.43), 3.636 (16.00), 6.945 (0.70), 6.960 (1.40 ), 6.975 (0.80), 6.999 (1.22), 7.016 (1.33), 7.285 (0.49), 7.300 (0.76), 7.314 (0.43), 7.474 (0.42), 7.482 (1.02), 7.490 (1.00), 7.494 (1.82 ), 7.499 (2.36), 7.514 (4.54), 7.522 (4.89), 7.526 (5.82), 7.538 (0.96), 7.596 (0.92), 7.610 (0.88), 7.818 (1.06), 7.822 (1.03), 7.836 (1.53 ), 7.840 (1.50), 7.903 (3.12), 7.921 (2.06), 8.485 (0.61), 8.497 (1.00), 8.508 (0.60).

1H-NMR (500 MHz, DMSO-d ₆ ) δ [ppm]: 8.50 (t, 1H), 7.91 (d, 1H), 7.83 (dd, 1H), 7.67 (br. s, 1H), 7.60 (d , 1H), 7.56-7.46 (m, 5H), 7.30 (t, 1H), 7.05-6.92 (m, 2H), 6.29 (br. s, 1H), 4.22 (br. s, 1H), 4.01 (br .s, 1H), 3.76 (s, 3H), 3.64 (s, 3H), 2.09 (br. s, 3H).

Example 172A. (+)-Methyl-3-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-2-hydroxy2-(2-methoxyphenyl)propanoate (enantiomer 2).

The separation of enantiomers described in Example 170A gave 137 mg (100% pure, ee value 99%) of the title compound as the later eluted enantiomer.

[a] _D20 = +71.8°, 589 nm, c = 0.33 g ^/ 100 mL, methanol.

LC-MS (Method 1): R _t = 2.00 min; MS (ESIpos): m/z = 549/551 [M+H] ⁺ .

1H-NMR (500 MHz, DMSO-d6) δ [ppm]: 2.095 (1.37), 3.762 (16.00), 6.946 (0.95), 6.960 (1.90), 6.975 (1.09), 7.000 (1.66), 7.016 (1.81) , 7.286 (0.67), 7.300 (1.05), 7.315 (0.59), 7.475 (0.56), 7.484 (1.38) , 7.527 (7.88), 7.539 (1.35), 7.596 (1.28), 7.611 (1.22), 7.821 (1.43), 7.824 (1.40), 7.839 (2.07), 7.842 (2.05), 7.905 (4.13), 7.923 (2.71) , 8.488 (0.85), 8.499 (1.37), 8.511 (0.83).

1H-NMR (500 MHz, DMSO-d ₆ ) δ [ppm]: 8.50 (t, 1H), 7.91 (d, 1H), 7.83 (dd, 1H), 7.68 (br. s, 1H), 7.60 (d , 1H), 7.55-7.44 (m, 5H), 7.30 (t, 1H), 7.07-6.91 (m, 2H), 6.28 (br. s, 1H), 4.22 (br. s, 1H), 4.01 (br s, 1H), 3.76 (s, 3H), 3.64 (s, 3H), 2.10 (br. s, 3H).

Example 173A. (+/-)-tert-Butyl-3-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-2-(2fluoro-6-methoxyphenyl)propanoate (racemate)

HATU (256 mg , 673 µmol) and DIPEA (230 µl, 1.3 mmol) and the mixture was stirred for 15 min at RT. Then (+/-) tert-butyl-3-amino-2-(2-fluoro-6-methoxyphenyl)propanoate (213 mg, 71% pure, 561 µmol, example 88A) was added and the mixture was stirred for 2 h at 60°C . After cooling to RT, the mixture was mixed with ethyl acetate and water (respectively 50 ml) and shaken. After phase separation, the aqueous phase was extracted once with ethyl acetate (30 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 previously purified by flash column chromatography (50 g of Biotage Snap-Cartridge KP-Sil, cyclohexane/ethyl acetate 93:7 ^ 7:3, Isolera One). The prepurified product was then further purified by preparative HPLC (Method 15). The combined desired fractions were concentrated and the residue was dried in vacuo. 192 mg (100% pure, 58% thor.) of the title compound were obtained.

LC-MS (Method 2): Rt = 1.30 min; MS (ESIpos): m/z = 593/595 [M+H] ⁺ .

1H-NMR (500 MHz, DMSO-d6) δ [ppm]: 8.80 (t, 1H), 7.94 (d, 1H), 7.86 (dd, 1H), 7.78 (br. s, 1H), 7.557.47 ( m, 5H), 7.34-7.26 (m, 1H), 6.88 (d, 1H), 6.82 (t, 1H), 4.34 (dd, 1H), 4.14-4.05 (m, 1H), 3.80 (s, 3H) , 3.71 (br. s, 1H), 2.18 (s, 3H), 1.37 (s, 9H).

Separation of enantiomers.

The title target compound (224 mg, combined with the amount obtained from the preliminary test) in methanol (10 ml) was dissolved and separated into enantiomers by preparative SLC (supercritical liquid chromatography) on a chiral phase (see examples 174A and 175A) [column: Chiralpak AD SFC, 5 µm, 250 mm x 20 mm; flow: 60 ml/min; detection: 210 nm; temperature: 40°C; sample injection: 0.50 ml; eluent: 70% carbon dioxide/30% ethanol; duration

- 82 040284 action 11 min, isocratic]. The combined desired fractions were concentrated and the residue was dried in vacuo.

Example 174A. (-)-tert-Butyl-3-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-2-(2fluoro-6-methoxyphenyl)propanoate (enantiomer 1).

The separation of enantiomers described in Example 173A gave 81 mg (100% pure, ee value 100%) of the title compound as the previously eluted enantiomer.

[a]D ²⁰ = -62.0°, 589 nm, c = 0.33 g/100 ml, chloroform.

LC-MS (Method 2): Rt = 1.30 min; MS (ESIpos): m/z = 593/595 [M+H]+.

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.364 (16.00), 2.181 (2.78), 3.794 (5.53), 6.818 (0.64), 6.869 (0.67), 6.890 (0.73), 7.289 (0.41) , 7.307 (0.40), 7.502 (0.87), 7.510 (0.77), 7.522 (2.43), 7.526 (2.34), 7.534 (1.34), 7.840 (0.46), 7.846 (0.40), 7.863 (0.71), 7.868 (0.66) , 7.930 (1.25), 7.952 (0.76), 8.795 (0.59).

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 8.79 (t, 1H), 7.94 (d, 1H), 7.86 (dd, 1H), 7.77 (br. s, 1H), 7.567.46 ( m, 5H), 7.35-7.25 (m, 1H), 6.88 (d, 1H), 6.82 (t, 1H), 4.34 (dd, 1H), 4.14-4.04 (m, 1H), 3.79 (s, 3H) , 3.753.65 (m, 1H), 2.18 (s, 3H), 1.36 (s, 9H).

Example 175A. (+)-tert-Butyl-3-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-2-(2fluoro-6-methoxyphenyl)propanoate (enantiomer 2).

The separation of enantiomers described in Example 173A gave 92 mg (100% pure, ee value 100%) of the title compound as the later eluted enantiomer.

[a] _D20 = +60.9°, 589 nm ^, c = 0.32 g/100 ml, chloroform.

LC-MS (Method 2): R _t = 1.30 min; MS (ESIpos): m/z = 593/595 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 1.364 (16.00), 2.181 (2.95), 3.795 (5.53), 6.818 (0.67), 6.841 (0.40), 6.870 (0.70), 6.891 (0.77 ), 7.290 (0.44), 7.308 (0.43), 7.502 (0.93), 7.510 (0.82), 7.523 (2.63), 7.526 (2.55), 7.841 (0.47), 7.846 (0.41), 7.863 (0.72), 7.868 (0.67 ), 7.930 (1.24), 7.953 (0.76), 8.795 (0.63).

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.79 (t, 1H), 7.94 (d, 1H), 7.86 (dd, 1H), 7.77 (br. s, 1H), 7.567.46 (m, 5H), 7.35-7.24 (m, 1H), 6.88 (d, 1H), 6.82 (t, 1H), 4.34 (dd, 1H), 4.16-4.03 (m, 1H), 3.79 (s, 3H ), 3.71 (br. s, 1H), 2.18 (s, 3H), 1.36 (s, 9H).

Example 176A. (+/-)-tert-Butyl-3-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-2-(2methoxyphenyl)-2-methylpropanoate (racemate)

HATU (1.30 g , 3.43 mmol) and DIPEA (1.2 ml, 6.9 mmol) and the mixture was stirred for 30 min at RT. Then (+/-)-tert-butyl-3-amino-2-(2-methoxyphenyl)-2-methylpropanoate (1.30 g, 70% pure, 3.43 mmol, example 89A) dissolved in DMF (5 ml) was added and the mixture was stirred overnight at 60°C. After cooling to RT, the mixture was mixed with ethyl acetate and water (respectively 50 ml). After shaking and phase separation, the aqueous phase was extracted twice with ethyl acetate (corresponding to 50 ml). The combined organic phases were washed once with saturated aqueous sodium chloride, dried over sodium sulfate, filtered and concentrated, and the residue was adsorbed into dichloromethane and purified by flash column chromatography (100 g silica gel, Biotage Snap-Cartridge KP-Sil, cyclohexane/ethyl acetate 93: 7 ^ 6:4, Isolera One). The combined target fractions were concentrated and the residue was lyophilized in acetonitrile/water. 1.09 g (98% pure, 79% th. y.) of the title compound was obtained.

LC-MS (Method 1): R _t = 2.55 min; MS (ESIpos): m/z = 589/591 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 8.39 (dd, 1H), 7.92 (d, 1H), 7.84 (dd, 1H), 7.65 (br. s, 1H), 7.557.45 ( m, 5H), 7.30-7.20 (m, 2H), 6.98 (d, 1H), 6.93 (t, 1H), 4.29 (dd, 1H), 3.78 (s, 3H), 3.72 (dd, 1H), 2.08 (br. s, 3H), 1.57 (s, 3H), 1.36 (s, 9H).

Separation of enantiomers.

The title target compound (1.00 g) was dissolved in ethanol (25 ml) and separated into enantiomers by chiral phase preparative SLC (see examples 177A and 178A) [column: Daicel Chiralpak AD, 20 μm, 360 mm x 50 mm; flow: 140 ml/min; detection: 210 nm; temperature: 38°C; sample injection: 2.0 ml; eluent: 70% carbon dioxide/30% ethanol ^ 50% carbon dioxide/50% ethanol; duration of action 9 minutes]. The combined desired fractions were concentrated and the residue was dried in vacuo.

- 83 040284

Example 177A. (-)-tert-Butyl-3-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-2-(2methoxyphenyl)-2-methylpropanoate (enantiomer 1)

The separation of enantiomers described in Example 176A gave the prepurified title compound as the previously eluted enantiomer (ee value 100%) and further purified by preparative HPLC (Method 20). The combined target fractions were concentrated and lyophilized. 440 mg (98% pure) of the title compound were obtained.

[a] _D20 = -95.7°, 589 nm ^, c = 0.35 g/100 ml, chloroform.

LC-MS (Method 2): Rt = 1.35 min; MS (ESIpos): m/z = 589/591 [M+H]+.

1H-NMR (600 MHz, DMSO-d ₆ ) δ [ppm]: 8.41 (dd, 1H), 7.92 (d, 1H), 7.84 (dd, 1H), 7.60 (br. s, 1H), 7.557.46 (m, 5H), 7.30-7.20 (m, 2H), 6.98 (d, 1H), 6.93 (t, 1H), 4.30 (dd, 1H), 3.78 (s, 3H), 3.75-3.68 (m, 1H ), 2.08 (br. s, 3H), 1.57 (s, 3H), 1.36 (s, 9H).

Example 178A. (+)-tert-Butyl-3-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-2-(2methoxyphenyl)-2-methylpropanoate (enantiomer 2).

The separation of enantiomers described in Example 176A gave the prepurified title compound as a later eluting enantiomer (ee value 100%) and further purified by preparative HPLC (Method 20). The combined target fractions were concentrated and lyophilized. 450 mg (98% pure) of the title compound were obtained.

[a] _D20 = +93.1°, 589 nm, c = 0.36 g/100 ml ^, chloroform.

LC-MS (Method 2): R _t = 1.35 min; MS (ESIpos): m/z = 589/591 [M+H] ⁺ .

1H-NMR (600 MHz, DMSO-d6) δ [ppm]: 1.364 (16.00), 1.568 (2.53), 6.988 (0.40), 7.228 (0.68), 7.241 (0.64), 7.498 (0.58), 7.503 (0.80) , 7.517 (2.34), 7.524 (1.93), 7.848 (0.52), 7.850 (0.50), 7.917 (0.99), 7.931 (0.69), 8.408 (0.45).

1H-NMR (600 MHz, DMSO-d ₆ ) δ [ppm]: 8.41 (dd, 1H), 7.92 (d, 1H), 7.84 (dd, 1H), 7.63 (br. s, 1H), 7.557.46 (m, 5H), 7.31-7.19 (m, 2H), 6.98 (d, 1H), 6.93 (t, 1H), 4.29 (dd, 1H), 3.78 (s, 3H), 3.75-3.67 (m, 1H ), 2.08 (br. s, 3H), 1.57 (s, 3H), 1.36 (s, 9H).

Example 179A. (+/-)-tert-Butyl-3-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-2-(2chloro-6-fluorophenyl)-2-methylpropanoate ( racemate)

HATU (1.16 g , 3.04 mmol) and DIPEA (1.1 ml, 6.1 mmol) and the mixture was stirred for 30 min at RT. Then (+/-)-tert-butyl-3-amino-2-(2-chloro-6-fluorophenyl)-2-methylpropanoate (1.25 g, 70% pure, 3.04 mmol, example 90A) dissolved in DMF (5 ml ) and the mixture was stirred overnight at 60°C. After cooling to RT, the mixture was mixed with ethyl acetate and water (respectively 50 ml). After shaking and phase separation, the aqueous phase was extracted twice with ethyl acetate (corresponding to 50 ml). The combined organic phases were washed once with saturated aqueous sodium chloride, dried over sodium sulfate, filtered and concentrated, and the residue was adsorbed into dichloromethane and purified by flash column chromatography (100 g silica gel, Biotage Snap-Cartridge KP-Sil, cyclohexane/ethyl acetate 93: 7 ^ 6:4, Isolera One). The combined target fractions were concentrated and the residue was lyophilized in acetonitrile/water. 960 mg (83% pure, 64% thor.) of the title compound were obtained.

LC-MS (Method 1): R _t = 2.63 min; MS (ESIpos): m/z = 611/613 [M+H]+ LC-MS (Method 7): R _t = 1.71 min.

Separation of enantiomers.

The title target compound (960 mg) in methanol (35 ml) was dissolved and separated into enantiomers by chiral phase preparative SLC (see examples 180A and 181A) [column: Daicel Chiralpak AD, 250 mm x 20 mm; flow: 80 ml/min; detection: 210 nm; temperature: 40°C; sample injection: 0.8 ml; eluent: 80% carbon dioxide / 20% methanol; duration of action 7 min, isocratic]. The combined desired fractions were concentrated and the residue was dried in vacuo.

Example 180A. (+)-tert-Butyl-3-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-2-(2chloro-6-fluorophenyl)-2-methylpropanoate (enantiomer 1 ).

The separation of enantiomers described in Example 179A gave the prepurified title compound as the previously eluted enantiomer (ee value >99%) and was further purified twice by preparative HPLC (Method 20). The combined desired fractions were concentrated and the residue dried in vacuo. 205 mg (98% pure, 21% thor.) of the title compound were obtained.

[a] _D20 = +65.8°, 589 nm, c = 0.40 g/100 mL ^, methanol.

LC-MS (Method 1): R _t = 2.65 min; MS (ESIpos): m/z = 611/613 [M+H] ⁺ .

1H-NMR (500 MHz, DMSO-d ₆ ) δ [ppm]: 8.77 (t, 1H), 7.94 (d, 1H), 7.86 (dd, 1H), 7.68 (br. s, 1H), 7.587.47 (m, 5H), 7.42-7.28 (m, 2H), 7.23-7.13 (m, 1H), 4.47 (br. s, 1H), 3.81 (br. s, 1H), 2.16 (br. s, 3H) , 1.84 (d, 3H), 1.42 (s, 9H).

Example 181A. (-)-tert-Butyl-3-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-2-(2chloro-6-fluorophenyl)-2-methylpropanoate (enantiomer 2 ).

The separation of enantiomers described in Example 179A gave the prepurified title compound as a later eluting enantiomer (ee value >99%) and further purified by preparative HPLC (Method 20). The combined desired fractions were concentrated and the residue was dried in vacuo. 289 mg (98% pure, 30% theoretical) of the title compound were obtained.

[a] _D20 = -70.6°, 589 nm, c = 0.36 ^g /100 ml, methanol.

LC-MS (Method 1): R _t = 2.67 min; MS (ESIpos): m/z = 611/613 [M+H] ⁺ .

1H-NMR (500 MHz, DMSO-d6) δ [ppm]: 8.76 (t, 1H), 7.94 (d, 1H), 7.85 (dd, 1H), 7.68 (br. s, 1H), 7.577.46 ( m, 5H), 7.41-7.28 (m, 2H), 7.22-7.13 (m, 1H), 4.47 (br. s, 1H), 3.80 (br. s, 1H), 2.16 (br. s, 3H), 1.83 (d, 3H), 1.42 (s, 9H).

Example 182A. (+/-)-tert-Butyl-4-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-(2chlorophenyl)butanoate (racemate)

HATU (846 mg , 2.22 mmol) and DIPEA (770 μl, 4.4 mmol) and the mixture was stirred for 30 min at RT. Then (+/-)-tert-butyl-4-amino-3-(2-chlorophenyl)butanoate (600 mg, 2.22 mmol, example 91A) dissolved in DMF (4 ml) was added and the mixture was stirred overnight at 60°C . After cooling to RT, the mixture was purified by preparative HPLC (Method 22). 527 mg (98% pure, 58% thor.) of the title compound were obtained.

LC-MS (Method 1): R _t = 2.54 min; MS (ESIpos): m/z = 593/595 [M+H] ⁺ .

1H-NMR was prepared from a batch of product (104 mg, 98% pure, 89% theoretical) from a similar test (based on 66 mg, 19.3 mmol 6-bromo-3-methyl-2-phenylquinoline-4-carboxylic acids):

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 8.86 (t, 1H), 7.95 (d, 1H), 7.86 (dd, 1H), 7.78-7.62 (m, 1H), 7.58-7.47 ( m, 6H), 7.44 (dd, 1H), 7.35 (t, 1H), 7.27 (t, 1H), 4.00-3.87 (m, 1H), 3.84-3.57 (br. m, 2H, partially hidden), 2.82 -2.60 (m, 2H), 2.16 (s, 3H), 1.25 (s, 9H).

Example 183A. (+/-)-tert-Butyl-4-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-(3chlorophenyl)butanoate (racemate)

HATU (166 mg , 436 µmol) and DIPEA (150 µl, 870 µmol) and the mixture was stirred for 30 min at RT. Then (+/-)-tert-butyl 4-amino-3-(3-chlorophenyl)butanoate (294 mg, 40% pure, 436 µmol, Example 92A) dissolved in DMF (1 ml) was added and the mixture was stirred overnight at 60°C. After cooling to RT, the mixture was purified by preparative HPLC (Method 21). 224 mg (66% pure, 86% thor.) of the title compound were obtained.

LC-MS (Method 1): R _t = 2.53 min; MS (ESIpos): m/z = 591/593 [M+H] ⁺ .

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Example 184A. (+/-)-tert-Butyl-4-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-(2methylphenyl)butanoate (racemate)

HATU (1.05 g , 2.76 mmol) and DIPEA (960 μl, 5.5 mmol) and the mixture was stirred for 30 min at RT. Then (+/-)-tert-butyl-4-amino-3-(2-methylphenyl)butanoate (724 mg, 95% pure, 2.76 mmol, example 93A) dissolved in DMF (3.5 ml) was added and the mixture was stirred overnight at 60°C. After cooling to RT, the mixture was purified by preparative HPLC (Method 21). 778 mg (95% pure, 70% thor.) of the title compound were obtained.

LC-MS (Method 1): R _t = 2.56 min; MS (ESIpos): m/z = 573/575 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 8.88 (t, 1H), 7.95 (d, 1H), 7.86 (dd, 1H), 7.69 (br. s, 1H), 7.597. 44 (m, 5H), 7.34 (d, 1H), 7.26-7.03 (m, 3H), 3.80-3.62 (m, 2H), 3.57-3.38 (m, 1H), 2.78-2.67 (m, 1H), 2.642.56 (m, 1H), 2.39 (s, 3H), 2.14 (br. s, 2H), 1.22 (s, 9H).

Example 185A. (+/-)-tert-Butyl-4-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-(2,6dichlorophenyl)butanoate

HATU (300 mg , 788 µmol) and DIPEA (270 µl, 1.6 mmol) and the mixture was stirred for 30 min at RT. Then (+/-) tert-butyl-4-amino-3-(2,6-dichlorophenyl)butanoate (255 mg, 94% pure, 788 µmol, Example 94A) dissolved in DMF (2 ml) was added and the mixture stirred overnight at 60°C. After cooling to RT, the mixture was purified by preparative HPLC (Method 21). 150 mg (91% pure, 41% thor.) of the title compound were obtained.

LC-MS (Method 2): Rt = 1.41 min; MS (ESIpos): m/z = 627/629/631 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6): δ [ppm] = 8.96 (t, 1H), 7.99-7.93 (m, 1H), 7.90-7.83 (m, 1H), 7.60-7.38 (m, 8H) , 7.36-7.26 (m, 1H), 4.38 (br. s, 1H), 4.07 (br. s, 1H), 3.78 (br. s, 1H, hidden), 3.04 (dd, 1H), 2.82 (dd, 1H), 2.19 (br. s, 3H), 1.24 (s, 9H).

Example 186A. (+/-)-tert-Butyl-4-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-(3methoxyphenyl)butanoate (racemate)

HATU (645 mg , 1.70 mmol) and DIPEA (590 µl, 3.4 mmol) and the mixture was stirred for 30 min at RT. Then (+/-)-tert-butyl-4-amino-3-(3-methoxyphenyl)butanoate (500 mg, 90% pure, 1.70 mmol, example 95A) was added, dissolved in DMF (2 ml) was added and the mixture was stirred for nights at 60°C. After cooling to RT, the mixture was purified by preparative HPLC (Method 21). 225 mg (93% pure, 31% thor.) of the title compound were obtained.

LC-MS (Method 1): Rt = 2.42 min; MS (ESIpos): m/z = 589/591 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6): δ [ppm] = 8.81 (t, 1H), 7.94 (d, 1H), 7.86 (dd, 1H), 7.66 (br. s, 1H), 7.577.46 (m, 5H), 7.23 (t, 1H), 6.92-6.86 (m, 2H), 6.83-6.74 (m, 1H), 3.80-3.66 (m, 1H, partially hidden), 3.72 (s,

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3H), 3.66-3.48 (m, 1H), 3.43-3.23 (m, 1H), 2.72 (dd, 1H), 2.59-2.52 (m, 1H, partially hidden), 2.11 (br. s, 3H),

1.27(s, 9H).

Example 187A. (+/-)-tert-Butyl-4-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-(3chloropyridin-2-yl)-3-methylbutanoate ( racemate)

HATU (822 mg , 2.16 mmol) and DIPEA (0.75 ml, 4.33 mmol) and the mixture was stirred for 30 min at RT. Then (+/-)-tert-butyl-4-amino-3-(3-chloropyridin-2-yl)-3-methylbutanoate (616 mg, 2.16 mmol, example 96A) dissolved in DMF (4 ml) was added and the mixture stirred overnight at 60°C. After cooling to RT, the mixture was purified by preparative HPLC (Method 21). 694 mg (98% pure, 77% thor.) of the title compound were obtained.

LC-MS (Method 2): Rt = 1.35 min; MS (ESIpos): m/z = 608/610 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6): δ [ppm] = 8.69 (t, 1H), 8.48 (dd, 1H), 7.94 (d, 1H), 7.86 (dd, 2H), 7.71 (d, 1H ), 7.58-7.44 (m, 5H), 7.32 (dd, 1H), 4.12 (br. s, 1H), 3.99 (br. s, 1H), 3.32 (d, 1H), 2.67 (d, 1H), 2.16 (s, 3H), 1.68 (s, 3H), 1.20 (s, 9H).

Example 188A. (+/-)-tert-Butyl-4-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-(2chloro-6-fluorophenyl)butanoate (racemate)

HATU (8.26 g , 21.7 mmol) and DIPEA (7.6 ml, 43 mmol) and the mixture was stirred for 30 min at RT. (+/-)-tert-Butyl-4amino-3-(2-chloro-6-fluorophenyl)butanoate (5.00 g, 17.4 mmol, example 97A) dissolved in DMF (20 ml) was then added and the mixture was stirred overnight at 60°C. After cooling to RT, the mixture was concentrated and the residue was mixed with 200 ml of ethyl acetate and water, respectively, and shaken. The aqueous phase was extracted once with ethyl acetate. The combined organic phases were washed once with 200 ml saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated, and the residue was adsorbed in dichloromethane and purified by flash column chromatography (500 g of Biotage Snap-Cartridge KP-Sil, cyclohexane/ethyl acetate 9: 1 ^ 8:2). 5.23 g (100% pure, 59% th. y.) of the title compound were obtained.

LC-MS (Method 2): R _t = 1.33 min; MS (ESIpos): m/z = 611/613 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6): δ [ppm] = 8.97 (t, 1H), 7.95 (d, 1H), 7.86 (dd, 1H), 7.78-7.59 (br. m, 1H), 7.60 -7.44 (m, 5H), 7.38-7.29 (m, 2H), 7.26-7.12 (m, 1H), 4.16-3.98 (m, 1H), 3.93-3.56 (br. m, 2H), 2.852.61 ( m, 2H), 2.17 (br. s, 3H), 1.24 (s, 9H).

Separation of enantiomers.

The title target compound (5.15 g) was adsorbed in 50 ml methanol, filtered and separated into enantiomers by preparative SLC on a chiral phase (see examples 189A and 190A) [column: Daicel Chiralcel OJ-H, 5 µm, 250 mm x 30 mm; flow: 175 ml/min; detection: 210 nm; temperature: 38°C; sample injection: 0.4 ml; eluent: 80% carbon dioxide / 20% isopropanol; duration of action 8 min, isocratic].

Example 189A. (-)-tert-Butyl-4-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-(2chloro-6-fluorophenyl)butanoate (enantiomer 1).

Separation of enantiomers as described in Example 188A gave 1.89 g (100% pure, 97% ee) of the title compound as the previously eluted enantiomer.

[a] _D20 = -16.6°, 589 nm, c = 0.50 g ^/ 100 ml, chloroform.

LC-MS (Method 1): Rt = 2.52 min; MS (ESIpos): m/z = 611/613 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 8.97 (t, 1H), 7.95 (d, 1H), 7.86 (dd, 1H), 7.78-7.57 (m, 1H),

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7.58-7.43 (m, 5H), 7.40-7.28 (m, 2H), 7.26-7.13 (m, 1H), 4.17-3.99 (m, 1H), 3.94-3.59 (br. m, 2H), 2.88-2.61 (m, 2H), 2.17 (br. s, 3H), 1.24 (s, 9H).

Example 190A. (+)-tert-Butyl-4-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-(2chloro-6-fluorophenyl)butanoate (enantiomer 2).

The separation of enantiomers described in Example 188A gave 1.85 g (98% pure, ee value 95%) of the title compound as the later eluted enantiomer.

[a] _D20 = +16.1°, 589 nm, c = 0.52 g/100 ml ^, chloroform.

LC-MS (Method 1): Rt = 2.52 min; MS (ESIpos): m/z = 611/613 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 8.97 (t, 1H), 7.95 (d, 1H), 7.86 (dd, 1H), 7.79-7.60 (br. m, 1H), 7.56-7.44 (m, 5H), 7.41-7.27 (m, 2H), 7.26-7.13 (m, 1H), 4.18-4.00 (m, 1H), 3.97-3.61 (br. m, 2H), 2.85-2.61 (m, 2H), 2.17 (br. s, 3H), 1.24 (s, 9H).

Example 191A. (+/-)-tert-Butyl-4-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-(4methylphenyl)butanoate (racemate)

HATU (244 mg , 642 µmol) and DIPEA (220 µl, 1.3 mmol) and the mixture was stirred for 30 min at RT. Then (+/-) tert-butyl-4-amino-3-(4-methylphenyl)butanoate (160 mg, 642 µmol), example 98A) dissolved in DMF (1 ml) was added and the mixture was stirred overnight at 60 °C After cooling to RT, the mixture was purified by preparative HPLC (Method 21). 138 mg (98% pure, 55% thor.) of the title compound were obtained.

LC-MS (Method 1): Rt = 2.54 min; MS (ESIpos): m/z = 573/575 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 8.80 (t, 1H), 7.94 (d, 1H), 7.85 (dd, 1H), 7.78-7.57 (br. s, 1H), 7.56-7.45 (m, 5H), 7.21 (d, 2H), 7.13 (d, 2H), 3.89-3.40 (br. m, 2H, hidden), 3.39-3.26 (m, 1H), 2.71 (dd, 1H ), 2.50 (1H, hidden), 2.26 (s, 3H), 2.14 (br. s, 3H), 1.27 (s, 9H).

Example 192A. (+/-)-tert-Butyl-4-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-(3methylphenyl)butanoate (racemate)

HATU (197 mg , 518 µmol) and DIPEA (180 µl, 1.0 mmol) and the mixture was stirred for 30 min at RT. Then (+/-) tert-butyl-4-amino-3-(3-methylphenyl)butanoate (170 mg, 76% pure, 518 µmol, Example 99A) dissolved in DMF (1.0 ml) was added and the mixture was stirred for nights at 60°C. After cooling to RT, the mixture was purified by preparative HPLC (Method 21). 128 mg (98% pure, 63% thor.) of the title compound were obtained.

LC-MS (Method 1): Rt = 2.54 min; MS (ESIpos): m/z = 573/575 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 8.81 (t, 1H), 7.94 (d, 1H), 7.85 (dd, 1H), 7.80-7.58 (br. s, 1H), 7.56-7.46 (m, 5H), 7.24-7.00 (m, 4h), 3.80-3.52 (br. m, 2H, hidden), 3.40-3.28 (m, 1H), 2.72 (dd, 1H), 2.542.45 (1H, hidden), 2.27 (s, 3h), 2.13 (br. s, 3H), 1.26 (s, 9H).

Example 193A. (+/-)-tert-Butyl-4-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-(2methoxyphenyl)butanoate (racemate)

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HATU (5.54 g, 14.6 mmol) and DIPEA (5.1 ml, 29 mmol) and the mixture was stirred for 30 min at RT. Then (+/-)-tert-butyl-4amino-3-(2-methoxyphenyl)butanoate (4.20 g, 92% pure, 14.6 mmol, example 100A) dissolved in DMF (20 ml) was added and the mixture was stirred overnight at 60°C. After cooling to RT, the mixture was concentrated and the residue was adsorbed in ethyl acetate and water (respectively 200 ml) and shaken. After phase separation, the aqueous phase was extracted once with ethyl acetate and the combined organic phases were washed once with saturated aqueous sodium chloride solution (200 ml), dried over sodium sulfate, filtered and evaporated. The residue was adsorbed into dichloromethane and purified by flash column chromatography (340 g Biotage Snap-Cartridge KP-Sil, cyclohexane/ethyl acetate 97:3^8:2, Isolera One). 4.50 g (98% pure, 77% theoretical) of the title compound were obtained.

LC-MS (Method 1): Rt = 2.50 min; MS (ESIpos): m/z = 589/591 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6): δ [ppm] = 8.77 (t, 1H), 7.94 (d, 1H), 7.85 (dd, 1H), 7.71 (br. s, 1H), 7.577.45 (m, 5H), 7.27-7.17 (m, 2H), 6.98 (d, 1H), 6.91 (t, 1H), 3.80 (s, 3H), 3.78-3.61 (m, 3H), 2.71-2.58 (m , 2H), 2.15 (s, 3H), 1.25 (s, 9H).

Example 194A. (+/-)-tert-Butyl-4-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-[2(trifluoromethoxy)phenyl]butanoate (racemate)

HATU (792 mg , 2.08 mmol) and DIPEA (730 µl, 4.2 mmol) and the mixture was stirred for 30 min at RT. Then (+/-)-tert-butyl-4-amino-3-[2-(trifluoromethoxy)phenyl]butanoate (700 mg, 95% pure, 2.08 mmol, Example 101A) dissolved in DMF (3 ml) was added and the mixture was stirred overnight at 60°C. After cooling to RT, the mixture was mixed with ethyl acetate and water (respectively 20 ml) and shaken. The aqueous phase was extracted twice with ethyl acetate (20 ml). The combined organic phases were washed with saturated aqueous sodium chloride, dried over sodium sulfate, filtered and concentrated, and the residue was adsorbed into dichloromethane and purified by flash column chromatography (100 g Biotage Snap-Cartridge KP-Sil, cyclohexane/ethyl acetate 85:15). 367 mg (98% pure, 40% thor.) of the title compound were obtained.

LC-MS (Method 1): R _t = 2.60 min; MS (ESIpos): m/z = 643/645 [M+H] ⁺ .

1H-NMR (600 MHz, DMSO-d ₆ ): δ [ppm] = 8.91 (t, 1H), 7.95 (d, 1H), 7.86 (dd, 1H), 7.81-7.61 (br. m, 1H), 7.61-7.47 (m, 6H), 7.43-7.30 (m, 3H), 3.85-3.70 (m, 2H), 3.69-3.57 (m, 1H), 2.76 (dd, 1H), 2.60 (dd, 1H), 2.16 (br. s, 3H), 1.26 (s, 9H).

Example 195A. (+/-)-tert-Butyl-4-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3(pyridin-2-yl)butanoate (racemate)

HATU (708 mg , 1.86

- 89 040284 mmol) and DIPEA (650 μl, 3.7 mmol) and the mixture was stirred for 30 min at RT. Then (+/-)-tert-butyl-4-amino-3-(pyridin-2-yl)butanoate (550 mg, 80% pure, 1.86 mmol, example 102A) was added, dissolved in DMF (2 ml) was added and the mixture was stirred overnight at 60°C. After cooling to RT, the mixture was purified by preparative HPLC (Method 21). Received 659 mg (98% pure,

93% theory out) specified in the connection header.

LC-MS (Method 1): R _t = 2.16 min; MS (ESIpos): m/z = 560/562 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6): δ [ppm] = 8.88 (t, 1H), 8.69 (d, 1H), 8.09-7.98 (m, 1H), 7.95 (d, 1H), 7.86 (dd , 1H), 7.80-7.57 (br. m, 2H), 7.57-7.46 (m, 6H), 3.91-3.78 (m, 1H), 3.75-3.58 (m, 2H), 2.89-2.72 (m, 2H) , 2.14 (br. s, 3H), 1.28 (s, 9H).

Example 196A. (+/-)-tert-Butyl-4-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-[2(trifluoromethyl)phenyl]butanoate (racemate)

HATU (1.43 g , 3.76 mmol) and DIPEA (1.3 ml, 7.5 mmol) and the mixture was stirred for 30 min at RT. Then (+/-)-tert-butyl-4-amino-3-[2-(trifluoromethyl)phenyl]butanoate (1.90 g, 60% pure, 3.76 mmol, example 103A) dissolved in DMF (3 ml) was added and the mixture was stirred overnight at 60°C. The mixture was then mixed with ethyl acetate and water (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 washed with saturated aqueous sodium chloride, 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 85:15, Isolera One) . The combined target fractions were concentrated and the residue was lyophilized. 1.10 g (98% pure, 68% th. y.) of the title compound was obtained.

LC-MS (Method 1): R _t = 2.58 min; MS (ESIpos): m/z = 627/629 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.249 (16.00), 1.397 (4.44), 2.161 (1.10), 2.687 (0.40), 2.706 (0.41), 2.735 (0.40), 2.751 (0.41) , 3.314 (1.68), 7.474 (0.59), 7.492 (0.67), 7.506 (1.12), 7.525 (1.58), 7.539 (2.10), 7.558 (0.44), 7.685 (0.56), 7.718 (0.64) , 7.760 (0.65), 7.779 (0.41), 7.838 (0.41), 7.861 (0.63), 7.865 (0.57), 7.939 (1.09), 7.962 (0.71), 8.902 (0.54).

1H-NMR (400 MHz, DMSO-d6): δ [ppm] = 8.90 (t, 1H), 7.95 (d, 1H), 7.85 (dd, 1H), 7.79-7.57 (m, 4H), 7.57-7.44 (m, 6H), 3.90-3.60 (m, 3H), 2.75 (dd, 1H), 2.69 (dd, 1H), 2.16 (br. s, 3H), 1.25 (s, 9H).

Example 197A. (+/-)-tert-Butyl-4- {[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino} -3-(3methoxypyridin-2-yl)butanoate (racemate)

HATU (2.73 g , 7.19 mmol) and DIPEA (2.5 ml, 14 mmol) and the mixture was stirred for 30 min at RT. (+/-)-tert-Butyl-4amino-3-(3-methoxypyridin-2-yl)butanoate (2.02 g, 95% pure, 7.19 mmol, Example 104A) dissolved in DMF (8 ml) was then added and the mixture stirred overnight at 60°C. After cooling to RT, the mixture was purified by preparative HPLC (Method 21). 1.73 g (98% pure, 60% th. y.) of the title compound was obtained.

LC-MS (Method 1): R _t = 2.24 min; MS (ESIpos): m/z = 590/592 [M+H] ⁺ .

'H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.255 (16.00), 2.192 (4.16), 5.754 (0.86), 7.506 (0.89), 7.511 (0.69), 7.524 (1.44), 7.536 (1.73 ), 7.538 (1.71), 7.543 (1.00), 7.546 (0.66), 7.843 (0.42), 7.865 (0.65), 7.871 (0.58), 7.937 (1.13), 7.959 (0.71), 8.128 (0.53), 8.131 (0.53 ), 8.140 (0.54).

‘H-NMR (400 MHz, DMSO-d6): δ [ppm] = 8.77 (t, 1H), 8.14 (dd, 1H), 7.95 (d, 1H), 7.86 (dd, 1H), 7.77 (s,

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1H), 7.58-7.47 (m, 5H), 7.43 (d, 1H), 7.27 (dd, 1H), 4.02-3.90 (m, 1H), 3.84 (s, 3H), 3.79-3.62 (m, 2H) , 2.87 (dd, 1H), 2.63 (dd, 1H), 2.19 (s, 3H), 1.25 (s, 9H).

Example 198A. (+/-)-tert-Butyl-4-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-(2chlorophenyl)-2,2-dimethylbutanoate (racemate)

HATU (443 mg , 1.16 mmol) and DIPEA (470 μl, 2.7 mmol) and the mixture was stirred for 30 min at RT. Then (+/-)-tert-butyl-4-amino-3-(2-chlorophenyl)-2,2-dimethylbutanoate (320 mg, 1.07 mmol, example 106A) dissolved in DMF (1 ml) was added and the mixture was stirred for nights on CT. The mixture was then purified by preparative HPLC (Method: Chromatorex C18, 10 µm, 30 x 125 mm, acetonitrile/water gradient: acetonitrile 10%^90%). 328 mg (99% pure, 59% thor.) of the title compound were obtained.

LC-MS (Method 2): Rt = 1.53 min; MS (ESIpos): m/z = 621/523 (M+H) ⁺ .

'H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 8.69 (t, 1H), 7.90 (d, 1H), 7.82 (dd, 1H), 7.58-7.22 (m, 10H), 4.17 -4.09 (m, 1H), 4.05-3.87 (m, 1H), 3.77-3.63 (m, 1H), 1.97 (br. s, 3H), 1.48 (s, 9H), 1.10 (s, 3H), 1.06 (s, 3H).

Example 199A. (+/-)-tert-Butyl-4-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-(2chlorophenyl)-3-methylbutanoate (racemate)

HATU (1.88 g , 4.93 mmol) and DIPEA (1.7 ml, 9.9 mmol) and the mixture was stirred for 30 min at RT. Then (+/-)-tert-butyl-4amino-3-(2-chlorophenyl)-3-methylbutanoate (2.00 g, 70% pure, 4.93 mmol, example 107A) dissolved in DMF (6 ml) was added and the mixture was stirred overnight at 60°C. After cooling to RT, the mixture was mixed with ethyl acetate and water (respectively 50 ml) and shaken. The aqueous phase was extracted twice with ethyl acetate (50 ml). The combined organic phases were washed with saturated aqueous sodium chloride, dried over sodium sulfate, filtered and concentrated, and the residue was adsorbed in dichloromethane and previously purified by flash column chromatography (100 g of Biotage Snap-Cartridge KP-Sil, cyclohexane/ethyl acetate 85:15) . 1.94 g (87% pure, 84% tho.) of the pre-purified title compound was obtained. Of these 1.94 g, 250 mg was further purified by preparative HPLC (Method 20). 144 mg (98% pure) of additionally purified title compound was obtained from niz (see section Analytics).

LC-MS (Method 1): R _t = 2.63 min; MS (ESIpos): m/z = 607/609 (M+H) ⁺ .

'H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 1.119 (16.00), 1.652 (2.39), 2.572 (0.66), 2.608 (0.71), 3.415 (0.53), 3.450 (0.49), 7.287 ( 0.59), 7.305 (0.42), 7.433 (0.75), 7.452 (0.44), 7.457 (0.42), 7.499 (0.89), 7.506 (0.75), 7.518 (1.75), 7.527 (1.66), 7.853 (0.53), 0.52), 7.927 (0.99), 7.950 (0.63), 8.664 (0.43).

'H-NMR (400 MHz, DMSO-d6): δ [ppm] = 8.66 (t, 1H), 7.94 (d, 1H), 7.85 (dd, 1H), 7.65 (br. s, 1H), 7.577. 47 (m, 5H), 7.46-7.37 (m, 2H), 7.33-7.23 (m, 2H), 4.37 (dd, 1H), 3.75 (dd, 1H), 3.43 (d, 1H), 2.59 (d, 1H), 2.12 (br. s, 3H), 1.65 (s, 3H), 1.12 (s, 9H).

Example 200A. (+/-)-tert-Butyl-4-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-(2fluorophenyl)-3-methylbutanoate (racemate)

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HATU (1.02 g , 2.68 mmol) and DIPEA (940 µl, 5.4 mmol) and the mixture was stirred for 30 min at RT. Then (+/-)-tert-butyl-4amino-3-(2-fluorophenyl)-3-methylbutanoate (810mg, 2.68mmol, uncorrected purity, example 108A) dissolved in DMF (3mL) was added and the mixture was stirred overnight at 60°C. After cooling to RT, the mixture was mixed with ethyl acetate and water (respectively 50 ml) and shaken. The aqueous phase was extracted twice with ethyl acetate (50 ml). The combined organic phases were washed with saturated aqueous sodium chloride, dried over sodium sulfate, filtered and concentrated, and the residue was adsorbed in dichloromethane and pre-purified by flash column chromatography (100 g Biotage Snap-Cartridge KP-Sil, cyclohexane/ethyl acetate 85:15). The prepurified product was further purified by preparative HPLC (Method 20). 255 mg (95% pure, 23% thor.) of the title compound were obtained.

LC-MS (Method 1): Rt = 2.55 min; MS (ESIpos): m/z = 591/593 (M+H) ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 1.126 (16.00), 1.197 (0.85), 1.569 (2.52), 2.976 (0.56), 3.011 (0.50), 7.139 (0.43), 7.157 (0.47 ), 7.172 (0.41), 7.315 (0.52), 7.335 (0.60), 7.502 (0.97), 7.509 (0.83), 7.520 (1.94), 7.529 (1.82), 7.857 (0.57), 7.862 (0.59), 7.931 (1.10 ), 7.954 (0.69), 8.726 (0.42).

Separation of enantiomers.

The title title compound (220 mg) was dissolved in a mixture of isopropanol (4 ml) and dichloromethane (2 ml) and separated into enantiomers by chiral phase preparative HPLC (see Examples 201A and 202A) [column: Daicel Chiralpak IE, 5 µm, 250 mm x 20 mm; flow: 15 ml/min; detection: 220 nm; temperature: 40°C; sample injection: 0.2 ml; eluent: 60% heptane/40% isopropanol; isocratic; duration of action 20 minutes].

Example 201A. (+)-tert-Butyl-4-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-(2fluorophenyl)-3-methylbutanoate (enantiomer 1).

The separation of enantiomers described in Example 200A gave 96 mg (98% pure, ee value 99%) of the title compound as the previously eluted enantiomer.

[a] _D20 = +20.7°, 589 nm ^, c = 0.25 g/100 mL, methanol.

LC-MS (Method 2): R _t = 1.35 min; MS (ESIpos): m/z = 591/593 (M+H) ⁺ .

1H-NMR (500 MHz, DMSO-d ₆ ) δ [ppm]: 1.126 (16.00), 1.197 (0.42), 1.569 (2.02), 2.979 (0.44), 3.007 (0.41), 7.335 (0.41), 7.501 (0.66 ), 7.505 (0.68), 7.517 (1.25), 7.529 (1.41), 7.852 (0.41), 7.856 (0.41), 7.930 (0.88), 7.948 (0.60).

1H-NMR (500 MHz, DMSO-d6): δ [ppm] = 8.72 (t, 1H), 7.94 (d, 1H), 7.84 (dd, 1H), 7.68 (br. s, 1H), 7.567.47 (m, 5H), 7.37-7.28 (m, 2H), 7.19-7.10 (m, 2H), 4.08 (dd, 1H), 3.62 (dd, 1H), 2.99 (d, 1H), ~2.5 (1H, hidden), 2.08 (br. s, 3H), 1.57 (s, 3H), 1.13 (s, 9H).

Example 202A. (-)-tert-Butyl-4-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-(2fluorophenyl)-3-methylbutanoate (enantiomer 2).

The separation of enantiomers described in Example 200A gave 97 mg (98% pure, ee value 99%) of the title compound as the later eluted enantiomer.

[a] _D20 = -17.2°, 589 nm, c = 0.25 ^g /100 ml, methanol.

LC-MS (Method 2): Rt = 1.35 min; MS (ESIpos): m/z = 591/593 (M+H) ⁺ .

1H-NMR (500 MHz, DMSO-d ₆ ) δ [ppm]: 1.126 (16.00), 1.569 (2.16), 2.979 (0.47), 3.007 (0.43), 7.335 (0.45), 7.501 (0.71), 7.504 (0.72 ), 7.517 (1.33), 7.528 (1.50), 7.851 (0.44), 7.855 (0.42), 7.930 (0.90), 7.948 (0.61).

1H-NMR (500 MHz, DMSO-d ₆ ): δ [ppm] = 8.72 (t, 1H), 7.94 (d, 1H), 7.84 (dd, 1H), 7.65 (br. s, 1H), 7.567. 45 (m, 5H), 7.37-7.26 (m, 2H), 7.20-7.07 (m, 2H), 4.08 (dd, 1H), 3.62 (dd, 1H), 2.99 (d, 1H), -2.5 (1H , hidden), 2.10 (br. s, 3H), 1.57 (s, 3H), 1.17–1.07 (m, 9H).

Example 203A. (+/-)-tert-Butyl-4-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3methyl-3-(pyridin-2-yl)butanoate (racemate )

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HATU (4.01 g , 10.5 mmol) and DIPEA (3.7 ml, 21 mmol) and the mixture was stirred for 30 min at RT. Then the mixture obtained in example 109A (4.00 g) from (+/-)-tert-butyl-4-amino-3-methyl-3-(pyridin-2-yl)butanoate and (+/-)-tert-butyl- 4-amino-3-(3-chloropyridin-2-yl)-3-methylbutanoate was dissolved in DMF (10 ml) and the reaction mixture was stirred overnight at 60°C. After cooling to RT, the mixture was mixed with ethyl acetate and water (respectively 50 ml), shaken and the phases were separated. The aqueous phase was extracted twice with ethyl acetate (50 ml). The combined organic phases were washed with saturated aqueous sodium chloride, dried over sodium sulfate, filtered and concentrated, and the residue was adsorbed in dichloromethane and previously purified by flash column chromatography (100 g of Biotage Snap-Cartridge KP-Sil, cyclohexane/ethyl acetate 85:15) . The combined target fractions were concentrated and the residue was lyophilized. Then further purified by preparative HPLC (Method 20). 1.07 g (98% pure) of the title compound was obtained, as well as 1.56 g (98% pure) of tert-butyl-4-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino }-3-(3-chloropyridin-2-yl)-3-methylbutanoate.

LC-MS (Method 1): R _t = 2.37 min; MS (ESIpos): m/z = 574/576 (M+H) ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.180 (1.07), 1.205 (16.00), 1.552 (2.74), 2.141 (0.81), 2.159 (0.47), 2.610 (0.47), 2.647 (0.55) , 3.049 (0.44), 3.162 (0.58), 7.499 (0.90), 7.506 (0.72), 7.517 (1.45), 7.529 (1.88), 7.836 (0.42), 7.858 (0.63), 7.864 (0.59) , 7.955 (0.91).

1H-NMR (400 MHz, DMSO-d6): δ [ppm] = 8.73 (br. t, 1H), 8.64 (br. d, 1H), 7.95 (d, 1H), 7.86 (dd, 1H), 7.69 -7.61 (m, 2H), 7.57-7.47 (m, 6H), 7.46-7.38 (m, 1H), 3.96 (dd, 1H), 3.76 (dd, 1H), 3.08 (d, 1H), 2.64 (d , 1H), 2.16 (s, 3H), 1.56 (s, 3H), 1.21 (s, 9H).

Example 204A. (+/-)-tert-Butyl-4- {[(6-bromo-3 -methyl-2-phenylquinolin-4-yl)carbonyl]amino } -3 -(2methoxyphenyl)-3-methylbutanoate (racemate)

HATU (6.26 g , 16.5 mmol) and DIPEA (5.7 ml, 33 mmol) and the mixture was stirred for 30 min at RT. Then (+/-)-tert-butyl-4amino-3-(2-methoxyphenyl)-3-methylbutanoate (5.00 g, 92% pure, 16.5 mmol, example 110A) dissolved in DMF (20 ml) was added and the mixture was stirred overnight at 60°C. After cooling to RT, the mixture was mixed with ethyl acetate and water (respectively 50 ml) and shaken. The aqueous phase was extracted twice with ethyl acetate (50 ml). The combined organic phases were washed with saturated aqueous sodium chloride, 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 93:7^6 :4, Isolera One). 6.00 g (98% pure, 89% th. y.) of the title compound was obtained.

LC-MS (Method 7): Rt = 1.70 min; MS (ESIpos): m/z = 603/605 (M+H) ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: -0.008 (0.52), 0.008 (0.45), 1.095 (16.00), 1.398 (6.40), 1.553 (2.19), 2.433 (0.64), 2.466 ( 0.72), 3.181 (0.56), 3.214 (0.53), 3.309 (5.17), 6.889 (0.46), 6.986 (0.41), 7.006 (0.48), 7.188 (0.55), 7.208 (0.67), 7.495 (0.76), 0.70), 7.514 (1.98), 7.518 (1.79), 7.527 (1.04), 7.848 (0.57), 7.853 (0.55), 7.921 (1.07), 7.944 (0.68).

1H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 8.54 (t, 1H), 7.93 (d, 1H), 7.84 (dd, 1H), 7.70 (br. s, 1H), 7.567. 44 (m, 5H), 7.27-7.14 (m, 2H), 7.00 (d, 1H), 6.89 (t, 1H), 4.18 (dd, 1H), 3.68 (dd, 1H), 3.20 (d, 1H) , 2.45 (d, 1H), 2.10 (br. s, 3H), 1.55 (s, 3H), 1.09 (s, 9H).

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Separation of enantiomers.

The title title compound (2.0 g) was dissolved in a mixture (100 ml) of methanol and acetonitrile and separated into enantiomers by chiral phase preparative SLC (see Examples 205A and 206A) [column: Daicel Chiralpak AD-H, 5 µm, 250 mm x 30 mm; flow: 150 ml/min; detection: 210 nm; temperature: 38°C; sample injection: 0.4 ml; eluent: 75% carbon dioxide / 25% ethanol; isocratic; duration of action 6.5 min].

Example 205A. (+)-tert-Butyl-4-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-(2methoxyphenyl)-3-methylbutanoate (enantiomer 1).

The separation of enantiomers described in Example 204A gave 723 mg (98% pure, ee value 94%) of the title compound as the previously eluted enantiomer.

[a] _D20 = +16.2°, 589 nm, c = 0.50 g ^/ 100 mL, methanol.

LC-MS (Method 1): Rt = 2.60 min; MS (ESIpos): m/z = 603/605 (M+H) ⁺ .

1H-NMR (600 MHz, DMSO-d6) δ [ppm]: 1.091 (16.00), 1.555 (2.18), 2.434 (0.67), 2.456 (0.71), 3.193 (0.51), 3.215 (0.49), 3.858 (3.12) , 7.191 (0.53), 7.202 (0.46), 7.204 (0.48), 7.498 (0.54), 7.502 (0.74), 7.515 (1.28), 7.525 (1.65), 7.848 (0.47), 7.851 (0.46), 7.928 (0.94) , 7.942 (0.69).

1H-NMR (600 MHz, DMSO-d ₆ ): δ [ppm] = 8.56 (t, 1H), 7.93 (d, 1H), 7.84 (dd, 1H), 7.68 (br. s, 1H), 7.577. 43 (m, 5H), 7.28-7.16 (m, 2H), 7.00 (d, 1H), 6.89 (t, 1H), 4.19 (dd, 1H), 3.67 (dd, 1H), 3.20 (d, 1H) , 2.45 (d, 1H), 2.09 (br. s, 3H), 1.56 (s, 3H), 1.09 (s, 9H).

Example 206A. (-)-tert-Butyl-4-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-(2methoxyphenyl)-3-methylbutanoate (enantiomer 2).

The separation of enantiomers described in Example 204A gave 718 mg (98% pure, ee value 100%) of the title compound as the later eluted enantiomer.

[a] _D20 = -19.2°, 589 nm, c = 0.25 ^g /100 ml, methanol.

LC-MS (Method 1): R _t = 2.60 min; MS (ESIpos): m/z = 603/605 (M+H) ⁺ .

1H-NMR (600 MHz, DMSO-d6) δ [ppm]: 1.091 (16.00), 1.556 (2.09), 2.435 (0.66), 2.456 (0.70), 3.193 (0.49), 3.215 (0.48), 3.350 (1.37) , 7.189 (0.45), 7.191 (0.51), 7.202 (0.44), 7.204 (0.47), 7.497 (0.53), 7.501 (0.72), 7.514 (1.23), 7.525 (1.56), 7.847 (0.46), 7.851 (0.44) , 7.927 (0.96), 7.942 (0.69).

1H-NMR (600 MHz, DMSO-d ₆ ): δ [ppm] = 8.56 (t, 1H), 7.93 (d, 1H), 7.84 (dd, 1H), 7.67 (br. s, 1H), 7.567. 43 (m, 5H), 7.28-7.15 (m, 2H), 7.00 (d, 1H), 6.89 (t, 1H), 4.19 (dd, 1H), 3.67 (dd, 1H), 3.20 (d, 1H) , 2.45 (d, 1H), 2.13 (br. s, 1H), 1.56 (s, 3H), 1.09 (s, 9H).

Example 207A. (+/-)-tert-Butyl-4-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-(5fluoro-2-methoxyphenyl)butanoate (racemate)

HATU (143 mg , 375 µmol) and DIPEA (130 µl, 750 µmol) and the mixture was stirred for 30 min at RT. (+/-)-tert-Butyl-4amino-3-(5-fluoro-2-methoxyphenyl)butanoate hydrochloride (120 mg, 375 µmol, Example 111A) dissolved in DMF (1 ml) was then added and the mixture was stirred overnight at 60°C. After cooling to RT, the mixture was mixed with ethyl acetate and water (respectively 50 ml) and shaken. The aqueous phase was extracted twice with ethyl acetate (50 ml). The combined organic phases were washed with saturated aqueous sodium chloride, 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 93:7^6 :4, Isolera One). 100 mg (98% pure, 64% thor.) of the title compound were obtained.

LC-MS (Method 1): R _t = 2.49 min; MS (ESIpos): m/z = 607/609 (M+H) ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.235 (0.42), 1.266 (16.00), 2.145 (1.72), 2.621 (0.48), 2.641 (0.86), 2.654 (0.51), 3.741 (0.60) , 3.753 (0.58), 3.779 (4.38), 6.990 (0.70), 7.003 (0.83), 7.084 (0.46), 7.091 (0.40), 7.108 (0.45), 7.503 (1.00), 7.510 (0.84), 7.522 (2.12) , 7.529 (2.02), 7.837 (0.43), 7.859 (0.65), 7.864 (0.61), 7.933 (1.19), 7.956 (0.75), 8.783 (0.51).

Separation of enantiomers.

The title title compound (440 mg, from a similar repeat test) was dissolved in a mixture of acetonitrile (2 ml) and isopropanol (2 ml) and separated into enantiomers by chiral phase preparative HPLC (see Examples 208A and 209A) [ column: Daicel

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Chiralpak ID, 5 µm, 250 mm x 20 mm; flow: 20 ml/min; detection: 220 nm; temperature: 23°C; sample injection: 0.1 ml; eluent: 80% heptane / 20% ethanol; isocratic].

Example 208A. (-)-tert-Butyl-4-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-(5fluoro-2-methoxyphenyl)butanoate (enantiomer 1).

The separation of enantiomers described in Example 207A gave 181 mg (98% pure, ee value 98%) of the title compound as the previously eluted enantiomer.

[a] _D20 = -6.4°, 589 nm, c = 0.37 g ^/ 100 ml, chloroform.

LC-MS (Method 1): R _t = 2.49 min; MS (ESIpos): m/z = 607/609 (M+H) ⁺ .

1H-NMR (600 MHz, DMSO-d ₆ ) δ [ppm]: 1.265 (16.00), 2.146 (0.51), 2.688 (0.46), 6.992 (0.51), 7.000 (0.48), 7.506 (0.56), 7.511 (0.60 ), 7.521 (0.43), 7.524 (1.24), 7.534 (1.92), 7.537 (1.48), 7.862 (0.48), 7.865 (0.45), 7.940 (0.98), 7.955 (0.72), 8.804 (0.41).

1H-NMR (600 MHz, DMSO-d ₆ ): δ [ppm] = 8.80 (t, 1H), 7.95 (d, 1H), 7.86 (dd, 1H), 7.66 (br. s, 1H), 7.577. 46 (m, 5H), 7.11 (dd, 1H), 7.03 (td, 1H), 6.99 (dd, 1H), 3.79-3.70 (m, 2H), 3.78 (s, 3H), 3.68-3.62 (m, 1H), 2.69-2.60 (m, 2H), 2.15 (br. s, 3H), 1.27 (s, 9H).

Example 209A. (+)-tert-Butyl-4-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-(5fluoro-2-methoxyphenyl)butanoate (enantiomer 2).

The separation of enantiomers described in Example 207A gave 175 mg (98% pure, ee value 99%) of the title compound as the later eluted enantiomer.

[a] _D20 = +2.9°, 589 nm, c = 0.38 g/100 mL ^, chloroform.

LC-MS (Method 1): R _t = 2.49 min; MS (ESIpos): m/z = 607/609 (M+H) ⁺ .

1H-NMR (600 MHz, DMSO-d ₆ ) δ [ppm]: 1.266 (16.00), 2.146 (0.52), 6.992 (0.51), 7.000 (0.48), 7.506 (0.55), 7.511 (0.60), 7.521 (0.40 ), 7.524 (1.24), 7.534 (1.92), 7.537 (1.52), 7.862 (0.48), 7.865 (0.46), 7.940 (0.97), 7.955 (0.71), 8.805 (0.42).

1H-NMR (600 MHz, DMSO-d6): δ [ppm] = 8.80 (t, 1H), 7.95 (d, 1H), 7.86 (dd, 1H), 7.66 (br. s, 1H), 7.567.47 (m, 5H), 7.11 (dd, 1H), 7.03 (td, 1H), 6.99 (dd, 1H), 3.78 (s, 3H), 3.77-3.70 (m, 2H), 3.68-3.63 (m, 1H ), 2.69–2.59 (m, 2H), 2.15 (br. s, 3H), 1.27 (s, 9H).

Example 210A. (+/-)-tert-Butyl-4-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-(2fluoro-6-methoxyphenyl)butanoate (racemate)

HATU (778 mg , 2.04 mmol) and DIPEA (710 µl, 4.1 mmol) and the mixture was stirred for 15 min at RT. Then (+/-)-tert-butyl-4-amino-3-(2-fluoro-6-methoxyphenyl)butanoate (587 mg, 82% pure, 1.70 mmol, example 112A) dissolved in DMF (5 ml) was added and the mixture stirred 5 h at 60°C and then overnight at RT. The mixture was then mixed with ethyl acetate and water (respectively 100 ml) and shaken. The aqueous phase was extracted once with ethyl acetate (80 ml). The combined organic phases were washed with saturated aqueous sodium chloride (100 ml), dried over sodium sulfate, filtered and concentrated, and the residue was adsorbed in dichloromethane and purified by flash column chromatography (100 g of Biotage Snap-Cartridge KP-Sil silica gel, cyclohexane/ethyl acetate 93:7 ^ 7:3, Isolera One). 441 mg (100% pure, 43% thor.) of the title compound were obtained.

LC-MS (Method 1): R _t = 2.49 min; MS (ESIpos): m/z = 607/609 (M+H)+.

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 1.175 (0.67), 1.192 (0.45), 1.225 (16.00), 1.248 (0.75), 1.988 (1.21), 2.169 (0.92), 2.683 (0.52 ), 2.697 (0.66), 3.815 (4.33), 6.761 (0.45), 6.835 (0.52), 6.855 (0.58), 7.503 (0.81), 7.510 (0.71), 7.522 (1.95), 7.527 (1.89), 7.535 (1.21 ), 7.840 (0.42), 7.863 (0.64), 7.868 (0.60), 7.933 (1.20), 7.955 (0.74), 8.860 (0.46).

1H-NMR (400 MHz, DMSO-d6): δ [ppm] = 8.86 (t, 1H), 7.94 (d, 1H), 7.86 (dd, 1H), 7.72 (br. s, 1H), 7.567.47 (m, 5H), 7.29-7.16 (m, 1H), 6.85 (d, 1H), 6.76 (t, 1H), 3.99-3.88 (m, 1H), 3.82 (s, 3H), 3.84-3.64 (m , 2H), 2.76-2.62 (m, 2H), 2.17 (br. s, 3H), 1.23 (s, 9H).

Separation of enantiomers.

The title target compound (437 mg) was dissolved in methanol (35 ml) and separated into enantiomers by chiral phase preparative SLC (see examples 211A and 212A) [column: Daicel Chiralpak AD SFC, 250 mm x 20 mm; flow: 80 ml/min; detection: 210 nm; temperature: 40°C; sample injection: 0.3 ml; eluent: 80% carbon dioxide/20% ethanol; isocratic, duration of action 95 040284 8.0 min].

Example 211A. (+)-tert-Butyl-4-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-(2fluoro-6-methoxyphenyl)butanoate (enantiomer 1).

The separation of enantiomers described in Example 210A gave 203 mg (100% pure, ee value 100%) of the title compound as the previously eluted enantiomer.

[a]D ²⁰ = +12.9°, 589 nm, c = 0.39 g/100 ml, chloroform.

LC-MS (Method 2): R _t = 1.31 min; MS (ESIpos): m/z = 607/609 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.225 (16.00), 2.170 (1.08), 2.684 (0.57), 2.698 (0.77), 2.719 (0.41), 3.815 (4.50), 6.762 (0.50) , 6.834 (0.57), 6.855 (0.63), 7.503 (0.85), 7.510 (0.73), 7.522 (2.02), 7.528 (1.96), 7.862 (0.62), 7.867 (0.60), 7.933 (1.11), 7.955 (0.69) , 8.861 (0.53).

1H-NMR (400 MHz, DMSO-d6): δ [ppm] = 8.86 (t, 1H), 7.94 (d, 1H), 7.86 (dd, 1H), 7.72 (br. s, 1H), 7.577.46 (m, 5H), 7.24 (dd, 1H), 6.85 (d, 1H), 6.76 (t, 1H), 4.01-3.87 (m, 1H), 3.82 (s, 3H), 3.83-3.65 (m, 2H ), 2.772.61 (m, 2H), 2.17 (br. s, 3H), 1.23 (s, 9H).

Example 212A. (-)-tert-Butyl-4-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-(2fluoro-6-methoxyphenyl)butanoate (enantiomer 2).

The separation of enantiomers described in Example 210A gave 185 mg (99% pure, ee value 96%) of the title compound as the later eluted enantiomer.

[a] _D20 = -14.2°, 589 nm, c = 0.44 ^g /100 ml, chloroform.

LC-MS (Method 2): Rt = 1.31 min; MS (ESIpos): m/z = 607/609 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 1.225 (16.00), 1.249 (0.71), 2.170 (1.46), 2.684 (0.70), 2.698 (0.99), 2.720 (0.52), 3.314 (6.09 ), 3.719 (0.48), 3.796 (0.41), 6.762 (0.63), 6.785 (0.40), 6.834 (0.65), 6.855 (0.72), 7.226 (0.42), 7.503 (1.06), 7.508 (0.96), 7.527 (2.63 ), 7.843 (0.46), 7.866 (0.74), 7.933 (1.12), 7.955 (0.70), 8.861 (0.66).

1H-NMR (400 MHz, DMSO-d6): δ [ppm] = 8.86 (t, 1H), 7.94 (d, 1H), 7.86 (d, 1H), 7.72 (br. s, 1H), 7.567.47 (m, 5H), 7.24 (dd, 1H), 6.85 (d, 1H), 6.76 (t, 1H), 4.01-3.88 (m, 1H), 3.82 (s, 3H), 3.85-3.65 (m, 2H ), 2.782.62 (m, 2H), 2.17 (br. s, 3H), 1.23 (s, 9H).

Example 213A. (+/-)-tert-Butyl-4-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-(2ethoxyphenyl)butanoate (racemate)

HATU (457 mg , 1.20 mmol) and DIPEA (420 µl, 2.4 mmol) and the mixture was stirred for 15 min at RT. Then (+/-)-tert-butyl-4-amino-3-(2-ethoxyphenyl)butanoate hydrochloride (400 mg, 95% pure, 1.20 mmol, example 113A) dissolved in DMF (2 ml) was added and the mixture was stirred overnight at 60°C. The mixture was then mixed with ethyl acetate and water (respectively 20 ml) and shaken. After phase separation, the aqueous phase was extracted twice with ethyl acetate (20 ml). The combined organic phases were washed with saturated aqueous sodium chloride, dried over sodium sulfate, filtered and concentrated, and the residue was adsorbed in dichloromethane and purified by flash column chromatography (100 g of Biotage Snap-Cartridge KP-Sil, cyclohexane/ethyl acetate 85:15, Isolera one). 265 mg (98% pure, 54% th. y.) of the title compound were obtained.

LC-MS (Method 1): R _t = 2.62 min; MS (ESIpos): m/z = 603/605 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 1.245 (16.00), 1.356 (1.23), 1.373 (2.56), 1.391 (1.23), 2.151 (1.35), 2.661 (0.70), 2.675 (0.57 ), 2.682 (0.48), 3.660 (0.41), 4.040 (0.88), 4.058 (0.84), 6.884 (0.57), 6.954 (0.52), 6.974 (0.58), 7.193 (1.00), 7.212 (0.79), 7.502 (0.86 ), 7.509 (0.79), 7.521 (1.77), 7.527 (1.71), 7.530 (1.45), 7.534 (1.09), 7.538 (0.84), 7.836 (0.41), 7.858 (0.62), 7.864 (0.56), 7.932 (1.09 ), 7.955 (0.69).

1H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 8.76 (t, 1H), 7.94 (d, 1H), 7.85 (dd, 1H), 7.72 (br. s, 1H), 7.567. 45 (m, 5H), 7.23-7.14 (m, 2H), 6.96 (d, 1H), 6.88 (td, 1H), 4.05 (q, 2H), 3.87-3.75 (m, 1H), 3.73-3.58 ( m, 2H), 2.71-2.63 (m, 2H), 2.15 (br. s, 3H), 1.37 (t, 3H), 1.25 (s, 9H).

Separation of enantiomers.

The title target compound (240 mg) was dissolved in methanol (20 ml) and separated into enantiomers by chiral phase preparative SLC (see Examples 214A and 215A) [column: Daicel Chiralcel OJ-H, 250 mm x 20 mm; flow: 80 ml/min; detection: 210 nm; temperature: 40°C; sample injection: 0.5 ml; eluent: 83% carbon dioxide/17% ethanol; isocratic, duration of action 96 040284 8.0 min].

Example 214A. (-)-tert-Butyl-4-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-(2ethoxyphenyl)butanoate (enantiomer 1).

The separation of enantiomers described in Example 213A gave 79 mg (98% pure, ee value 100%) of the title compound as the previously eluted enantiomer.

[a] _D20 = -17.1°, 589 nm, c = ^0.35 g/100 ml, methanol.

LC-MS (Method 2): R _t = 1.39 min; MS (ESIpos): m/z = 603/605 [M+H]+.

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.245 (16.00), 1.356 (1.21), 1.373 (2.58), 1.391 (1.25), 2.151 (1.59), 2.661 (0.78), 2.676 (0.65) . , 7.521 (1.93), 7.527 (1.92), 7.836 (0.43), 7.858 (0.64), 7.863 (0.61), 7.932 (1.18), 7.955 (0.75), 8.764 (0.43).

1H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 8.77 (t, 1H), 7.94 (d, 1H), 7.85 (dd, 1H), 7.72 (br. s, 1H), 7.577. 45 (m, 5H), 7.23-7.14 (m, 2H), 6.96 (d, 1H), 6.89 (t, 1H), 4.05 (q, 2H), 3.88-3.77 (m, 1H), 3.74-3.58 ( m, 2H), 2.73-2.60 (m, 2H), 2.15 (br. s, 3H), 1.37 (t, 3H), 1.25 (s, 9H).

Example 215A. (+)-tert-Butyl-4-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-(2ethoxyphenyl)butanoate (enantiomer 2).

The separation of enantiomers described in Example 213A gave 72 mg (98% pure, ee value 98%) of the title compound as the later eluted enantiomer.

[a] _D20 = +10.9°, 589 nm ^, c = 0.34 g/100 mL, methanol.

LC-MS (Method 2): Rt = 1.39 min; MS (ESIpos): m/z = 603/605 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.245 (16.00), 1.356 (1.23), 1.374 (2.59), 1.391 (1.26), 2.151 (1.65), 2.661 (0.83), 2.676 (0.69) , 3.661 (0.50), 4.040 (0.98), 4.058 (0.96), 6.885 (0.67), 6.954 (0.60), 6.974 (0.70), 7.193 (1.11), 7.212 (0.86), 7.502 (0.92), 7.509 (0.79) , 7.521 (2.00), 7.528 (1.96), 7.836 (0.42), 7.858 (0.64), 7.863 (0.60), 7.932 (1.11), 7.955 (0.71), 8.764 (0.46).

1H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 8.76 (t, 1H), 7.94 (d, 1H), 7.85 (dd, 1H), 7.72 (br. s, 1H), 7.587. 46 (m, 5H), 7.27-7.12 (m, 2H), 6.96 (d, 1H), 6.89 (t, 1H), 4.05 (q, 2H), 3.88-3.75 (m, 1H), 3.71-3.59 ( m, 2H), 2.72-2.62 (m, 2H), 2.15 (br. s, 3H), 1.37 (t, 3H), 1.25 (s, 9H).

Example 216A. (+/-)-tert-Butyl-4- {[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-(5fluoro-2-methoxyphenyl)-3-methylbutanoate ( racemate)

HATU (1.35 g , 3.56 mmol) and DIPEA (1.2 ml, 7.1 mmol) and the mixture was stirred for 15 min at RT. (+/-)-tert-Butyl-4-amino-3-(5-fluoro-2-methoxyphenyl)-3-methylbutanoate hydrochloride (1.25 g, 95% pure, 3.56 mmol, Example 114A) dissolved in DMF (5 mL) was then added. ) and the mixture was stirred overnight at 60°C. The mixture was then mixed with ethyl acetate and water (respectively 20 ml) and shaken. After phase separation, the aqueous phase was extracted twice with ethyl acetate (20 ml). The combined organic phases were washed with saturated aqueous sodium chloride, 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 85:15, Isolera One) . 930 mg (98% pure, 62% thor.) of the title compound were obtained.

LC-MS (Method 1): R _t = 2.57 min; MS (ESIpos): m/z = 621/623 [M+H] ⁺ .

1H-NMR (600 MHz, DMSO-d ₆ ) δ [ppm]: 1.131 (16.00), 1.526 (2.14), 2.441 (0.62), 2.463 (0.66), 3.336 (6.15), 7.503 (0.52), 7.506 (0.69 ), 7.520 (1.18), 7.530 (1.38), 7.933 (0.73), 7.948 (0.54).

1H-NMR (600 MHz, DMSO-d6): δ [ppm] = 8.59 (t, 1H), 7.94 (d, 1H), 7.85 (dd, 1H), 7.69 (br. s, 1H), 7.567.47 (m, 5H), 7.09-6.99 (m, 2H), 6.97 (dd, 1H), 4.24 (br. s, 1H), 3.85 (s, 3H), 3.61 (br. d, 1H), 3.21 (d , 1H), 2.45 (d, 1H), 2.11 (br. s, 3H), 1.53 (s, 3H), 1.13 (s, 9H).

Separation of enantiomers.

The title target compound (775 mg) was adsorbed in isopropanol (30 ml), filtered and separated into enantiomers by chiral phase preparative SLC (see examples 217A and 218A) [column: Daicel Chiralpak AD, 360 mm x 50 mm; flow: 400 ml/min; detection: 210 nm; temperature: 40°C; sample injection: 2.0 ml; eluent: 75% carbon dioxide / 25% ethanol; isocratic, duration of action 9.0 min]. The combined target fractions were concentrated.

- 97 040284

Example 217A. (+)-tert-Butyl-4-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-(5fluoro-2-methoxyphenyl)-3-methylbutanoate (enantiomer 1).

Separation of enantiomers as described in Example 216A gave 377 mg (98% pure, isopropanol, 96% ee) of the title compound as the previously eluted enantiomer.

[a]D ²⁰ = +11.9°, 589 nm, c = 0.35 g/100 ml, methanol.

LC-MS (Method 1): R _t = 2.56 min; MS (ESIpos): m/z = 621/623 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 1.030 (5.33), 1.045 (5.34), 1.135 (16.00), 1.526 (2.20), 2.440 (0.63), 2.474 (0.74), 3.187 (0.48 ), 3.221 (0.45), 3.311 (4.42), 4.323 (0.65), 4.333 (0.62), 6.983 (0.48), 7.500 (0.81), 7.508 (0.72), 7.519 (1.81), 7.525 (1.58), 7.852 (0.52 ), 7.857 (0.51), 7.928 (1.03), 7.950 (0.65).

1H-NMR (400 MHz, DMSO-d6): δ [ppm] = 8.57 (t, 1H), 7.94 (d, 1H), 7.85 (dd, 1H), 7.68 (br. s, 1H), 7.567.46 (m, 5H), 7.10-6.99 (m, 2H), 6.97 (dd, 1H), 4.23 (dd, 1H), 3.85 (s, 3H), 3.62 (dd, 1H), 3.20 (d, 1H), 2.46 (d, 1H), 2.10 (br. s, 3H), 1.53 (s, 3H), 1.13 (s, 9H).

Example 218A. (-)-tert-Butyl-4-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-(5fluoro-2-methoxyphenyl)-3-methylbutanoate (enantiomer 2).

Separation of enantiomers as described in Example 216A gave 295 mg (98% pure, isopropanol containing, ee value 99%) of the title compound as the later eluting enantiomer.

[a] _D20 = -11.5°, 589 nm, c = 0.36 ^g /100 ml, methanol.

LC-MS (Method 1): R _t = 2.56 min; MS (ESIpos): m/z = 621/623 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 1.030 (4.50), 1.045 (4.53), 1.134 (16.00), 1.526 (2.35), 2.440 (0.64), 2.474 (0.74), 3.187 (0.51 ), 3.221 (0.47), 3.853 (4.12), 4.323 (0.65), 4.333 (0.62), 6.955 (0.42), 6.982 (0.50), 7.500 (0.85), 7.508 (0.76), 7.519 (1.92), 7.525 (1.68 ), 7.852 (0.53), 7.857 (0.52), 7.927 (1.00), 7.950 (0.64).

1H-NMR (400 MHz, DMSO-d6): δ [ppm] = 8.57 (t, 1H), 7.94 (d, 1H), 7.85 (dd, 1H), 7.68 (br. s, 1H), 7.567.46 (m, 5H), 7.10-6.99 (m, 2H), 6.96 (dd, 1H), 4.23 (dd, 1H), 3.85 (s, 3H), 3.62 (dd, 1H), 3.20 (d, 1H), 2.46 (d, 1H), 2.10 (br. s, 3H), 1.53 (s, 3H), 1.13 (s, 9H).

Example 219A. (+/-)-tert-Butyl-4- {[(6-bromo-3 -methyl-2-phenylquinolin-4-yl)carbonyl] amino }-3-(3,5 difluoro-2-methoxyphenyl)-3 -methylbutanoate (racemate)

HATU (1.37 g , 3.59 mmol) and DIPEA (1.3 ml, 7.2 mmol) and the mixture was stirred for 30 min at RT. Then (+/-)-tert-butyl-4amino-3-(3,5-difluoro-2-methoxyphenyl)-3-methylbutanoate hydrochloride (1.33 g, 95% pure, 3.59 mmol, example 115A) dissolved in DMF (5 ml) and the mixture was stirred overnight at 60°C. After cooling to RT, the mixture was mixed with ethyl acetate and water (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 washed with saturated aqueous sodium chloride, dried over sodium sulfate, filtered and concentrated, and the residue was adsorbed in dichloromethane and purified by flash column chromatography (100 g of Biotage Snap-Cartridge KP-Sil, cyclohexane/ethyl acetate 85:15, Isolera one). 988 mg (98% pure, 63% th. y.) of the title compound were obtained.

LC-MS (Method 1): R _t = 2.64 min; MS (ESIpos): m/z = 639/641 [M+H] ⁺ .

1H-NMR (600 MHz, DMSO-d6) δ [ppm]: 1.178 (16.00), 1.520 (2.02), 2.524 (0.70), 3.985 (2.10), 3.989 (2.04), 7.496 (0.44), 7.507 (0.63) , 7.511 (0.70), 7.525 (1.11), 7.536 (0.69), 7.538 (0.75), 7.542 (0.96), 7.945 (0.70), 7.960 (0.52), 8.665 (0.40).

1H-NMR (600 MHz, DMSO-d6): δ [ppm] = 8.67 (t, 1H), 7.95 (d, 1H), 7.86 (d, 1H), 7.67 (br. s, 1H), 7.577.48 (m, 5H), 7.30-7.22 (m, 1H), 6.88 (d, 1H), 4.10 (dd, 1H), 3.99 (d, 3H), 3.64 (dd, 1H), 3.16 (d, 1H), 2.53 (hidden, 1H), 2.33-1.97 (br., 3H), 1.52 (s, 3H), 1.18 (s, 9H).

Separation of enantiomers.

The title target compound (835 mg) was adsorbed in a mixture of isopropanol (25 ml) and acetonitrile (5 ml), heated to 50°C, filtered and separated into enantiomers by chiral phase preparative SLC (see Examples 220A and 221A) [column: Daicel Chiralpak IC, 250 mm x 20

- 98 040284 mm; flow: 100 ml/min; detection: 220 nm; temperature: 40°C; sample injection: 1.0 ml; eluent: 70% carbon dioxide/30% ethanol; isocratic, duration of action 4.0 min]. The combined desired fractions were concentrated and the residue was dried in vacuo.

Example 220A. (+)-tert-Butyl-4-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-(3,5difluoro-2-methoxyphenyl)-3-methylbutanoate ( enantiomer 1).

The separation of enantiomers described in Example 219A gave 300 mg (98% pure, ee value 93%) of the title compound as the previously eluted enantiomer.

[a] _D20 = +15.7°, 589 nm, c = 0.36 g ^/ 100 mL, methanol.

LC-MS (Method 1): Rt = 2.61 min; MS (ESIpos): m/z = 639/641 [M+H] ⁺ .

'H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.181 (16.00), 1.522 (2.09), 3.140 (0.40), 3.983 (2.49), 3.988 (2.48), 7.506 (0.89), 7.512 (0.70 ), 7.524 (1.38), 7.537 (1.67), 7.863 (0.49), 7.868 (0.47), 7.940 (0.97), 7.962 (0.62), 8.647 (0.41).

'H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 8.65 (t, 1H), 7.95 (d, 1H), 7.86 (dd, 1H), 7.63 (br. s, 1H), 7.577 .48 (m, 5H), 7.31-7.19 (m, 1H), 6.88 (br. d, 1H), 4.09 (dd, 1H), 3.99 (d, 3H), 3.65 (dd, 1H), 3.16 (d , 1H), 2.53 (hidden, 1H), 2.16 (br. s, 3H), 1.52 (s, 3H), 1.18 (s, 9H).

Example 221 A. (-)-tert-Butyl-4-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-(3,5 difluoro-2-methoxyphenyl) -3-methylbutanoate (enantiomer 2).

The separation of enantiomers described in Example 219A gave 310 mg (98% pure, ee value 97%) of the title compound as the later eluted enantiomer.

[a] _D20 = -15.6°, 589 nm, c = 0.34 ^g /100 ml, methanol.

LC-MS (Method 1): Rt = 2.61 min; MS (ESIpos): m/z = 639/641 [M+H] ⁺ .

'H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.180 (16.00), 1.521 (2.76), 3.140 (0.52), 3.175 (0.48), 3.983 (3.03), 3.988 (2.98), 6.865 (0.41 ), 6.891 (0.40), 7.492 (0.44), 7.506 (1.24), 7.524 (1.86), 7.537 (2.20), 7.841 (0.42), 7.863 (0.63), 7.939 (1.04), 7.962 (0.67), 8.646 (0.56 ).

'H-NMR (400 MHz, DMSO-d6): δ [ppm] = 8.65 (t, 1H), 7.95 (d, 1H), 7.85 (dd, 1H), 7.68 (br. s, 1H), 7.587. 46 (m, 5H), 7.31-7.19 (m, 1H), 6.88 (d, 1H), 4.09 (dd, 1H), 3.99 (d, 3H), 3.65 (dd, 1H), 3.16 (d, 1H) , 2.53 (hidden, 1H), 2.16 (br. s, 3H), 1.52 (s, 3H), 1.18 (s, 9H).

Example 222A. (+/-)-tert-Butyl-4-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino }-3-(4fluoro-2-methoxyphenyl)-3-methylbutanoate ( racemate)

HATU (2.56 g , 6.74 mmol) and DIPEA (2.3 ml, 13 mmol) and the mixture was stirred for 30 min at RT. Then (+/-)-tert-butyl-4amino-3-(4-fluoro-2-methoxyphenyl)-3-methylbutanoate hydrochloride (2.37 g, 95% pure, 6.74 mmol, Example 116A) dissolved in DMF ( 9 ml) and the mixture was stirred overnight at 60°C. After cooling to RT, the mixture was mixed with ethyl acetate and water (respectively 40 ml) and shaken. After phase separation, the aqueous phase was extracted twice with ethyl acetate (respectively 40 ml). The combined organic phases were washed with saturated aqueous sodium chloride, dried over sodium sulfate, filtered and concentrated, and the residue was adsorbed in dichloromethane and purified by flash column chromatography (100 g of Biotage Snap-Cartridge KP-Sil, cyclohexane/ethyl acetate 85:15, Isolera one). 1.89 g (98% pure, 66% theoretical) of the title compound was obtained.

LC-MS (Method 1): R _t = 2.59 min; MS (ESIpos): m/z = 621/623 [M+H] ⁺ .

'H-NMR (600 MHz, DMSO-d6) δ [ppm]: 1.116 (16.00), 1.531 (1.67), 2.388 (0.59), 2.410 (0.60), 3.169 (0.48), 3.191 (0.48), 3.336 (6.51 ), 7.500 (0.53), 7.504 (0.72), 7.517 (1.18), 7.528 (1.46), 7.929 (0.79), 7.943 (0.57).

'H-NMR (600 MHz, DMSO-d6): δ [ppm] = 8.57 (t, 1H), 7.94 (d, 1H), 7.84 (dd, 1H), 7.67 (br. s, 1H), 7.567. 47 (m, 5H), 7.18 (dd, 1H), 6.90 (d, 1H), 6.70 (br. t, 1H), 4.24 (dd, 1H), 3.87 (s, 3H), 3.57 (dd, 1H) , 3.18 (d, 1H), 2.40 (d, 1H), 2.10 (br. s, 3H), 1.53 (s, 3H), 1.12 (s, 9H).

Separation of enantiomers.

The title compound (1.73 g) was adsorbed in a mixture of isopropanol (95 ml) and acetonitrile (5 ml), heated to 50°C, filtered and separated into enantiomers by preparative SLC on the chiral phase (see Examples). 223A and 224A) [column: Daicel Chiralpak IC, 250 mm x 20 mm; flow: 100 ml/min; detection: 210 nm; temperature: 40°C; sample injection: 6.0 ml; eluent: carbon dioxide/ethanol/methanol 7:3:0 ^ 7:0:3; isocratic, duration of action 14.0 min]. The combined desired fractions were concentrated and the residue was dried in vacuo.

Example 223A. (+)-tert-Butyl-4-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-(4fluoro-2-methoxyphenyl)-3-methylbutanoate (enantiomer 1 ).

The separation of enantiomers described in Example 222A gave 750 mg (98% pure, ee value 100%) of the title compound as the previously eluted enantiomer.

[a] _D20 = +11.1°, 589 nm, c = 0.40 ^g /100 ml, methanol.

LC-MS (Method 2): Rt = 1.36 min; MS (ESIpos): m/z = 621/623 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 1.030 (0.95), 1.045 (0.95), 1.120 (16.00), 1.531 (2.02), 2.388 (0.61), 2.421 (0.65), 3.159 (0.56 ), 3.192 (0.53), 3.869 (3.82), 7.175 (0.44), 7.178 (0.42), 7.498 (0.82), 7.506 (0.74), 7.517 (1.89), 7.522 (1.69), 7.849 (0.54), 7.854 (0.51 ), 7.923 (1.03), 7.946 (0.64).

1H-NMR (400 MHz, DMSO-d6): δ [ppm] = 8.55 (t, 1H), 7.93 (d, 1H), 7.84 (dd, 1H), 7.67 (br. s, 1H), 7.557.47 (m, 5H), 7.18 (dd, 1H), 6.89 (dd, 1H), 6.70 (td, 1H), 4.23 (dd, 1H), 3.87 (s, 3H), 3.57 (dd, 1H), 3.18 ( d, 1H), 2.41 (d, 1H), 2.11 (br. s, 3H), 1.53 (s, 3H), 1.12 (s, 9H).

Example 224A. (-)-tert-Butyl-4-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-(4fluoro-2-methoxyphenyl)-3-methylbutanoate (enantiomer 2 ).

The separation of enantiomers described in Example 222A gave 820 mg (98% pure, ee value 99%) of the title compound as the later eluted enantiomer.

[a] _D20 = -11.5°, 589 nm, c = 0.38 ^g /100 ml, methanol.

LC-MS (Method 2): R _t = 1.36 min; MS (ESIpos): m/z = 621/623 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.030 (3.00), 1.046 (3.01), 1.120 (16.00), 1.531 (1.99), 2.389 (0.60), 2.422 (0.65), 3.160 (0.56) 3.193 (0.52), 3.869 (3.80), 7.175 (0.43), 7.179 (0.42), 7.498 (0.81), 7.506 (0.71), 7.517 (1.85), 7.523 (1.67), 7.849 (0.53), 7.854 (0.51) , 7.923 (1.03), 7.946 (0.65).

1H-NMR (400 MHz, DMSO-d6): δ [ppm] = 8.55 (t, 1H), 7.93 (d, 1H), 7.84 (dd, 1H), 7.67 (br. s, 1H), 7.567.46 (m, 5H), 7.18 (dd, 1H), 6.89 (dd, 1H), 6.70 (td, 1H), 4.23 (dd, 1H), 3.87 (s, 3H), 3.57 (dd, 1H), 3.18 ( d, 1H), 2.41 (d, 1H), 2.11 (br. s, 3H), 1.53 (s, 3H), 1.12 (s, 9H).

Example 225A. (+/-)-Ethyl-4-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-2,2-difluoro3 -(2-methoxyphenyl)butanoate (racemate) o |+>+o^CH3 O^NH ^FF

Br C H C ^ν To

HATU (137 mg , 361 µmol) and DIPEA (120 µl, 690 µmol) and the mixture was stirred for 30 min at RT. Then (+/-)-ethyl-4amino-2,2-difluoro-3-(2-methoxyphenyl)butanoate hydrochloride (86 mg, 278 µmol, example 118A) was added and the mixture was stirred overnight at RT. The mixture was then purified by preparative HPLC (Chromatorex C18, 10 µm, 125 x 30 mm, acetonitrile/water gradient with 0.01% TFA). The two separated fractions were collected, concentrated and both residues were lyophilized. From one residue, 46 mg (60% pure, 17% th. yield, see Analysis section) of the title compound were obtained. From another residue, after re-purification by preparative HPLC (Chromatorex C18, 10 µm, 125 x 30 mm, acetonitrile/water gradient with 0.01% TFA), 8.8 mg (96% pure, 5% theoretical yield) of the corresponding carboxylic acid ( +/-)-4-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-2,2difluoro-3-(2-methoxyphenyl)butanoic acid.

LC-MS (Method 7): Rt = 1.56 min; MS (ESIpos): m/z = 597/599 [M+H] ⁺ .

Example 226A. (+/-)-tert-Butyl-4-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-(2fluoro-6-methoxyphenyl)-3-methylbutanoate ( racemate)

- 100 040284

HATU (456 mg , 1.20 mmol) and DIPEA (420 µl, 2.4 mmol) and the mixture was stirred for 15 min at RT. Then added (+/-)-tert-butyl-4-amino-3-(2-fluoro-6-methoxyphenyl)-3-methylbutanoate (363 mg, 82% pure, 1.00 mmol, Example 119A) dissolved in DMF (3 ml ) and the mixture was stirred 3 h at 60°C and then overnight at RT. The mixture was then mixed with ethyl acetate and water (respectively 100 ml) and shaken. After phase separation, the aqueous phase was extracted once with ethyl acetate (80 ml). The combined organic phases were washed with saturated aqueous sodium chloride (100 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 KP-Sil, cyclohexane/ethyl acetate 97 :3 ^ 7:3, Isolera One). The combined desired fractions were concentrated and the residue was dried in vacuo. 288 mg (84% pure, 39% thor.) of the title compound were obtained.

LC-MS (Method 1): R _t = 2.57 min; MS (ESIpos): m/z = 621/623 [M+H] ⁺ .

1H-NMR (500 MHz, DMSO-d6): δ [ppm] = 8.68 (t, 1H), 7.94 (d, 1H), 7.84 (dd, 1H), 7.66 (br. s, 1H), 7.557.47 (m, 5H), 7.25-7.18 (m, 1H), 6.84 (d, 1H), 6.68 (dd, 1H), 4.24 (br. dd, 1H), 3.84 (s, 3H), 3.57 (br. dd , 1H), 3.34 (d, 1H), 2.35 (d, 1H), 2.12 (br. s, 3H), 1.69 (d, 3H), 1.17 (s, 9H).

Separation of enantiomers.

The title target compound (215 mg) purified by preparative HPLC was separated into enantiomers in the chiral phase (see examples 227A and 228A) [column: Daicel Chiralpak ID, 5 μm, 250 mm x 20 mm; flow: 15 ml/min; detection: 220 nm; temperature: 25°C; sample injection: 0.15 ml; eluent: 50% heptane/50% ethanol; duration of action 10 min, isocratic].

Example 227A. (-)-tert-Butyl-4-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-(2fluoro-6-methoxyphenyl)-3-methylbutanoate (enantiomer 1 ).

The separation of enantiomers described in Example 226A gave 76 mg (87% pure, ee value 97%) of the title compound as the previously eluted enantiomer.

[a] _D20 = -8.0°, 436 nm, c = ^0.34 g/100 ml, chloroform.

LC-MS (Method 1): R _t = 2.57 min; MS (ESIpos): m/z = 621/623 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 8.67 (t, 1H), 7.94 (d, 1H), 7.84 (dd, 1H), 7.64 (br. s, 1H), 7.557. 47 (m, 5H), 7.26-7.17 (m, 1H), 6.84 (d, 1H), 6.68 (dd, 1H), 4.24 (br. dd, 1H), 3.84 (s, 3H), 3.57 (br. dd, 1H), 3.34 (d, 1H, partially hidden), 2.35 (d, 1H), 2.11 (br. s, 3H), 1.69 (d, 3H), 1.17 (s, 9H).

Example 228A. (+)-tert-Butyl-4-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-(2fluoro-6-methoxyphenyl)-3-methylbutanoate (enantiomer 2 ).

The separation of enantiomers described in Example 226A gave 61 mg (100% pure, ee value 94%) of the title compound as the later eluted enantiomer.

[a] _D20 = +3.7°, 436 nm, c = 0.31 ^g /100 ml, chloroform.

LC-MS (Method 1): R _t = 2.57 min; MS (ESIpos): m/z = 621/623 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6): δ [ppm] = 8.68 (t, 1H), 7.94 (d, 1H), 7.85 (dd, 1H), 7.64 (br. s, 1H), 7.567.46 (m, 5H), 7.26-7.17 (m, 1H), 6.84 (d, 1H), 6.68 (dd, 1H), 4.24 (dd, 1H), 3.84 (s, 3H), 3.57 (dd, 1H), 3.34 (d, 1H, partially hidden), 2.35 (d, 1H), 2.11 (br. s, 3H), 1.69 (d, 3H), 1.17 (s, 9H).

Example 229A. tert-Butyl 4-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-(2-chlorophenyl)pentanoate (mixture of diastereoisomers)

HATU (552 mg , 1.45 mmol) and DIPEA (510 µl, 2.9 mmol) and the mixture was stirred for 15 min at RT. Then tert-butyl 4-amino-3-(2-chlorophenyl)pentanoate (462 mg, 74% pure, 1.21 mmol, example 120A) dissolved in DMF (3 ml) was added and the mixture was stirred for 22 h at 60°C. After cooling to RT, the mixture was directly (without further work-up) purified by preparative HPLC, in the chiral phase (method 14). The combined target fractions were respectively concentrated and the respective residues dried in vacuo (see Examples 230A and 231A).

Example 230A. (+/-)-tert-Butyl-4-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-(2chlorophenyl)pentanoate (racemate 1).

The separation of diastereomers described in Example 229A gave 123 mg (100% pure) of the title compound as the previously eluted racemate.

- 101 040284

LC-MS (Method 1): R _t = 2.61 min; MS (ESIpos): m/z = 607/609 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.200 (16.00), 1.234 (1.15), 1.245 (1.94), 1.262 (1.83), 2.710 (0.58), 2.734 (0.56), 2.760 (0.63) , 2.773 (0.67), 3.747 (0.40), 3.759 (0.42), 7.490 (0.69), 7.505 (2.14), 7.511 (1.76), 7.523 (3.09), 7.536 (1.81), 7.831 (0.42), 7.853 (0.59) , 7.929 (0.98), 7.951 (0.63).

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.72 (br. s, 1H), 7.94 (d, 1H), 7.84 (d, 1H), 7.78-7.15 (m, 10H), 4.72 -4.57 (m, 1H), 3.81-3.69 (m, 1H), 2.86-2.63 (m, 2H), 2.39-1.69 (br. m, 3H), 1.25 (d, 3H), 1.20 (s, 9H) .

Example 231A. (+/-)-tert-Butyl-4-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-(2chlorophenyl)pentanoate (racemate 2).

The separation of diastereomers described in Example 229A yielded 148 mg (75% pure) of the first batch, 56 mg (89% pure, see Analysis) of the second batch, and 57 mg (40% pure) of the third batch of the title compound as a later eluted racemate. As an auxiliary component, each batch contained the compound from Example 230A (racemate 1) in varying proportions.

LC-MS (Method 1): R _t = 2.66 min; MS (ESIpos): m/z = 607/609 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.89 (br. s, 1H), 7.99 (d, 1H), 7.89 (dd, 1H), 7.74 (br. s, 1H), 7.72 -7.24 (m, 10H), 4.52-4.39 (m, 1H), 3.82-3.71 (m, 1H), 2.95-2.75 (m, 2H), 2.30 (br. s, 3H), 1.21 (d, 3H) , 1.15(s, 9H).

Example 232A. (+/-)-tert-Butyl-5-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-4-(2chlorophenyl)pentanoate (racemate)

HATU (1.93 g , 5.07 mmol) and DIPEA (1.8 ml, 10 mmol) and the mixture was stirred for 30 min at RT. Then (+/-)-tert-butyl-5amino-4-(2-chlorophenyl)pentanoate (1.58 g, 91% pure, 5.07 mmol, example 121A) dissolved in DMF (5 ml) was added and the mixture was stirred overnight at 60°C. After cooling to RT, the mixture was mixed with ethyl acetate and water (respectively 30 ml) and shaken. After phase separation, the aqueous phase was extracted twice with ethyl acetate (corresponding to 30 ml). The combined organic phases were washed with saturated aqueous sodium chloride, dried over sodium sulfate, filtered and concentrated, and the residue was adsorbed in dichloromethane and previously purified by flash column chromatography (100 g of Biotage Snap-Cartridge KP-Sil, cyclohexane/ethyl acetate 85:15, Isolera One). Then further purified by preparative HPLC (Method 16). The combined desired fractions were concentrated and the residue was dried in vacuo. 1.43 g (98% pure, 68% th. y.) of the title compound was obtained.

LC-MS (Method 1): R _t = 2.63 min; MS (ESIpos): m/z = 607/609 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.152 (0.02), 1.206 (0.07), 1.290 (0.09), 1.311 (0.17), 1.334 (0.13), 1.367 (16.00), 1.393 (0.24) , 1.523 (0.07), 1.772 (0.06), 1.804 (0.16), 1.823 (0.21), 1.846 (0.12), 2.011 (0.07), 2.031 (0.17), 2.043 (0.78), 2.253 (0.04), 2.327 (0.17) , 7.264 (0.37), 7.283 (1.28), 7.507 (0.85), 7.518 (0.19), (0.03), (0.26), (3.11),

2.060

2.366

7.354

7.696 (0.23), 2.082 (1.29), (0.02), 2.670 (0.03), (0.23), 7.373 (0.41), (0.09), 7.830 (0.40),

2.094

2.710

7.391

7.835 (0.71), 2.111 (0.40), 2.119 (0.45), 2.139 (0.02), 3.611 (0.23), 3.718 (0.32), 7.246 (0.21), 7.436 (0.63), 7.456 (0.51), 7.499 (0.37), 7.853 (0.61), 7.858 (0.59), 7.928 (1.12), 7.950 (0.71), 8.837 (0.24), 8.851 (0.47), 8.865 (0.23).

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 8.85 (t, 1H), 7.94 (d, 1H), 7.85 (dd, 1H), 7.68 (br. s, 1H), 7.557.48 ( m, 6H), 7.45 (d, 1H), 7.37 (br. t, 1H), 7.27 (br. t, 1H), 3.81-3.53 (m, 3H), 2.20-1.98 (m, 6H), 1.89- 1.75 (m, 1H), 1.37 (s, 9H).

Example 233A. (+/-)-tert-Butyl-5- {[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino} -4-(2chlorophenyl)-4-methylpentanoate (racemate)

- 102 040284

HATU (783 mg , 2.06 mmol) and DIPEA (720 µl, 4.1 mmol) and the mixture was stirred for 30 min at RT. Then (+/-)-tert-butyl-5-amino-4-(2-chlorophenyl)-4-methylpentanoate (840 mg, 73% pure, 2.06 mmol, example 122A) dissolved in DMF (2 ml) was added and the mixture was stirred overnight at 60°C. After cooling to RT, the mixture was mixed with ethyl acetate and water (respectively 30 ml) and shaken. After phase separation, the aqueous phase was extracted twice with ethyl acetate (30 ml). The combined organic phases were washed with saturated aqueous sodium chloride, dried over sodium sulfate, filtered and concentrated, and the residue was adsorbed in dichloromethane and previously purified by flash column chromatography (100 g of Biotage Snap-Cartridge KP-Sil, cyclohexane/ethyl acetate 85:15, Isolera One). Then further purified by preparative HPLC (method 16). The combined desired fractions were concentrated and the residue was dried in vacuo. 309 mg (98% pure, 35% thor.) of the title compound were obtained.

LC-MS (Method 1): Rt = 2.70 min; MS (ESIpos): m/z = 621/623 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.188 (0.07), 1.233 (0.04), 1.280 (0.14), 1.297 (0.08), 1.348 (16.00), 1.375 (0.18), 1.512 (2.18) , 1.717 (0.11), 1.729 (0.13), 1.745 (0.17), 1.756 (0.28), 1.767 (0.15), 1.783

(0.21), 1.796 (0.20), 1.872 (0.19), 1.885 (0.21), 1.907 (0.24), 1.919 (0.23), 1.934 (0.12), 1.947 (0.19), 1.986 (0.23), 1.999 (0.19), 2.015 (0.27), 2.026 (0.35), 2.037 (0.22), 2.053 (0.26), 2.065 (0.24), 2.317 (0.06), 2.365 (0.04), 2.634 (0.12), 2.647 (0.13), 2.668 (0.22), 2.696 (0.12), 2.708 (0.12), 3.666 (0.28), 3.679 (0.31), 3.699 (0.33), 3.713 (0.31), 3.922 (0.27), 4.339 (0.22), 4.357 (0.24), 4.373 (0.22), 4.390 (0.20), 7.257 (0.12), 7.275 (0.32), 7.298 (0.40), 7.320 (0.41), 7.337 (0.21), 7.356 (0.06), 7.375 (0.04), 7.408 (0.57), 7.425 (0.69), 7.445 (0.29), 7.473 (0.11), 7.498 (0.83), 7.506 (0.76), 7.517 (2.01), 7.668 (0.07), 7.828 (0.36), 7.833 (0.33), 7.850

(0.55), 7.855 (0.52), 7.924 (1.00), 7.946 (0.64), 8.614 (0.25), 8.629 (0.41), 8.644 (0.25).

Separation of enantiomers.

The title title compound (220 mg) was dissolved in a mixture of ethanol (7 ml) and acetonitrile (3 ml) at elevated temperature and separated into enantiomers by chiral phase preparative HPLC (see examples 234A and 235 A) [column: Daicel Chiralpak IC, 5 µm, 250 mm x 20 mm; flow: 15 ml/min; detection: 210 nm; temperature: 25°C; sample injection: 0.5 ml; eluent: 20% ethanol / 80% heptane; duration of action 20 min, isocratic]. The combined target fractions were concentrated and the residue was lyophilized.

Example 234A. (-)-tert-Butyl-5-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-4-(2chlorophenyl)-4-methylpentanoate (enantiomer 1).

The separation of enantiomers described in Example 233A gave 91 mg (98% pure, ee value 99%) of the title compound as the previously eluted enantiomer.

[a] _D20 = -33.9°, 589 nm, c = 0.25 ^g /100 ml, methanol.

LC-MS (Method 1): Rt = 2.68 min; MS (ESIpos): m/z = 621/623 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.007 (0.49), 1.280 (0.15), 1.348 (16.00), 1.512 (1.93), 1.728 (0.12), 1.756 (0.24), 1.783 (0.19) , 1.795 (0.18), 1.872 (0.16), 1.884 (0.17), 1.919 (0.20), 1.946 (0.16), 1.986 (0.20), 2.026 (0.29), 2.053 (0.22), 2.669 (0.23), 2.708 (0.13) . , 7.322 (0.36), 7.337 (0.17), 7.405 (0.48), 7.428 (0.60), 7.446 (0.27), 7.497 (0.74), 7.505 (0.68), 7.516 (1.81), 7.826 (0.34), 7.831 (0.30) , 7.848 (0.52), 7.853 (0.49), 7.922 (1.01), 7.945 (0.63), 8.612 (0.22), 8.627 (0.35), 8.643 (0.21).

Example 235A. (+)-tert-Butyl-5-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-4-(2chlorophenyl)-4-methylpentanoate (enantiomer 2).

The separation of enantiomers described in Example 233A gave 96 mg (98% pure, ee value 99%) of the title compound as the later eluted enantiomer.

[a] _D20 = +35.1°, 589 nm, c = 0.26 g ^/ 100 mL, methanol.

LC-MS (Method 1): Rt = 2.68 min; MS (ESIpos): m/z = 621/623 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.007 (0.35), 1.188 (0.07), 1.280 (0.15), 1.297 (0.08), 1.348 (16.00), 1.512 (2.03), 1.717 (0.10) , 1.728 (0.12), 1.745 (0.16), 1.756 (0.26), 1.783 (0.20), 1.795 (0.19), 1.872

(0.16), 1.885 (0.19), 1.919 (0.22), 1.947 (0.17), 1.986 (0.21), 1.999 (0.17), 2.015 (0.24), 2.025 (0.30), 2.053 (0.24), 2.065 (0.21), 2.327 (0.07), 2.669 (0.22), 2.709 (0.13), 3.665 (0.24), 3.679 (0.26), 3.699 (0.29), 3.712 (0.27), 4.338 (0.20), 4.356 (0.22), 4.372 (0.20), 4.389 (0.18), 7.275 (0.30), 7.298 (0.38), 7.319 (0.38), 7.337 (0.18), 7.405 (0.51), 7.424 (0.63), 7.445 (0.28), 7.497 (0.77), 7.505 (0.71), 7.516 (1.87), 7.826 (0.34), 7.831

(0.31), 7.848 (0.52), 7.853 (0.49), 7.922 (1.02), 7.944 (0.64), 8.612 (0.23), 8.627 (0.37), 8.642 (0.22).

Example 236A. (+/-)-tert-Butyl-5-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-4-(2chloro-6-fluorophenyl)pentanoate (racemate)

- 103 040284

HATU (1.01 g , 2.66 mmol) and DIPEA (930 µl, 5.3 mmol) and the mixture was stirred for 30 min at RT. Then (+/-)-tert-butyl-5-amino-4-(2-chloro-6-fluorophenyl)pentanoate (1.20 g, 67% pure, 2.66 mmol, example 123 A) dissolved in DMF (2 ml) was added and the mixture was stirred overnight at 60°C. After cooling to RT, the mixture was mixed with ethyl acetate and water (respectively 20 ml) and shaken. After phase separation, the aqueous phase was extracted twice with ethyl acetate (20 ml). The combined organic phases were washed with saturated aqueous sodium chloride, dried over sodium sulfate, filtered and concentrated, and the residue was adsorbed in dichloromethane and previously purified by flash column chromatography (100 g of Biotage Snap-Cartridge KP-Sil, cyclohexane/ethyl acetate 85:15, Isolera One). Then further purified by preparative HPLC (Method 16). The combined desired fractions were concentrated and the residue was dried in vacuo. 604 mg (98% pure, 53% thor.) of the title compound were obtained.

LC-MS (Method 1): R _t = 2.60 min; MS (ESIpos): m/z = 625/627 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.361 (16.00), 2.119 (0.88), 2.135 (0.88), 2.158 (1.67), 7.330 (0.95), 7.501 (0.94), 7.509 (0.86) , 7.521 (3.11), 7.838 (0.48), 7.843 (0.44), 7.860 (0.72), 7.865 (0.69), 7.933 (1.26), 7.955 (0.78), 8.938 (0.47).

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 8.94 (t, 1H), 7.94 (d, 1H), 7.85 (dd, 1H), 7.72 (br. s, 1H), 7.567.45 ( m, 5H), 7.37-7.28 (m, 2H), 7.27-7.16 (m, 1H), 3.89-3.53 (m, 3H), 2.21-1.90 (m, 7H), 1.36 (s, 9H).

Example 237A. (+/-)-tert-Butyl-5-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-4-(2methylphenyl)pentanoate (racemate)

HATU (667 mg , 1.75 mmol) and DIPEA (610 µl, 3.5 mmol) and the mixture was stirred for 30 min at RT. Then (+/-)-tert-butyl-5-amino-4-(2-methylphenyl)pentanoate (486 mg, 95% pure, 1.75 mmol, example 124A) dissolved in DMF (2.5 ml) was added and the mixture was stirred overnight at 60°C. After cooling to RT, the mixture was mixed with ethyl acetate and water (respectively 20 ml) and shaken. After phase separation, the aqueous phase was extracted twice with ethyl acetate (20 ml). The combined organic phases were washed with saturated aqueous sodium chloride, 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 85:15, Isolera One) . The combined target fractions were concentrated and the residue was lyophilized. 429 mg (98% pure, 61% th. y.) of the title compound were obtained.

LC-MS (Method 1): R _t = 2.61 min; MS (ESIpos): m/z = 587/589 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.009 (0.21), 0.007 (0.23), 1.202 (0.07), 1.304 (0.08), 1.336 (0.13), 1.362 (16.00), 1.397 (0.14 ), 1.518 (0.06), 1.747 (0.05), 1.779 (0.15), 1.804 (0.19), 1.821 (0.13), 2.029 (0.20), 2.041 (0.22), 2.060 (1.22), 2.072 (0.80), 2.093 (0.46 ), 2.109 (0.40), 2.328 (3.10), 2.365 (0.05), 2.669 (0.05), 2.709 (0.04), 3.483 (0.10), 3.496 (0.14), 3.515 (0.18), 3.530 (0.18), 3.545 (0.11 ), 3.698 (0.14), 3.716 (0.22), 3.734 (0.20), 3.749 (0.17), 3.768 (0.10), 7.094 (0.13), 7.112 (0.34), 7.130 (0.30), 7.165 (0.56), 7.183 (0.32 ), 7.211 (0.34), 7.229 (0.18), 7.301 (0.55), 7.321 (0.38), 7.490 (0.23), 7.500 (0.69), 7.508 (0.67), 7.519 (2.17), 7.530 (0.94), 7.694 (0.12 ), 7.835 (0.37), 7.840 (0.34), 7.857 (0.56), 7.863 (0.55), 7.933 (1.02), 7.955 (0.65), 8.820 (0.21), 8.835 (0.34), 8.848 (0.21).

Separation of enantiomers.

The title title compound (390 mg) was dissolved in isopropanol (4 ml) and separated into enantiomers by chiral phase preparative HPLC (see Examples 238A and 23 9A) [column: Daicel Chiralpak AD-H, 5 µm , 250 mm x 20 mm; flow: 20 ml/min; detection: 210 nm; temperature: 23°C; sample injection: 0.25 ml; eluent: 20% isopropanol / 80% heptane; duration of action 10 min, isocratic]. The combined target fractions were concentrated and the residue was lyophilized.

Example 23 8A. (-)-tert-Butyl-5-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-4-(2methylphenyl)pentanoate (enantiomer 1).

The separation of enantiomers described in Example 237A gave 128 mg (98% pure, ee value 99%) of the title compound as the previously eluted enantiomer.

[a] _D20 = -11.1°, 589 nm, c = ^0.35 g/100 ml, methanol.

LC-MS (Method 1): Rt = 2.63 min; MS (ESIpos): m/z = 587/589 [M+H]+.

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 1.201 (0.07), 1.304 (0.09), 1.336 (0.15), 1.362 (16.00), 1.518 (0.06), 1.748 (0.06), 1.779 (0.16 ), 1.804 (0.20), 1.822 (0.14), 1.853 (0.04), 2.014 (0.16), 2.029 (0.22), 2.041 (0.25), 2.060 (1.31), 2.072 (0.85), 2.093 (0.49), 2.108 (0.42 ), 2.328 (3.28), 2.365 (0.04), 2.669 (0.03), 2.709 (0.03), 3.304 (0.19), 3.321 (0.20), 3.483 (0.12), 3.496 (0.16), 3.515 (0.20), 3.530 (0.20 ), 3.545 (0.13), 3.698 (0.18), 3.716 (0.28), 3.734 (0.25), 3.750 (0.23), 3.768 (0.17), 3.876 (0.18), 7.093 (0.14), 7.111 (0.36), 7.130 (0.32 ), 7.164 (0.60), 7.182 (0.34), 7.211 (0.36), 7.229 (0.19), 7.301 (0.59), 7.320 (0.41), 7.490 (0.25), 7.501 (0.75), 7.508 (0.71), 7.520 (2.27 ), 7.531 (0.97), 7.695 (0.13), 7.836 (0.38), 7.841 (0.34), 7.859 (0.59), 7.864 (0.56), 7.934 (1.07), 7.956 (0.68), 8.821 (0.23), 8.836 (0.36 ), 8.850 (0.22).

Example 239A. (+)-tert-Butyl-5-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-4-(2methylphenyl)pentanoate (enantiomer 2).

The separation of enantiomers described in Example 237A gave 128 mg (98% pure, ee value 99%) of the title compound as the later eluted enantiomer.

[a] _D20 = +16.8°, 589 nm, c = 0.37 ^g /100 ml, methanol.

LC-MS (Method 2): Rt = 1.40 min; MS (ESIpos): m/z = 587/589 [M+H]+.

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: -0.009 (0.32), 0.008 (0.27), 1.078 (0.08), 1.093 (0.08), 1.202 (0.06), 1.261 (0.17), 1.304 ( 0.08), 1.336 (0.13), 1.362 (16.00), 1.518 (0.06), 1.779 (0.14), 1.804 (0.18), 2.029 (0.18), 2.060 (1.12), 2.072 (0.73), 2.094 (0.42), 2.92), 3.496 (0.13), 3.515 (0.16), 3.530 (0.17), 3.697 (0.14), 3.716 (0.21), 3.733 (0.18), 3.749 (0.16), 3.768 (0.09), 7.093 (0.12), 0.31), 7.130 (0.28),7.165 (0.53), 7.182 (0.29), 7.211 (0.31), 7.229 (0.17), 7.302 (0.51), 7.320 (0.35), 7.490 (0.22), 7.500 (0.67), 0.64), 7.519 (2.04), 7.531 (0.90), 7.695 (0.12), 7.835 (0.38), 7.840 (0.34), 7.857 (0.57), 7.863 (0.55),7.933 (1.05), 7.955 (0.66), 8.820 ( 0.19), 8.835 (0.31), 8.849 (0.19).

Example 240A. (+/-)-tert-Butyl-5-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino }-4-(2chloro-5-fluorophenyl)pentanoate (racemate)

HATU (5.29 g , 13.9 mmol) and DIPEA (4.8 ml, 28 mmol) and the mixture was stirred for 30 min at RT. Then (+/-)-tert-butyl-5amino-4-(2-chloro-5-fluorophenyl)pentanoate (7.00 g, 60% pure, 13.9 mmol, example 125A) dissolved in DMF (20 ml) was added and the mixture stirred overnight at 60°C. After cooling to RT, the mixture was mixed with ethyl acetate and water (respectively 150 ml) and shaken. After phase separation, the aqueous phase was extracted twice with ethyl acetate (150 ml). The combined organic phases were washed with saturated aqueous sodium chloride, dried over sodium sulfate, filtered and concentrated, and the residue was adsorbed into dichloromethane and purified by flash column chromatography (100 g Biotage Snap-Cartridge Ultra silica gel, cyclohexane/ethyl acetate 85:15, Isolera One). The combined target fractions were concentrated and the residue was lyophilized. 4.03 g (91% pure, 63% th. y.) of the title compound was obtained.

LC-MS (Method 1): R _t = 2.61 min; MS (ESIpos): m/z = 625/627 [M+H]+.

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: -0.008 (0.22), 0.008 (0.21), 0.018 (0.08), 0.838 (0.09), 0.863 (0.04), 1.211 (0.07), 1.283 ( 1.313 (0.11), 1.344 (4.94), 1.359 (0.72), 1.371 (16.00), 1.397 (0.20), 1.499 (0.04), 1.528 (0.07), 1.663 (0.06), 1.785 (0.14), 1.801 ( 0.16), 1.820 (0.18), 1.842 (0.14), 1.928 (0.06), 1.947 (0.07), 1.971 (0.19), 1.988 (0.26), 2.009 (0.25), 2.022 (0.23), 2.041 (0.26), 0.24), 2.074 (0.21), 2.093 (0.72), 2.110 (0.92), 2.139 (1.05), 2.328 (0.05), 2.366 (0.05), 2.690 (0.17), 2.710 (0.12), 3.223 (0.06), 3.607 ( 0.19), 3.735 (0.37), 7.035 (0.07), 7.056 (0.12), 7.077 (0.09), 7.116 (0.18), 7.140 (0.30), 7.155 (0.21), 7.181 (0.08), 7.188 (0.07), 0.10), 7.411 (0.36), 7.418 (0.38), 7.436 (0.38), 7.444 (0.32), 7.478 (0.47), 7.491

- 105 040284 (0.59), 7.500 (1.12), 7.508 (0.83), 7.518 (2.77), 7.530 (1.02), 7.664 (0.06), 7.832 (0.42), 7.837 (0.37), 7.854 (0.64), 7.859 (0.60 ), 7.929 (1.10), 7.951 (0.71), 8.842 (0.20), 8.856 (0.39), 8.870 (0.19).

Separation of enantiomers.

The title target compound (4.00 g) was dissolved in ethanol (40 ml) and separated into enantiomers by chiral phase preparative HPLC (see examples 241A and 242A) [column: Daicel Chiralcel OX-H, 5 µm, 250 mm x 20 mm; flow: 40 ml/min; sample injection: 0.13 ml; eluent: 20% ethanol / 80% heptane; duration of action 9 min, isocratic]. The combined target fractions were concentrated and the residue was lyophilized.

Example 241A. (-)-tert-Butyl-5-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-4-(2chloro-5-fluorophenyl)pentanoate (enantiomer 1).

The separation of enantiomers described in Example 240A gave 1.57 g (86% pure, ee value 99%) of the title compound as the previously eluted enantiomer.

[a] _D20 = -15.8°, 589 nm, c = 0.34 ^g /100 ml, methanol.

LC-MS (Method 1): R _t = 2.60 min; MS (ESIpos): m/z = 625/627 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 1.312 (0.15), 1.344 (1.32), 1.370 (16.00), 1.819 (0.18), 2.021 (0.25), 2.043 (0.26), 2.059 (0.27 ), 2.073 (0.28), 2.092 (0.75), 2.109 (0.94), 2.139 (1.11), 3.607 (0.20), 3.734 (0.39), 7.136 (0.32), 7.410 (0.34), 7.417 (0.34), 7.435 (0.33 ), 7.477 (0.49), 7.490 (0.63), 7.499 (1.20), 7.507 (0.89), 7.517 (3.06), 7.831 (0.45), 7.836 (0.40), 7.853 (0.69), 7.858 (0.64), 7.928 (1.16 ), 7.951 (0.73), 8.856 (0.39).

Example 242A. (+)-tert-Butyl-5-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-4-(2chloro-5-fluorophenyl)pentanoate (enantiomer 2).

The separation of enantiomers described in Example 240A gave 1.28 g (98% pure, ee value 95%) of the title compound as the later eluted enantiomer.

[a]D ²⁰ = +15.1°, 589 nm, c = 0.36 g/100 ml, methanol.

LC-MS (Method 1): R _t = 2.60 min; MS (ESIpos): m/z = 625/627 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.009 (0.20), 0.007 (0.19), 0.857 (0.07), 1.027 (0.03), 1.044 (0.04), 1.086 (0.04), 1.101 (0.04 ), 1.210 (0.07), 1.282 (0.09), 1.331 (0.14), 1.344 (1.33), 1.370 (16.00), 1.526 (0.07), 1.784 (0.13), 1.800 (0.15), 1.818 (0.17), 1.841 (0.13 ), 2.008 (0.20), 2.021 (0.22), 2.039 (0.22), 2.059 (0.19), 2.073 (0.16), 2.092 (0.70), 2.109 (0.92), 2.138 (1.04), 2.327 (0.05), 2.365 (0.04 ), 2.669 (0.05), 2.709 (0.05), 3.607 (0.18), 3.733 (0.37), 7.136 (0.24), 7.409 (0.33), 7.417 (0.34), 7.435 (0.34), 7.442 (0.32), 7.477 (0.47 ), 7.490 (0.59), 7.499 (1.11), 7.507 (0.79), 7.517 (2.61), 7.529 (0.96), 7.532 (0.87), 7.664 (0.06), 7.831 (0.42), 7.836 (0.38), 7.853 (0.64 ), 7.858 (0.61), 7.928 (1.12), 7.950 (0.71), 8.841 (0.20), 8.855 (0.39), 8.869 (0.19).

Example 243A. (+/-)-tert-Butyl-5-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-4-(2methoxyphenyl)pentanoate (racemate)

HATU (308 mg , 811 µmol) and DIPEA (280 µl, 1.6 mmol) and the mixture was stirred for 30 min at RT. Then (+/-) tert-butyl-5-amino-4-(2-methoxyphenyl)pentanoate (267 mg, 85% pure, 811 µmol, Example 126A) dissolved in DMF (1.5 ml) was added and the mixture was stirred for nights at 60°C. After cooling to RT, the mixture was mixed with ethyl acetate and water (respectively 20 ml) and shaken. After phase separation, the aqueous phase was extracted twice with ethyl acetate (20 ml). The combined organic phases were washed with saturated aqueous sodium chloride, dried over sodium sulfate, filtered and concentrated, and the residue was adsorbed in dichloromethane and purified by flash column chromatography (100 g of Biotage Snap-Cartridge KP-Sil, cyclohexane/ethyl acetate 85:15, Isolera one). The combined target fractions were concentrated and the residue was lyophilized. 213 mg (98% pure, 64% thor.) of the title compound were obtained.

LC-MS (Method 1): Rt = 2.57 min; MS (ESIpos): m/z = 603/605 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.009 (0.16), 0.007 (0.13), 1.200 (0.07), 1.300 (0.10), 1.325 (0.17), 1.360 (16.00), 1.516 (0.06 ), 1.788 (0.12), 1.806 (0.16), 1.841 (0.08), 1.948 (0.06), 1.969 (0.15), 1.981 (0.17), 1.988 (0.17), 1.999 (0.19), 2.004 (0.19), 2.028 (0.97 ), 2.044 (0.74), 2.062 (0.26), 2.143 (0.93), 2.263 (0.03), 2.327 (0.03), 2.365 (0.02), 2.669 (0.03), 2.709 (0.02), 3.233 (0.02), 3.393 (0.17 ), 3.591 (0.02), 3.618 (0.08), 3.633 (0.14), 3.651 (0.25), 3.666 (0.31), 3.688 (0.23), 3.704 (0.25), 3.724 (0.23), 3.737 (0.12), 3.749

- 106 040284 (0.18), 3.773 (4.01), 6.922 (0.24), 6.941 (0.52), 6.959 (0.32), 6.976 (0.54), 6.997 (0.63), 7.197 (0.27), 7.217 (0.50), 7.223 (0.64) ), 7.241 (0.53), 7.488 (0.24), 7.498 (0.72), 7.507 (0.67), 7.518 (2.34), 7.529 (0.96), 7.714 (0.21), 7.829 (0.39), 7.834 (0.34), 7.852 (0.59 ), 7.857 (0.55), 7.926 (1.07), 7.948 (0.68), 8.752 (0.22), 8.767 (0.44), 8.781 (0.22).

Separation of enantiomers.

The title target compound (160 mg) was dissolved in isopropanol (3 ml) and separated into enantiomers by chiral phase preparative HPLC (see examples 244A and 245A) [column: Daicel Chiralcel AD-H, 5 μm, 250 mm x 20 mm; flow: 25 ml/min; sample injection: 0.10 ml; eluent: 40% isopropanol/60% heptane; duration of action 14 min, isocratic]. The combined target fractions were concentrated and the residue was lyophilized.

Example 244A. (-)-tert-Butyl-5-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-4-(2methoxyphenyl)pentanoate (enantiomer 1).

The separation of enantiomers described in Example 243A gave 63 mg (98% pure, ee value 99%) of the title compound as the previously eluted enantiomer.

[a] _D20 = -9.6°, 589 nm, c ⁼ 0.32 g/100 ml, methanol.

LC-MS (Method 1): Rt = 2.57 min; MS (ESIpos): m/z = 603/605 [M+H]+.

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.154 (0.03), 0.141 (0.03), 1.100 (0.05), 1.116 (0.05), 1.195 (0.06), 1.296 (0.11), 1.321 (0.16 ), 1.356 (16.00), 1.512 (0.06), 1.801 (0.16), 1.964 (0.14), 1.976 (0.16), 1.994 (0.18), 2.023 (0.95), 2.039 (0.73), 2.057 (0.25), 2.138 (0.05 ), 2.705 (0.05), 3.614 (0.08), 3.629 (0.14), 3.646 (0.23), 3.732 (0.12), 3.769 (4.00), 6.918 (0.24), 6.936 (0.27), 7.213 (0.50), 7.218 (0.64 ), 7.236 (0.53), 7.484 (0.97), 7.710 (0.21), 7.826 (0.38), 7.831 (0.34), 7.848 (0.92), 2.258 (0.03), 2.322 (0.24), 3.662 (0.31), 3.683 (0.22 ), 8.762 (0.43), 8.777 (0.21).

(0.52), 6.955 (0.22), 7.494 (0.59), 7.853 (0.30), 6.972 (0.69), 7.502 (0.56), 7.922 (0.04), 2.361 (0.22), 3.699 (0.54), 6.992 (0.66) (1.07), 7.944 (0.05), 2.664 (0.25), 3.719 (0.62), 7.193 (2.37), 7.525 (0.68), 8.748

Example 245A. (+)-tert-Butyl-5-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-4-(2methoxyphenyl)pentanoate (enantiomer 2).

The separation of enantiomers described in Example 243A gave 59 mg (98% pure, ee value 98%) of the title compound as the later eluted enantiomer.

[a] _D20 = +11.3°, 589 nm, c = 0.36 ^g /100 mL, methanol.

LC-MS (Method 1): Rt = 2.57 min; MS (ESIpos): m/z = 603/605 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.029 (0.07), 1.045 (0.07), 1.105 (0.15), 1.120 (0.15), 1.200 (0.07), 1.300 (0.10), 1.325 (0.15) , 1.360 (16.00), 1.516 (0.07), 1.805 (0.17), 1.968 (0.15), 1.980 (0.18), 1.999 (0.19), 2.028 (1.00), 2.044 (0.78), 2.062 (0.27), 2.143 (1.00) , 2.327 (0.06), 2.668 (0.05), 3.394 (0.20), 3.618 (0.13), 3.633 (0.18), 3.651 (0.28), 3.667 (0.35), 3.688 (0.25), 3.704 (0.27), 3.724 (0.25) . . , 7.949 (0.70), 8.753 (0.23), 8.768 (0.46), 8.782 (0.23).

Example 246A. (+/-)-tert-Butyl-5-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-4-(2chloro-5-fluorophenyl)-4-methylpentanoate ( racemate)

HATU (1.22 g , 3.22 mmol) and DIPEA (1.1 ml, 6.4 mmol) and the mixture was stirred for 30 min at RT. Then added (+/-)-tert-butyl-5amino-4-(2-chloro-5-fluorophenyl)-4-methylpentanoate (1.54 g, 66% pure, 3.22 mmol, Example 127A) dissolved in DMF (4 ml ) and the mixture was stirred overnight at 60°C. After cooling to RT, the mixture was mixed with ethyl acetate and water (respectively 20 ml) and shaken. After phase separation, the aqueous phase was extracted twice with ethyl acetate (20 ml). The combined organic phases were washed with saturated aqueous sodium chloride, dried over sodium sulfate, filtered and concentrated, and the residue was adsorbed in dichloromethane and previously purified by flash column chromatography (100 g of Biotage Snap-Cartridge KP-Sil, cyclohexane/ethyl acetate 85:15, Isolera One). Then further purified by preparative HPLC (Method 16). The combined desired fractions were concentrated and the residue was dried in vacuo. 377 mg (98% pure, 27% thor.) of the title compound were obtained.

- 107 040284

LC-MS (Method 1): Rt = 2.69 min; MS (ESIpos): m/z = 639 [M+H]+.

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.151 (0.01), 1.192 (0.07), 1.280 (0.14), 1.306 (0.08), 1.352 (16.00), 1.500 (2.15), 1.740 (0.11 ), 1.753 (0.13), 1.768 (0.17), 1.780 (0.27), 1.791 (0.14), 1.807 (0.22), 1.819 (0.21), 1.874 (0.19), 1.885 (0.20), 1.908 (0.23), 1.914 (0.22 ), 1.919 (0.23), 1.936 (0.13), 1.948 (0.17), 2.029 (0.24), 2.042 (0.24), 2.058 (0.29), 2.069 (0.37), 2.080 (0.23), 2.096 (0.26), 2.108 (0.23 ), 2.324 (0.06), 2.365 (0.03), 2.618 (0.11), 2.630 (0.12), 2.659 (0.18), 2.680 (0.11), 2.692 (0.09), 3.634 (0.20), 3.647 (0.21), 3.668 (0.23 ), 3.680 (0.21), 4.384 (0.18), 4.401 (0.20), 4.417 (0.19), 4.434 (0.16), 4.863 (0.04), 7.148 (0.15), 7.176 (0.57), 7.183 (0.42), 7.204 (0.43 ), 7.211 (0.30), 7.248 (0.02), 7.489 (0.48), 7.503 (0.99), 7.509 (0.84), 7.521 (1.70), 7.530 (1.54), 7.833 (0.32), 7.838 (0.30), 7.856 (0.49 ), 7.860 (0.47), 7.931 (0.97), 7.953 (0.62), 8.629 (0.23), 8.644 (0.37), 8.658 (0.23).

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.65 (t, 1H), 7.94 (d, 1H), 7.85 (dd, 1H), 7.63 (br. s, 1H), 7.567.46 (m, 6H), 7.23-7.13 (m, 2H), 4.41 (dd, 1H), 3.66 (dd, 1H), 2.73-2.59 (m, 1H), 2.15 (br. s, 3H), 2.13-2.01 (m, 1H), 1.97-1.86 (m, 1H), 1.84-1.72 (m, 1H), 1.50 (s, 3H), 1.35 (s, 9H).

Separation of enantiomers.

The title title compound (330 mg) was dissolved in methanol (25 ml) and separated into enantiomers by chiral phase preparative SLC (see Examples 247A and 248A) [column: Daicel Chiralpak AD-H, 5 μm, 250 mm x 20 mm; flow: 80 ml/min; detection: 210 nm; temperature: 40°C; sample injection: 0.5 ml; eluent: 88% carbon dioxide/12% methanol; duration of action 18 min, isocratic]. The combined desired fractions were concentrated and the residue was suitably dried in vacuo.

Example 247A. (-)-tert-Butyl-5-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-4-(2chloro-5-fluorophenyl)-4-methylpentanoate (enantiomer 1 ).

The separation of enantiomers described in Example 246A gave 146 mg (98% pure, ee value 99%) of the title compound as the previously eluted enantiomer.

[a] _D20 = -29.3°, 589 nm, c = 0.34 ^g /100 ml, methanol.

LC-MS (Method 1): Rt = 2.69 min; MS (ESIpos): m/z = 639/671 [M+H]+.

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.352 (16.00), 1.499 (2.16), 1.778 (0.27), 1.805 (0.23), 1.884 (0.21), 1.906 (0.23), 2.068 (0.37) . , 7.853 (0.51), 7.929 (0.99), 7.951 (0.63), 8.641 (0.36).

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.64 (t, 1H), 7.94 (d, 1H), 7.85 (dd, 1H), 7.68 (br. s, 1H), 7.577.45 (m, 6H), 7.24-7.13 (m, 2H), 4.41 (dd, 1H), 3.66 (dd, 1H), 2.71-2.60 (m, 1H), 2.15 (br. s, 3H), 2.12-2.01 (m, 1H), 1.97-1.86 (m, 1H), 1.83-1.73 (m, 1H), 1.50 (s, 3H), 1.35 (s, 9H).

Example 248A. (+)-tert-Butyl-5-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-4-(2chloro-5-fluorophenyl)-4-methylpentanoate (enantiomer 2 ).

The separation of enantiomers described in Example 246A gave 139 mg (98% pure, ee value 99%) of the title compound as the later eluted enantiomer.

[a] _D20 = +26.7°, 589 nm, c = 0.32 ^g /100 mL, methanol.

LC-MS (Method 1): Rt = 2.69 min; MS (ESIpos): m/z = 639/641 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.192 (0.07), 1.233 (0.06), 1.280 (0.16), 1.307 (0.07), 1.352 (16.00), 1.499 (1.97), 1.738 (0.10) , 1.750 (0.12), 1.766 (0.16), 1.778 (0.25), 1.789 (0.13), 1.805 (0.21), 1.817 (0.20), 1.871 (0.17), 1.883 (0.19), 1.905 (0.21), 1.918 (0.21) , 1.933 (0.12), 1.946 (0.16), 2.028 (0.23), 2.040 (0.22), 2.057 (0.26), 2.068 (0.33), 2.095 (0.24), 2.107 (0.21), 2.322 (0.09) , 2.627 (0.12), 2.659 (0.17), 2.709 (0.05), 3.632 (0.18), 3.644 (0.19), 3.665 (0.21), 3.678 (0.19), 4.382 (0.16), 4.399 (0.17), 4.415 (0.16) . , 7.836 (0.27), 7.853 (0.45), 7.858 (0.43), 7.929 (0.89), 7.951 (0.57), 8.625 (0.20), 8.640 (0.33), 8.655 (0.20).

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 8.64 (t, 1H), 7.94 (d, 1H), 7.85 (dd, 1H), 7.66 (br. s, 1H), 7.577.44 ( m, 6H), 7.23-7.13 (m, 2H), 4.41 (dd, 1H), 3.66 (dd, 1H), 2.72-2.59 (m, 1H), 2.15 (br. s, 3H), 2.13-2.02 ( m, 1H), 1.96-1.86 (m, 1H), 1.84-1.72 (m, 1H), 1.50 (s, 3H), 1.35 (s, 9H).

Example 249A. (+/-)-tert-Butyl-5-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-4-(2chloro-3,6-difluorophenyl)pentanoate (racemate )

O. NH about sleep

To a mixture of 6-bromo-3-methyl-2-phenylquinoline-4-carboxylic acid (963 mg, 2.81 mmol, you get

HATU (1.28 g, 3.38 mmol) and DIPEA (1.2 ml, 6.8 mmol) were added to DMF (10 ml) and the mixture was stirred for 15 min at RT. Then (+/-)-tert-butyl-5-amino-4-(2-chloro-3,6-difluorophenyl)pentanoate (900 mg, 2.81 mmol, example 128A) dissolved in DMF (8 ml) was added and the mixture was stirred 2 h at 60°C and then brought to RT overnight with stirring. The mixture was then mixed with ethyl acetate and water (respectively 150 ml) and shaken. After phase separation, the aqueous phase was extracted once with ethyl acetate (80 ml). The combined organic phases were washed with saturated aqueous sodium chloride (200 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 97 :3 ^ 7:3, Isolera One). The combined desired fractions were concentrated and the residue was dried in vacuo. 1.06 g (95% pure, 56% th. y.) of the title compound was obtained.

LC-MS (Method 1): Rt = 2.60 min; MS (ESIpos): m/z = 643/645 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: -0.150 (0.03), -0.009 (0.28), 0.007 (0.25), 0.145 (0.03), 0.888 (0.03), 1.156 (0.13), 1.174 (0.26), 1.192 (0.14), 1.198 (0.07), 1.255 (0.06), 1.311 (0.14), 1.358 (16.00), 1.396 (2.64) (0.22), 2.089 (0.23), 2.109 (0.21), 2.156 (1.59), 2.320 (0.10), 2.365 (0.04) (0.22) (0.16) 7.402 (0.22) (0.08), 7.841 (0.43), 7.846 (0.38), 7.863 (0.66), 7.869 (0.62), 7.936 (1.19) (0.21).

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 8.95 (t, 1H), 7.95 (d, 1H), 7.86 (dd, 1H), 7.70 (br. s, 1H), 7.567.47 ( m, 5H), 7.45-7.36 (m, 1H), 7.35-7.25 (m, 1H), 3.88-3.66 (m, 3H), 2.21-1.91 (m, 7H), 1.36 (s, 9H).

Separation of enantiomers.

The title target compound (925 mg) was dissolved in isopropanol (20 ml) and separated into enantiomers by chiral phase preparative HPLC (see examples 250A and 251A) [column: Daicel Chiralpak AD-H, 5 μm, 250 mm x 20 mm; flow: 20 ml/min; detection: 220 nm; temperature: 23°C; sample injection: 0.2 ml; eluent: 70% heptane / 30% isopropanol; isocratic].

The combined target fractions were concentrated and the corresponding residue was lyophilized in acetonitrile/water.

Example 250A. (-)-tert-Butyl-5-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-4-(2chloro-3,6-difluorophenyl)pentanoate (enantiomer 1) .

The separation of enantiomers described in Example 249A gave 289 mg (100% pure, ee value 99%) of the title compound as the previously eluted enantiomer.

R _t = 1.40 min (chiral analytical HPLC; Daicel Chiralpak AD-3, 3 µm, 50 mm x 4.6 mm, heptane/isopropanol 80:20 eluent; flow 1 ml/min; detection 220 nm).

[a] _D20 = -20.2°, 589 nm, c = 0.35 g ^/ 100 ml, chloroform.

LC-MS (Method 1): Rt = 2.63 min; MS (ESIpos): m/z = 643/645 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.310 (0.15), 1.358 (16.00), 1.979 (0.12), 2.072 (0.24), 2.088 (0.24), 2.155 (1.70), 3.719 (0.24) 3.805 (0.25), 7.302 (0.26), 7.317 (0.20), 7.400 (0.24), 7.502 (0.87), 7.510 (0.83), 7.521 (3.00), 7.841 (0.45), 7.846 (0.39), 7.863 (0.68) , 7.868 (0.64), 7.935 (1.27), 7.958 (0.78), 8.948 (0.41).

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.95 (t, 1H), 7.94 (d, 1H), 7.86 (dd, 1H), 7.71 (br. s, 1H), 7.567.48 (m, 5H), 7.45-7.36 (m, 1H), 7.35-7.26 (m, 1H), 3.90-3.66 (m, 3H), 2.23-1.89 (m, 7H), 1.36 (s, 9H).

Example 251A. (+)-tert-Butyl-5-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-4-(2chloro-3,6-difluorophenyl)pentanoate (enantiomer 2) .

The separation of enantiomers described in Example 249A gave 298 mg (97% pure, ee value 98%) of the title compound as the later eluted enantiomer.

Rt = 1.51 min (chiral analytical HPLC; Daicel Chiralpak AD-3, 3 µm, 50 mm x 4.6 mm, heptane/isopropanol 80:20 eluent; flow 1 ml/min; detection 220 nm).

[a] _D20 = +19.1°, 589 nm, c = 0.38 g/100 ml ^, chloroform.

LC-MS (Method 1): Rt = 2.63 min; MS (ESIpos): m/z = 643/645 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.846 (0.07), 0.859 (0.09), 1.087 (0.05), 1.103 (0.06), 1.199 (0.08), 1.256 (0.09), 1.312 (0.15) , 1.359 (16.00), 1.515 (0.08), 1.984 (0.14), 2.074 (0.28), 2.090 (0.28) . , 7.722 (0.07), 7.843 (0.44), 7.865 (0.68), 7.869 (0.67), 7.937 (1.19), 7.959 (0.74), 8.951 (0.47).

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 8.95 (t, 1H), 7.95 (d, 1H), 7.86 (dd, 1H), 7.72 (br. s, 1H), 7.577.47 ( m, 5H), 7.45-7.36 (m, 1H), 7.34-7.24 (m, 1H), 3.90-3.65 (m, 3H), 2.22-1.89 (m, 7H), 1.36 (s, 9H).

Example 252A. (+/-)-tert-Butyl-5-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-4-(2fluorophenyl)pentanoate (racemate)

- 109 040284

HATU (3.07 g , 8.08 mmol) and DIPEA (2.8 ml, 16 mmol) and the mixture was stirred for 30 min at RT. Then (+/-)-tert-butyl-5amino-4-(2-fluorophenyl)pentanoate (3.00 g, 60% pure, 6.73 mmol, example 129A) dissolved in DMF (15 ml) was added and the mixture was stirred overnight at 60°C. The mixture was then mixed with ethyl acetate and water (respectively 150 ml) and shaken. After phase separation, the aqueous phase was extracted once with ethyl acetate (80 ml). The combined organic phases were washed with saturated aqueous sodium chloride (200 ml), dried over sodium sulfate, filtered and concentrated, and the residue was adsorbed in dichloromethane and previously purified by flash column chromatography (100 g Biotage Snap-Cartridge Ultra silica gel, cyclohexane/ethyl acetate- gradient 97:3 ^ 7:3, Isolera One). The pooled target fractions were concentrated and the residue in acetonitrile (40 ml) was dissolved and further purified by preparative HPLC [column: Chromatorex Spring Column

C18, 5 µm, 370 mm x 100 mm; flow: 250 ml/min; detection: 210 nm; temperature: 22°C; sample entry:

ml; acetonitrile-water-gradient 1:1^9:1; duration of action 45 minutes]. The combined desired fractions were concentrated and the residue was dried in vacuo. 2.49 g (98% pure, 61% th. y.) of the title compound were obtained.

LC-MS (Method 2): Rt = 1.33 min; MS (ESIpos): m/z = 591/593 [M+H]+.

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.022 (0.16), 0.007 (0.06), 0.851 (0.03), 1.205 (0.07), 1.230 (0.37), 1.291 (0.07), 1.321 (0.08 ), 1.366 (16.00), 1.522 (0.07), 1.654 (0.02), 1.679 (0.02), 1.685 (0.03), 1.691 (0.04), 1.704 (0.03), 1.711 (0.04), 1.741 (0.09), 1.749 (0.11 ), 1.757 (0.24), 1.766 (0.12), 1.774 (0.15), 1.793 (0.16), 1.810 (0.21), 1.818 (0.19), 1.835 (0.15), 1.869 (0.04), 1.910 (0.03), 1.925 (0.03 ), 1.949 (0.03), 1.957 (0.04), 1.964 (0.03), 1.999 (0.08), 2.021 (0.17), 2.037 (0.25), 2.049 (0.25), 2.074 (1.23), 2.088 (0.95), 2.110 (0.59 ), 2.297 (0.02), 2.327 (0.02), 2.365 (0.02), 2.669 (0.01), 2.709 (0.01), 3.314 (3.22), 3.339 (0.19), 3.352 (0.19), 3.361 (0.18), 3.387 (0.07 ), 3.584 (0.08), 3.600 (0.17), 3.616 (0.08), 3.633 (0.08), 3.647 (0.15), 3.665 (0.20), 3.680 (0.25), 3.693 (0.14), 3.724 (0.12), 3.742 (0.18 ), 3.761 (0.18), 3.779 (0.15), 3.797 (0.11), 3.805 (0.06), 3.817 (0.04), 5.210 (0.02), 5.308 (0.01), 5.364 (0.03), 5.369 (0.03), 5.379 (0.03 ), 5.384 (0.03), 5.840 (0.02), 5.8 51 (0.02), 7.142 (0.23), 7.163 (0.37), 7.188 (0.45), 7.203 (0.42), 7.222 (0.30), 7.283 (0.24), 7.298 (0.24), 7.320 (0.10), 7.340 (0.05), 7.396 (0.25), 7.399 (0.25), 7.415 (0.45), 7.433 (0.22), 7.486 (0.24),7.498 (0.71), 7.505 (0.76), 7.516 (2.97), 7.527 (0.95), 7.679 (0.06), 7.829 (0.36), 7.834 (0.32), 7.851 (0.56), 7.856 (0.52), 7.926 (1.08), 7.948 (0.69), 8.850 (0.24), 8.864 (0.42), 8.878 (0.23), 11.682 (0.15).

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.86 (t, 1H), 7.93 (d, 1H), 7.84 (dd, 1H), 7.68 (br. s, 1H), 7.557.47 (m, 5H), 7.44-7.38 (m, 1H), 7.36-7.25 (m, 1H), 7.24-7.12 (m, 2H), 3.84-3.71 (m, 1H), 3.70-3.57 (m, 1H) , 3.41-3.32 (m, 1H), 2.21-1.96 (m, 6H), 1.86-1.72 (m, 1H), 1.37 (s, 9H).

Example 253A. (+/-)-tert-Butyl-5-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-4-[2(difluoromethoxy)phenyl]pentanoate (racemate)

HATU (3.36 g , 8.83 mmol) and DIPEA (3.1 ml, 18 mmol) and the mixture was stirred for 30 min at RT. (+/-)-tert-Butyl-5amino-4-[2-(difluoromethoxy)phenyl]pentanoate (2.90 g, 80% pure, 7.36 mmol, Example 130A) dissolved in DMF (15 ml) was then added and the mixture was stirred overnight at 60°C. The mixture was then mixed with ethyl acetate and water (respectively 150 ml) and shaken. After phase separation, the aqueous phase was extracted once with ethyl acetate (80 ml). The combined organic phases were washed with saturated aqueous sodium chloride (200 ml), dried over sodium sulfate, filtered and concentrated, and the residue was dissolved in acetonitrile (100 ml) at elevated temperature and purified by preparative HPLC [column: Chromatorex Spring Column C18, 5 μm, 370 mm x 100 mm; flow:

- 110 040284

250 ml/min; detection: 210 nm; temperature: 22°C; sample injection: 18 ml; acetonitrile-water-gradient

6:4 ^ 95:5; duration of action 37 minutes]. The combined desired fractions were concentrated and the residue was dried in vacuo. 4.03 g (98% pure, 84% th. y.) of the title compound was obtained.

LC-MS (Method 1): R _t = 2.56 min; MS (ESIpos): m/z = 639/641 [M+H]+.

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 1.333 (1.41), 1.356 (16.00), 1.759 (0.42), 2.060 (1.16), 2.070 (0.62), 2.076 (0.47), 2.124 (0.42) ), 6.998 (0.43), 7.156 (0.47), 7.176 (0.61), 7.183 (0.92), 7.257 (0.45), 7.368 (0.42), 7.423 (0.47), 7.427 (0.46), 7.501 (0.72), 7.508 (0.71 ), 7.520 (2.29), 7.531 (0.99), 7.534 (0.88), 7.857 (0.56), 7.862 (0.54), 7.931 (1.04), 7.953 (0.66), 8.840 (0.43).

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 8.84 (t, 1H), 7.94 (d, 1H), 7.85 (dd, 1H), 7.68 (br. s, 1H), 7.567.47 ( m, 5H), 7.43 (dd, 1H), 7.36-7.22 (m, 2H), 7.20-6.97 (m, 2H), 3.81-3.62 (m, 2H), 3.43-3.34 (m, 1H), 2.181. 98 (m, 6H), 1.92-1.79 (m, 1H), 1.36 (s, 9H).

Example 254A. (+/-)-tert-Butyl-5-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-4-(2,6difluorophenyl)pentanoate (racemate)

HATU (5.12 g , 13.5 mmol) and DIPEA (4.7 ml, 27 mmol) and the mixture was stirred for 30 min at RT. Then (+/-)-tert-butyl-5amino-4-(2,6-difluorophenyl)pentanoate (4.00 g, 80% pure, 11.2 mmol, example 131A) dissolved in DMF (20 ml) was added and the mixture was stirred for overnight at 60°C. The mixture was then mixed with ethyl acetate and water (respectively 150 ml) and shaken. After phase separation, the aqueous phase was extracted once with ethyl acetate (80 ml). The combined organic phases were washed with saturated aqueous sodium chloride solution (200 ml), dried over sodium sulfate, filtered and concentrated and the residue was dissolved in acetonitrile (100 ml) and purified by preparative HPLC [column: Chromatorex Spring Column C18, 5 μm, 370 mm x 100 mm; flow: 250 ml/min; detection: 210 nm; temperature: 22°C; sample injection: 18 ml; acetonitrile-water-gradient 6:4 ^ 95:5; duration of action 37 minutes]. The combined desired fractions were concentrated and the residue was dried in vacuo. 5.91 g (98% pure, 85% th. y.) of the title compound were obtained.

LC-MS (Method 1): R _t = 2.55 min; MS (ESIpos): m/z = 609/611 [M+H]+.

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 1.201 (0.08), 1.231 (0.03), (0.10), 1.361 (16.00), 1.518 (0.07), 1.711 (0.04), 1.742 (0.16) , 1.758 (0.40), (0.21), 1.912 (0.26), 1.936 (0.62), 2.121 (1.21), 2.141 (0.36), 3.615 (0.15), 3.647 (0.38), 3.795 (0.23), 5.314 (0.22), 7.347 (0.28), 7.365 (0.23), 1.957 (0.11), 2.026 (1.42), 2.326 (0.04), 2.365 (0.03), 3.663 (0.03), 3.701 (0.02), 5.363 (0.02), 5.378 (0.19), 7.488 (0.30), 7.499 (0.09), 2.044 (0.23), (0.02), 2.670 (0.02), (0.08), 3.715 (0.15), (0.02), 7.053 (0.56), (0.85), 7.508 (0.85) ,

1.272

1.765

2.058

3.509

3.733

7.075

7.518 (0.06), 1.297 (0.04), 1.312 (0.20), 1.774 (0.16), 1.897 (0.29), 2.079 (0.50), (0.23), 3.584 (0.16), (0.32), 3.749 (0.50), (1.05 ), 7.099 (0.65), (3.58), 7.718 (0.08),

2.105

3.600

3.761

7.329

7.836 (0.43), 7.859 (0.68), 7.930 (1.14), 7.952 (0.72), 8.934 (0.31), 8.949 (0.60), 8.963 (0.30), 11.681 (0.05).

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 8.95 (t, 1H), 7.94 (d, 1H), 7.85 (dd, 1H), 7.72 (br. s, 1H), 7.557.46 ( m, 5H), 7.39-7.29 (m, 1H), 7.08 (t, 2H), 3.85-3.67 (m, 2H), 3.57-3.45 (m, 1H), 2.22-2.01 (m, 6H), 1.981. 85 (m, 1H), 1.36 (s, 9H).

Example 255A. (+/-)-tert-Butyl-5-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-4-(2chloro-3-fluorophenyl)pentanoate (racemate)

HATU (1.37 g , 3.60 mmol) and DIPEA (1.3 ml, 7.2 mmol) and the mixture was stirred for 15 min at RT. (+/-)-tert-Butyl-5amino-4-(2-chloro-3-fluorophenyl)pentanoate (905 mg, 3.00 mmol, uncorrected purity, Example 132A) was then added,

- 111 040284 dissolved in DMF (9 ml) and the mixture was stirred for 3 hours at 60°C. The mixture was then mixed with ethyl acetate and water (respectively 100 ml) and shaken. After phase separation, the aqueous phase was extracted once with ethyl acetate (80 ml). The combined organic phases were washed with saturated aqueous sodium chloride (100 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 98 :2 ^ 8:2, Isolera One). The combined desired fractions were concentrated and the residue was dried in vacuo. Received 855 mg (97% pure, 44% theoretical. yield.) specified in the title compound.

LC-MS (Method 1): Rt = 2.59 min; MS (ESIpos): m/z = 625/627 [M+H]+.

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.151 (0.02), 0.007 (0.14), 0.144 (0.02), 0.887 (0.03), 1.156 (0.19), 1.174 (0.37), 1.192 (0.19 ), 1.206 (0.07), 1.232 (0.04), 1.284 (0.08), 1.308 (0.04), 1.328 (0.12), 1.366 (16.00), 1.395 (0.14), 1.522 (0.07), 1.786 (0.05), 1.805 (0.11 ), 1.820 (0.15), 1.837 (0.19), 1.987 (0.69), 2.018

(0.08), 2.039 (0.17), 2.052 (0.21), 2.068 (0.21), 2.095 (1.18), 2.110 (0.92), 2.131 (0.68), 2.143 (0.72), 2.265 (0.04), 2.320 (0.06), 2.365 (0.02), 2.669 (0.02), 2.709 (0.02), 3.630 (0.22), 3.661 (0.10), 3.743 (0.27), 4.002 (0.05), 4.020 (0.16), 4.038 (0.16), 4.055 (0.05), 7.142 (0.03), 7.279 (0.16), 7.299 (0.32), 7.320 (0.21), 7.362 (0.26), 7.380 (0.55), 7.396 (0.23), 7.415 (0.26), 7.430 (0.23), 7.449 (0.08), 7.476 (0.10), 7.490 (0.27), 7.499 (0.80), 7.508 (0.75), 7.519 (2.46), 7.530 (1.09), 7.646 (0.06), 7.830 (0.39), 7.836 (0.35), 7.853 (0.59), 7.858

(0.56), 7.929 (1.11), 7.951 (0.72), 8.849 (0.24), 8.863 (0.47), 8.878 (0.23).

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 8.87 (t, 1H), 7.94 (d, 1H), 7.85 (dd, 1H), 7.65 (br. s, 1H), 7.567.47 ( m, 5H), 7.46-7.35 (m, 2H), 7.34-7.26 (m, 1H), 3.74 (br. s, 2H), 3.67-3.58 (m, 1H), 2.21-2.00 (m, 6H), 1.89-1.77 (m, 1H), 1.37 (s, 9H).

Separation of enantiomers.

The title title compound (715 mg) was dissolved in methanol (30 ml) and separated into enantiomers by chiral phase preparative SLC (see Examples 256A and 257A) [column: Daicel Chiralcel OZ-H, 5 µm, 250 mm x 30 mm; flow: 80 ml/min; detection: 210 nm; temperature: 40°C; sample injection: 0.5 ml; eluent: 85% carbon dioxide/15% methanol; duration of action 12 min, isocratic]. The combined desired fractions were concentrated and the residue was dried in vacuo.

Example 256A. (-)-tert-Butyl-5-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-4-(2chloro-3-fluorophenyl)pentanoate (enantiomer 1).

The separation of enantiomers described in Example 255A gave 298 mg (100% pure, ee value 96%) of the title compound as the previously eluted enantiomer.

[a] _D20 = -5.1°, 436 nm, c = ^0.46 g/100 ml, chloroform.

LC-MS (Method 1): R _t = 2.60 min; MS (ESIpos): m/z = 625/627 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.208 (0.07), 1.286 (0.07), 1.329 (0.13), 1.368 (16.00), 1.524 (0.07), 1.821 (0.18), 1.839 (0.23) , 2.040 (0.19), 2.054 (0.23), 2.074 (0.29), 2.097 (1.32), 2.111 (1.07), 2.133 (0.84), 2.145 (0.88), 2.266 (0.04), 2.329 (0.03) . . , 7.953 (0.72), 8.852 (0.28), 8.866 (0.53), 8.880 (0.27).

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 8.87 (t, 1H), 7.94 (d, 1H), 7.85 (dd, 1H), 7.65 (br. s, 1H), 7.567.47 ( m, 5H), 7.46-7.35 (m, 2H), 7.34-7.26 (m, 1H), 3.75 (br. s, 2H), 3.67-3.58 (m, 1H), 2.22-2.00 (m, 6H), 1.89-1.76 (m, 1H), 1.37 (s, 9H).

Example 257A. (+)-tert-Butyl-5-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-4-(2chloro-3-fluorophenyl)pentanoate.

The separation of enantiomers described in Example 255A gave 310 mg (100% pure, ee value 96%) of the title compound as the later eluted enantiomer.

[a] _D20 = +8.4°, 436 nm, c = 0.47 ^g /100 mL, chloroform.

LC-MS (Method 1): R _t = 2.60 min; MS (ESIpos): m/z = 625/627 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.208 (0.07), 1.285 (0.08), 1.329 (0.15), 1.367 (16.00), 1.524 (0.07), 1.837 (0.24), 2.053 (0.25) , 2.074 (0.30), 2.096 (1.35), 2.110 (1.11), 2.132 (0.89), 2.143 (0.92), 2.328 (0.04), 2.367 (0.04), 2.671 (0.04), 3.630 (0.28), 3.743 (0.35) , 7.281 (0.20) . , 8.879 (0.27).

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 8.86 (t, 1H), 7.94 (d, 1H), 7.85 (dd, 1H), 7.65 (br. s, 1H), 7.567.47 ( m, 5H), 7.46-7.35 (m, 2H), 7.34-7.26 (m, 1H), 3.74 (br. s, 2H), 3.68-3.55 (m, 1H), 2.19-2.00 (m, 6H), 1.89-1.76 (m, 1H), 1.37 (s, 9H).

Example 258A. (+/-)-tert-Butyl-N-[2-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-1(2-chlorophenyl)ethyl]-N- methylglycinate (racemate)

- 112 040284

HATU (713 mg , 1.87 mmol) and DIPEA (650 μl, 3.7 mmol) and the mixture was stirred for 30 min at RT. Then (+/-)-tert-butyl-N-[2-amino-1-(2-chlorophenyl)ethyl]-N-methylglycinate (800 mg, 41% pure, 1.01 mmol, Example 133A) dissolved in DMF (3 ml) and the mixture was stirred overnight at 60°C. The mixture was then mixed with ethyl acetate and water (respectively 20 ml) and shaken. After phase separation, the aqueous phase was extracted twice with ethyl acetate (20 ml). The combined organic phases were washed with saturated aqueous sodium chloride, dried over sodium sulfate, filtered and concentrated, and the residue was adsorbed in dichloromethane and previously purified by flash column chromatography (100 g Biotage silica gel, cyclohexane/ethyl acetate 85:15, Isolera One). Then further purified by preparative HPLC (Method 16). The combined target fractions were concentrated and the residue was lyophilized. 150 mg (98% pure, 19% theoretical) of the title compound were obtained.

LC-MS (Method 1): Rt = 2.68 min; MS (ESIpos): m/z = 622/624 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 8.85 (br. s, 1H), 7.94 (d, 1H), 7.85 (dd, 1H), 7.72 (br. d, 2H), 7.58- 7.37 (m, 9H), 4.99 (br. s, 1H), 4.14 (br. s, 1H), 4.00 (br. s, 1H), 3.72 (br. s, 1H), 3.53 (br. s, 1H ), 2.59 (br. s, 3H), 2.10 (s, 3H), 1.43 (s, 9H).

Example 259A. (+/-)-tert-Butyl-N-[2-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-1(2-chlorophenyl)ethyl]glycinate (racemate ) o^. ν n about sn ₃ ^{V |} A^^^ ^CH s XI ^ν %ο

HATU (1.10 g , 2.89 mmol) and DIPEA (1.0 ml, 5.8 mmol) and the mixture was stirred for 30 min at RT. Then added (+/-)-tert-butyl-N[2-amino-1-(2-chlorophenyl)ethyl]glycinate (1.64 g, 50% pure, 2.89 mmol, example 134A) dissolved in DMF (4 ml) and the mixture was stirred overnight at 60°C. The mixture was then mixed with ethyl acetate and water (respectively 20 ml) and shaken. After phase separation, the aqueous phase was extracted twice with ethyl acetate (20 ml). The combined organic phases were washed with saturated aqueous sodium chloride, dried over sodium sulfate, filtered and concentrated, and the residue was adsorbed in dichloromethane and previously purified by flash column chromatography (100 g Biotage silica gel, cyclohexane/ethyl acetate 85:15, Isolera One). Then further purified by preparative HPLC (Method 16). The combined target fractions were concentrated and the residue was lyophilized. 300 mg (98% pure, 25% thor.) of the title compound were obtained.

LC-MS (Method 1): R _t = 2.45 min; MS (ESIpos): m/z = 608/610 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 8.99 (t, 1H), 8.03-7.80 (m, 3H), 7.77-7.42 (m, 9H), 4.99 (br. s, 1H), 4.18-3.99 (br. m, 2H), 3.78-3.64 (br. s, 2H), 2.09 (br. s, 3H), 1.44 (s, 9H).

Example 260A. (+/-)-ethyl-[2- {[(6-Bromo-3 -methyl-2-phenylquinolin-4-yl)carbonyl] amino }-1 -(2-chlorophenyl)ethoxy]acetate (racemate)

- 113 040284

HATU (2.11 g , 5.55 mmol) and DIPEA (2.7 ml, 16 mmol) and the mixture was stirred for 15 min at RT. Then (+/-)-ethyl-[2-amino-1(2-chlorophenyl)ethoxy]acetate-hydrochloride (1.89 g, 72% pure, 4.63 mmol, example 137A) dissolved in DMF (10 ml) was added and the mixture 1 h at 60°C was stirred and then left for 16 h at RT. The mixture was then concentrated and mixed with ethyl acetate and water (respectively 80 ml) and shaken. After phase separation, the aqueous phase was extracted twice with ethyl acetate (80 ml). The combined organic phases were washed with saturated aqueous sodium chloride (100 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. 1.11 g (92% pure, 38% th. y.) of the title compound was obtained.

LC-MS (Method 1): Rt = 2.41 min; MS (ESIpos): m/z = 581/583 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.97 (t, 1H), 7.96 (d, 1H), 7.90-7.84 (m, 2H), 7.62-7.47 (m, 7H), 7.47 -7.36 (m, 2H), 5.20 (t, 1H), 4.21-3.99 (m, 4H), 3.78 (br. s, 2H), 2.26 (s, 3H), 1.13 (t, 3H).

Separation of enantiomers.

The title title compound (1.10 g) was dissolved in ethanol-acetonitrile (60 ml) and separated into enantiomers by preparative chiral phase SLC (see Examples 261A and 262A) [column: Daicel Chiralpak AD-H, 5 µm, 250 mm x 30 mm; flow: 125 ml/min; detection: 210 nm; temperature: 38°C; sample injection: 1.6 ml; eluent: 67% carbon dioxide / 33% ethanol ^ 50% carbon dioxide / 50% ethanol; duration of action 12 minutes]. The combined desired fractions were concentrated and the residue was dried in vacuo.

Example 261A. (+)-Ethyl-[2-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-1-(2-chlorophenyl)ethoxy]acetate (enantiomer 1).

The separation of enantiomers described in Example 260A gave 440 mg (94% pure, ee value 100%) of the title compound as the previously eluted enantiomer.

[a] _D20 = +24.9°, 489 nm ^, c = 1.00 g/100 mL, methanol.

LC-MS (Method 2): Rt = 1.25 min; MS (ESIpos): m/z = 581/583 [M+H] ⁺ .

(6.76), 2.239 (0.40), 2.261 (6.37), 4.085 (6.28), 4.103

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 1.117 (6.52), 1.135 (13.59), 1.152 (16.00), 2.321 (0.41), 3.782 (1.32), 4.001 (2.96), 4.042 (5.07 ), 4.050 (2.37), 4.068

(2.07), 4.137 (4.91), 4.178 (2.81), 5.188 (1.29), 5.203 (2.36), 5.217 (1.26), 7.372 (0.70), 7.376 (0.76), 7.390 (2.05), 7.394 (2.03), 7.409 (2.14), 7.414 (2.18), 7.419 (1.71), 7.422 (1.81), 7.438 (2.33), 7.440 (2.37), 7.456 (1.05), 7.491 (3.36), 7.495 (3.57), 7.513 (7.07), 7.533 (5.81), 7.556 (6.72), 7.575 (2.46), 7.583 (3.18), 7.588 (2.62), 7.603 (2.30), 7.607 (2.01), 7.854 (2.78), 7.873 (4.22), 7.948 (4.77), 7.971 (2.98), 8.951 (1.24), 8.965

(2.55), 8.979 (1.23).

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 8.97 (t, 1H), 7.96 (d, 1H), 7.89-7.83 (m, 2H), 7.64-7.47 (m, 7H), 7.47- 7.35 (m, 2H), 5.20 (t, 1H), 4.19-3.98 (m, 4H), 3.78 (br. s, 2H), 2.26 (s, 3H), 1.13 (t, 3H).

Example 262A. (-)-Ethyl-[2-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-1-(2-chlorophenyl)ethoxy]acetate (enantiomer 2).

The separation of enantiomers described in Example 260A gave 415 mg (100% pure, ee value 100%) of the title compound as the later eluted enantiomer.

[a] _D20 = -28.3°, 489 nm, c = 1.00 ^g /100 ml, methanol.

LC-MS (Method 2): Rt = 1.25 min; MS (ESIpos): m/z = 581/583 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 0.008 (0.63), 1.056 (0.45), 1.117 (7.22), 1.135 (15.06), 1.153

4.137 (5.01), 4.177 (2.86), 5.188 (1.31), 5.202 (2.36), 5.216 7.395 (2.25), 7.409 (2.27), 7.414 (2.40), 7.419 (1.79), 7.423 7.491 (3.48), 7.495 (3.85), 7.514 (7.54), 7.534 (5.99), 7.555 7.588 (2.71), 7.602 (2.27), 7.606 (2.08), 7.855 (3.17), 7.873

(2.50), 4.068 (1.26), 7.372 (1.97), 7.438 (6.98), 7.559 (4.31), 7.948 (7.43), 1.235 (0.42), 2.261 (16.00) (2.99), 4.041 (5.13), 4.050 (6.74), 4.086 (6.66), 4.103 (2.18), (0.74), 7.376 (0.87), 7.391 (2.15) ), (5.88), 7.575 (2.51), 7.583 (3.31), (5.06), 7.971 (3.14), 8.951 (1.27), 8.965 (2.55), 8.980 (1.20).

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 8.97 (t, 1H), 7.96 (d, 1H), 7.89-7.83 (m, 2H), 7.62-7.47 (m, 7H), 7.47- 7.36 (m, 2H), 5.20 (t, 1H), 4.19-3.98 (m, 4H), 3.78 (br. s, 2H), 2.26 (s, 3H), 1.13 (t, 3H).

Example 263A. (+/-)-Methyl-{[2-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-1-(2chlorophenyl)ethyl]sulfanyl}acetate (racemate)

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HATU (2.39 g , 6.29 mmol) and DIPEA (2.2 ml, 13 mmol) and the mixture was stirred for 30 min at RT. Then (+/-)-methyl-{[2-amino1-(2-chlorophenyl)ethyl]sulfanyl}acetate (3.27 g, 50% pure, 6.29 mmol), example 138A) dissolved in DMF (4 ml) was added and the mixture was stirred overnight at 60°C. After cooling to RT, the mixture was mixed with ethyl acetate and water (respectively 20 ml) and shaken. After phase separation, the aqueous phase was extracted twice with ethyl acetate (20 ml). The combined organic phases were washed with saturated aqueous sodium chloride, dried over sodium sulfate, filtered and concentrated, and the residue was taken up in acetonitrile and prepurified by preparative HPLC (Method 16). Then further purified by flash column chromatography (340 g Biotage Snap-Cartridge KP-Sil, cyclohexane/ethyl acetate gradient 93:7^6:4, Isolera One).

The combined target fractions were concentrated and the residue was lyophilized. 388 mg (87% pure, 14% th. y.) of the title compound were obtained.

LC-MS (Method 2): R _t = 1.20 min; MS (ESIpos): m/z = 583/585 [M+H]+.

Example 264A. (+/-)-Methyl-{[2-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-1-(2chlorophenyl)ethyl]sulfonyl}acetate (racemate)

DiDG ^CH S SC NH O O

H ₃

XdX^ ⁿ XQ

HATU (83 mg , 219 µmol) and DIPEA (76 µl, 440 µmol) and the mixture was stirred for 30 min at RT. Then (+/-)-methyl-{[2-amino-1-(2-chlorophenyl)ethyl]sulfonyl}acetate hydrochloride (60 mg, 183 µmol, Example 141A) dissolved in DMF (0.5 ml) was added and the mixture was stirred overnight at 60°C. After cooling to RT, the mixture was mixed with ethyl acetate and water (respectively 150 ml) and shaken. After phase separation, the aqueous phase was extracted once with ethyl acetate (80 ml). The combined organic phases were washed with saturated aqueous sodium chloride (200 ml), dried over sodium sulfate, filtered and concentrated, and the residue was adsorbed in dichloromethane and purified by preparative HPLC (Method 17). The combined target fractions were concentrated and the residue was lyophilized. 66 mg (93% pure, 55% thor.) of the title compound were obtained.

LC-MS (Method 1): Rt = 2.04 min; MS (ESIpos): m/z = 615/617 [M+H]+.

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 9.14 (t, 1H), 7.93 (d, 1H), 7.84 (dd, 1H), 7.75-7.56 (m, 3H), 7.55-7.41 ( m, 7H), 5.75 (dd, 1H), 4.81 (d, 1H), 4.49 (d, 1H), 4.41 (td, 1H), 4.26-4.10 (m, 1H), 3.75 (s, 3H), 2.02 (br. s, 3H).

Example 265A. (+/-)-tert-Butyl-5-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-4-(6chloro-2,3-difluorophenyl)pentanoate (racemate )

HATU (829 mg , 2.18 mmol) and DIPEA (760 µl, 4.4 mmol) and the mixture was stirred for 15 min at RT. Then added (+/-)-tert

- 115 040284 butyl 5-amino-4-(6-chloro-2,3-difluorophenyl)pentanoate (600 mg, 97% pure, 1.82 mmol, example 142A) dissolved in DMF (4 ml) and the mixture was stirred for 3 h at 60°C and then 2 h at RT. The mixture was then mixed with ethyl acetate and water (respectively 100 ml) and shaken. After phase separation, the aqueous phase was extracted once with ethyl acetate (80 ml). The combined organic phases were washed with saturated aqueous sodium chloride (100 ml), dried over sodium sulfate, filtered and concentrated, and the residue was adsorbed into 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 154 mg (100% pure, 13% theoretical. yield) of the first batch of the title compound. A pre-purified fraction was then obtained, which was adsorbed in acetonitrile and further purified by preparative HPLC (Method 15). This yielded 497 mg (100% pure, 42% th. y., see Analysis section) of a second batch of the title compound.

LC-MS (Method 2): Rt = 1.37 min; MS (ESIpos): m/z = 643/645 [M+H]+.

'H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.95 (t, 1H), 7.94 (d, 1H), 7.86 (dd, 1H), 7.69 (br. s, 1H), 7.597. 47 (m, 5H), 7.46-7.32 (m, 2H), 3.81 (br. s, 2H), 3.72 (br. s, 1H), 2.22-1.93 (m, 7H), 1.36 (s, 9H).

Separation of enantiomers.

The title target compound (480 mg) was dissolved in methanol (25 ml) and separated into enantiomers by chiral phase preparative SLC (see examples 266A and 267A) [column: Daicel Chiralpak AD SFC, 5 μm, 250 mm χ 20 mm ; flow: 80 ml/min; detection: 210 nm; temperature: 40°C; sample injection: 0.2 ml; eluent: 75% carbon dioxide / 25% methanol; duration of action 4 min, isocratic]. The combined target fractions were concentrated and the residue was lyophilized.

Example 266A. (-)-tert-Butyl-5-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-4-(6chloro-2,3-difluorophenyl)pentanoate (enantiomer 1) .

The separation of enantiomers described in Example 265A gave 154 mg (100% pure, ee value 100%) of the title compound as the previously eluted enantiomer.

[a] _D20 = -32.8°, 589 nm, c = 0.29 ^g /100 ml, methanol.

LC-MS (Method 1): Rt = 2.61 min; MS (ESIpos): m/z = 643/645 [M+H] ⁺ .

'H-NMR (400 MHz, DMSO-d6) δ [ppm]: 8.95 (t, 1H), 7.94 (d, 1H), 7.86 (dd, 1H), 7.72 (br. s, 1H), 7.577.46 (m, 5H), 7.46-7.32 (m, 2H), 3.91-3.63 (m, 3H), 2.25-1.86 (m, 7H), 1.36 (s, 9H).

Example 267A. (+)-tert-Butyl-5-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-4-(6chloro-2,3-difluorophenyl)pentanoate (enantiomer 2) .

The separation of enantiomers described in Example 265A gave 162 mg (97% pure, ee value 93%) of the title compound as the later eluted enantiomer.

[a] _D20 = +28.7°, 589 nm, c = 0.39 g ^/ 100 mL, methanol.

LC-MS (Method 1): R _t = 2.60 min; MS (ESIpos): m/z = 643/645 [M+H]+.

'H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.95 (t, 1H), 7.94 (d, 1H), 7.86 (dd, 1H), 7.72 (br. s, 1H), 7.557. 46 (m, 5H), 7.46-7.33 (m, 2H), 3.89-3.65 (m, 3H), 2.25-1.86 (m, 7H), 1.36 (s, 9H).

Example 268A. (+/-)-Methyl-5-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-4-[2(trifluoromethyl)phenyl]pentanoate (racemate)

HATU (7.02 g , 18.5 mmol) and DIPEA (6.4 ml, 37 mmol) and the mixture was stirred for 30 min at RT. Then (+/-)-methyl-5-amino-4[2-(trifluoromethyl)phenyl]pentanoate (5.50 g, 77% pure, 15.4 mmol, example 143A) dissolved in DMF (30 ml) was added and the mixture was stirred for overnight at 60°C. After cooling to RT, the mixture was mixed with ethyl acetate and water (respectively 150 ml) and shaken. After phase separation, the aqueous phase was extracted once with ethyl acetate (80 ml). The combined organic phases were washed with saturated aqueous sodium chloride (200 ml), dried over sodium sulfate, filtered and concentrated, and the residue was adsorbed in dichloromethane and purified by flash column chromatography (340 g of Biotage Snap-Cartridge KP-Sil, cyclohexane/ethyl acetate gradient 97 :3 ^ 7:3, Isolera One). The combined desired fractions were concentrated and the residue was dried in vacuo. 4.31 g (96% pure, 45% th. y.) of the title compound was obtained.

LC-MS (Method 1): Rt = 2.33 min; MS (ESIpos): m/z = 599/601 [M+H] ⁺ .

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1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 8.92 (t, 1H), 7.95 (d, 1H), 7.85 (dd, 1H), 7.80-7.60 (m, 4H),

7.58-7.45 (m, 6H), 3.85-3.72 (m, 1H), 3.72-3.62 (m, 1H), 3.52 (s, 3H), 3.40-3.30 (m, 1H), 2.26-2.04 (m, 6H ),

2.02-1.89 (m, 1H).

Example 269A. (+/-)-tert-Butyl-5-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-4-(5fluoro-2-methylphenyl)pentanoate (racemate)

HATU (899 mg , 2.37 mmol) and DIPEA (820 µl, 4.7 mmol) and the mixture was stirred for 15 min at RT. Then (+/-)-tert-butyl-5-amino-4-(5-fluoro-2-methylphenyl)pentanoate (600 mg, 92% pure, 1.97 mmol, Example 144A) dissolved in DMF (4.8 ml) was added and the mixture stirred 3 h at 60°C and then two days at RT. The mixture was then mixed with ethyl acetate and water (respectively 100 ml) and shaken. After phase separation, the aqueous phase was extracted once with ethyl acetate (80 ml). The combined organic phases were washed with saturated aqueous sodium chloride (100 ml), dried over sodium sulfate, filtered and concentrated, and the residue was adsorbed into 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. 625 mg (100% pure, 52% th. y.) of the title compound were obtained.

LC-MS (Method 1): Rt = 2.61 min; MS (ESIpos): m/z = 605/607 [M+H]+.

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.889 (0.03), 1.156 (0.17), 1.174 (0.34), 1.192 (0.17), 1.207 (0.07), 1.233 (0.06), 1.303 (0.07) , 1.336 (0.11), 1.367 (16.00), 1.396 (0.60), 1.524 (0.07), 1.744 (0.05), 1.761 (0.12), 1.778 (0.15), 1.786 (0.15), 1.795 (0.19), 1.819 (0.16) , 1.834 (0.08), 1.988 (0.79), 2.001 (0.21), 2.018 (0.22), 2.038 (0.21), 2.051 (0.22), 2.069 (0.82), 2.086 (1.18), 2.104 (0.81), 2.292 (2.47) , 2.669 (0.03), 2.730 (0.08), 2.889 (0.07), 3.510 (0.11), 3.523 (0.17), 3.543 (0.19), 3.557 (0.22), 3.570 (0.13), 3.708 (0.15), 3.725 (0.22) , 3.745 (0.19), 3.759 (0.16), 3.779 (0.10), 4.002 (0.05), 4.020 (0.15), 4.038 (0.15), 4.056 (0.05) , 7.155 (0.34), 7.162 (0.35), 7.189 (0.63), 7.204 (0.37), 7.225 (0.27), 7.489 (0.25), 7.499 (0.76), 7.507 (0.72), 7.518 (2.36), 7.529 (1.05) , 7.647(0.10), 7.834(0.40), 7.839(0.37),7.856(0.60), 7.861(0.59), 7.932(1.08), 7.955(0.69), 8.829(0.23), 8.843(0.35), 8.858(0.22) .

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.84 (t, 1H), 7.94 (d, 1H), 7.85 (dd, 1H), 7.65 (br. s, 1H), 7.567.45 (m, 5H), 7.25-7.13 (m, 2H), 6.94 (td, 1H), 3.81-3.68 (m, 1H), 3.59-3.47 (m, 1H), 3.38-3.29 (m, 1H, partially hidden ), 2.29 (s, 3H), 2.18-1.94 (m, 6H), 1.86-1.72 (m, 1H), 1.37 (s, 9H).

Separation of enantiomers.

The title target compound (400 mg) in methanol (18 ml) was dissolved and separated into enantiomers by preparative SLC on a chiral phase (see examples 270A and 271A) [column: Daicel Chiralcel OX-H, 5 μm, 250 mm x 20 mm; flow: 80 ml/min; detection: 210 nm; temperature: 40°C; sample injection: 0.3 ml; eluent: 80% carbon dioxide/20% ethanol; duration of action 6 min, isocratic]. The combined target fractions were concentrated and the residue was lyophilized.

Example 270A. (-)-tert-Butyl-5-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-4-(5fluoro-2-methylphenyl)pentanoate (enantiomer 1).

The separation of enantiomers described in Example 269A gave 152 mg (100% pure, ee value 100%) of the title compound as the previously eluted enantiomer.

[a] _D20 = -13.7°, 589 nm, c = 0.38 ^g /100 ml, methanol.

LC-MS (Method 1): R _t = 2.73 min; MS (ESIpos): m/z = 605/607 [M+H]+.

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.368 (16.00), 2.070 (0.80), 2.087 (1.16), 2.105 (0.78), 2.293 (2.42), 7.190 (0.62), 7.500 (0.72) , 7.508 (0.68), 7.519 (2.28), 7.530 (1.02), 7.534 (0.89), 7.857 (0.58), 7.862 (0.57), 7.933 (1.05), 7.955 (0.68).

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 8.84 (t, 1H), 7.94 (d, 1H), 7.85 (dd, 1H), 7.65 (br. s, 1H), 7.567.46 ( m, 5H), 7.25-7.14 (m, 2H), 6.94 (td, 1H), 3.81-3.68 (m, 1H), 3.59-3.49 (m, 1H), 3.37-3.30 (1H, hidden), 2.29 ( s, 3H), 2.18-1.95 (m, 6H), 1.85-1.73 (m, 1H), 1.37 (s, 9H).

Example 271A. (+)-tert-Butyl-5-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-4-(5fluoro-2-methylphenyl)pentanoate (enantiomer 2).

The separation of enantiomers described in Example 269A gave 150 mg (100% pure, ee value 97%) of the title compound as the later eluted enantiomer.

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[a] _D20 = +16.9°, 589 nm, c = 0.37 g/100 mL ^, methanol.

LC-MS (Method 1): Rt = 2.73 min; MS (ESIpos): m/z = 605/507 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 8.84 (t, 1H), 7.94 (d, 1H), 7.85 (dd, 1H), 7.65 (br. s, 1H), 7.567.45 ( m, 5H), 7.25-7.13 (m, 2H), 6.94 (td, 1H), 3.81-3.68 (m, 1H), 3.59-3.48 (m, 1H), 3.37-3.30 (1H, hidden), 2.29 ( s, 3H), 2.17-1.95 (m, 6H), 1.85-1.72 (m, 1H), 1.37 (s, 9H).

Example 272A. (+/-)-tert-Butyl-5-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-4-[2(trifluoromethoxy)phenyl]pentanoate (racemate)

HATU (3.41 g , 8.96 mmol) and DIPEA (3.1 ml, 18 mmol) and the mixture was stirred for 30 min at RT. Then (+/-)-tert-butyl-5amino-4-[2-(trifluoromethoxy)phenyl]pentanoate (3.00 g, 83% pure, 7.47 mmol, Example 145A) dissolved in DMF (10 ml) was added and the mixture was stirred overnight at 60°C. The mixture was then mixed with ethyl acetate and water (respectively 150 ml) and shaken. After phase separation, the aqueous phase was extracted once with ethyl acetate (80 ml). The combined organic phases were washed with saturated aqueous sodium chloride (200 ml), dried over sodium sulfate, filtered and concentrated, and the residue was adsorbed in dichloromethane and purified by flash column chromatography (100 g of Biotage Snap-Cartridge KP-Sil, cyclohexane/ethyl acetate gradient 97 :3 ^ 7:3, Isolera One). The combined desired fractions were concentrated and the residue was dried in vacuo. 3.79 g (98% pure, 76% th. y.) of the title compound were obtained.

LC-MS (Method 2): R _t = 1.40 min; MS (ESIpos): m/z = 657/659 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.357 (16.00), 1.371 (0.55), 1.397 (3.24), 2.060 (0.44), 2.075 (1.67), 2.148 (0.51), 7.359 (0.52) , 7.398 (0.71), 7.408 (0.54), 7.417 (0.67), 7.504 (0.92), 7.511 (0.82),7.523 (2.03), 7.530 (1.95), 7.562 (0.55), 7.838 (0.42), 7.861 (0.65) , 7.865 (0.54), 7.937 (1.07), 7.959 (0.70), 8.875 (0.47).

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 8.87 (t, 1H), 7.95 (d, 1H), 7.85 (dd, 1H), 7.67 (br s, 1H), 7.607.47 (m , 6H), 7.46-7.31 (m, 3H), 3.81-3.58 (m, 2H), 3.46-3.34 (m, 1H), 2.21-2.02 (m, 6H), 1.89-1.76 (m, 1H), 1.36 (s, 9H).

Separation of enantiomers.

The title title compound (3.50 g) was dissolved in isopropanol (55 ml) at elevated temperature, filtered and separated into enantiomers by chiral phase preparative SLC (see Examples 273A and 274A) [column: Daicel Chiralpak OD, 20 μm, 360 mm x 50 mm; flow: 300 ml/min; detection: 210 nm; temperature: 40°C; sample injection: 1.0 ml; eluent: 80% carbon dioxide / 20% isopropanol; duration of action 7.8 min, isocratic]. The combined desired fractions were concentrated and the residue was dried in vacuo.

Example 273A. (+)-tert-Butyl-5-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-4-[2(trifluoromethoxy)phenyl]pentanoate (enantiomer 1).

Separation of enantiomers as described in Example 272A gave 1.10 g (98% pure, ee value 100%) of the title compound as the previously eluted enantiomer.

[a] _D20 = +17.0°, 589 nm, c = 0.50 g ^/ 100 mL, methanol.

LC-MS (Method 1): Rt = 2.67 min; MS (ESIpos): m/z = 657/659 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 8.88 (t, 1H), 7.95 (d, 1H), 7.85 (dd, 1H), 7.68 (br. s, 1H), 7.607.47 ( m, 6H), 7.45-7.33 (m, 3H), 3.83-3.59 (m, 2H), 3.46-3.36 (m, 1H), 2.24-2.00 (m, 6H), 1.91-1.76 (m, 1H), 1.36(s, 9H).

Example 274A. (-)-tert-Butyl-5-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-4-[2(trifluoromethoxy)phenyl]pentanoate (enantiomer 2).

The separation of enantiomers described in Example 272A gave 1.10 g (95% pure, ee value 98%) of the title compound as the later eluted enantiomer.

[a] _D20 = -19.7°, 589 nm, c = ^0.31 g/100 ml, methanol.

LC-MS (Method 1): Rt = 2.67 min; MS (ESIpos): m/z = 657/659 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 8.88 (t, 1H), 7.95 (d, 1H), 7.85 (dd, 1H), 7.67 (br. s, 1H), 7.607.47 ( m, 6H), 7.45-7.32 (m, 3H), 3.83-3.60 (m, 2H), 3.46-3.35 (m, 1H), 2.26-1.99 (m, 6H), 1.90-1.76 (m, 1H), 1.36(s, 9H).

Example 275A. (+/-)-tert-Butyl-5-{[(6-bromo-3-chloro-2-phenylquinolin-4-yl)carbonyl]amino}-4-(2- 118 040284 chlorophenyl)pentanoate (racemate)

To a mixture of 6-bromo-3-chloro-2-phenylquinoline-4-carboxylic acid (1.99 g, 5.50 mmol, uncorrected purity, obtained according to WO 2016146602 A1, page 70, example 37A) in DMF (30 ml) was added HATU (3.14 g, 8.25 mmol) and DIPEA (2.9 ml, 16 mmol) and the mixture was stirred for 20 min at RT. Then (+/-)-tert-butyl-5-amino-4-(2-chlorophenyl)pentanoate (2.34 g, 8.25 mmol, example 121A) dissolved in DMF (10 ml) was added and the mixture was stirred overnight at 60 °C After cooling to RT, the mixture was mixed with ethyl acetate and water (respectively 75 ml) and shaken. After phase separation, the aqueous phase was extracted once with ethyl acetate. 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 KP-Sil, cyclohexane/ethyl acetate gradient 97:3^85:15 , Isolera One). The combined desired fractions were concentrated and the residue was dried in vacuo. 2.17 g (98% pure, 62% th. y.) of the title compound were obtained.

LC-MS (Method 1): R _t = 2.68 min; MS (ESIpos): m/z = 627/629/631 [M+H]+.

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 9.00 (t, 1H), 8.01 (d, 1H), 7.96 (dd, 1H), 7.71-7.64 (m, 3H), 7.58-7.43 (m, 5H), 7.41-7.34 (m, 1H), 7.31-7.24 (m, 1H), 3.77-3.67 (m, 2H), 3.66-3.56 (m, 1H), 2.17-1.99 (m, 3H) , 1.90-1.76 (m, 1H), 1.36 (s, 9H).

Separation of enantiomers.

The title target compound (2.0 g) was dissolved in ethanol (15 ml) and separated into enantiomers by chiral phase preparative HPLC (see examples 276A and 277A) [column: Daicel Chiralpak IA, 5 μm, 250 mm x 30 mm; flow: 60 ml/min; detection: 240 nm; temperature: 30°C; sample injection: 0.1 ml; eluent: 80% heptane / 20% isopropanol; duration of action 7.5 min, isocratic]. The combined desired fractions were concentrated and the residue was dried in vacuo.

Example 276A. (-)-tert-Butyl-5-{[(6-bromo-3-chloro-2-phenylquinolin-4-yl)carbonyl]amino}-4-(2chlorophenyl)pentanoate (enantiomer 1).

The separation of enantiomers described in Example 275A gave 734 mg (100% pure, ee value 99%) of the title compound as the previously eluted enantiomer.

R _t = 1.45 min (chiral analytical HPLC; Daicel Chiralpak IA-3, 3 µm, 50 mm x 4.6 mm, eluent heptane/isopropanol 80:20; flow 1 ml/min; detection 220 nm).

[a] _D20 = -6.5°, 589 nm, c = 0.38 g ^/ 100 ml, methanol.

LC-MS (Method 1): R _t = 2.66 min; MS (ESIpos): m/z = 627/629/631 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 9.00 (t, 1H), 8.01 (d, 1H), 7.96 (dd, 1H), 7.71-7.63 (m, 3H), 7.58-7.42 (m, 5H), 7.38 (t, 1H), 7.31-7.22 (m, 1H), 3.79-3.67 (m, 2H), 3.65-3.54 (m, 1H), 2.15-2.00 (m, 3H), 1.92 -1.75 (m, 1H), 1.36 (s, 9H).

Example 277A. (+)-tert-Butyl-5-{[(6-bromo-3-chloro-2-phenylquinolin-4-yl)carbonyl]amino}-4-(2chlorophenyl)pentanoate (enantiomer 2).

The separation of enantiomers described in Example 275A gave 751 mg (100% pure, ee value 99%) of the title compound as the later eluted enantiomer.

R _t = 1.92 min (chiral analytical HPLC; Daicel Chiralpak IA-3, 3 µm, 50 mm x 4.6 mm, heptane/isopropanol 80:20 eluent; flow 1 ml/min; detection 220 nm).

[a] _D20 = +7.4°, 589 nm ^, c = 0.38 g/100 mL, methanol.

LC-MS (Method 1): Rt = 2.67 min; MS (ESIpos): m/z = 627/629/631 [M+H]+.

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 9.00 (t, 1H), 8.01 (d, 1H), 7.96 (dd, 1H), 7.71-7.63 (m, 3H), 7.58-7.43 (m, 5H), 7.38 (t, 1H), 7.31-7.23 (m, 1H), 3.78-3.66 (m, 2H), 3.65-3.56 (m, 1H), 2.17-2.00 (m, 3H), 1.91 -1.75 (m, 1H), 1.36 (s, 9H).

Example 278A. (+/-)-tert-Butyl-4-cyano-4-[2-(trifluoromethyl)phenyl]butanoate (racemate)

A 2M solution of LDA in THF ( 48 ml, 96 mmol), while the internal temperature was maintained between -70 and -60°C.

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The mixture was brought to 0°C and after 15 min further cooled to -70°C. A solution of tert-butyl-3-bromopropanoate (15 ml, 96 mmol) in THF (70 ml) was then slowly added dropwise with stirring at -70°C. The mixture was further stirred overnight while the cooling bath (dry ice/acetone) was slowly brought to RT. Then the mixture at approx. 0°C was slowly mixed with water (200 ml) and ethyl acetate (250 ml) 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]+.

1H-NMR (400 MHz, DMSO-d ₆ ) 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 279A. (+/-)-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 278A) in tert-butanol (200 ml) was mixed with Raney nickel ( 3.49 g, 59.5 mmol) and hydrogenated for 24 h at normal pressure. 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 280A. (+/-)-tert-Butyl-5-{[(6-bromo-3-chloro-2-phenylquinolin-4-yl)carbonyl]amino}-4-[2(trifluoromethyl)phenyl]pentanoate (racemate)

To a mixture of 6-bromo-3-chloro-2-phenylquinoline-4-carboxylic acid (500 mg, 1.38 mmol, uncorrected purity, obtained according to WO 2016146602 A1, page 70, example 37A) in DMF (6.0 ml) was added HATU (629 mg, 1.65 mmol) and DIPEA (580 µl, 3.3 mmol) and the mixture was stirred for 15 min at RT. Then (+/-)-tert-butyl-5-amino-4-[2-(trifluoromethyl)phenyl]pentanoate (535 mg, 82% pure, 1.38 mmol, Example 279A) dissolved in DMF (3 ml) was added and the mixture was stirred for 18 h at 60°C. The mixture was then mixed with ethyl acetate and water (respectively 100 ml) and shaken. After phase separation, the aqueous phase was extracted once with ethyl acetate (80 ml). The combined organic phases were washed once with saturated aqueous sodium chloride (100 ml), dried over sodium sulfate, filtered and concentrated, and the residue was 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. 324 mg (100% pure, 36% thor.) of the title compound were obtained.

LC-MS (Method 1): R _t = 2.69 min; MS (ESIpos): m/z = 661/663 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 9.06 (t, 1H), 8.03 (d, 1H), 7.97 (dd, 1H), 7.81-7.60 (m, 6H), 7.59-7.44 (m, 4H), 3.82-3.59 (m, 2H), 3.40-3.32 (m, 1H), 2.26-1.84 (m, 4H), 1.34 (s, 9H).

Separation of enantiomers.

The title target compound (228 mg) was dissolved in isopropanol (6.7 ml) and separated into enantiomers by chiral phase preparative HPLC (see examples 281A and 282A) [column: Daicel Chiralcel OZ-H, 5 µm, 250 mm x 20 mm; flow: 20 ml/min; detection: 220 nm; sample injection: 0.17 ml; eluent: 80% heptane / 20% isopropanol; duration of action 20 min, isocratic]. The combined desired fractions were concentrated and the residue was dried in vacuo.

Example 281A. (-)-tert-Butyl-5-{[(6-bromo-3-chloro-2-phenylquinolin-4-yl)carbonyl]amino}-4-[2(trifluoromethyl)phenyl]pentanoate (enantiomer 1).

The separation of enantiomers described in Example 280A gave 108 mg (100% pure, ee value 97%) of the title compound as the previously eluted enantiomer.

R _t = 1.52 min (chiral analytical HPLC; Daicel Chiralpak OZ-3, 3 µm, 50 mm x 4.6 mm, eluent heptane/isopropanol 80:20; flow 1 ml/min; detection 220 nm).

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[a] _D20 = -8.9°, 589 nm, c = ^0.45 g/100 ml, methanol.

LC-MS (Method 1): Rt = 2.68 min; MS (ESIpos): m/z = 661/663 [M+H]+.

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 9.06 (t, 1H), 8.03 (d, 1H), 7.97 (dd, 1H), 7.80-7.60 (m, 6H), 7.597.52 ( m, 3H), 7.49 (t, 1H), 3.81-3.60 (m, 2H), 3.4-3.3 (1H, hidden), 2.26-1.81 (m, 4H), 1.37-1.30 (m, 9H).

Example 282A. (+)-tert-Butyl-5-{[(6-bromo-3-chloro-2-phenylquinolin-4-yl)carbonyl]amino}-4-[2(trifluoromethyl)phenyl]pentanoate (enantiomer 2).

The separation of enantiomers described in Example 280A gave 102 mg (100% pure, ee value 97%) of the title compound as the later eluted enantiomer.

R _t = 2.57 min (chiral analytical HPLC; Daicel Chiralpak OZ-3, 3 µm, 50 mm x 4.6 mm, heptane/isopropanol 80:20 eluent; flow 1 ml/min; detection 220 nm).

[a] _D20 = +10.0°, 589 nm, c = 0.37 ^g /100 mL, methanol.

LC-MS (Method 1): Rt = 2.68 min; MS (ESIpos): m/z = 661/663 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 9.06 (t, 1H), 8.03 (d, 1H), 7.97 (dd, 1H), 7.80-7.60 (m, 6H), 7.59-7.51 (m, 3H), 7.49 (t, 1H), 3.80-3.61 (m, 2H), 3.4-3.3 (m, 1H, partially hidden), 2.25-1.82 (m, 4H), 1.371.30 (m, 9H ).

Example 283A. (+/-)-tert-Butyl-4-(2-chlorophenyl)-5-{[(6-ethynyl-3-methyl-2-phenylquinolin-4yl)carbonyl]amino}pentanoate (racemate)

To a mixture of 6-ethynyl-3-methyl-2-phenylquinoline-4-carboxylic acid (540 mg, 95% pure, 1.77 mmol, obtained according to WO 2016146602 A1, page 109, example 97A) in DMF (8 ml) was added HATU (810 mg, 2.13 mmol) and DIPEA (740 µl, 4.3 mmol) and the mixture was stirred for 15 min at RT. Then (+/-)-tert-butyl-5-amino-4-(2-chlorophenyl)pentanoate (603 mg, 83% pure, 1.77 mmol, Example 121A) dissolved in DMF (4 ml) was added and the mixture was stirred for overnight at 60°C. After cooling to RT, the mixture was mixed with ethyl acetate and water (respectively 150 ml) and shaken. After phase separation, the aqueous phase was extracted once with ethyl acetate (100 ml). The combined organic phases were washed with saturated aqueous sodium chloride (200 ml), dried over sodium sulfate, filtered and concentrated, and the residue was 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. 626 mg (100% pure, 64% thor.) of the title compound were obtained.

LC-MS (Method 1): R _t = 2.50 min; MS (ESIpos): m/z = 553 [M+H] ⁺ .

'H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.83 (t, 1H), 7.97 (d, 1H), 7.72 (dd, 1H), 7.7-7.4 (br. m, 1H), 7.56-7.48 (m, 6H), 7.44 (d, 1H), 7.37 (t, 1H), 7.26 (t, 1H), 4.42 (s, 1H), 3.86-3.50 (m, 3H), 2.26-1.97 ( m, 6H), 1.91-1.72 (m, 1H), 1.35 (s, 9H).

Separation of enantiomers.

The title title compound (481 mg) was dissolved in a mixture of ethanol (3.5 ml) and heptane (3.5 ml) and separated into enantiomers by chiral phase preparative HPLC (see Examples 284A and 285A) [column: Daicel Chiralcel OX-H , 5 µm, 250 mm x 20 mm; flow: 15 ml/min; detection: 220 nm; sample injection: 0.13 ml; eluent: 80% heptane/20% ethanol; duration of action 10 min, isocratic]. The combined target fractions were concentrated and the residue was lyophilized.

Example 284A. (-)-tert-Butyl-4-(2-chlorophenyl)-5-{[(6-ethynyl-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}pentanoate (enantiomer 1).

The separation of enantiomers described in Example 283A gave 205 mg (98% pure, ee value 99%) of the title compound as the previously eluted enantiomer.

[a] _D20 = -17.9°, 589 nm, c = 0.44 ^g /100 ml, methanol.

LC-MS (Method 1): Rt = 2.48 min; MS (ESIpos): m/z = 553 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.83 (t, 1H), 7.97 (d, 1H), 7.72 (dd, 1H), 7.7-7.4 (br. m, 1H), 7.56 -7.47 (m, 6H), 7.44 (d, 1H), 7.37 (t, 1H), 7.26 (t, 1H), 4.42 (s, 1H), 3.84-3.51 (m, 3H), 2.23-1.94 (m , 6H), 1.89–1.71 (m, 1H), 1.37 (s, 9H).

Example 285A.

(+)-tert-Butyl-4-(2-chlorophenyl)-5-{[(6-ethynyl-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}pentanoate (enantiomer 2).

The separation of enantiomers described in Example 283A gave 217 mg (100% pure, ee value 99%) of the title compound as the later eluted enantiomer.

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[a] _D20 = +15.9°, 589 nm, c = 0.44 g ^/ 100 mL, methanol.

LC-MS (Method 1): R _t = 2.48 min; MS (ESIpos): m/z = 553 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.83 (t, 1H), 7.97 (d, 1H), 7.72 (dd, 1H), 7.7-7.4 (br. m, 1H), 7.56 -7.48 (m, 6H), 7.44 (d, 1H), 7.37 (t, 1H), 7.26 (t, 1H), 4.41 (s, 1H), 3.84-3.52 (m, 3H), 2.24-1.98 (m , 6H), 1.90-1.74 (m, 1H), 1.37 (s, 9H).

Example 286A. (+/-)-tert-Butyl-5-{[(6-bromo-3-chloro-2-phenylquinolin-4-yl)carbonyl]amino}-4-(2chloro-3,6-difluorophenyl)pentanoate (racemate )

To a mixture of 6-bromo-3-chloro-2-phenylquinoline-4-carboxylic acid (500 mg, 1.38 mmol, uncorrected purity, obtained according to WO 2016146602 A1, page 70, example 37A) in DMF (6.0 ml) was added HATU (629 mg, 1.65 mmol) and DIPEA (580 µl, 3.3 mmol) and the mixture was stirred for 15 min at RT. (+/-)-tert-Butyl-5-amino-4-(2-chloro-3,6-difluorophenyl)pentanoate (548 mg, 81% pure, 1.38 mmol, Example 128A) dissolved in DMF (3 ml) and the mixture was stirred for 3 h at 60°C at RT. After cooling to RT, the mixture was mixed with ethyl acetate and water (respectively 100 ml) and shaken. After phase separation, the aqueous phase was extracted once with ethyl acetate (80 ml). The combined organic phases were washed once with saturated aqueous sodium chloride (100 ml), dried over sodium sulfate, filtered and concentrated, and the residue was 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. 296 mg (100% pure, 32% thor.) of the title compound were obtained.

LC-MS (Method 1): R _t = 2.67 min; MS (ESIpos): m/z = 663/665/667 [M+H] ⁺ .

'H-NMR (400 MHz, DMSO-d6) δ [ppm]: 9.10 (t, 1H), 8.02 (d, 1H), 7.98 (dd, 1H), 7.75-7.63 (m, 3H), 7.59-7.50 (m, 3H), 7.41 (td, 1H), 7.30 (td, 1H), 3.91-3.63 (m, 3H), 2.23-1.86 (m, 4H), 1.36 (s, 9H).

Separation of enantiomers.

The title target compound (215 mg) was dissolved in ethanol (6 ml) and separated into enantiomers by chiral phase preparative HPLC (see examples 287A and 288A) [column: Daicel Chiralpak AD-H, 5 μm, 250 mm x 30 mm; flow: 40 ml/min; detection: 240 nm; temperature: 30°C; sample injection: 0.35 ml; eluent: 80% heptane / 20% isopropanol; isocratic]. The combined target fractions were concentrated and the residue was lyophilized in acetonitrile/water.

Example 287A. (-)-tert-Butyl-5-{[(6-bromo-3-chloro-2-phenylquinolin-4-yl)carbonyl]amino}-4-(2-chloro3,6-difluorophenyl)pentanoate (enantiomer 1) .

The separation of enantiomers described in Example 286A gave 66 mg (96% pure, ee value 99%) of the title compound as the previously eluted enantiomer.

R _t = 1.28 min (chiral analytical HPLC; Daicel Chiralpak AD 3 µm, 50 mm x 4.6 mm, eluent heptane/isopropanol 80:20; flow 1 ml/min; detection 220 nm).

[a] _D20 = -27.1°, 589 nm, c = 0.38 ^g /100 ml, methanol.

LC-MS (Method 1): R _t = 2.64 min; MS (ESIpos): m/z = 663/665/667 [M+H] ⁺ .

'H-NMR (400 MHz, DMSO-d6) δ [ppm]: 9.10 (t, 1H), 8.02 (d, 1H), 7.98 (dd, 1H), 7.77-7.61 (m, 3H), 7.597.50 (m, 3H), 7.41 (td, 1H), 7.30 (td, 1H), 3.91-3.65 (m, 3H), 2.22-2.04 (m, 3H), 1.98 (br. s, 1H), 1.36 (s , 9H).

Example 28 8A. (+)-tert-Butyl-5 - {[(6-bromo-3 -chloro-2-phenylquinolin-4-yl)carbonyl]amino}-4-(2chloro-3,6-difluorophenyl)pentanoate (enantiomer 2) .

The separation of enantiomers described in Example 286A gave 64 mg (92% pure, ee value 98%) of the title compound as the later eluted enantiomer.

R _t = 1.42 min (chiral analytical HPLC; Daicel Chiralpak AD 3 µm, 50 mm x 4.6 mm, eluent heptane/isopropanol 80:20; flow 1 ml/min; detection 220 nm).

[a] _D20 = +24.9°, 589 nm, c = 0.38 g ^/ 100 mL, methanol.

LC-MS (Method 1): Rt = 2.65 min; MS (ESIpos): m/z = 663/665/667 [M+H] ⁺ .

'H-NMR (400 MHz, DMSO-d6) δ [ppm]: 9.10 (t, 1H), 8.02 (d, 1H), 7.98 (dd, 1H), 7.75-7.62 (m, 3H), 7.59-7.50 (m, 3H), 7.41 (td, 1H), 7.30 (td, 1H), 4.17-3.64 (m, 3H, partially hidden), 2.24-2.03 (m, 3H), 1.98 (br. s, 1H), 1.36(s, 9H).

Example 289A. (+/-)-tert-Butyl-5-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-4(pyridin-2-yl)pentanoate (racemate)

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6-Bromo-3-methyl-2-phenylquinoline-4-carboxylic acid (213 mg, 622 µmol, prepared according to WO 2016146602 A1, page 70, example 37A) was adsorbed in DMF (7 ml) and mixed with HATU (284 mg , 747 µmol). After 5 min stirring at RT under nitrogen atmosphere, DIPEA (330 μl, 1.9 mmol) was added and the mixture was further stirred for 30 min at RT. Then (+/-)-tert-butyl-5-amino-4(pyridin-2-yl)pentanoate (187 mg, 747 µmol, example 146A, uncorrected purity) was dissolved in 20 ml of DMF and added to the reaction mixture. The mixture was further stirred for 2 h at RT. The reaction mixture was directly (without further workup) purified by chromatography (Biotage Isolera Four, LiChroprep RP-18 (40-63 µm); gradient 30% ^ 90% acetonitrile in 0.1% aqueous ammonia). 100 mg (80% pure, 1% theoretical yield in 3 steps) of the title compound were obtained.

LC-MS (Method 6): Rt = 1.43 min; MS (ESIpos): m/z = 574/576 [M+H] ⁺ .

Example 290A. (+/-)-tert-Butyl-5-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-4-[2fluoro-6-(trifluoromethyl)phenyl]pentanoate ( racemate)

HATU (1.25 g, 3.29 mmol) and DIPEA (1.1 ml, 6.6 mmol). The mixture was stirred for 15 min at RT. Added a solution of (+/-)-tert-butyl-5-amino-4-[2-fluoro-6-(trifluoromethyl)phenyl]pentanoate (1.00 g, 92% pure, 2.74 mmol, Example 147A) in a small amount of DMF and the reaction mixture stirred for 1 h at 60°C, then another 30 min at RT. The mixture was mixed with 200 ml each of water and ethyl acetate. The phases are separated. The organic phase was washed with 200 ml of water, then with 200 ml of saturated sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. The residue was dissolved in a small amount of DMSO and purified by preparative HPLC (Method 28). The appropriate fractions were concentrated together and dried in vacuo. 1.29 g (93% pure, 66% th. y.) of the title compound was obtained.

LC-MS (Method 1): R _t = 2.64 min; MS (ESIpos): m/z = 659/661 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 8.95 (t, 1H), 7.95 (d, 1H), 7.85 (dd, 1H), 7.80-7.45 (m, 9H), 3.93 (br. s, 1H), 3.74 (br. s, 1H), 3.33 (1H, latent, experimental), 2.28-2.00 (m, 7H), 1.34 (s, 9H).

Separation of enantiomers.

The racemate thus obtained (1.2 g) was dissolved in 140 ml of acetonitrile and a small amount of methanol and portionwise separated into enantiomers by preparative SLC on a chiral phase (see Examples 291A and 292A) [Method: Daicel Chiralpak AD-H column 5 µm, 250 mm x 20 mm; eluent carbon dioxide/isopropanol 80:20 isocratic; flow 80 ml/min; temperature 40°C; detection 210 nM]. The combined target fractions were concentrated and the residue was lyophilized in acetonitrile/water.

Example 291A. tert-Butyl 5-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-4-[2-fluoro-6(trifluoromethyl)phenyl]pentanoate (enantiomer 1).

The separation of enantiomers described in Example 290A gave 444 mg (97% pure, ee value 100%) of the title compound as the previously eluted enantiomer.

R _t = 1.41 min (chiral analytical HPLC; Daicel Chiralpak AD 3 µm, 100 mm x 4 mm, eluent carbon dioxide/isopropanol 80:20; flow 3 ml/min; temperature 40°C; detection 210 nm).

LC-MS (Method 1): Rt = 2.62 min; MS (ESIpos): m/z = 659/661 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (0.41), 1.030 (1.89), 1.046 (1.90), 1.336 (16.00), 2.086 (0.51), 2.107 (0.49), 2.125 (0.65 ), 2.152 (0.53), 2.167 (0.49), 7.507 (0.85), 7.513 (0.68), 7.525 (1.40), 7.538 (1.61), 7.555 (0.43), 7.562 (0.47), 7.573 (0.50), 7.595 (0.46 ), 7.861 (0.58), 7.867 (0.57), 7.939 (1.06), 7.961 (0.69).

- 123 040284

Example 292A. tert-Butyl 5-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-4-[2-fluoro-6(trifluoromethyl)phenyl]pentanoate (enantiomer 2).

The separation of enantiomers described in Example 290A gave 416 mg (97% pure, ee value 100%) of the title compound as the later eluted enantiomer.

Rt = 2.01 min (chiral analytical HPLC; Daicel Chiralpak AD 3 µm, 100 mm x 4 mm, carbon dioxide/isopropanol 80:20 eluent; flow 3 ml/min; temperature 40°C; detection 210 nm).

LC-MS (Method 1): Rt = 2.62 min; MS (ESIpos): m/z = 659 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: -0.008 (0.56), 0.008 (0.56), 1.030 (1.54), 1.045 (1.55), 1.336 (16.00), 2.085 (0.51), 2.107 ( 0.48), 2.124 (0.65), 2.152 (0.53), 2.167 (0.49), 7.506 (0.83), 7.513 (0.67), 7.524 (1.38), 7.537 (1.60), 7.555 (0.43), 7.562 (0.46), 7.573 0.51), 7.594 (0.46), 7.861 (0.58), 7.867 (0.58), 7.938 (1.06), 7.961 (0.68).

Example 293A. (+/-)-tert-Butyl-5-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-4(2,3,5,6-tetrafluorophenyl)pentanoate ( racemate)

HATU (791 mg , 2.08 mmol) and DIPEA (720 µl, 4.2 mmol). The mixture was stirred for 15 min at RT. A solution of (+/-)-tert-butyl-5-amino-4-(2,3,5,6-tetrafluorophenyl)pentanoate (586 mg, 95% pure, 1.73 mmol, Example 148A) in a small amount of DMF was added and the reaction mixture was stirred 1 h at 60°C, then further overnight at RT. The mixture was mixed with 100 ml each of water and ethyl acetate. The phases are separated. The aqueous phase was extracted with 100 ml of ethyl acetate. The combined organic phases were washed with 200 ml of saturated sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. The residue was dissolved in a small amount of DMSO and purified by preparative HPLC (Method 28). The combined desired fractions were concentrated and the residue was dried in vacuo. 700 mg (100% pure, 63% th. y.) of the title compound were obtained.

LC-MS (Method 1): Rt = 2.56 min; MS (ESIpos): m/z = 645/647 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (0.52), 0.008 (0.56), 1.366 (16.00), 2.073 (0.62), 2.156 (1.15), 2.178 (0.49), 2.196 (0.50 ), 2.212 (0.40), 2.228 (0.44), 3.789 (0.44), 3.805 (0.64), 7.506 (0.79), 7.513 (0.77), 7.524 (2.69), 7.535 (1.15), 7.539 (1.01), 7.849 (0.47 ), 7.854 (0.43), 7.871 (0.67), 7.877 (0.67), 7.941 (1.24), 7.964 (0.76), 8.981 (0.50).

Separation of enantiomers.

The title title compound (658 mg) was dissolved in methanol (30 ml) and separated into enantiomers by chiral phase preparative SLC (see Examples 294A and 295A) [column: Saule Daicel Chiralpak AD-H 5 µm, 250 mm x 20 mm; eluent carbon dioxide/isopropanol 80:20 isocratic; flow 80 ml/min; temperature 40°C; detection 210 nm; isocratic]. The combined target fractions were concentrated and the residue was lyophilized in acetonitrile/water.

Example 294A. tert-Butyl 5-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-4-(2,3,5,6tetrafluorophenyl)pentanoate (enantiomer 1).

The separation of enantiomers described in Example 293A gave 266 mg (100% pure, ee value 100%) of the title compound as the previously eluted enantiomer.

R _t = 1.37 min (chiral analytical HPLC; Daicel Chiralpak AD 3 µm, 100 mm x 4 mm, eluent carbon dioxide/isopropanol 80:20; flow 3 ml/min; temperature 40°C; detection 210 nm).

Example 295A. tert-Butyl 5-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-4-(2,3,5,6tetrafluorophenyl)pentanoate (enantiomer 2).

The separation of enantiomers described in Example 293A gave 275 mg (99% pure, ee value 99%) of the title compound as the later eluted enantiomer.

R _t = 1.67 min (chiral analytical HPLC; Daicel Chiralpak AD 3 µm, 100 mm x 4 mm, eluent carbon dioxide/isopropanol 80:20; flow 3 ml/min; temperature 40°C; detection 210 nm).

Example 296A. (+/-)-tert-Butyl-5-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-4(2,3,5-trifluorophenyl)pentanoate (racemate)

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HATU (289 mg, 760 µmol) and DIPEA (260 µl, 1.5 mmol). The mixture was stirred for 15 min at RT. A solution of (+/-) tert-butyl-5-amino-4-(2,3,5-trifluorophenyl)pentanoate (200 mg, 96% pure, 633 µmol, Example 149A) in a small amount of DMF was added and the reaction mixture was stirred 3 h at 60°C. The mixture was mixed with water and ethyl acetate (respectively 100 ml). The phases are separated. The aqueous phase was extracted with ethyl acetate (50 ml). The combined organic phases were washed with saturated sodium chloride solution (100 ml), dried over sodium sulfate and concentrated in vacuo. The residue was dissolved in a small amount of dichloromethane and purified by flash chromatography (Biotage, 50 g silica gel, cyclohexane/ethyl acetate gradient 100:0^80:20). Pure fractions according to DC were concentrated and the residue was dried in vacuo. Received 115 mg (100% pure, 29% theoretical yield, see section Analysis) of the first batch of the title compound. The resulting impure fraction was concentrated and the residue was purified by preparative HPLC (Method 32). The combined desired fractions were concentrated and the residue was dried in vacuo. Received 25 mg (100% pure, 6% theoretical. yield) of the second batch of the title compound.

LC-MS (Method 1): Rt = 2.56 min; MS (ESIpos): m/z = 627/629 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 1.371 (16.00), 1.398 (9.99), 1.826 (0.18), 2.038 (0.21), 2.127 (0.89), 3.413 (0.18), 3.714 (0.27 ), 7.233 (0.22), 7.413 (0.17), 7.504 (0.77), 7.512 (0.75), 7.523 (2.51), 7.839 (0.38), 7.844 (0.35), 7.861 (0.58), 7.866 (0.56), 7.935 (1.13 ), 7.957 (0.72), 8.889 (0.46).

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.89 (t, 1H), 7.94 (d, 1H), 7.85 (dd, 1H), 7.66 (br. s, 1H), 7.557.48 (m, 5H), 7.46-7.34 (m, 1H), 7.30-7.17 (m, 1H), 3.86-3.63 (m, 2H), 3.48-3.37 (m, 1H), 2.23-1.93 (m, 6H) , 1.90–1.75 (m, 1H), 1.37 (s, 9H).

Separation of enantiomers.

The title title compound (108 mg) was dissolved in methanol (12 ml) and separated into enantiomers by chiral phase preparative SLC (see Examples 297A and 298A) [column: Saule Daicel Chiralpak AD-H 5 µm, 250 mm x 20 mm; eluent carbon dioxide/isopropanol 80:20 isocratic; flow 80 ml/min; temperature 40°C; detection 210 nm; isocratic]. The combined target fractions were concentrated and the residue was lyophilized in acetonitrile/water.

Example 297A. tert-Butyl 5-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-4-(2,3,5trifluorophenyl)pentanoate (enantiomer 1).

The separation of enantiomers described in Example 296A gave 39 mg (97% pure, ee value 100%) of the title compound as the previously eluted enantiomer.

R _t = 0.82 min (chiral analytical HPLC; Daicel Chiralpak AD 3 µm, 100 mm x 4 mm, eluent carbon dioxide/isopropanol 75:25; flow 3 ml/min; temperature 40°C; detection 210 nm)

Example 298A. tert-Butyl 5-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-4-(2,3,5trifluorophenyl)pentanoate (enantiomer 2).

The separation of enantiomers described in Example 296A gave 41 mg (99% pure, ee value 99%) of the title compound as the later eluted enantiomer.

R _t = 1.03 min (chiral analytical HPLC; Daicel Chiralpak AD 3 µm, 100 mm x 4 mm, eluent carbon dioxide/isopropanol 75:25; flow 3 ml/min; temperature 40°C; detection 210 nm).

Example 299A. (+/-)-tert-Butyl-5 - {[(6-bromo-3 -methyl-2-phenylquinolin-4-yl)carbonyl]amino}-4(2,3,6-trichlorophenyl)pentanoate (racemate)

HATU (806 mg, 2.12 mmol) and DIPEA (740 µl, 4.2 mmol). The mixture was stirred for 15 min at RT. A solution of (+/-)-tert-125 040284 butyl-5-amino-4-(2,3,6-trichlorophenyl)pentanoate (700 mg, 89% pure, 1.77 mmol, Example 150A) in a small amount of DMF was added and reaction the mixture was stirred 1 h at 60°C and then 30 min at RT. The mixture was mixed with water and ethyl acetate (respectively 100 ml). The phases are separated. The organic phase was washed with water (200 ml) and then with saturated aqueous sodium chloride solution (200 ml), dried over sodium sulfate and concentrated in vacuo. The residue was dissolved in a small amount of DMSO and purified by preparative HPLC (Method 28). The combined target fractions were concentrated in vacuo and the residue was dried in vacuo. 745 mg (100% pure, 62% thor.) of the title compound were obtained.

LC-MS (Method 1): R _t = 2.78 min; MS (ESIpos): m/z = 675/677/679 [M+H]+.

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: -0.008 (1.61), 0.008 (1.78), 1.331 (0.43), 1.349 (15.88), 1.353 (16.00), 2.073 (1.05), 2.092 ( 0.49), 2.106 (0.54), 2.120 (0.68), 2.133 (1.11), 2.146 (1.43), 2.163 (1.36), 2.179 (3.06), 2.523 (0.43), 4.067 (0.43), 4.090 (0.45), 7.472 ( 0.45), 7.494 (0.94), 7.504 (1.43), 7.509 (1.14), 7.512 (1.16), 7.528 (4.20), 7.550 (1.61), 7.582 (0.54), 7.591 (0.58), 7.604 (0.41), 0.50), 7.847 (0.60), 7.864 (0.75), 7.869 (0.95), 7.876 (0.57), 7.935 (1.21), 7.942 (1.11), 7.958 (0.77), 7.964 (0.67), 8.920 (0.47), 8.935 ( 0.54).

Separation of enantiomers.

The title target compound (604 mg) was dissolved in isopropanol (12 ml) and separated into enantiomers by chiral phase preparative HPLC (see examples 300A and 301A) [column: Daicel Chiralpak IE, 5 μm, 250 mm x 20 mm; eluent heptane/isopropanol 80:20 isocratic; flow 15 ml/min; temperature 40°C; detection at 220 nm, duration of action 18 min]. The combined target fractions were concentrated and the residue was lyophilized, respectively, in acetonitrile/water.

Example 300A. tert-Butyl 5-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-4-(2,3,6trichlorophenyl)pentanoate (enantiomer 1).

The separation of enantiomers described in Example 299A gave 321 mg (93% pure, ee value 96%) of the title compound as the previously eluted enantiomer.

R _t = 7.19 min (chiral analytical HPLC; Daicel Chiralpak IE 5 µm, 250 mm x 4.6 mm, eluent heptane/0.2% diethylamine in isopropanol 50:50, isocratic; flow 1 ml/min; temperature 40°C; detection 210 nm ).

Example 301 tert-Butyl 5-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-4-(2,3,6trichlorophenyl)pentanoate (enantiomer 1)

The separation of enantiomers described in Example 299A gave 291 mg (99% pure, ee value 100%) of the title compound as the later eluted enantiomer.

R _t = 8.98 min (chiral analytical HPLC; Daicel Chiralpak IE 5 µm, 250 mm x 4.6 mm, eluent heptane/0.2% diethylamine in isopropanol 50:50, isocratic; flow 1 ml/min; temperature 40°C; detection 210 nm ).

Example 302A. (+/-)-tert-Butyl-6-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-5-(2chlorophenyl)hexanoate (racemate)

HATU (1.37 g , 3.60 mmol) and DIPEA (1.3 ml, 7.2 mmol) and the mixture was stirred for 15 min at RT. Then (+/-)-tert-butyl-6amino-5-(2-chlorophenyl)hexanoate (893 mg, 3.00 mmol, example 151A) dissolved in DMF (9 ml) was added and the mixture was stirred for 3 h at 60°C. The mixture was then mixed with ethyl acetate and water (respectively 100 ml) and shaken. After phase separation, the aqueous phase was extracted twice with ethyl acetate (80 ml). The combined organic phases were washed with saturated aqueous sodium chloride (100 ml), dried over sodium sulfate, filtered and concentrated, and the residue was adsorbed in dichloromethane and purified by flash column chromatography (100 g of Biotage Snap-Cartridge ultra silica gel, cyclohexane/ethyl acetate 98:2 ^ 8:2, Isolera One). 1.19 g (93% pure, 59% th. y.) of the title compound was obtained.

LC-MS (Method 1): R _t = 2.66 min; MS (ESIpos): m/z = 621/623 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 8.84 (t, 1H), 7.94 (d, 1H), 7.85 (dd, 1H), 7.72 (br. s, 1H), 7.567.41 ( m, 7H), 7.41-7.17 (m, 2H), 3.70 (br. s, 2H), 3.62-3.52 (m, 1H), 2.25-2.05 (m, 5H), 1.86-1.70 (m, 1H), 1.69-1.55 (m, 1H), 1.54-1.30 (m, 2H), 1.35 (s, 9H).

- 126 040284

Separation of enantiomers.

The title title compound (1.06 g) was dissolved in methanol (50 ml) and separated into enantiomers by chiral phase preparative SLC (see examples 303A and 304A) [column: Daicel Chiralcel OJ-H, 5 µm, 250 mm x 30 mm; flow: 100 ml/min; detection: 210 nm; temperature: 38°C; sample injection: 1.0 ml; eluent: 82% carbon dioxide/18% methanol^67% carbon dioxide/33% methanol; duration of action 11 minutes]. The combined target fractions were concentrated and the corresponding residue was dried in vacuo.

Example 303A. tert-Butyl 6-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-5-(2-chlorophenyl)hexanoate (enantiomer 1).

The separation of enantiomers described in Example 302A gave 480 mg (100% pure, ee value 100%) of the title compound as the previously eluted enantiomer.

R _t = 0.90 min (chiral analytical HPLC; Daicel Chiralpak OJ-3, 3 µm, 100 mm x 4.6 mm, eluent carbon dioxide/methanol 8:2, isocratic; flow 3 ml/min; pressure 130 bar, temperature 40°C ; detection at 210 nm).

LC-MS (Method 1): R _t = 2.67 min; MS (ESIpos): m/z = 621/623 [M+H]+.

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.149 (0.03), 0.146 (0.03), 1.194 (0.07), 1.320 (0.16), 1.354 (16.00), 1.398 (0.17), 1.421 (0.14 ), 1.438 (0.18), 1.448 (0.18), 1.463 (0.20), 1.480 (0.15), 1.496 (0.09), 1.511 (0.11), 1.576 (0.08), 1.609 (0.19), 1.622 (0.17), 1.634 (0.20 ), 1.732 (0.19), 1.745 (0.20), 1.759 (0.20), 1.792 (0.11), 2.145 (0.99), 2.165 (0.66), 2.171 (0.59), 2.183 (0.80), 2.189 (0.76), 2.201 (0.39 ), 2.207 (0.38), 2.229 (0.08), 2.328 (0.04), 2.366 (0.04), 2.670 (0.04), 2.710 (0.03), 3.581 (0.25), 3.597 (0.22), 3.701 (0.39), 7.236 (0.19 ), 7.254 (0.40), 7.273 (0.28), 7.298 (0.08), 7.317 (0.06), 7.350 (0.24), 7.369 (0.43), 7.387 (0.23), 7.433 (0.65), 7.453 (0.54), 7.478 (0.65 ), 7.499 (1.20), 7.507 (0.82), 7.519 (2.58), 7.719 (0.09), 7.833 (0.38), 7.838 (0.36), 7.856 (0.58), 7.860 (0.57), 7.930 (1.03), 7.953 (0.66 ), 8.832 (0.24), 8.846 (0.48), 8.859 (0.24).

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.85 (t, 1H), 7.94 (d, 1H), 7.85 (dd, 1H), 7.72 (br. s, 1H), 7.567.42 (m, 7H), 7.40-7.20 (m, 2H), 3.70 (br. s, 2H), 3.63-3.50 (m, 1H), 2.24-2.08 (m, 5H), 1.88-1.71 (m, 1H) , 1.69-1.54 (m, 1H), 1.53-1.30 (m, 2H), 1.35 (s, 9H).

Example 304A. tert-Butyl 6-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-5-(2chlorophenyl)hexanoate (enantiomer 2).

The separation of enantiomers described in Example 302A gave 438 mg (100% pure, ee value 100%) of the title compound as the later eluted enantiomer.

R _t = 3.05 min (chiral analytical HPLC; Daicel Chiralpak OJ-3, 3 µm, 100 mm x 4.6 mm, eluent carbon dioxide/methanol 8:2, isocratic; flow 3 ml/min; pressure 130 bar, temperature 40°C ; detection at 210 nm).

LC-MS (Method 1): R _t = 2.68 min; MS (ESIpos): m/z = 621/623 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.194 (0.07), 1.354 (16.00), 1.420 (0.16), 1.462 (0.21), 1.480 (0.16), 1.510 (0.11), 1.609 (0.19) , 1.633 (0.21), 1.731 (0.19), 1.757 (0.21), 2.144 (1.03), 2.164 (0.69), 2.182 (0.84), 2.188 (0.79), 2.200 (0.42), 2.327 (0.06), 2.669 (0.05) . . , 7.952 (0.67), 8.829 (0.26), 8.844 (0.49), 8.857 (0.25).

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.84 (t, 1H), 7.94 (d, 1H), 7.85 (dd, 1H), 7.71 (br. s, 1H), 7.577.42 (m, 7H), 7.37 (t, 1H), 7.26 (t, 1H), 3.70 (br. s, 2H), 3.63-3.51 (m, 1H), 2.26-2.06 (m, 5H), 1.85-1.70 (m, 1H), 1.69-1.55 (m, 1H), 1.53-1.30 (m, 2H), 1.35 (s, 9H).

Example 305A. (+/-)-tert-Butyl-6-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-5-(2chlorophenyl)-5-methylhexanoate (racemate)

HATU (1.19 g , 3.14 mmol) and DIPEA (1.1 ml, 6.3 mmol) and the mixture was stirred for 15 min at RT. (+/-)-tert-butyl-6-amino-5-(2-chlorophenyl)-5-methylhexanoate (816 mg, 2.62 mmol, example 152A, uncorrected purity) was then added, mixed with (+/-)-tert- butyl 6-amino-5-methyl-5-phenylhexanoate) dissolved in DMF (8 ml) and the mixture was stirred 3 h at 60° C. and then 18 h at RT. The mixture was then mixed with ethyl acetate and water (respectively 150 ml) and shaken. After phase separation, the aqueous phase was extracted twice with ethyl acetate (80 ml). The combined organic phases were washed with saturated aqueous chloride solution for

- 127 040284 triium (200 ml), dried over sodium sulfate, filtered and concentrated and the residue was adsorbed in dichloromethane and purified by flash column chromatography (100 g of Biotage Snap-Cartridge KP-Sil silica gel, cyclohexane/ethyl acetate 97:3 ^ 7: 3, Isolera One). After concentration and drying of the residues in vacuo, two mixed fractions were obtained containing the title compound respectively in a mixture with the dechlorinated product (tert-butyl-6-{[(6-bromo-3-methyl-2-phenylquinolin-4yl)carbonyl]amino }-5-methyl-5-phenylhexanoate). The first mixed fraction (866 mg) was used for the corresponding subsequent reaction (see example 240). The second mixed fraction (386 mg) was dissolved in a mixture of DMSO, acetonitrile and THF and purified by preparative HPLC (Method 15). The combined target fractions were concentrated and the residues were lyophilized. 161 mg (100% pure) of the title compound were obtained. In addition, 148 mg (97% pure) of the dechlorinated product (tert-butyl-6-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-5methyl-5-phenylhexanoate , see example 306A).

LC-MS (Method 1): Rt = 2.76 min; MS (ESIpos): m/z = 635/637 [M+H]+.

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.074 (0.18), 1.359 (16.00), 1.526 (2.00), 1.618 (0.24), 2.118 (0.75), 2.136 (1.16), 2.154 (0.58) , 2.394 (0.20), 3.672 (0.21), 3.693 (0.22), 4.298 (0.36), 4.316 (0.38) , 7.327 (0.20), 7.411 (0.44), 7.430 (0.78), 7.446 (0.42), 7.498 (0.93), 7.506 (0.92), 7.517 (2.01), 7.828 (0.37), 7.850 (0.53), 7.855 (0.48) , 7.924 (0.98), 7.946 (0.60), 8.599 (0.40).

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.60 (t, 1H), 7.93 (d, 1H), 7.84 (dd, 1H), 7.69 (br. s, 1H), 7.56-7.47 (m, 5H), 7.46-7.38 (m, 2H), 7.34-7.23 (m, 2H), 4.32 (dd, 1H), 3.68 (dd, 1H), 2.42-2.32 (m, 1H), 2.22-2.02 (m, 5H), 1.62 (td, 1H), 1.53 (s, 3H), 1.4-1.3 (m, 1H, partially hidden), 1.39 (s, 3H), 1.36 (s, 9H), 1.14-0.99 ( m, 1H).

Example 306A. (+/-)-tert-Butyl-6- {[(6-bromo-3 -methyl-2-phenylquinolin-4-yl)carbonyl] amino }-5 methyl-5-phenylhexanoate (racemate)

As described in Example 305A, 148 mg (97% pure) of the title compound was obtained. LC-MS (Method 1): Rt = 2.70 min; MS (ESIpos): m/z = 601/603 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.162 (0.17), 1.351 (16.00), 1.388 (3.98), 1.599 (0.22), 1.631 (0.15), 1.762 (0.14), 1.784 (0.20) , 2.099 (0.70), 2.118 (1.20), 2.136 (0.63), 2.365 (0.12), 3.540 (0.21) , 3.893 (0.21), 7.215 (0.39), 7.233 (0.26), 7.326 (0.43), 7.345 (0.86), 7.364 (0.54), 7.405 (1.12), 7.424 (0.66), 7.499 (0.78), 7.506 (0.68) , 7.517 (1.61), 7.525 (1.49), 7.827 (0.35), 7.850 (0.51), 7.855 (0.50), 7.927 (0.97), 7.950 (0.62), 8.608 (0.38).

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 8.61 (t, 1H), 7.94 (d, 1H), 7.84 (dd, 1H), 7.67 (br. s, 1H), 7.567.46 ( m, 5H), 7.44-7.39 (m, 2H), 7.35 (t, 2H), 7.22 (t, 1H), 3.87 (dd, 1H), 3.55 (dd, 1H), 2.22-2.02 (m, 5H) , 1.79 (td, 1H), 1.60 (td, 1H), 1.4-1.3 (m, 1H, partially hidden), 1.39 (s, 3H), 1.35 (s, 9H), 1.23-1.07 (m, 1H).

Example 307A. 2-(Bromomethyl)-1-(difluoromethoxy)-3-fluorobenzene

A solution of 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 sodium hydrogen carbonate solution, water and dichloromethane (respectively 100 ml) and shaken. After phase separation, the organic phase was washed with saturated 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 was obtained.

GC-MS (Method 12): R _t = 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).

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

Example 308A. [2-(Difluoromethoxy)-6-fluorophenyl]acetonitrile

- 128 040284

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 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 12): Rt = 3.70 min, MS (EIpos): m/z = 201 [M] ⁺ LC-MS (Method 1): Rt = 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-d6) δ [ppm]: 7.58-7.43 (m, 1H), 7.39-7.05 (m, 3H), 3.95 (s, 2H).

Example 309A. (+/-)-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 308A) in THF (30 ml) in argon at approx. (-70) - (-60)°C slowly with stirring was added a 2M solution of LDA in THF (22 ml, 43 mmol). The mixture was brought to 0°C and after 15 min further cooled to -70°C. Then slowly with stirring at approx. (-70) - (-60)°C was added dropwise a solution of tert-butyl-3-bromopropanoate (6.8 ml, 43 mmol) in THF (15 ml). The mixture was further stirred overnight while the cooling bath (dry ice/isopropanol) was slowly brought to RT. Then the mixture at approx. 0°C was slowly mixed 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 (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): Rt = 1.10 min; MS (ESIpos): m/z = 330 [M+H] ⁺ .

Example 310A. (+/-)-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 309A) in tert-butanol (97 ml) was mixed with Raney nickel (937 mg, 16.0 mmol) and hydrogenated for three days at normal pressure. The catalyst was then filtered through silica gel 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% th. y.) of the title compound was obtained.

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

Example 311A. (+/-)-tert-Butyl-5-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-4-[2(difluoromethoxy)-6-fluorophenyl]pentanoate ( racemate)

HATU (639 mg, 1.68 mmol ) and DIPEA (570 µl, 3.3 mmol) and the mixture was stirred for 15 min at RT. Then added (+/-)-tert-butyl-5-amino-4- 129 040284

[2-(difluoromethoxy)-6-fluorophenyl]pentanoate (751 mg, 65% pure, 1.46 mmol, example 310A) dissolved in DMF (3 ml) and the mixture was stirred for 16 h at 60°C. After cooling to RT, the mixture was mixed with ethyl acetate and water (respectively 100 ml) and shaken. After phase separation, the aqueous phase was extracted once with ethyl acetate (80 ml). The combined organic phases were washed with saturated sodium chloride solution (100 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 97: 3 4 7:3, Isolera One). The combined desired fractions were concentrated and the residue was dried in vacuo. 749 mg (88% pure, 69% theoretical) of the title compound were obtained.

LC-MS (Method 1): R _t = 2.54 min; MS (ESIpos): m/z = 657/659 [M+H]+.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.92 (t, 1H), 7.94 (d, 1H), 7.86 (dd, 1H), 7.70 (br. s, 1H), 7.587. 45 (m, 5H), 7.45-7.22 (m, 2H), 7.16-6.99 (m, 2H), 3.92-3.67 (m, 2H), 3.60-3.44 (m, 1H), 2.22-1.87 (m, 7H ), 1.35 (s, 9H).

Separation of enantiomers.

The title title compound (640 mg, 88% pure) was dissolved in a warm mixture of acetonitrile (7 mL) and isopropanol (3 mL) and separated into enantiomers by chiral phase preparative HPLC (see Examples 312A and 313A) [column: Daicel Chiralpak IE, 5 µm, 250 mm x 20 mm; flow: 15 ml/min; detection: 210 nm; temperature: 25°C; sample injection: 0.50 ml; eluent: 70% heptane; 30% isopropanol; duration of action 19 min, isocratic]. The combined target fractions were concentrated and the residue was lyophilized in acetonitrile/water.

Example 312A. (+)-tert-Butyl-5-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-4-[2(difluoromethoxy)-6-fluorophenyl]pentanoate (enantiomer 1 ).

The separation of enantiomers described in Example 311A gave three batches of the title compound as the previously eluted enantiomer: 78 mg (batch 1, 76% pure, 99% ee value, see rotation angle and LC-MS), 21 mg ( lot 2, 75% pure, ee-value 92%) and 186 mg (lot 3, 88% purity, ee-value 94%).

[a] _D20 = +24.6°, 589 nm, c = 0.33 g ^/ 100 mL, methanol.

LC-MS (Method 1): R _t = 2.56 min; MS (ESIpos): m/z = 657/659 [M+H]+.

Example 313A. (-)-tert-Butyl-5-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-4-[2(difluoromethoxy)-6-fluorophenyl]pentanoate (enantiomer 2 ).

The separation of enantiomers described in Example 311A provided two batches of the title compound as the later eluting enantiomer: 76 mg (batch 1, 97% pure, 95% ee value) and 118 mg (batch 2, 97% pure, ee value). 99%, see rotation angle and LC-MS).

[a] _D20 = -29.1°, 589 nm, c = 0.34 ^g /100 ml, methanol.

LC-MS (Method 1): R _t = 2.56 min; MS (ESIpos): m/z = 657/659 [M+H]+.

Example 314A. (+/-)-tert-Butyl-4-cyano-4-(2,5-difluorophenyl)butanoate (racemate)

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 (1.6M in hexane, 44 ml, mmol). After the addition was completed, the solution was further stirred for 10 min at 0°C.

This LDA solution was added slowly 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 after 15 min was further cooled to

-78°C. A solution of tert-butyl-3-bromopropanoate (13 ml, 97% pure, mmol) in 44 ml THF was then added slowly dropwise and the mixture was stirred an additional 1 h at -78°C, then heated to RT and further stirred overnight at RT . 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 successively twice with 1M 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 residue was dissolved in a small amount of DMSO and purified in 4 portions by preparative HPLC (Method 30). 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): Rt = 2.11 min; MS (ESIpos): m/z = 282 [M+H]+.

¹ H-NMR (400 MHz, DMSO-d6) 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).

- 130 040284

Example 315A. (+/-)-tert-Butyl-5-amino-4-(2,5-difluorophenyl)pentanoate (racemate)

Provided (+/-)-tert-butyl-4-cyano-4-(2,5-difluorophenyl)butanoate (racemate, 8.05 g, 100% pure, 28.6 mmol, Example 314A) 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 silica gel and washed three times with methanol (respectively 30 ml). The filtrate was evaporated and the residue was adsorbed in ethyl acetate (200 ml). The organic phase was extracted twice with 1M hydrochloric acid (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): Rt = 1.12 min; MS (ESIpos): m/z = 286 [M+H]+.

'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).

'H-NMR (400 MHz, DMSO-d ₆ ) 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 316A. (+/-)-tert-Butyl-5-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-4-(2,5difluorophenyl)pentanoate (racemate)

To a solution of 6-bromo-3-methyl-2-phenylquinoline-4-carboxylic acid (1.01 g, 2.94 mmol, obtained according to WO 2016/146602, example 3A) in DMF (34 ml) was added HATU (1.34 g, 3.53 mmol) and DIPEA (1.2 ml, 7.1 mmol). The mixture was stirred for 15 min at RT. A solution of (+/-)-tert-butyl-5-amino-4(2,5-difluorophenyl)pentanoate (840 mg, 2.94 mmol, example 315A) in a small amount of DMF was added and the reaction mixture was stirred for 2 h at 60°C, then allowed to cool to RT. The mixture was diluted with ethyl acetate and washed twice successively with 1M hydrochloric acid and twice with saturated sodium hydrogen carbonate solution. The organic phase was dried, filtered and concentrated. The residue was dissolved in a small amount of DMSO and purified by preparative HPLC (Method 30). The appropriate fractions were concentrated together and dried in vacuo. 1.16 g (100% pure, 65% th. y.) of the title compound was obtained.

LC-MS (Method 1): Rt = 2.52 min; MS (ESIpos): m/z = 609/611 [M+H]+.

‘H-NMR (400 MHz, DMSO-d6) δ [ppm]: 8.88 (t, 1H), 7.94 (d, 1H); 7.85 (dd, 1H), 7.65 (br. s, 1H), 7.557.46 (m, 5H), 7.32 (ddd, 1H), 7.23 (dt, 1H), 7.17-7.07 (m, 1H), 3.81- 3.63 (m, 2H), 3.43-3.33 (m, 1H), 2.20-1.96 (m. 6H), 1.86-1.74 (m, 1H), 1.37 (m, 9H).

Separation of enantiomers.

The title title compound (1.09 g) was dissolved in a mixture (12 ml) of acetonitrile, methanol and dichloromethane and separated into enantiomers by preparative chiral phase SLC (see Examples 317A and 318A) [column: Daicel Chiralcel OX-H, 5 µm, 250 mm x 30 mm; flow: 100 ml/min; detection: 210 nm; temperature: 40°C; sample injection: 0.30 ml; eluent: 81% carbon dioxide; 19% methanol; duration of action 9.5 min, isocratic]. The combined target fractions were concentrated and the residue was lyophilized from acetonitrile/water.

Example 317A. tert-Butyl 5-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-4-(2,5difluorophenyl)pentanoate (enantiomer 1).

The separation of enantiomers described in Example 316A gave 432 mg (>99% pure, >99% ee) of the title compound as the previously eluted enantiomer.

LC-MS (Method 1): Rt = 2.51 min; MS (ESIpos): m/z = 609/611 [M+H]+.

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (0.20), 0.008 (0.20), 1.030 (0.22), 1.045 (0.22), 1.369 (16.00), 1.806 (0.17), 2.012 (0.19 ), 2.029 (0.20), 2.049 (0.19), 2.061 (0.17), 2.087 (0.74), 2.104 (1.03), 2.123 (0.70), 3.368 (0.17), 3.673 (0.18), 3.687 (0.27), 7.117 (0.18 ), 7.200 (0.20), 7.211 (0.21), 7.223 (0.32), 7.234

- 131 040284 (0.32), 7.293 (0.17), 7.300 (0.20), 7.306 (0.21), 7.315 (0.30), 7.324 (0.21), 7.330 (0.20), 7.338 (0.17), 7.489 (0.21), 7.501 (0.68) ), 7.508 (0.70), 7.519 (2.70), 7.529 (0.88), 7.533 (0.82), 7.833 (0.36), 7.838 (0.33), 7.856 (0.56), 7.861 (0.54), 7.929 (1.06), 7.952 (0.68 ), 8.860 (0.22), 8.874 (0.39), 8.888 (0.21).

Example 318A. tert-Butyl 5-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-4-(2,5difluorophenyl)pentanoate (enantiomer 2).

The separation of enantiomers described in Example 316A gave 366 mg (97% pure, ee value 94%) of the title compound as the later eluted enantiomer.

LC-MS (Method 1): Rt = 2.51 min; MS (ESIpos): m/z = 609/611 [M+H]+.

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.030 (0.69), 1.046 (0.70), 1.369 (16.00), 1.806 (0.20), 1.814 (0.17), 1.831 (0.17), 1.999 (0.17) 2.012 (0.22), 2.029 (0.23), 2.049 (0.21), 2.061 (0.19), 2.088 (0.84), 2.104 (1.17), 2.124 (0.83), 3.369 (0.20), 3.674 (0.22), 3.688 (0.31) . , 7.301 (0.23) , 7.833 (0.37), 7.838 (0.35), 7.856 (0.57), 7.861 (0.57), 7.929 (1.08), 7.952 (0.68), 8.860 (0.25), 8.875 (0.45), 8.888 (0.24).

Implementation examples.

Example 1 (+/-)-3-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-2-phenylpropionic acid (racemate)

Tone

To a solution of (+/-)-methyl-3-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}hydrotropate (153 mg, 304 µmol, Example 153A) in THF ( 3.8 ml) and methanol (750 μl) at RT was added 1 M sodium hydroxide solution (1.8 ml, 1.8 mmol) and the mixture was stirred for 2 h at RT. The pH of the mixture was then adjusted to 3 with TFA (160 μl, 2.1 mmol) and purified by preparative HPLC (Method 15). The combined target fractions were concentrated and lyophilized. Received 147 mg (100% pure, 99% theoretical. yield.) specified in the title compound.

LC-MS (Method 1): R _t = 1.84 min; MS (ESIpos): m/z = 489/491 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: -0.008 (1.54), 0.008 (1.39), 2.146 (3.32), 3.839 (1.33), 3.859 (2.67), 3.875 (2.66), 3.890 ( 1.71), 3.987 (2.43), 4.006 (3.60), 4.025 (1.43), 7.300 (0.95), 7.310 (1.56), 7.322 (1.64), 7.332 (1.06), 7.359 (0.74), 7.383 (13.34), 16.00) 5.18) 1.28).

Separation of enantiomers.

The title target compound (120 mg) was dissolved in methanol (20 ml) and separated into enantiomers by chiral phase preparative SLC (see Examples 2 and 3) [column: Daicel Chiralcel OJ, 10 μm, 250 mm x 20 mm; flow: 80 ml/min; detection: 210 nm; temperature: 40°C; sample injection: 1.5 ml; eluent: 70% carbon dioxide / 30% methanol; duration of action 7 min, isocratic]. The combined desired fractions were concentrated and the residue was dried in vacuo.

Example 2 (-)-3-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-2-phenylpropionic acid (enantiomer 1).

The separation of the enantiomers described in Example 1 gave 48 mg (99% pure, ee value 100%) of the title compound as the previously eluted enantiomer.

[a] _D20 = -52.4°, 589 nm, c = 0.37 ^g /100 ml, methanol.

LC-MS (Method 1): Rt = 1.87 min; MS (ESIpos): m/z = 489/491 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (1.61), 0.008 (1.51), 2.145 (3.84), 3.390 (2.69), 3.838 (1.45), 3.858 (2.86), 3.873 (2.92 ), 3.888 (1.79), 3.986 (2.43), 4.005 (3.66), 4.025 (1.42), 5.754 (0.57), 7.300 (1.16), 7.310 (1.79), 7.321 (1.90), 7.331 (1.21), 7.359 (0.97 ), 7.382 (14.91), 7.392 (16.00), 7.490 (1.45), 7.494 (1.60), 7.503 (4.56), 7.511 (4.16), 7.523 (12.91), 7.527 (12.16), 7.532 (8.26), 7.536 (6.68 ), 7.539 (5.57), 7.547 (1.36), 7.746 (0.83), 7.838 (2.39), 7.844 (2.10), 7.861 (3.53), 7.866 (3.29), 7.935 (6.47), 7.957 (4.09), 8.950 (1.42 ), 8.963 (2.65), 8.977 (1.37), 12.636 (0.94).

Example 3 (+)-3-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-2-phenylpropionic acid (enantiomer 2).

The separation of the enantiomers described in Example 1 gave 45 mg (98% pure, ee value 97%) of the title compound as the later eluted enantiomer.

- 132 040284

[a] _D20 = +53.3°, 589 nm ^, c = 0.36 g/100 mL, methanol.

LC-MS (Method 1): R _t = 1.86 min; MS (ESIpos): m/z = 489/491 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: -0.008 (2.72), 0.008 (2.08), 2.145 (4.80), 3.837 (1.65), 3.857 (3.14), 3.873 (3.24), 3.887 ( 1.86), 3.983 (2.11), 4.002 (3.05), 4.021 (1.23), 5.754 (1.78), 7.308 (2.12) 16.00), 7.479 (1.30), 7.490 (2.31), 7.493 (2.50), 7.503 (5.97), 7.511 (5.63), 7.523 (15.28), 7.527 (14.25), 7.531 (9.97), 7.535 (8.05), 7.539 ( 6.55) 2.62), 8.975 (1.38).

Example 4 (+/-)-3-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-2-(2-chlorophenyl)propionic acid (racemate)

To a solution of (+/-)-ethyl-3-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-2-(2-chlorophenyl)propanoate (2.20 g, 3.99 mmol, example 154A) in THF (32 ml) and methanol (6.0 ml) at RT was added 1M sodium hydroxide solution (24 ml, 24 mmol) and the mixture was stirred for 2 h at RT. The mixture was then mixed with water and ammonium chloride solution (respectively 100 ml) and shaken. The aqueous phase was extracted once with ethyl acetate (100 ml). The combined organic phases were dried over sodium sulfate, filtered and concentrated, and the residue was dried in vacuo. 1.89 g (99% pure, 90% theoretical) of the title compound (crude) was obtained. About 100 mg of the crude product was further purified by preparative HPLC (Method 23). The combined desired fractions were concentrated and the residue was dried in vacuo. 91 mg (100% pure) of additionally purified title compound was obtained (see Analysis section).

LC-MS (Method 1): R _t = 1.93 min; MS (ESIpos): m/z = 523/525 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (1.46), 0.008 (1.40), 1.194 (0.46), 1.211 (0.50), 2.164 (12.91), 3.881 (1.03), 3.897 (1.02 ), 3.984 (0.85), 3.998 (1.39), 4.013 (1.29), 4.032 (0.91), 4.483 (1.81), 4.501 (3.08), 4.520 (1.58), 5.754 (3.50), 7.319 (0.99), 7.338 (2.47 ), 7.353 (2.26), 7.370 (2.06), 7.388 (2.94), 7.405 (1.31), 7.479 (0.74), 7.492 (5.81), 7.495 (5.88), 7.504 (8.98), 7.511 (8.29), 7.514 (6.53 ), 7.523 (16.00), 7.528 (13.36), 7.536 (7.86), 7.547 (1.66), 7.748 (0.97), 7.838 (2.95), 7.844 (2.54), 7.860 (4.43), 7.866 (4.14), 7.934 (7.94 ), 7.956 (4.98), 8.959 (1.61), 8.973 (3.20), 8.987 (1.57), 12.794 (0.56).

Separation of enantiomers.

The title title compound (1.79 g, crude) was dissolved in methanol (80 ml), filtered and separated into enantiomers by preparative chiral phase SLC (see Examples 5 and 6) [column: Daicel Chiralcel OJ-H, 5 µm , 250 mm x 30 mm; flow: 175 ml/min; detection: 210 nm; temperature: 38°C; sample injection: 3 ml; eluent: 67% carbon dioxide/33% methanol; duration of action 4.5 min, isocratic]. The combined desired fractions were concentrated and the residue was dried in vacuo.

Example 5 (-)-3-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-2-(2-chlorophenyl)propionic acid (enantiomer 1)

Separation of the enantiomers as described in Example 4 gave the title compound prepurified and further purified by preparative HPLC (Method 24). The combined target fractions were concentrated and lyophilized. 819 mg (100% pure, 95% ee) of the title compound were obtained.

[a] _D20 = -37.1°, 589 nm, c = 0.39 ^g /100 ml, methanol.

LC-MS (Method 1): R _t = 1.91 min; MS (ESIpos): m/z = 523/525 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 0.008 (1.48), 2.164 (12.99), 3.897 (1.37), 3.998 (2.04), 4.015 (1.92), 4.033 (1.57), 4.483 (2.11) ), 4.502 (3.31), 4.521 (1.70), 7.318 (1.23), 7.334 (2.69), 7.353 (2.42), 7.370 (2.04), 7.385 (2.99), 7.404 (1.34), 7.491 (6.69), 7.495 (6.78 ), 7.504 (9.81), 7.511 (8.77), 7.523 (16.00), 7.529 (12.90), 7.537 (7.20), 7.540 (5.52), 7.548 (1.34), 7.750 (1.01), 7.840 (2.91), 7.845 (2.34 ), 7.862 (4.23), 7.868 (3.62), 7.935 (7.28), 7.957 (4.47), 8.960 (1.77), 8.974 (3.16), 8.989 (1.52).

Example 6 (+)-3-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-2-(2-chlorophenyl)propionic acid (enantiomer 2).

Separation of the enantiomers as described in Example 4 gave the title compound prepurified and further purified by preparative HPLC (Method 24). The combined target fractions were concentrated and lyophilized. 638 mg (100% pure, ee-value 100%) of the title compound were obtained.

- 133 040284

[a]D ²⁰ = +45.6°, 589 nm, c = 0.44 g/100 ml, methanol.

LC-MS (Method 1): R _t = 1.94 min; MS (ESIpos): m/z = 523/525 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: -0.008 (2.12), 0.008 (1.86), 2.164 (13.01), 3.882 (1.00), 3.899 (1.02), 3.983 (0.83), 3.997 ( 1.35), 4.014 (1.32), 4.033 (0.88), 4.483 (1.84), 4.501 (3.12), 4.520 (1.60), 7.315 (0.92), 7.319 (1.02), 7.334 (2.42), 7.338 (2.53), 2.23) 8.86) 2.88), 7.843 (2.47), 7.860 (4.34), 7.865 (4.05), 7.934 (7.79), 7.956 (4.95), 8.958 (1.67), 8.973 (3.28), 8.987 (1.62), 12.797 (2.25).

Example 7 (+/-)-3-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-2-(2-methoxyphenyl)propionic acid (racemate)

To a solution of (+/-)-methyl-3-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-2-(2-methoxyphenyl)propanoate (1.11 g, 2.08 mmol, example 155A) in THF (18 ml) and methanol (3.6 ml) at RT was added 1M sodium hydroxide solution (12 ml, 12 mmol) and the mixture was stirred for 3 h at RT. The mixture was then mixed with water (100 ml) and 1M hydrochloric acid (15 ml) and shaken. The aqueous phase was extracted once with ethyl acetate (100 ml). The combined organic phases were dried over sodium sulfate, filtered and concentrated, and the residue was dried in vacuo. Received 1.08 g (100% pure, 100% theoretical. out.) specified in the title compound.

LC-MS (Method 1): R _t = 1.85 min; MS (ESIpos): m/z = 519/521 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (0.61), 1.181 (0.40), 1.908 (0.42), 2.176 (6.04), 3.162 (0.99), 3.175 (1.01), 3.735 (0.58 ), 3.750 (0.98), 3.769 (0.95), 3.784 (1.09), 3.797 (16.00), 3.911 (0.54), 3.925 (0.72), 3.929 (0.71), 3.944 (0.99), 3.958 (0.52), 3.962 (0.55 ), 3.976 (0.48), 4.267 (1.11), 4.286 (2.15), 4.305 (0.88), 6.937 (0.89), 6.955 (1.87), 6.974 (1.09), 7.019 (1.64), 7.039 (1.89), 7.260 (1.06 ), 7.279 (4.03), 7.298 (2.96), 7.478 (0.47), 7.490 (0.95), 7.504 (2.64), 7.511 (2.38), 7.524 (5.63), 7.530 (5.48), 7.537 (3.68), 7.550 (0.79 ), 7.774 (0.66), 7.837 (1.35), 7.843 (1.11), 7.860 (2.00), 7.865 (1.77), 7.932 (3.50), 7.955 (2.22), 8.845 (0.81), 8.860 (1.54), 8.873 (0.73 ), 12.396 (0.79).

Separation of enantiomers.

The title target compound (1.0 g) was dissolved in 45 ml of a mixture of methanol and acetonitrile and separated into enantiomers by preparative chiral phase SLC (see examples and 9) [column: Daicel Chiralcel OJ-H, 5 μm, 250 mm x 20 mm; flow: 80 ml/min; detection: 210 nm; temperature: 40°C; sample injection: 0.4 ml; eluent: 70% carbon dioxide / 30% methanol; duration of action 4 min, isocratic]. The combined desired fractions were concentrated and the residue was dried in vacuo.

Example 8 (-)-3-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-2-(2-methoxyphenyl)propionic acid (enantiomer 1)

Separation of the enantiomers as described in Example 7 gave 450 mg (100% pure, ee value 100%) of the title compound as the previously eluted enantiomer.

[a] _D20 = -57.5°, 589 nm, c = 0.35 g ^/ 100 ml, methanol.

LC-MS (Method 1): Rt = 1.84 min; MS (ESIpos): m/z = 519/521 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: -0.008 (0.89), 2.073 (0.62), 2.176 (6.14), 3.750 (1.00), 3.768 (1.06), 3.784 (1.16), 3.797 ( 16.00), 3.943 (0.98), 4.267 (1.10), 4.286 (2.10), 4.305 (0.86), 6.935 (0.87), 6.938 (0.93), 6.954 (1.81), 6.957 (1.81), 6.973 (1.03), 1.06), 7.020 (1.67), 7.039 (1.87), 7.256 (0.87), 7.260 (1.12), 7.279 (4.03), 7.298 (2.95) 2.81) 1.16), 7.860 (2.02), 7.865 (1.80), 7.933 (3.43), 7.955 (2.18), 8.846 (0.84), 8.860 (1.54).

Example 9 (+)-3-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-2-(2-methoxyphenyl)propionic acid (enantiomer 2)

Separation of the enantiomers as described in Example 7 gave 318 mg (99% pure, ee value 100%) of the title compound as the later eluted enantiomer.

[a] _D20 = +60.3°, 589 nm ^, c = 0.36 g/100 mL, methanol.

LC-MS (Method 1): R _t = 1.84 min; MS (ESIpos): m/z = 519/521 [M+H] ⁺ .

'H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (0.62), 0.008 (0.54), 2.073 (1.05), 2.176 (6.09), 2.523

- 134 040284 (0.51), 3.735 (0.50), 3.750 (0.84), 3.767 (0.73), 3.784 (0.75), 3.797 (16.00), 3.911 (0.48), 3.925 (0.66), 3.929 (0.67), 3.943 (0.92) ), 3.962 (0.53), 3.976 (0.46), 4.266 (1.00), 4.285 (2.02), 4.304 (0.83), 6.937 (0.86), 6.956 (1.82), 6.975 (1.04), 7.019 (1.64), 7.039 (1.88 ), 7.260 (0.98), 7.279 (3.91), 7.298 (2.92), 7.490 (0.78), 7.505 (2.48), 7.511 (2.19), 7.525 (5.43), 7.531 (5.42), 7.537 (3.79), 7.550 (0.84 ), 7.773 (0.66), 7.838 (1.35), 7.843 (1.13), 7.860 (2.02), 7.865 (1.87), 7.933 (3.53), 7.955 (2.27), 8.847 (0.74), 8.861 (1.48), 8.875 (0.72 ), 12.407 (0.66).

Example 10 (+/-)-3-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-2-(4-fluorophenyl)propionic acid (racemate)

To a solution of (+/-)-methyl-3-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-2-(4-fluorophenyl)propanoate (192 mg, 368 µmol, example 156A) in THF (3.1 ml) and methanol (630 µl) at RT was added 1M sodium hydroxide solution (2.2 ml, 2.2 mmol) and the mixture was stirred overnight at RT. The mixture was then adjusted to pH 3 with TFA (198 μl, 2.6 mmol) and concentrated. The residue was adsorbed into DMSO and purified by preparative HPLC (Method 15). The combined desired fractions were concentrated and the residue was dried in vacuo. 143 mg (100% pure, 76% thor.) of the title compound were obtained.

LC-MS (Method 1): Rt = 1.88 min; MS (ESIpos): m/z = 507/509 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 2.086 (1.66), 2.158 (5.56), 3.802 (1.49), 3.854 (3.59), 3.871 (5.34), 3.885 (3.88), 4.000 (2.74) , 4.019 (4.23), 4.039 (1.71), 5.754 (1.63), 7.190 (4.07), 7.212 (8.57), 7.234 (4.78), 7.417 (5.22), 7.430 (6.34), 7.437 (5.67), 7.451 (4.32) . , 7.865 (4.06), 7.936 (7.11), 7.958 (4.55), 8.939 (2.18), 8.953 (4.25), 8.966 (2.12).

Separation of enantiomers.

The title title compound (120 mg) was dissolved in 12 ml of a mixture of acetonitrile and methanol and separated into enantiomers by preparative HPLC on a chiral phase (see examples 11 and 12) [column: Daicel Chiralpak IA, 5 μm, 250 mm x 4.6 mm; flow: 20 ml/min; detection: 220 nm; temperature: 23°C; sample injection: 0.08 ml; eluent: 55% heptane/(45% ethanol + 0.2% TFA + 1% water); isocratic]. The combined target fractions were concentrated and lyophilized.

Example 11 3-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-2-(4-fluorophenyl)propionic acid (enantiomer 1).

The separation of enantiomers described in Example 10 gave the prepurified title compound as the previously eluted enantiomer (ee-value 100%), then adsorbed in acetonitrile and further purified by preparative HPLC (Method 15). The combined target fractions were concentrated and lyophilized. 17 mg (100% pure) of further purified title compound was obtained.

LC-MS (Method 1): R _t = 1.86 min; MS (ESIpos): m/z = 507/509 [M+H] ⁺ .

'H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (0.75), 0.008 (0.71), 2.157 (0.45), 2.523 (2.18), 2.670 (0.40), 3.800 (0.54), 3.853 ( 3.11) 3.06) 7.451 (5.25) 2.99), 7.506 (7.45), 7.513 (6.73), 7.525 (16.00), 7.530 (15.37), 7.534 (12.62), 7.538 (9.71), 7.542 (7.43) 3.05), 7.842 (2.87), 7.859 (4.50), 7.864 (4.25), 7.934 (8.30), 7.956 (5.24), 8.937 (2.32), 8.951 (4.34), 8.965 (2.05), 12.695 (0.72).

Example 12 3-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-2-(4-fluorophenyl)propionic acid (enantiomer 2)

The separation of enantiomers described in Example 10 gave the prepurified title compound as the later eluted enantiomer (ee value 97%), then adsorbed in acetonitrile and further purified by preparative HPLC (Method 15). The combined target fractions were concentrated and lyophilized. Received 18 mg (100% purity) additionally purified specified in the title compound.

LC-MS (Method 1): Rt = 1.86 min; MS (ESIpos): m/z = 507/509 [M+H] ⁺ .

'H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 0.008 (0.59), 2.157 (4.91), 2.523 (1.21), 3.852 (2.68), 3.870

- 135 040284 (4.44), 3.885 (3.20), 3.999 (2.66), 4.018 (4.37), 4.037 (1.66), 7.189 (4.59), 7.194 (2.01), 7.211 (9.94), 7.216 (2.80), 7.228 (2.29) ), 7.233 (5.54), 7.241 (0.79), 7.408 (0.93), 7.415 (5.86), 7.421 (3.02), 7.429 (6.70), 7.437 (5.97), 7.446 (2.54), 7.451 (5.00), 7.459 (0.67 ), 7.480 (0.87), 7.491 (2.04), 7.506 (6.75), 7.513 (5.85), 7.525 (16.00), 7.531 (15.10), 7.534 (12.59), 7.538 (9.63), 7.542 (7.55), 7.550 (2.09 ), 7.683 (0.64), 7.836 (3.11), 7.842 (2.87), 7.859 (4.78), 7.864 (4.59), 7.934 (9.03), 7.957 (5.79), 8.937 (2.16), 8.951 (4.37), 8.965 (2.06 ), 12.698 (1.19).

Example 13 (+/-)-3-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-2-methyl-2-phenylpropionic acid (racemate)

To a solution of (+/-)-ethyl-3-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-2-methylhydrotropate (204 mg, 383 µmol, Example 157A) in THF (3.2 ml) and methanol (1.6 ml) at RT was added 1 M sodium hydroxide solution (2.3 ml, 2.3 mmol) and the mixture was stirred for 20 h at RT. The pH of the mixture was then adjusted to 3 with TFA (210 μl, 2.7 mmol) and purified by preparative HPLC (Method 20). The combined target fractions were concentrated and lyophilized. Received 195 mg (100% pure, 100% theoretical. w. containing solvent) specified in the title compound.

LC-MS (Method 2): R _t = 1.03 min; MS (ESIpos): m/z = 503/505 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (0.49), 0.008 (0.58), 1.647 (16.00), 2.072 (0.68), 2.116 (2.00), 3.806 (1.36), 3.818 (1.54) ), 3.840 (1.77), 3.852 (1.63), 4.176 (1.56), 4.194 (1.70), 4.210 (1.46), 4.228 (1.38), 5.754 (1.35), 7.274 (0.78), 7.292 (2.20), 7.310 (1.67 ), 7.364 (2.52), 7.384 (5.10), 7.402 (3.22), 7.434 (6.71), 7.452 (3.72), 7.477 (0.50), 7.489 (1.51), 7.504 (4.49), 7.510 (3.58), 7.522 (7.48 ), 7.535 (8.74), 7.552 (1.68), 7.682 (0.67), 7.832 (2.05), 7.837 (1.89), 7.854 (3.10), 7.860 (3.04), 7.931 (5.79), 7.953 (3.72), 8.650 (1.26 ), 8.663 (1.77), 8.667 (1.79), 8.680 (1.25).

Separation of enantiomers.

The title target compound (175 mg) was dissolved in methanol (15 ml) and separated into enantiomers by preparative chiral phase SLC (see Examples 14 and 15) [column: Daicel Chiralpak AD-H, 5 μm, 250 mm x 20 mm; flow: 80 ml/min; detection: 210 nm; temperature: 40°C; sample injection: 2.0 ml; eluent: 70% carbon dioxide / 30% methanol; duration of action 10 min, isocratic]. The combined desired fractions were concentrated and the residue was dried in vacuo.

Example 14 (-)-3-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-2-methyl-2-phenylpropionic acid (enantiomer 1)

Separation of the enantiomers as described in Example 13 gave 71 mg (95% pure, ee value 100%) of the title compound as the previously eluted enantiomer.

[a] _D20 = -42.9°, 589 nm, c = ^0.40 g/100 ml, methanol.

LC-MS (Method 2): R _t = 1.05 min; MS (ESIpos): m/z = 503/505 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: -0.008 (0.44), 0.008 (0.44), 1.645 (16.00), 2.116 (2.04), 2.523 (0.51), 3.805 (1.39), 3.817 ( 1.53), 3.838 (1.78), 3.851 (1.61), 4.174 (1.57), 4.192 (1.69), 4.208 (1.45), 4.226 (1.35) 0.46), 7.363 (2.56), 7.383 (5.10), 7.402 (3.25), 7.433 (6.81), 7.451 (3.69), 7.475 (0.57), 7.487 (1.54), 7.502 (4.49), 7.508 (3.60), 7.86) 1.26), 8.665 (1.77), 8.678 (1.22), 12.658 (1.38).

Example 15 (+)-3-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-2-methyl-2-phenylpropionic acid (enantiomer 2)

Separation of the enantiomers as described in Example 13 gave 69 mg (98% pure, ee value 100%) of the title compound as the later eluted enantiomer.

[a] _D20 = +42.4°, 589 nm ^, c = 0.37 g/100 mL, methanol.

LC-MS (Method 2): R _t = 1.05 min; MS (ESIpos): m/z = 503/505 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.640 (16.00), 2.114 (2.43), 3.804 (1.41), 3.816 (1.55), 3.838 (1.81), 3.850 (1.64), 4.167 (1.52) , 4.184 (1.64), 4.200 (1.40), 4.218 (1.31), 7.272 (0.86), 7.290 (2.36) . , 7.828 (2.05), 7.833 (1.89), 7.850 (3.15), 7.855 (3.08), 7.928 (5.67), 7.950 (3.76), 8.654 (1.26), 8.670 (1.87), 8.684 (1.24).

Example 16 (+/-)-2-({[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}methyl)-2-phenylbutanoic acid (racemate)

- 136 040284

To a solution of (+/-)-methyl-2-({[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}methyl)-2phenylbutanoate (540 mg, 1.02 mmol, example 158A ) in THF (8.7 mL) and methanol (1.7 mL) at RT with 1 M sodium hydroxide solution (6.1 mL, 6.1 mmol) and the mixture was stirred for 16 h at RT. Then again sodium hydroxide solution (6.1 ml, 6.1 mmol) was added and the mixture was stirred for an additional 4 hours at RT. Then Methanol (5 ml) was added and the mixture was stirred overnight at 40°C. The pH of the mixture was then adjusted to 3 with TFA and purified by preparative HPLC (Method 16). The combined target fractions were concentrated and lyophilized. 495 mg (98% pure, 92% theoretical) of the title compound were obtained.

LC-MS (Method 2): R _t = 1.07 min; MS (ESIpos): m/z = 517/519 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 0.883 (5.29), 0.901 (12.03), 0.919 (5.67), 2.085 (2.56), 2.101 (3.71), 2.118 (4.29), 2.138 (4.09) ), 2.158 (2.91), 2.175 (1.49), 2.193 (0.81), 2.689 (1.35), 2.731 (1.66), 2.890 (1.78), 3.947 (1.70), 3.960 (1.84), 3.981 (2.25), 3.994 (2.15 ), 4.206 (2.25), 4.223 (2.29), 4.240 (1.89), 4.257 (1.73), 7.274 (2.20), 7.291 (1.79), 7.349 (2.00), 7.370 (6.65), 7.387 (16.00), 7.404 (2.33 ), 7.475 (0.67), 7.487 (1.79), 7.501 (5.73), 7.507 (4.68), 7.519 (11.55), 7.529 (11.24), 7.546 (1.98), 7.642 (0.69), 7.827 (2.51), 7.832 (2.35 ), 7.849 (3.86), 7.854 (3.80), 7.923 (7.49), 7.946 (4.75), 8.501 (1.66), 8.516 (2.84), 8.530 (1.64).

Separation of enantiomers.

The title target compound (450 mg) was dissolved in methanol (25 ml) and separated into enantiomers by chiral phase preparative SLC (see Examples 17 and 18) [column: Daicel Chiralpak AD, 10 μm, 250 mm x 20 mm; flow: 80 ml/min; detection: 210 nm; temperature: 40°C; sample injection: 1.0 ml; eluent: 78% carbon dioxide / 22% isopropanol; duration of action 10 min, isocratic]. The combined desired fractions were concentrated and the residue was dried in vacuo.

Example 17 (-)-2-({[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}methyl)-2-phenylbutanoic acid (enantiomer 1)

Separation of the enantiomers as described in Example 16 gave 156 mg (98% pure, ee value 100%) of the title compound as the previously eluted enantiomer.

[a] _D20 = -10.0°, 436 nm, c = 0.32 ^g /100 ml, chloroform.

LC-MS (Method 1): R _t = 2.02 min; MS (ESIpos): m/z = 517/519 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 0.882 (5.37), 0.901 (12.17), 0.919 (5.68), 2.084 (2.60), 2.100 (3.68), 2.118 (4.29), 2.137 (4.05 ), 2.157 (2.89), 2.174 (1.48), 2.193 (0.80), 2.327 (0.48), 2.669 (0.45), 2.890 (0.40), 3.781 (1.39), 3.946 (1.76), 3.958 (1.82), 3.980 (2.11 ), 3.993 (1.96), 4.205 (1.71), 4.222 (1.83), 4.238 (1.49), 4.256 (1.36), 7.273 (2.16), 7.290 (1.78), 7.349 (1.96), 7.369 (6.67), 7.386 (16.00 ), 7.403 (2.35), 7.473 (0.68), 7.486 (1.79), 7.500 (5.74), 7.507 (4.75), 7.518 (11.53), 7.528 (11.13), 7.636 (0.69), 7.826 (2.62), 7.831 (2.41 ), 7.848 (4.00), 7.853 (3.91), 7.923 (7.83), 7.945 (4.94), 8.499 (1.66), 8.515 (2.83), 8.530 (1.61).

Example 18 (+)-2-({[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}methyl)-2-phenylbutanoic acid (enantiomer 2)

X ^NC rV° ^H

Ο^ΝΗ Oh

XX χ_ ^Ν χχ

Separation of the enantiomers as described in Example 16 gave 162 mg (98% pure, ee value 100%) of the title compound as the later eluted enantiomer.

[a] _D20 = +11.4°, 436 nm ^, c = 0.35 g/100 ml, chloroform.

LC-MS (Method 1): R _t = 2.02 min; MS (ESIpos): m/z = 517/519 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (3.29), 0.008 (3.13), 0.882 (5.46), 0.900 (12.52), 0.918 (5.74), 2.083 (2.56), 2.100 (3.63) ), 2.117 (4.23), 2.137 (4.00), 2.157 (2.86), 2.174 (1.47), 2.192 (0.78), 2.327 (0.67), 2.366 (0.54), 2.518 (2.78), 2.523 (2.15), 2.669 (0.64 ), 2.674 (0.48), 2.710 (0.52), 3.555 (5.62), 3.945

- 137 040284 (1.41), 3.958 (1.52), 3.980 (1.88), 3.992 (1.71), 4.204 (1.66), 4.221 (1.78), 4.238 (1.44), 4.255 (1.31), 7.258 (0.94), 7.274 (2.11) ), 7.290 (1.78), 7.348 (2.01), 7.369 (6.76), 7.386 (16.00), 7.403 (2.20), 7.473 (0.73), 7.485 (1.95), 7.499 (5.70), 7.506 (5.02), 7.519 (11.25 ), 7.526 (10.60), 7.529 (10.35), 7.545 (1.82), 7.638 (0.61), 7.825 (2.75), 7.830 (2.53), 7.847 (4.20), 7.853 (4.05), 7.922 (7.81), 7.944 (4.98 ), 8.498 (1.69), 8.514 (2.76), 8.528 (1.61), 12.630 (0.48).

Example 19 (+/-)-3-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-2-hydroxy-2-phenylpropionic acid (racemate)

To a solution of (6-bromo-3-methyl-2-phenylquinolin-4-yl)(1H-imidazol-1-yl)methanone (1.10 g, 2.80 mmol, prepared according to WO 2016/037954, example 2A, page 58 ) in DMF (15 ml) at RT was added (+/-)-methyl-3-amino-2-hydroxy-2-phenylpropanoate (602 mg, 3.08 mmol, obtained by adding 1M sodium hydroxide solution to a mixture of (+/- )-methyl-3-amino-2-hydroxy-2-phenylpropanoate hydrochloride (example 79A) in water to neutral pH-, followed by extraction with dichloromethane and concentration of the organic phase). Then, a 1M solution of potassium tert-butoxide (7.0 ml, 7.0 mmol) in THF was slowly added dropwise with stirring, and the reaction mixture was stirred for 2 days at

CT. The mixture was then mixed with 10% citric acid (150 ml) and extracted twice with ethyl acetate (respectively 100 ml). The combined organic phases were washed once with saturated aqueous sodium chloride (100 ml) and dried over sodium sulfate, filtered and concentrated. The residue was stirred in a milliliter of a mixture of DMSO, water and acetonitrile at elevated temperature and the solid present was filtered off. The filtrate was purified by preparative HPLC (Method 22). The combined desired fractions were concentrated and the residue was dried in vacuo. 149 mg (100% pure, 11% th. y.) of the title compound were obtained.

LC-MS (Method 1): R _t = 1.75 min; MS (ESIpos): m/z = 505/507 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: -0.008 (0.84), 2.710 (0.84), 3.641 (0.45), 3.964 (4.57), 3.985 (2.47), 4.205 (2.62), 4.222 ( 2.06) 3.50), 3.998 (3.54), 4.019 (3.77), 4.032 (3.54), 4.188 (6.52), 7.299 (0.99), 7.317 (2.55), 7.335 (2.34), 7.370 (1.84), 7.488 (1.95), 5.68) 4.40), 7.907 (9.09), 7.929 (5.81), 8.669 (1.65), 8.683 (2.81), 8.697 (1.59).

Separation of enantiomers.

The title target compound (140 mg) was dissolved in 17 ml of a mixture of methanol and acetonitrile and separated into enantiomers by preparative SLC on a chiral phase (see examples and 21) [column: Daicel Chiralpak AZ-H, 5 μm, 250 mm x 20 mm; flow: 80 ml/min; detection: 210 nm; temperature: 40°C; sample injection: 0.5 ml; eluent: 70% carbon dioxide / 30% methanol; duration of action 8 min, isocratic]. The combined target fractions were concentrated and the residue was dried in vacuo.

Example 20 (+)-3-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-2-hydroxy-2-phenylpropionic acid (enantiomer 1)

Separation of the enantiomers as described in Example 19 gave the prepurified title compound as the previously eluted enantiomer (ee value 98%) and further purified by preparative HPLC (Method 23). The combined target fractions were concentrated and lyophilized. 19 mg (95% pure) of the title compound were obtained.

[a] _D20 = +22.3°, 589 nm, c = 0.16 g ^/ 100 mL, methanol.

LC-MS (Method 2): Rt = 0.93 min; MS (ESIpos): m/z = 505/507 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 2.091 (2.15), 3.987 (1.42), 3.998 (1.50), 4.021 (1.95), 4.032 (1.77), 4.189 (2.04), 4.205 (2.06) 4.223 (1.62), 4.239 (1.51), 4.964 (0.51), 7.317 (2.50), 7.335 (2.35), 7.370 (4.32), 7.389 (6.47), 7.408 (2.86), 7.488 (1.95), 7.499 (5.60) , 7.506 (5.19), 7.519 (16.00), 7.641 (8.95), 7.659 (7.59), 7.810 (2.80), 7.833 (4.18), 7.838 (4.16), 7.908 (8.05), 7.930 (5.10), 8.671 (1.74) , 8.684 (2.84).

Example 21 (-)-3-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-2-hydroxy-2-phenylpropionic acid (enantiomer 2)

Separation of the enantiomers as described in Example 19 gave the prepurified title compound as a later eluting enantiomer (ee value 96%) and further purified by preparative HPLC (Method 23). The combined target fractions were concentrated and lyophilized. 21 mg (96% pure) of the title compound were obtained.

- 138 040284

[o]d ²⁰ = -18.9°, 589 nm, c = 0.34 g/100 ml, methanol LC-MS (Method 2): Rt = 0.93 min; MS (ESIpos): m/z = 505/507 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 2.096 (2.18), 3.987 (1.37), 3.999 (1.50), 4.021 (1.98), 4.033 (1.83), 4.190 (1.98), 4.207 (2.14 ), 4.224 (1.65), 4.241 (1.49), 7.300 (1.10), 7.317 (2.65), 7.335 (2.43), 7.370 (4.60), 7.389 (6.63), 7.407 (3.06), 7.476 (0.94), 7.491 (2.08 ), 7.501 (5.89), 7.508 (5.53), 7.521 (16.00), 7.641 (8.97), 7.660 (7.96), 7.720 (0.57), 7.815 (2.82), 7.820 (2.60), 7.837 (4.27), 7.842 (4.07 ), 7.911 (7.89), 7.933 (5.02), 8.673 (1.77), 8.687 (3.01), 8.701 (1.71).

Example 22 (+/-)-3-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-2-[3-(trifluoromethyl)phenyl]propionic acid (racemate)

To a solution of (+/-)-ethyl-3-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-2-[3-(trifluoromethyl)phenyl]propanoate (35 mg, 59.8 µmol, example 159A) in THF (510 µl) and methanol (100 µl) at RT was added 1M sodium hydroxide solution (360 µl, 360 µmol) and the mixture was stirred for four days at RT. The mixture was then adjusted to pH 3 with TFA (32 µl, 420 µmol) and then concentrated. The residue was adsorbed into DMSO and purified by preparative HPLC (Method 15). The combined target fractions were concentrated and lyophilized. Received 147 mg (100% pure, 99% theoretical. yield.) specified in the title compound.

LC-MS (Method 2): Rt = 1.07 min; MS (ESIneg): m/z = 557/559 [MH] ^- .

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 2.083 (1.10), 3.925 (1.15), 3.938 (1.69), 3.957 (2.04), 3.972 (1.05), 4.125 (1.30), 4.145 (2.27) ), 4.164 (0.90), 7.517 (16.00), 7.617 (0.69), 7.636 (1.82), 7.655 (1.80), 7.685 (2.15), 7.720 (6.05), 7.738 (1.73), 7.838 (1.37), 7.843 (1.35 ), 7.861 (2.08), 7.866 (2.10), 7.933 (3.89), 7.955 (2.44), 8.949 (0.93), 8.962 (1.72), 8.975 (0.94).

Example 23 (+/-)-2-(1,3-Benzodioxol-5-yl)-3-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}propionic acid (racemate)

To a solution of (+/-)-ethyl-2-(1,3-benzodioxol-5-yl)-3-{[(6-bromo-3-methyl-2-phenyl-quinolin-4yl)carbonyl]amino} propanoate (110 mg, 196 µmol, example 160A) in THF (1.7 ml) and methanol (330 µl) 1M sodium hydroxide solution (1.2 ml, 1.2 mmol) was added at RT and the mixture was stirred for four days at RT. The pH of the mixture was then adjusted to 3 with TFA (110 μl, 1.4 mmol) and purified by preparative HPLC (Method 15). The combined target fractions were concentrated and dried in vacuo. Received 84 mg (98% pure, 79% theoretical. yield.) specified in the title compound.

LC-MS (Method 2): R _t = 0.96 min; MS (ESIpos): m/z = 533/535 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (2.23), 0.008 (1.80), 2.185 (7.83), 2.328 (0.82), 2.367 (0.43), 2.523 (2.13), 2.670 (0.77 ), 3.823 (3.68), 3.906 (3.23), 3.925 (4.20), 3.944 (1.59), 4.869 (0.78), 5.966 (0.46), 6.000 (16.00), 6.830 (3.16), 6.835 (3.38), 6.851 (5.93 ), 6.855 (6.40), 6.893 (11.41), 6.913 (5.88), 6.935 (8.97), 6.938 (8.35), 7.483 (0.92), 7.495 (2.38), 7.510 (7.43), 7.516 (6.51), 7.529 (14.53 ), 7.536 (14.85), 7.540 (13.69), 7.556 (2.60), 7.725 (1.16), 7.841 (3.81), 7.846 (3.40), 7.864 (5.64), 7.869 (5.36), 7.938 (10.63), 7.961 (6.64 ), 8.928 (2.17), 8.941 (4.35), 8.955 (2.07).

Separation of enantiomers.

The title target compound (60 mg) was dissolved in isopropanol (3 ml) and separated into enantiomers by chiral phase preparative HPLC (see Examples 24 and 25) [column: Chiralpak ID, 5 μm, 250 mm x 20 mm; flow: 9 ml/min; detection: 220 nm; temperature: 50°C; input

- 139 040284 samples: 0.25 ml; eluent: 35% heptane/(65% isopropanol + 0.2% acetic acid); duration of action 15 min, isocratic]. The combined target fractions were concentrated and the residue was lyophilized in acetonitrile/water.

Example 24 2-(1,3-Benzodioxol-5-yl)-3-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}propionic acid (enantiomer 1)

Separation of the enantiomers as described in Example 23 gave the prepurified title compound as the previously eluted enantiomer (ee value 99%) and further purified by preparative HPLC (Method 20). The combined target fractions were concentrated and the residue was lyophilized in acetonitrile/water. 20 mg (98% pure) of the title compound were obtained.

LC-MS (Method 2): Rt = 0.97 min; MS (ESIpos): m/z = 533/535 [M+H] ⁺ .

'H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 5 [ppm] = 8.94 (t, 1H), 7.95 (d, 1H), 7.86 (d, 1H), 7.72 (br. s, 1H), 7.60-7.46 (m, 5H), 6.98-6.81 (m, 3H), 6.00 (s, 2H), 3.98-3.76 (m, 3H), 2.19 (br. s, 3H).

Example 25 2-(1,3-Benzodioxol-5-yl)-3-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}propionic acid (enantiomer 2)

The separation of the enantiomers described in Example 23 gave the prepurified title compound as a later eluting enantiomer (ee-value 94%) and further purified by preparative HPLC (Method 20). The combined target fractions were concentrated and the residue was lyophilized in acetonitrile/water. 22 mg (98% pure) of the title compound were obtained.

LC-MS (Method 2): R _t = 0.97 min; MS (ESIpos): m/z = 533/535 [M+H] ⁺ .

'H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (2.29), 0.008 (1.90), 2.185 (7.94), 2.231 (0.87), 2.328 (0.42), 2.523 (1.81), 2.670 ( 0.47), 3.906 (3.19), 3.925 (4.18), 3.944 (1.62), 5.966 (0.64), 6.000 (16.00), 6.831 (3.05), 6.834 (3.25), 6.851 (5.68), 6.855 (6.08), 9.85), 6.913 (5.14), 6.935 (8.46), 6.938 (7.99), 7.484 (0.74), 7.495 (2.17), 7.510 (7.02), 7.517 (6.12), 7.529 (13.81), 7.537 (14.58), 13.71), 7.556 (2.98), 7.725 (1.12), 7.842 (3.36), 7.847 (3.10), 7.864 (5.17), 7.869 (5.04), 7.939 (9.15) 4.33), 8.955 (2.18).

'H-NMR (400 MHz, DMSO-d6) δ [ppm]: 12.63 (br. s, 1H), 8.94 (t, 1H), 7.95 (d, 1H), 7.86 (dd, 1H), 7.73 (br . s, 1H), 7.58-7.44 (m, 5H), 6.98-6.80 (m, 3H), 6.00 (s, 2H), 3.99-3.75 (m, 3H), 2.19 (br. s, 3H).

Example 26 (+/-)-3-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-2-(3-chloropyridin-2yl)-2-methylpropionic acid ( racemate)

To a solution of (+/-)-tert-butyl-3-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-2-(3chloropyridin-2-yl)-2 -methylpropanoate (200 mg, 336 μmol, example 161A) in dichloromethane (2.3 ml) TFA (520 μl, 6.7 mmol) was added and the mixture was stirred overnight at RT. The mixture was then concentrated and mixed successively with dichloromethane several times and re-concentrated. The residue was adsorbed into dichloromethane and prepurified by flash column chromatography (100 g Biotage Snap-Cartridge KP-Sil, 8:2 cyclohexane/ethyl acetate, Isolera One). The combined desired fractions were concentrated and the residue was dried in vacuo. The residue was then further purified by preparative HPLC (Method 20). The combined target fractions were concentrated and the resulting residue was dried in vacuo. 103 mg (98% pure, 56% thor.) of the title compound were obtained.

LC-MS (Method 2): Rt = 1.01 min; MS (ESIpos): m/z = 538/540 [M+H] ⁺ .

'H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 0.008 (0.65), 1.195 (1.04), 1.211 (1.05), 1.261 (0.69), 1.277 (0.68), 1.683 (16.00), 2.190 ( 5.52), 3.930 (0.60), 3.950 (0.64), 4.471 (0.79), 4.488 (0.91), 4.505 (0.80), 4.523 (0.74), 7.373 (1.45), 7.384 (1.58), 7.392 (1.71), 1.68), 7.493 (1.05), 7.508 (3.75), 7.514 (2.97), 7.526 (6.99), 7.538 (8.33), 7.555 (1.93) 2.99) 2.05), 8.728 (1.14).

Separation of enantiomers.

The title target compound (70 mg) was dissolved in isopropanol (3 ml) and separated into enantiomers by chiral phase preparative HPLC (see examples 27 and 28) [column: YMC Chiralart Amylose SA, 5 μm, 250 mm x 30 mm ; flow: 30 ml/min; detection: 220 nm; temperature: 140 040284: 40°C; sample injection: 0.40 ml; eluent: 50% heptane/(50% isopropanol + 0.2% acetic acid); duration of action 15 min, isocratic]. The combined target fractions were concentrated and the residue was lyophilized.

Example 27 3-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-2-(3-chloropyridin-2-yl)-2methylpropionic acid (enantiomer 1)

Separation of the enantiomers as described in Example 26 gave 21 mg (98% pure, ee value 99%) of the title compound as the previously eluted enantiomer.

LC-MS (Method 1): Rt = 1.89 min; MS (ESIpos): m/z = 538/540 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.008 (0.93), 1.261 (0.44), 1.278 (0.45), 1.682 (16.00), 2.190 (4.78), 3.929 (0.64), 3.949 (0.69) , 3.962 (0.61), 4.471 (0.86), 4.488 (0.94), 4.505 (0.85), 4.522 (0.76), 7.373 (1.63), 7.384 (1.74), 7.392 (1.79), 7.404 (1.73), 7.481 (0.56) , 7.493 (1.46), 7.507 (4.12), 7.514 (3.34), 7.526 (7.32), 7.535 (7.73), 7.537 (7.88), 7.554 (1.42), 7.844 (2.38), 7.849 (1.82), 7.866 (3.25) , 7.871 (2.70), 7.898 (2.33), 7.902 (2.45), 7.919 (2.31), 7.922 (2.43), 7.929 (4.94), 7.952 (2.91), 8.526 (2.14), 8.535 (2.04), 8.694 (1.14) , 8.711 (2.11), 8.726 (1.06).

Example 28 3-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-2-(3-chloropyridin-2-yl)-2methylpropionic acid (enantiomer 2)

The separation of the enantiomers described in Example 26 gave 23 mg (98% pure, ee value 99%) of the title compound as the later eluted enantiomer.

LC-MS (Method 2): R _t = 1.00 min; MS (ESIpos): m/z = 538/540 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.008 (0.69), 1.682 (16.00), 2.185 (4.45), 2.189 (4.42), 3.928 (0.63), 3.949 (0.69), 4.470 (0.86) , 4.488 (0.93), 4.505 (0.85), 4.522 (0.76), 7.373 (1.62), 7.384 (1.73), 7.392 (1.78), 7.404 (1.73), 7.480 (0.54), 7.493 (1.42), 7.507 (4.03) 7.514 (3.20), 7.525 (7.19), 7.535 (7.70), 7.554 (1.36), 7.844 (2.33), 7.849 (1.76), 7.866 (3.18), 7.871 (2.61), 7.899 (2.36), 7.902 (2.37) , 7.919 (2.31), 7.922 (2.36), 7.930 (4.92), 7.952 (2.84), 8.523 (2.07), 8.526 (2.09), 8.535 (2.06), 8.694 (1.13), 8.711 (2.10), 8.727 (1.06) .

Example 29 (+/-)-3-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-2-(2-fluorophenyl)-2methylpropionic acid (racemate)

To a solution of (+/-)-methyl-3-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-2-(2fluorophenyl)-2-methylpropanoate (189 mg, 354 µmol, example 162A) in THF (3.0 ml) and methanol (1.5 ml) at RT was added 1M sodium hydroxide solution (2.1 ml, 2.1 mmol) and the mixture was stirred for 24 h at RT. The pH of the mixture was then adjusted to 3 with TFA (190 μl, 2.5 mmol) and purified by preparative HPLC (Method 20). The combined desired fractions were concentrated and the residue was dried in vacuo. 154 mg (100% pure, 83% th. y.) of the title compound were obtained.

LC-MS (Method 2): Rt = 1.01 min; MS (ESIpos): m/z = 521/523 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 0.008 (1.16), 1.234 (0.44), 1.637 (16.00), 2.085 (1.65), 3.769 (1.31), 3.781 (1.45), 3.803 (1.60 ), 3.816 (1.47), 4.251 (1.65), 4.269 (1.82), 4.284 (1.61), 4.304 (1.50), 5.754 (2.61), 7.153 (1.37), 7.173 (1.89), 7.183 (1.90), 7.206 (3.41 ), 7.226 (1.71), 7.353 (1.43), 7.365 (1.34), 7.389 (2.06), 7.409 (2.94), 7.429 (1.47), 7.477 (0.62), 7.488 (1.54), 7.491 (1.60), 7.501 (5.13 ), 7.509 (4.63), 7.521 (12.78), 7.525 (11.60), 7.533 (6.95), 7.831 (2.36), 7.836 (2.20), 7.853 (3.67), 7.858 (3.58), 7.922 (7.11), 7.944 (4.32 ), 8.624 (1.49), 8.638 (2.12), 8.656 (1.47).

Separation of enantiomers.

The title target compound (137 mg) was dissolved in methanol (17 ml) and separated into enantiomers by chiral phase preparative SLC (see Examples 30 and 31) [column: Daicel Chiralpak AD, 250 mm x 20 mm; flow: 80 ml/min; detection: 210 nm; temperature: 40°C; sample injection: 1.0 ml; eluent: 70% carbon dioxide / 30% methanol; duration of action 7 min, isocratic]. The combined desired fractions were concentrated and the residue was dried in vacuo.

Example 30 (+)-3-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-2-(2-fluorophenyl)-2methylpropionic acid (enantiomer 1)

Separation of the enantiomers as described in Example 29 gave 46 mg (97% pure, ee value 100%) of the title compound as the previously eluted enantiomer.

[a] _D20 = +71.4°, 589 nm, c = 0.37 ^g /100 ml, methanol.

LC-MS (Method 2): Rt = 1.03 min; MS (ESIpos): m/z = 521/523 [M+H] ⁺ .

- 141 040284

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 0.008 (0.62), 1.636 (16.00), 2.093 (1.40), 3.768 (1.33), 3.781 (1.46), 3.801 (1.60), 3.814 (1.48) ), 4.249 (1.59), 4.268 (1.74), 4.283 (1.54), 4.302 (1.43), 7.153 (1.34), 7.173 (1.85), 7.183 (1.86), 7.205 (3.32), 7.226 (1.68), 7.335 (0.83 ), 7.352 (1.42), 7.366 (1.32), 7.388 (2.03), 7.409 (2.90), 7.428 (1.48), 7.475 (0.62), 7.490 (1.52), 7.500 (4.83), 7.507 (4.32), 7.519 (12.55 ), 7.523 (11.56), 7.828 (2.08), 7.833 (2.00), 7.850 (3.30), 7.855 (3.33), 7.920 (6.27), 7.942 (3.91), 8.622 (1.47), 8.639 (2.12), 8.653 (1.46 ), 12.650 (2.52).

Example 31 (-)-3-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-2-(2-fluorophenyl)-2methylpropionic acid (enantiomer 2)

Separation of the enantiomers as described in Example 29 gave 56 mg (96% pure, ee value 100%) of the title compound as the later eluted enantiomer.

[a] _D20 = -70.5°, 589 nm, c = 0.39 ^g /100 ml, methanol.

LC-MS (Method 2): Rt = 1.03 min; MS (ESIpos): m/z = 521/523 [M+H]+.

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (1.52), 0.008 (1.28), 1.030 (0.98), 1.045 (0.99), 1.283 (0.68), 1.636 (16.00), 2.092 (1.46) ), 2.522 (0.81), 3.768 (1.38), 3.780 (1.48), 3.801 (1.63), 3.814 (1.48), 4.249 (1.59), 4.267 (1.73), 4.282 (1.55), 4.301 (1.42), 7.152 (1.36 ), 7.173 (1.90), 7.182 (1.95), 7.205 (3.39), 7.225 (1.73), 7.335 (0.87), 7.350 (1.46), 7.366 (1.37), 7.388 (2.08), 7.408 (2.98), 7.428 (1.53 ), 7.475 (0.67), 7.486 (1.54), 7.490 (1.62), 7.499 (5.05), 7.507 (4.63), 7.519 (12.83), 7.523 (11.68), 7.531 (7.29), 7.827 (2.24), 7.833 (2.09 ), 7.850 (3.52), 7.855 (3.45), 7.919 (6.36), 7.942 (3.96), 8.622 (1.51), 8.636 (2.17), 8.653 (1.48), 12.654 (2.75).

Example 32 (+/-)-3-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-2-(2,6-difluorophenyl)2-methylpropionic acid (racemate )

To a solution of (+/-)-tert-butyl-3-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-2-(2,6difluorophenyl)-2-methylpropanoate (625 mg, 98% pure, 1.03 mmol, example 163A) in dichloromethane (7.3 ml) was added TFA (1.6 ml, 21 mmol) and the mixture was stirred overnight at RT. The mixture was then concentrated and mixed successively with dichloromethane several times and re-concentrated. The residue was purified by preparative HPLC (Method 20). The combined target fractions were concentrated and the resulting residue was dried in vacuo. 492 mg (98% pure, 87% thor.) of the title compound were obtained.

LC-MS (Method 2): Rt = 1.01 min; MS (ESIpos): m/z = 539/541 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (1.84), 0.008 (1.73), 1.761 (12.93), 2.073 (2.77), 2.159 (3.62), 2.327 (0.40), 2.523 (1.15) ), 3.787 (1.42), 3.800 (1.55), 3.820 (1.75), 3.834 (1.59), 4.196 (1.88), 4.214 (2.04), 4.230 (1.79), 4.248 (1.62), 7.047 (3.11), 7.069 (5.05 ), 7.094 (3.52), 7.377 (1.49), 7.394 (2.01), 7.410 (1.37), 7.480 (1.03), 7.492 (2.99), 7.507 (8.37), 7.513 (6.86), 7.525 (13.93), 7.538 (16.00 ), 7.555 (3.11), 7.839 (3.67), 7.845 (3.43), 7.862 (5.71), 7.867 (5.61), 7.933 (10.68), 7.955 (6.66), 8.796 (2.23), 8.812 (3.84), 8.828 (2.16 ), 12.833 (0.42).

Separation of enantiomers.

The title target compound (450 mg) was dissolved in isopropanol (5 ml) and separated into enantiomers by chiral phase preparative HPLC (see Examples 33 and 34) [column: Daicel Chiralpak AF, 5 μm, 250 mm x 20 mm; flow: 15 ml/min; detection: 220 nm; temperature: 55°C; sample injection: 0.3 ml; eluent: 50% heptane/(50% isopropanol + 0.2% acetic acid); duration of action 10 min, isocratic]. The combined target fractions were concentrated and the residue was lyophilized.

Example 33 (+)-3-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-2-(2,6-difluorophenyl)2-methylpropionic acid (enantiomer 1) .

Separation of the enantiomers as described in Example 32 gave 211 mg (98% pure, ee value 99%) of the title compound as the previously eluted enantiomer.

[a] _D20 = +62.7°, 589 nm ^, c = 0.25 g/100 mL, methanol.

LC-MS (Method 1): Rt = 1.92 min; MS (ESIpos): m/z = 539/541 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.762 (13.17), 2.073 (4.25), 2.160 (3.79), 3.788 (1.60), 3.801 (1.75), 3.821 (1.98), 3.835 (1.83) , 4.197 (1.96), 4.215 (2.12), 4.231 (1.85), 4.249 (1.66), 7.047 (3.15), 7.070 (5.21), 7.094 (3.51), 7.376 (1.54), 7.393 (2.06), 7.411 (1.42) . , 7.861 (5.25), 7.867

- 142 040284 (4.98), 7.933 (9.45), 7.955 (5.90), 8.797 (2.25), 8.813 (3.94), 8.829 (2.17), 12.831 (0.43).

Example 34 (-)-3-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-2-(2,6-difluorophenyl)-2methylpropionic acid (enantiomer 2)

Separation of enantiomers as described in Example 32 yielded 209 mg (98% pure, ee value

99%) of the title compound as the later eluted enantiomer.

[a]D ²⁰ = -50.8°, 589 nm, c = 0.42 g/100 ml, methanol.

LC-MS (Method 1): R _t = 1.92 min; MS (ESIpos): m/z = 539/541 [M+H]+.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 1.761 (13.10), 2.073 (1.14), 2.159 (3.74), 2.328 (0.45), 2.669 (0.41), 3.787 (1.42), 3.801 ( 1.54), 3.821 (1.75), 3.835 (1.60), 4.196 (1.84), 4.213 (2.00), 4.230 (1.78),4.248 (1.62), 7.047 (3.13), 7.069 (5.21), 7.094 (3.54), 1.52) 3.42), 7.846 (3.18), 7.864 (5.38), 7.869 (5.24), 7.934 (10.00), 7.956 (6.16), 8.797 (2.20), 8.814 (3.90), 8.829 (2.18).

Example 35 (+/-)-3-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-2-(2-chlorophenyl)-2methylpropionic acid (racemate)

To a solution of (+/-)-methyl-3-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-2-(2-chlorophenyl)-2-methylpropanoate (540 mg, 978 µmol, example 164A) in THF (8.4 ml) and methanol (120 µl) at RT was added 1M sodium hydroxide solution (5.9 ml, 5.9 mmol) and the mixture was stirred for 8 h at 40°C. Then sodium hydroxide solution (5.9 ml, 5.9 mmol) was added again and the mixture was stirred for an additional 56 h at 40°C. The pH of the mixture was then adjusted to 3 with TFA and purified by preparative HPLC (Method 16). The combined target fractions were concentrated and the residue was lyophilized. 296 mg (98% pure, 55% th. y.) of the title compound were obtained.

LC-MS (Method 2): R _t = 1.03 min; MS (ESIpos): m/z = 537/539 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: -0.007 (1.18), 0.008 (0.90), 1.646 (1.14), 1.688 (14.53), 2.073 (1.84), 2.523 (0.85), 2.731 ( 5.71), 2.890 (7.16), 3.792 (1.39), 3.804 (1.61), 3.825 (1.65), 3.838 (1.60), 4.526 (1.74), 4.545 (1.94) 1.71) 5.16) 4.22), 7.952 (1.10), 8.563 (1.62), 8.576 (2.18), 8.581 (2.18), 8.595 (1.59).

Separation of enantiomers.

The title target compound (275 mg) was dissolved in ethanol (10 ml) and separated into enantiomers by chiral phase preparative HPLC (see examples 36 and 37) [column: YMC Chiralart Amylose SA, 5 μm, 250 mm x 30 mm ; flow: 30 ml/min; detection: 220 nm; temperature: 40°C; sample injection: 0.5 ml; eluent: 50% heptane/(50% ethanol + 0.2% acetic acid); duration of action 9.5 min, isocratic]. The combined target fractions were concentrated and the residue was lyophilized.

Example 36 (-)-3-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-2-(2-chlorophenyl)-2methylpropionic acid (enantiomer 1)

Separation of the enantiomers as described in Example 35 gave the prepurified title compound as the previously eluted enantiomer (ee value 99%) and further purified by preparative HPLC (Method 15). 68 mg (98% pure) of the title compound were obtained.

[a] _D20 = -94.8°, 589 nm ^, c = 0.40 g/100 ml, chloroform.

LC-MS (Method 2): R _t = 1.03 min; MS (ESIpos): m/z = 357/539 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: -0.008 (3.09), 0.008 (2.81), 1.294 (0.51), 1.645 (0.42), 1.687 (14.26), 2.073 (1.20), 2.328 ( 0.54), 2.366 (0.43), 2.518 (2.16), 2.523 (1.63), 2.670 (0.50), 3.790 (1.44), 3.803 (1.59), 3.824 (1.70), 3.837 (1.59), 4.395 (0.60), 2.20), 4.544 (2.37), 4.559 (2.19), 4.579 (2.04), 7.323 (1.68), 7.340 (3.24), 7.354 (2.51), 7.372 (1.03) 4.68) 2.22), 7.834 (2.09), 7.851 (3.55), 7.856 (3.52), 7.917 (6.88), 7.939 (4.19), 8.561 (1.60), 8.575 (2.13), 8.580 (2.12), 8.593 (1.54).

Example 3 7. (+)-3-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-2-(2-chlorophenyl)-2methylpropionic acid (enantiomer 2)

- 143 040284

The separation of enantiomers described in Example 35 gave the prepurified title compound as a later eluting enantiomer (ee value 99%) and further purified by preparative HPLC (Method 15). 99 mg (98% pure) of the title compound were obtained.

[a] _D20 = +96.8°, 589 nm, c = 0.33 g/100 mL ^, chloroform.

LC-MS (Method 2): R _t = 1.03 min; MS (ESIpos): m/z = 537/539 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: -0.008 (2.30), 0.008 (1.81), 1.645 (1.12), 1.687 (14.19), 2.072 (1.44), 2.522 (1.04), 3.790 ( 1.48), 3.803 (1.68), 3.824 (1.74), 3.837 (1.71), 4.174 (0.72), 4.191 (0.70), 4.207 (0.68), 4.226 (0.65), 4.525 (1.83), 4.544 (1.97), 1.83) 4.578 (1.68) 7.322 (1.70) 7.339 (3.25) 2.82) 6.47), 7.929 (0.56), 7.939 (3.95), 8.561 (1.58), 8.575 (2.15), 8.579 (2.13), 8.593 (1.54).

Example 38 (+/-)-3-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-2-fluoro-2-phenyl propionic acid (racemate)

To a solution of (+/-)-ethyl-3-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-2-fluorohydrotropate (196 mg, 366 µmol, Example 165A) in THF (3.0 ml) and methanol (1.5 ml) at RT was added 1 M sodium hydroxide solution (2.2 ml, 2.2 mmol) and the mixture was stirred for 2.5 h at RT. The pH of the mixture was then adjusted to 3 with TFA (200 μl, 2.6 mmol) and purified by preparative HPLC (Method 16). The combined desired fractions were concentrated and the residue was dried in vacuo. Received 167 mg (100% pure, 90% theoretical. yield.) specified in the title compound.

LC-MS (Method 2): R _t = 0.95 min; MS (ESIpos): m/z = 507/509 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 2.085 (1.43), 2.149 (1.02), 2.327 (0.60), 2.347 (0.53), 3.169 (1.97), 3.184 (1.79), 4.255 (1.04) . . , 7.849 (4.09), 7.926 (8.71), 7.949 (5.53), 9.118 (2.79), 13.835 (1.53).

Separation of enantiomers.

The title target compound (140 mg) was dissolved in 15 ml of a mixture of methanol acetonitrile and separated into enantiomers by preparative chiral phase SLC (see Examples 39 and 40) [column: Daicel Chiralpak AD, 250 mm x 20 mm; flow: 80 ml/min; detection: 210 nm; temperature: 40°C; sample injection: 2.0 ml; eluent: 75% carbon dioxide / 25% isopropanol; duration of action 8 min, isocratic]. The combined desired fractions were concentrated and the residue was dried in vacuo.

Example 39 (-)-3-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-2-fluoro-2-phenylpropionic acid (enantiomer 1)

Separation of the enantiomers as described in Example 38 gave 58 mg (95% pure, ee value 100%) of the title compound as the previously eluted enantiomer.

[a] _D20 = -27.0°, 589 nm, c = 0.38 ^g /100 ml, methanol.

LC-MS (Method 1): Rt = 1.77 min; MS (ESIpos): m/z = 507/509 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: -0.008 (2.19), 0.008 (1.92), 2.119 (0.93), 2.263 (1.83), 2.327 (0.73), 2.366 (0.41), 2.429 ( 0.68), 2.669 (0.47), 4.200 (0.52), 4.238 (0.96), 4.280 (0.77), 4.353 (0.80), 4.370 (0.83), 4.389 (0.64), 4.414 (1.03), 4.432 (0.89), 0.62), 4.468 (0.55), 7.453 (4.07), 7.472 (5.44), 7.488 (4.67), 7.502 (7.86), 7.509 (6.85), 7.522 (16.00), 7.562 (1.88), 7.580 (9.87), 7.25), 7.826 (2.75),7.830 (2.82), 7.848 (3.96), 7.852 (3.89), 7.863 (0.90), 7.886 (0.77), 7.891 (0.73), 7.924 (8.83), 7.947 (5.69), 1.16), 7.985 (0.86), 9.102 (2.47), 9.170 (0.44), 13.870 (0.52).

Example 40 (+)-3-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-2-fluoro-2phenylpropionic acid (enantiomer 2)

Separation of the enantiomers as described in Example 38 gave 41 mg (100% pure, ee value 100%) of the title compound as the later eluted enantiomer.

[a] _D20 = +26.2°, 589 nm, c = 0.40 g ^/ 100 mL, methanol.

LC-MS (Method 1): R _t = 1.77 min; MS (ESIpos): m/z = 507/509 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 2.148 (1.06), 2.327 (0.82), 2.668 (0.55), 4.238 (1.10), 4.283

- 144 040284 (0.84), 4.370 (0.89), 4.414 (1.03), 7.454 (4.26), 7.473 (5.72), 7.488 (4.83), 7.502 (7.38), 7.509 (6.94), 7.522 (16.00), 7.580 (9.88) ), 7.599 (7.46), 7.826 (2.84), 7.848 (4.32), 7.924 (9.20), 7.947 (5.83), 9.103 (2.71), 13.871 (0.63).

Example 41 (+/-)-3-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-2-methyl-2-[3-(trifluoromethyl)phenyl]propionic acid (racemate)

F

To a solution of (+/-)-ethyl-3-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-2-methyl-2-[3(trifluoromethyl)phenyl] propanoate (550 mg, 939 µmol, Example 166A) in THF (8.0 mL) and methanol (4.0 mL) 1M sodium hydroxide solution (5.6 mL, 5.6 mmol) was added at RT and the mixture was stirred for 24 h at RT. The pH of the mixture was then adjusted to 3 with TFA (510 μl, 6.6 mmol) and purified by preparative HPLC (Method 20). The combined desired fractions were concentrated and the residue was dried in vacuo. 480 mg (98% pure, 88% thor.) of the title compound were obtained.

LC-MS (Method 1): R _t = 2.10 min; MS (ESIpos): m/z = 571/573 [M+H]+.

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: -0.008 (0.47), 0.008 (0.41), 1.693 (15.91), 2.040 (0.83), 2.073 (0.93), 3.652 (0.97), 3.817 ( 1.22), 3.829 (1.29), 3.851 (1.44), 3.863 (1.30), 4.293 (0.94), 4.311 (1.01), 4.326 (0.92), 4.345 (0.81), 7.486 (1.18), 7.499 (3.81), 4.35) 1.86), 7.831 (1.75),7.848 (2.83), 7.853 (2.78), 7.925 (5.80), 7.947 (3.73), 8.700 (1.33), 8.713 (1.87), 8.717 (1.87), 8.730 (1.32).

Separation of enantiomers.

The title target compound (430 mg) was dissolved in 20 ml of methanol acetonitrile and separated into enantiomers by preparative chiral phase SLC (see Examples 42 and 43) [column: Daicel Chiralpak AD, 250 mm x 20 mm; flow: 80 ml/min; detection: 210 nm; temperature: 40°C; sample injection: 0.8 ml; eluent: 82% carbon dioxide / 18% ethanol; duration of action 10 min, isocratic]. The combined desired fractions were concentrated and the residue was dried in vacuo.

Example 42 (-)-3-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-2-methyl-2-[3-(trifluoromethyl)phenyl]propionic acid ( enantiomer 1).

Separation of the enantiomers as described in Example 41 gave the prepurified title compound as the previously eluted enantiomer (ee value 100%) and further purified by preparative HPLC (Method 20). The combined target fractions were concentrated and lyophilized. 180 mg (98% pure) of the title compound were obtained.

[a] _D20 = -36.7°, 589 nm, c = 0.40 ^g /100 ml, methanol.

LC-MS (Method 1): Rt = 2.08 min; MS (ESIpos): m/z = 571/573 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 1.195 (0.51), 1.211 (0.52), 1.694 (15.62), 2.042 (0.84), 2.073 (0.85), 3.819 (1.17), 3.831 (1.22 ), 3.853 (1.38), 3.865 (1.24), 4.294 (1.09), 4.311 (1.14), 4.327 (1.03), 4.347 (0.92), 7.499 (4.11), 7.507 (4.61), 7.517 (16.00), 7.621 (1.03 ), 7.640 (2.46), 7.659 (2.45), 7.675 (2.86), 7.695 (1.30), 7.728 (4.32), 7.762 (2.63), 7.781 (1.95), 7.827 (2.02), 7.832 (1.88), 7.849 (3.02 ), 7.854 (2.93), 7.926 (6.33), 7.948 (3.99), 8.701 (1.33), 8.714 (1.83), 8.732 (1.24).

Example 43 (+)-3-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-2-methyl-2-[3-(trifluoromethyl)phenyl]propionic acid ( enantiomer 2).

The separation of enantiomers described in Example 41 gave the prepurified title compound as a later eluting enantiomer (ee value 99%) and further purified by preparative HPLC (Method 20). The combined target fractions were concentrated and lyophilized. 164 mg (98% pure) of the title compound were obtained.

[a] _D20 = +30.4°, 589 nm ^, c = 0.43 g/100 mL, methanol.

LC-MS (Method 1): Rt = 2.08 min; MS (ESIpos): m/z = 571/573 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: -0.008 (0.61), 0.008 (0.58), 1.693 (16.00), 2.038 (0.80), 2.523 (0.55), 3.818 (1.10), 3.830 ( 1.19), 3.852 (1.36), 3.864 (1.22), 4.293 (0.93), 4.311 (1.02), 4.327 (0.93), 4.345 (0.81) 4.56), 7.518 (15.96), 7.531 (4.11), 7.621 (0.98), 7.639 (2.40), 7.659 (2.40), 7.676 (2.70) 1.92) 1.29).

- 145 040284

Example 44 (+/-)-3-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-2-(3-methoxyphenyl)propionic acid (racemate)

To a suspension of (+/-)-tert-butyl-3-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-2-(3methoxyphenyl)propanoate (940 mg, 1.63 mmol, example 167A) in dichloromethane (26 ml) at RT was added TFA (13 ml, 160 mmol) and the mixture was stirred 16 h at RT. The mixture was then concentrated and the residue was mixed successively with dichloromethane several times and re-concentrated. The residue was then dried in vacuo. 1.01 g (99% pure, >100% th. y., TFA-resp. containing solvent) of the title compound was obtained.

LC-MS (Method 1): R= 1.85 min; MS (ESIpos): m/z = 519/521 [M+H] ⁺ .

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: -0.149 (0.58), 0.008 (5.19), 0.147 (0.63), 2.160 (5.22), 2.327 (1.01), 2.366 (0.56), 2.670 (1.08), 3.760 (1.54), 3.826 (1.78), 3.845 (3.51), 3.861 (3.56), 3.877 (2.29) (2.53) (16.00) (1.64).

Separation of enantiomers.

The title target compound (400 mg) was dissolved in a mixture of ethanol, methanol and acetonitrile (respectively 5 ml) at elevated temperature and separated into enantiomers by chiral phase preparative HPLC (see Examples 45 and 46) [column: Daicel Chiralpak ID , 5 µm,

250 mm x 20 mm; flow: 15 ml/min; detection: 210 nm; temperature: 25°C; sample injection: 0.50 ml; eluent: 50% heptane/(50% ethanol + 0.2% acetic acid + 1% water); duration of action 18 min, isocratic]. The combined target fractions were concentrated and the residue was lyophilized in acetonitrile/water.

Example 45 (-)-3-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-2-(3-methoxyphenyl)propionic acid (enantiomer 1)

Separation of the enantiomers as described in Example 44 gave 122 mg (95% pure, ee value 99%) of the title compound as the previously eluted enantiomer.

[a] _D20 = -39.2°, 589 nm, c = 0.44 ^g /100 ml, methanol.

LC-MS (Method 1): Rt = 1.86 min; MS (ESIpos): m/z = 519/529 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 1.030 (1.19), 1.045 (1.18), 1.154 (0.57), 1.375 (0.48), 2.159 (6.15), 2.213 (1.48), 3.313 (8.74 ), 3.723 (2.36), 3.792 (0.68), 3.812 (1.00), 3.825 (2.18), 3.844 (3.99), 3.860 (4.09), 3.875 (2.49), 3.895 (0.83), 3.908 (0.70), 3.922 (0.42 ), 3.955 (3.11), 3.974 (4.32), 3.994 (1.63), 6.873 (2.90), 6.893 (3.29), 6.923 (6.09), 6.947 (3.91), 6.966 (4.03), 7.276 (3.32), 7.296 (5.16 ), 7.315 (2.59), 7.481 (1.36), 7.495 (2.74), 7.506 (6.47), 7.513 (6.14), 7.526 (16.00), 7.529 (15.41), 7.756 (1.44), 7.839 (2.93), 7.844 (2.59 ), 7.861 (4.27), 7.867 (3.96), 7.937 (7.45), 7.959 (4.74), 8.944 (1.97), 8.958 (3.49), 8.971 (1.77), 12.609 (0.55).

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 12.61 (br. s, 1H), 8.96 (t, 1H), 7.95 (d, 1H), 7.86 (dd, 1H), 7.76 (br. s, 1H), 7.59-7.40 (m, 5H), 7.30 (t, 1H), 7.01-6.83 (m, 3H), 4.03-3.93 (m, 1H), 3.92-3.77 (m, 2H), 3.74 ( s, 3H), 2.16 (br. s, 3H).

Example 46 (+)-3-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-2-(3-methoxyphenyl)propionic acid (enantiomer 1)

Separation of the enantiomers as described in Example 44 gave 123 mg (95% pure, ee value 98%) of the title compound as the later eluted enantiomer.

[a] _D20 = +49.0°, 589 nm, c = 0.37 g/100 mL ^, methanol.

LC-MS (Method 1): Rt = 1.86 min; MS (ESIpos): m/z = 519/521 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 0.008 (1.50), 1.030 (3.72), 1.045 (3.75), 1.156 (0.53), 1.283 (0.56), 1.909 (0.81), 2.159 (5.77) ), 2.213 (1.18), 2.523 (1.58), 3.313 (11.20), 3.650 (0.45), 3.723 (1.63), 3.792 (0.55), 3.812 (0.80), 3.825 (1.95), 3.845 (3.74), 3.861 (3.87 ), 3.876 (2.36), 3.896 (0.75), 3.909 (0.60), 3.957 (2.87), 3.976 (4.15), 3.995 (1.55), 6.869 (2.25), 6.874 (2.64), 6.889 (2.52), 6.895 (3.00 ), 6.923 (5.90), 6.947 (3.79), 6.966 (4.00), 7.277 (3.34), 7.296 (5.24), 7.316 (2.69), 7.481 (0.79), 7.493 (1.86), 7.496 (2.08), 7.506 (5.87 ), 7.514 (5.67), 7.526 (16.00), 7.529 (15.28), 7.538 (8.90), 7.756 (1.29), 7.840 (2.99), 7.845 (2.60), 7.862 (4.46), 7.868 (4.12), 7.938 (7.77 ), 7.960 (5.00), 8.945 (1.80), 8.958 (3.36), 8.972 (1.72), 12.595 (0.45).

- 146 040284

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 12.59 (br. s, 1H), 8.96 (t, 1H), 7.95 (d, 1H), 7.86 (dd, 1H), 7.76 (br s, 1H), 7.58-7.47 (m, 5H), 7.30 (t, 1H), 7.00-6.85 (m, 3H), 4.02-3.94 (m, 1H), 3.92-3.78 (m, 2H), 3.75 (s,

3H), 2.16 (br. s, 3H).

Example 47 (+/-)-3-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-2-(3-chlorophenyl)propionic acid (racemate)

To a solution of (+/-)-tert-butyl-3-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-2-(3chlorophenyl)propanoate (430 mg, 741 µmol, example 168A) in dichloromethane (12 ml) was added TFA (5.7 ml, 74 mmol) and the mixture was stirred for 16 h at RT. The mixture was then concentrated and mixed successively with dichloromethane several times and re-concentrated. The residue was dried in vacuo. 420 mg (96% pure, >100% theoretical yield, TFA-resp. containing solvent) of the title compound were obtained.

LC-MS (Method 1): Rt = 1.97 min; MS (ESIpos): m/z = 523/525 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (2.98), 0.008 (2.34), 2.134 (3.31), 2.328 (0.48), 2.670 (0.49), 3.878 (2.54), 3.896 (4.45) ), 3.911 (3.63), 4.017 (2.62), 4.036 (3.82), 4.056 (1.58), 5.754 (0.64), 7.358 (2.19), 7.376 (5.07), 7.394 (4.03), 7.406 (5.31), 7.424 (3.24 ), 7.438 (6.04), 7.483 (0.52), 7.497 (1.49), 7.507 (4.79), 7.515 (4.57), 7.526 (16.00), 7.537 (7.13), 7.703 (0.59), 7.842 (2.44), 7.848 (2.23 ), 7.865 (3.83), 7.870 (3.74), 7.937 (7.12), 7.959 (4.51), 8.944 (1.58), 8.958 (3.38), 8.972 (1.65).

Separation of enantiomers.

The title target compound (350 mg) was dissolved in a mixture of ethanol, methanol and acetonitrile (respectively 5 ml) at elevated temperature and separated into enantiomers by chiral phase preparative HPLC (see Examples 48 and 49) [column: Daicel Chiralpak AD -H, 5 µm, 250 mm x 20 mm; flow: 15 ml/min; detection: 210 nm; temperature: 25°C; sample injection: 0.50 ml; eluent: 40% heptane/(60% ethanol + 0.2% acetic acid + 1% water); duration of action 25 min, isocratic]. The combined target fractions were concentrated and the residue was lyophilized in acetonitrile/water.

Example 48 (-)-3-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-2-(3-chlorophenyl)propionic acid (enantiomer 1)

Separation of the enantiomers as described in Example 47 gave 124 mg (98% pure, ee value 99%) of the title compound as the previously eluted enantiomer.

[a] _D20 = -47.8°, 589 nm, c = 0.35 ^g /100 ml, methanol.

LC-MS (Method 2): R _t = 1.04 min; MS (ESIpos): m/z = 523/525 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (0.80), 0.008 (0.84), 1.140 (0.42), 1.158 (0.83), 1.177 (0.45), 1.234 (0.68), 1.909 (0.61 ), 2.135 (3.30), 2.188 (0.80), 2.269 (0.47), 2.523 (1.08), 2.788 (0.47), 3.182 (0.45), 3.878 (2.56), 3.897 (4.40), 3.911 (3.57), 4.018 (2.57 ), 4.036 (3.71), 4.056 (1.54), 7.358 (2.47), 7.362 (1.62), 7.376 (5.32), 7.380 (4.48), 7.394 (4.20), 7.406 (5.47), 7.424 (3.37), 7.438 (6.11 ), 7.471 (0.46), 7.482 (0.72), 7.495 (1.84), 7.505 (5.22), 7.513 (5.03), 7.524 (16.00), 7.532 (9.04), 7.536 (7.10), 7.539 (6.31), 7.547 (1.52 ), 7.701 (0.63), 7.839 (2.61), 7.844 (2.37), 7.861 (4.00), 7.867 (3.82), 7.935 (7.41), 7.957 (4.72), 8.943 (1.63), 8.957 (3.35), 8.971 (1.56 ), 12.729 (0.57).

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 12.73 (br. s, 1H), 8.96 (t, 1H), 7.94 (d, 1H), 7.86 (dd, 1H), 7.70 (br . s, 1H), 7.57-7.46 (m, 5H), 7.45-7.33 (m, 4H), 4.03 (t, 1H), 3.90 (t, 2H), 2.14 (br. s, 3H).

Example 49 (+)-3-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-2-(3-chlorophenyl)propionic acid (enantiomer 2)

Separation of the enantiomers as described in Example 47 gave 106 mg (98% pure, ee value 99%) of the title compound as the later eluted enantiomer.

[a] _D20 = +46.2°, 589 nm, c = 0.34 ^g /100 mL, methanol.

LC-MS (Method 2): R _t = 1.04 min; MS (ESIpos): m/z = 523/525 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 1.140 (0.54), 1.158 (1.07), 1.176 (0.63), 1.234 (1.23), 2.134 (3.40), 2.188 (0.86), 2.327 (0.41 ), 2.669 (0.41), 3.877 (2.52), 3.895 (4.35), 3.910 (3.44), 4.016 (2.32), 4.035 (z.40), 4.054 (1.39), 7.357 (2.29), 7.375 (5.14), 7.393 (4.06) (0.66)

- 147 040284 (0.42).

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 12.67 (br. s, 1H), 8.96 (t, 1H), 7.94 (d, 1H), 7.86 (dd, 1H), 7.70 (br . s, 1H), 7.57-7.47 (m, 5H), 7.46-7.33 (m, 4H), 4.03 (t, 1H), 3.90 (t, 2H), 2.13 (br. s, 3H).

Example 50 (+/-)-3-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-2-(3-methylphenyl)propionic acid (racemate)

To a solution of (+/-)-tert-butyl-3-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-2-(3methylphenyl)propanoate (830 mg, 1.48 mmol, example 169A) in dichloromethane (24 ml) was added TFA (11 ml, 150 mmol) and the mixture was stirred for 16 h at RT. The mixture was then concentrated and mixed successively with dichloromethane several times and re-concentrated. The residue was dried in vacuo. 920 mg (92% pure, >100% theoretical yield, TFA-resp. containing solvent) of the title compound were obtained.

LC-MS (Method 2): R _t = 1.03 min; MS (ESIpos): m/z = 503/505 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 0.008 (1.20), 2.167 (3.60), 2.303 (16.00), 2.327 (0.50), 2.523 (1.18), 3.782 (0.63), 3.797 (1.15) ), 3.814 (1.25), 3.831 (0.97), 3.846 (0.81), 3.864 (1.13), 3.878 (1.33), 3.898 (0.70), 3.910 (0.64), 3.940 (2.04), 3.959 (2.94), 3.978 (1.10 ), 4.359 (1.54), 7.112 (1.44), 7.131 (1.85), 7.161 (1.65), 7.189 (3.89), 7.247 (2.11), 7.265 (3.01), 7.284 (1.15), 7.498 (0.97), 7.508 (3.33 ), 7.515 (2.94), 7.528 (8.62), 7.532 (8.10), 7.540 (4.93), 7.752 (0.56), 7.846 (1.70), 7.851 (1.50), 7.868 (2.62), 7.873 (2.47), 7.940 (4.71 ), 7.962 (2.96), 8.943 (1.05), 8.957 (2.00), 8.971 (1.04).

Separation of enantiomers.

The title target compound (400 mg) was dissolved in a mixture of ethanol, methanol and acetonitrile (respectively 5 ml) at elevated temperature and separated into enantiomers by chiral phase preparative HPLC (see examples 51 and 52) [column: Daicel Chiralpak AD -H, 5 µm, 250 mm x 20 mm; flow: 15 ml/min; detection: 210 nm; temperature: 25°C; sample injection: 0.50 ml; eluent: 30% heptane/(70% ethanol + 0.2% acetic acid + 1% water); duration of action 26 min, isocratic]. The combined target fractions were concentrated and the residue was lyophilized in acetonitrile/water.

Example 51 (-)-3-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-2-(3-methylphenyl)propionic acid (enantiomer 1)

The separation of the enantiomers described in Example 50 gave 131 mg (98% pure, 99% ee) of the title compound as the previously eluted enantiomer.

[a] _D20 = -53.2°, 589 nm, c = 0.33 ^g /100 ml, methanol.

LC-MS (Method 2): R _t = 1.03 min; MS (ESIpos): m/z = 503/505 [M+H] ⁺ .

'H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 0.008 (0.44), 1.908 (0.56), 2.167 (3.72), 2.222 (0.42), 2.303 (16.00), 2.523 (0.60), 3.782 ( 0.58), 3.797 (1.07), 3.814 (1.15), 3.831 (0.87), 3.845 (0.72), 3.864 (1.03),3.877 (1.20), 3.896 (0.58), 3.909 (0.55), 3.938 (1.86), 3.957 ( 2.71), 3.976 (0.92), 7.111 (1.46), 7.129 (1.89), 7.161 (1.67), 7.189 (3.87), 7.245 (2.14), 7.264 (2.99), 7.283 (1.16), 7.481 (0.44), 1.04) 2.54), 7.869 (2.37), 7.938 (4.63), 7.960 (2.95), 8.940 (1.05), 8.954 (1.95), 8.968 (1.01).

'H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 12.60 (br. s, 1H), 8.95 (t, 1H), 7.95 (d, 1H), 7.86 (dd, 1H), 7.75 ( br. s, 1H), 7.58-7.46 (m, 5H), 7.26 (t, 1H), 7.22-7.08 (m, 3H), 4.01-3.73 (m, 3H), 2.30 (s, 3H), 2.17 ( br. s, 3H).

Example 52 (+)-3-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-2-(3-methylphenyl)propionic acid (enantiomer 2)

The separation of enantiomers described in Example 50 gave 119 mg (98% pure, 99% ee) of the title compound as the later eluted enantiomer.

[a] _D20 = +53.0°, 589 nm, c = 0.39 g/100 mL ^, methanol.

LC-MS (Method 2): R _t = 1.04 min; MS (ESIpos): m/z = 503/505 [M+H] ⁺ .

'H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (0.54), 0.008 (0.51), 1.235 (0.42), 2.166 (3.68), 2.303 (16.00), 2.522 (0.63), 3.782 ( 0.56), 3.796 (1.05), 3.814 (1.14), 3.830 (0.86), 3.845 (0.71), 3.864 (1.03), 3.877 (1.20), 3.897 (0.57), 3.909 (0.53), 3.939 (1.82), 2.69), 3.976 (0.91), 7.111 (1.46), 7.129 (1.86), 7.161 (1.64), 7.188 (3.81), 7.245 (2.14), 7.264 (3.00), 7.283 (1.16), 7.480 (0.47), 1.02), 7.495 (1.04),7.506 (3.33), 7.513 (2.98), 7.525 (8.39), 7.530 (7.87), 7.538 (4.96), 7.550 (0.96), 7.747 (0.57), 7.841 (1.72), 1.49), 7.863 (2.61), 7.869 (2.43), 7.937 (4.76), 7.960 (3.01), 8.940 (1.06), 8.953 (1.97), 8.967 (1.00).

- 148 040284

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 12.53 (br. s, 1H), 8.95 (t, 1H), 7.95 (d, 1H), 7.86 (dd, 1H), 7.75 (br. s, 1H), 7.58-7.46 (m, 5H), 7.26 (t, 1H), 7.21-7.08 (m, 3H), 4.01-3.74 (m, 3H), 2.30 (s, 3H), 2.17 (br. s, 3H).

Example 5 3. (+/-)-3-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino }-2-hydroxy-2-(2methoxyphenyl)propionic acid (racemate)

But-

To a solution of (+/-)-methyl-3-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-2-hydroxy2-(2-methoxyphenyl)propanoate (220 mg , 400 µmol, example 170A) in THF (3.4 ml) and methanol (680 µl) was added 1 M sodium hydroxide solution (2.4 ml, 2.4 mmol) and the mixture was stirred for 4.5 h at RT. The pH of the mixture was then adjusted to 2-3 with TFA (220 μl, 2.8 mmol) and purified by preparative HPLC (Method 15). The combined target fractions were concentrated and the residue was lyophilized in acetonitrile/water. 202 mg (96% pure, 91% thor.) of the title compound were obtained.

LC-MS (Method 2): R _t = 0.93 min; MS (ESIpos): m/z = 535/537 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (1.70), 0.008 (1.71), 2.072 (3.41), 2.391 (0.68), 2.523 (0.85), 3.952 (0.89), 3.985 (1.08 ), 4.271 (0.86), 6.925 (1.75), 6.944 (3.55), 6.962 (2.03), 6.987 (2.93), 7.007 (3.32), 7.261 (1.33), 7.280 (2.11), 7.299 (1.08), 7.473 (0.64 ), 7.483 (1.54), 7.486 (1.71), 7.496 (4.98), 7.504 (4.81), 7.516 (16.00), 7.523 (8.90), 7.527 (7.34), 7.595 (2.60), 7.614 (2.38), 7.816 (2.42 ), 7.821 (2.23), 7.838 (3.87), 7.843 (3.77), 7.898 (7.48), 7.921 (4.40), 8.410 (1.49), 8.424 (2.08), 8.440 (1.37).

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 12.40 (br. s, 1H), 8.43 (t, 3H), 7.91 (d, 1H), 7.83 (dd, 1H), 7.69 (br. s, 1H), 7.61 (d, 1H), 7.55-7.46 (m, 5H), 7.28 (t, 1H), 7.06-6.88 (m, 2H), 6.41 (br. s, 1H), 4.35-4.20 ( m, 1H), 4.02–3.87 (m, 1H), 3.77 (s, 3H), 2.07 (br. s, 3H).

Example 54 (-)-3-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-2-hydroxy-2-(2-methoxyphenyl)propionic acid (enantiomer 1) .

To a solution of (-)-methyl-3-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-2-hydroxy-2(2-methoxyphenyl)propanoate (128 mg, 233 µmol, example 171A) in THF (2.0 ml) and methanol (500 µl) was added 1M sodium hydroxide solution (1.4 ml, 1.4 mmol) and the mixture was stirred for 4.5 h at RT. The pH of the mixture was then adjusted to 2-3 with TFA (130 μl, 1.6 mmol) and purified by preparative HPLC (Method 15). The combined desired fractions were concentrated and the residue was dried in vacuo. 120 mg (97% pure, ee 100%, 94% thor.) of the title compound were obtained.

[a] _D20 = -72.0°, 589 nm, c = 0.44 ^g /100 ml, methanol.

LC-MS (Method 2): R _t = 0.93 min; MS (ESIpos): m/z = 535/537 [M+H] ⁺ .

¹ H-NMR (500 MHz, DMSO-d6) δ [ppm]: -0.007 (0.79), 2.075 (3.30), 2.084 (3.40), 2.392 (0.65), 2.518 (0.53), 3.918 (0.70), 3.954 ( 0.92), 3.985 (1.11), 4.276 (1.10), 5.752 (1.38), 6.930 (2.20), 6.945 (4.59), 6.960 (2.58), 6.989 (3.67), 7.005 (4.06), 7.266 (1.49), 7.280 ( 2.47), 7.295 (1.31), 7.475 (0.99), 7.484 (2.53), 7.489 (1.94), 7.496 (5.04), 7.499 (4.90) 15.74) 1.89), 8.426 (2.86), 8.438 (1.97).

1H-NMR (500 MHz, DMSO-d ₆ ) δ [ppm]: 12.40 (br. s, 1H), 8.43 (t, 1H), 7.91 (d, 1H), 7.83 (dd, 1H), 7.67 (br s, 1H), 7.61 (d, 1H), 7.56-7.44 (m, 5H), 7.28 (t, 1H), 7.03-6.90 (m, 2H), 5.95 (br. s, 1H), 4.33-4.20 (m, 1H), 4.01-3.90 (m, 1H), 3.78 (s, 3H), 2.07 (br. s, 3H).

Example 55 (+)-3-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-2-hydroxy-2-(2-methoxyphenyl)propionic acid (enantiomer 2) .

To a solution of (+)-methyl-3-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-2-hydroxy-2(2-methoxyphenyl)propanoate (120 mg, 219 µmol, example 172A) in THF (1.9 ml) and methanol (470 µl) was added 1 M sodium hydroxide solution (1.3 ml, 1.3 mmol) and the mixture was stirred for 4.5 h at RT. The pH of the mixture was then adjusted to 2-3 with TFA (120 μl, 1.5 mmol) and purified by preparative HPLC (Method 15). The combined desired fractions were concentrated and the residue was dried in vacuo. 111 mg (96% pure, 99% ee, 91% thor.) of the title compound were obtained.

[a] _D20 = +71.7°, 589 nm, c = 0.41 g ^/ 100 mL, methanol.

LC-MS (Method 2): Rt = 0.93 min; MS (ESIpos): m/z = 535/537 [M+H] ⁺ .

1H-NMR (500 MHz, DMSO-d6) δ [ppm]: -0.006 (0.57), 2.085 (16.00), 2.392 (0.51), 2.518 (0.41), 3.918 (0.50), 3.949 (0.64), 3.985 (0.83 ), 4.275 (0.78), 5.752 (0.88), 6.931 (1.61), 6.945 (3.28), 6.961 (1.85), 6.989 (2.65), 7.006 (2.89), 7.265 (1.10), 7.280 (1.77), 7.295 (0.95 ), 7.476 (0.77), 7.485 (1.85), 7.490 (1.46), 7.497 (3.71), 7.500 (3.61), 7.502 (4.50), 7.516 (11.56), 7.521 (11.31), 7.526 (11.01), 7.600 (2.23 ), 7.614 (2.12), 7.820 (2.41), 7.824 (2.30), 7.838 (3.56), 7.842 (3.54), 7.902 (7.29), 7.920 (4.74), 8.415 (1.36), 8.427 (2.04), 8.439

- 149 040284 (1.38).

1H-NMR (500 MHz, DMSO-d ₆ ) δ [ppm]: 12.50 (br. s, 1H), 8.43 (t, 1H), 7.91 (d, 1H), 7.83 (dd, 1H), 7.68 (br . s, 1H), 7.61 (d, 1H), 7.55-7.46 (m, 5H), 7.28 (t, 1H), 7.04-6.90 (m, 2H), 5.94 (br. s, 1H), 4.36-4.19 (m, 1H), 4.03-3.88 (m, 1H), 3.78 (s, 3H), 2.08 (s, 3H).

Example 56 (+/-)-3-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-2-(2-fluoro-6-methoxyphenyl)propionic acid (racemate )

To a solution of (+/-)-tert-butyl-3-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-2-(2fluoro-6-methoxyphenyl)propanoate ( 40 mg, 67 µmol, example 173A) in dichloromethane (2 ml) was added with TFA (420 µl, 5.4 mmol) and the mixture was left for 5 days at RT. The mixture was then concentrated and mixed successively with dichloromethane several times and re-concentrated. The residue was adsorbed into dichloromethane and purified by preparative HPLC (Method 15). The combined target fractions were concentrated and the residue was lyophilized in acetonitrile/water. 34 mg (100% pure, 93% thor.) of the title compound were obtained.

LC-MS (Method 1): Rt = 1.85 min; MS (ESIpos): m/z = 537/539 [M+H] ⁺ .

1H-NMR (500 MHz, DMSO-d ₆ ) δ [ppm]: 1.234 (0.96), 2.173 (16.00), 3.754 (0.79), 4.098 (1.28), 4.109 (2.39), 4.121 (1.80), 4.135 (2.09) ), 4.147 (1.18), 4.356 (2.32), 4.367 (2.60), 4.373 (2.60), 4.385 (1.98), 6.804 (2.49), 6.822 (4.41), 6.840 (2.56), 6.878 (4.65), 6.895 (4.96 ), 7.273 (1.25), 7.289 (2.73), 7.303 (2.62), 7.320 (1.09), 7.474 (0.53), 7.477 (0.66), 7.482 (1.13), 7.491 (2.50), 7.493 (2.21), 7.497 (2.17 ), 7.503 (4.94), 7.505 (4.96), 7.508 (5.85), 7.522 (12.63), 7.528 (14.25), 7.532 (14.52), 7.544 (2.43), 7.753 (0.65), 7.843 (3.64), 7.847 (3.30 ), 7.860 (5.06), 7.865 (4.82), 7.932 (9.02), 7.949 (6.02), 8.785 (2.08), 8.797 (3.93), 8.809 (2.00).

1H-NMR (500 MHz, DMSO-d6) δ [ppm]: 12.51 (br. s, 1H), 8.80 (t, 1H), 7.94 (d, 1H), 7.85 (dd, 1H), 7.75 (br. s, 1H), 7.57-7.47 (m, 5H), 7.34-7.25 (m, 1H), 6.89 (d, 1H), 6.82 (t, 1H), 4.37 (dd, 1H), 4.19-4.06 (m, 1H), 3.84-3.73 (m, 1H, partially hidden), 3.80 (s, 3H), 2.17 (s, 3H).

Example 57 (-)-3-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-2-(2-fluoro-6-methoxyphenyl)propionic acid (enantiomer 1) .

To a solution of (-)-tert-butyl-3-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-2-(2fluoro-6-methoxyphenyl)propanoate (60 mg , 101 μmol, example 174A) in dichloromethane (3 ml) was added TFA (620 μl, 8.1 mmol) and the mixture was left for one day at RT. The mixture was then concentrated and mixed successively with dichloromethane several times and re-concentrated. The residue was adsorbed into dichloromethane and purified by preparative HPLC (Method 15). The combined target fractions were concentrated and the residue was lyophilized in acetonitrile/water. 55 mg (100% pure, >99% ee, 100% th. yield) of the title compound were obtained.

[a] _D20 = -82.2°, 589 nm, c = 0.42 ^g /100 ml, methanol.

LC-MS (Method 1): Rt = 1.86 min; MS (ESIpos): m/z = 537/539 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 2.171 (16.00), 3.743 (0.65), 3.764 (1.01), 4.088 (1.12), 4.102 (2.09), 4.117 (1.58), 4.136 (1.82) 4.150 (1.08), 4.348 (2.38), 4.363 (2.62), 4.370 (2.64), 4.385 (2.12), 6.799 (1.98), 6.821 (3.50), 6.843 (2.15), 6.876 (3.79), 6.897 (4.17) , 7.267 (1.10), 7.288 (2.42), 7.306 (2.34), 7.326 (0.97), 7.479 (0.56), 7.493 (1.54), 7.503 (4.89), 7.511 (4.31), 7.523 (14.02), 7.526 (13.66) , 7.535 (7.39), 7.744 (0.75), 7.842 (2.43), 7.846 (2.19), 7.864 (3.90), 7.869 (3.73), 7.930 (6.87), 7.952 (4.18), 8.781 (1.59), 8.796 (3.17) , 8.811 (1.58).

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 12.50 (br. s, 1H), 8.80 (t, 1H), 7.94 (d, 1H), 7.86 (dd, 1H), 7.74 (br. s, 1H), 7.56-7.46 (m, 5H), 7.35-7.25 (m, 1H), 6.89 (d, 1H), 6.82 (t, 1H), 4.37 (dd, 1H), 4.17-4.06 (m, 1H), 3.84-3.73 (m, 1H, partially hidden), 3.80 (s, 3H), 2.17 (s, 3H).

Example 58 (+)-3-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-2-(2-fluoro-6-methoxyphenyl)propionic acid (enantiomer 2) .

To a solution of (+)-tert-butyl-3-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-2-(2fluoro-6-methoxyphenyl)propanoate (70 mg , 118 μmol, example 175A) in dichloromethane (3.5 ml) was added TFA (730 μl, 9.4 mmol) and the mixture was left for one day at RT. The mixture was then concentrated and mixed successively with dichloromethane several times and re-concentrated. The residue was adsorbed into dichloromethane and purified by preparative HPLC (Method 15). The combined target fractions were concentrated and the residue was lyophilized in acetonitrile/water. Received first 65 mg (100% pure, ee-value > 99%, >100% theoretical yield, containing solvent) specified in

- 150 040284 connection header (see angle of rotation).

[a]D ²⁰ = +80.0°, 589 nm, c = 0.40 g/100 ml, methanol.

The solvent-containing product was lyophilized again in acetonitrile/water (see section Analytics). 55 mg (100% pure, 87% thor.) of the title compound were obtained.

LC-MS (Method 2): Rt = 0.99 min; MS (ESIpos): m/z = 537/539 [M+H] ⁺ .

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: -0.149 (0.69), -0.008 (7.09), 0.008 (5.65), 0.146 (0.72), 2.169 (16.00), 2.327 (1.61), 2.366 (1.38), 2.523 (5.32), 2.669 (1.64), 2.710 (1.35), 4.086 (1.44), 4.100 (2.33), 4.115 (1.73), 4.133 (1.97), 4.147 (1.20), 4.347 (1.94), 4.362 (2.18), 4.369 (2.15), 4.383 (1.61), 6.798 (2.06), 6.820 (3.56), 6.842 (2.21), 6.875 (3.83), 6.896 (4.19), 7.267 (1.14), 7.288 (2.39), 7.305 (2.39), 7.326 (0.99), 7.492 (1.61), 7.502 (5.02), 7.510 (4.52), 7.522 (14.71), 7.534 (7.06), 7.741 (0.81), 7.839 (2.60) 7.862 (4.10), 7.867 (3.83), 7.928 (7.33), 7.951 (4.46), 8.778 (1.59), 8.793 (3.14), 8.807 (1.59).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 12.52 (br. s, 1H), 8.79 (t, 1H), 7.94 (d, 1H), 7.86 (dd, 1H), 7.74 ( br. s, 1H), 7.56-7.46 (m, 5H), 7.35-7.24 (m, 1H), 6.89 (d, 1H), 6.82 (t, 1H), 4.37 (dd, 1H), 4.18-4.08 ( m, 1H), 3.80 (s, 3H), ca. 3.8 (1H, hidden), 2.17 (s, 3H).

Example 59 (-)-3-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-2-(2-methoxyphenyl)-2methylpropionic acid (enantiomer 1)

To a solution of (-)-tert-butyl-3-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-2-(2methoxyphenyl)-2-methylpropanoate (400 mg, 678 μmol, example 177A) in dichloromethane (10 ml) was added TFA (1.0 ml, 14 mmol) and the mixture was stirred overnight at RT. The mixture was then concentrated and mixed successively with dichloromethane several times and re-concentrated. The residue was purified by preparative HPLC (Method 16). The combined desired fractions were concentrated and the residue was dried in vacuo. 303 mg (98% pure, 99% ee, 82% thor.) of the title compound were obtained.

[a] _D20 = -85.8°, 589 nm, c = 0.30 g ^/ 100 ml, methanol.

LC-MS (Method 2): R _t = 1.01 min; MS (ESIpos): m/z = 533/535 [M+H] ⁺ .

¹ H-NMR (500 MHz, DMSO-d ₆ ) δ [ppm]: -0.007 (0.46), 1.594 (16.00), 2.071 (2.90), 2.085 (1.42), 3.718 (1.59), 3.728 (1.74), 3.744 (1.87), 3.755 (1.76), 4.314 (1.91), 4.329 (2.11), 4.341 (1.94), 4.356 (1.79) (3.20) 7.251 (5.49) (11.88), 7.523 (11.44), 7.528 (10.05), 7.539 (1.98), 7.831 (2.65), 7.836 (2.51), 7.849 (3.84) (1.69), 8.428 (2.27), 8.432 (2.33), 8.443 (1.73).

¹ H-NMR (500 MHz, DMSO-d6) δ [ppm]: 12.15 (br. s, 1H), 8.43 (dd, 1H), 7.93 (d, 1H), 7.84 (dd, 1H), 7.64 (br s, 1H), 7.56-7.45 (m, 5H), 7.31-7.22 (m, 2H), 7.01 (d, 1H), 6.95 (t, 1H), 4.34 (dd, 1H), 3.78 (s, 3H ), 3.74 (dd, 1H), 2.08 (br. s, 3H), 1.59 (s, 3H).

Example 60 (+)-3-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-2-(2-methoxyphenyl)-2methylpropionic acid (enantiomer 2)

To a solution of (+)-tert-butyl-3-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-2-(2methoxyphenyl)-2-methylpropanoate (400 mg, 678 μmol, example 178A) in dichloromethane (10 ml) was added TFA (1.0 ml, 14 mmol) and the mixture was stirred overnight at RT. The mixture was then concentrated and mixed successively with dichloromethane several times and re-concentrated. The residue was purified by preparative HPLC (Method 16). The combined desired fractions were concentrated and the residue was dried in vacuo. 133 mg (98% pure, 95% ee, 36% thor.) of the title compound were obtained.

[a] _D20 = +76.7°, 589 nm, c = 0.30 g/100 mL ^, methanol.

LC-MS (Method 2): R _t = 1.01 min; MS (ESIpos): m/z = 533/535 [M+H] ⁺ .

¹ H-NMR (500 MHz, DMSO-d6) δ [ppm]: -0.007 (0.43), 1.595 (16.00), 2.071 (2.05), 2.086 (1.47), 3.720 (1.58), 3.730 (1.73), 3.746 ( 1.89), 3.757 (1.78), 4.315 (1.89), 4.330 (2.10), 4.342 (1.94), 4.357 (1.78) 3.24), 7.252 (5.37), 7.267 (5.93), 7.281 (1.28), 7.481 (0.66), 7.490 (1.70), 7.492 (1.49), 7.494 (1.37), 7.502 (4.46), 7.507 (4.51), 11.46) 7.33), 7.938 (4.95), 8.419 (1.68), 8.430 (2.29), 8.434 (2.40), 8.444 (1.78).

¹ H-NMR (500 MHz, DMSO-d6) δ [ppm]: 8.43 (dd, 1H), 7.93 (d, 1H), 7.84 (dd, 1H), 7.64 (br. s, 1H), 7.56-151 040284

7.46 (m, 5H), 7.30-7.22 (m, 2H), 7.01 (d, 1H), 6.95 (t, 1H), 4.34 (dd, 1H), 3.79 (s, 3H), 3.74 (dd, 1H) , 2.09 (br. s,

3H), 1.60 (s, 3H).

Example 61 (+)-3-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-2-(2-chloro-6-fluorophenyl)-2-methylpropionic acid ( enantiomer 1)

To a solution of (+)-tert-butyl-3-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-2-(2chloro-6-fluorophenyl)-2-methylpropanoate (150 mg, 245 µmol, example 180A) in dichloromethane (1.7 ml) was added TFA (380 µl, 4.9 mmol) and the mixture was stirred for 7 h at RT. The mixture was then concentrated and mixed successively with dichloromethane several times and re-concentrated. The residue was purified by preparative HPLC (Method 20). The combined desired fractions were concentrated and the residue was dried in vacuo. 96 mg (98% pure, 99% ee, 69% thor.) of the title compound were obtained.

[a] _D20 = +68.8°, 589 nm, c = 0.38 g/100 mL ^, methanol.

LC-MS (Method 1): Rt = 1.97 min; MS (ESIpos): m/z = 555/557 [M+H] ⁺ .

1H-NMR (500 MHz, DMSO-d6) δ [ppm]: -0.006 (0.85), 0.006 (0.57), 1.196 (0.41), 1.209 (0.41), 1.838 (8.67), 1.851 (8.44), 2.073 (1.43) ), 2.167 (1.73), 2.270 (0.45), 2.518 (0.69), 2.522 (0.48), 3.850 (1.19), 4.466 (1.35), 7.168 (1.13), 7.185 (1.55), 7.208 (1.27), 7.314 (1.99 ), 7.329 (3.87), 7.351 (1.75), 7.482 (1.18), 7.485 (1.27), 7.494 (3.79), 7.501 (3.73), 7.507 (6.74), 7.511 (8.03), 7.525 (12.08), 7.537 (16.00 ), 7.553 (3.51), 7.843 (3.37), 7.847 (3.18), 7.861 (4.71), 7.865 (4.52), 7.934 (9.34), 7.952 (6.28), 8.769 (2.37), 8.783 (3.82), 8.795 (2.25 ).

1H-NMR (500 MHz, DMSO-d6) δ [ppm]: 12.85 (br. s, 1H), 8.78 (t, 1H), 7.94 (d, 1H), 7.85 (dd, 1H), 7.68 (br. s, 1H), 7.57-7.47 (m, 5H), 7.41-7.28 (m, 2H), 7.23-7.14 (m, 1H), 4.54-4.39 (m, 1H), 3.91-3.79 (m, 1H), 2.17 (br. s, 3H), 1.84 (d, 3H).

Example 62 (-)-3-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-2-(2-chloro-6-fluorophenyl)-2-methylpropionic acid ( enantiomer 2).

To a solution of (-)-tert-butyl-3-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-2-(2chloro-6-fluorophenyl)-2-methylpropanoate (150 mg, 245 µmol, example 181A) in dichloromethane (1.7 ml) was added TFA (380 µl, 4.9 mmol) and the mixture was stirred for 7 h at RT. The mixture was then concentrated and mixed successively with dichloromethane several times and re-concentrated. The residue was purified by preparative HPLC (Method 20). The combined desired fractions were concentrated and the residue was dried in vacuo. 112 mg (98% pure, 97% ee, 81% thor.) of the title compound were obtained.

[a] _D20 = -71.7°, 589 nm, c = 0.29 ^g /100 ml, methanol.

LC-MS (Method 1): Rt = 1.97 min; MS (ESIpos): m/z = 555/557 [M+H] ⁺ .

1H-NMR (500 MHz, DMSO-d6) δ [ppm]: -0.007 (0.55), 0.006 (0.41), 1.840 (8.88), 1.853 (8.69), 2.073 (1.64), 2.168 (1.72), 2.271 (0.47 ), 2.518 (0.46), 3.837 (1.10), 3.851 (1.13), 4.468 (1.32), 4.480 (1.27), 7.168 (1.13), 7.185 (1.52), 7.208 (1.24), 7.315 (1.97), 7.329 (3.96 ), 7.351 (1.73), 7.477 (0.77), 7.482 (1.15), 7.485 (1.17), 7.494 (3.97), 7.502 (3.56), 7.507 (6.91), 7.511 (8.58), 7.525 (12.45), 7.539 (16.00 ), 7.554 (3.71), 7.843 (3.54), 7.848 (3.35), 7.861 (4.95), 7.866 (4.81), 7.935 (10.19), 7.953 (6.90), 8.772 (2.46), 8.785 (3.96), 8.798 (2.37 ).

1H-NMR (500 MHz, DMSO-d ₆ ) δ [ppm]: 12.87 (br. s, 1H), 8.79 (t, 1H), 7.94 (d, 1H), 7.85 (dd, 1H), 7.70 (br s, 1H), 7.59-7.46 (m, 5H), 7.42-7.27 (m, 2H), 7.24-7.12 (m, 1H), 4.53-4.41 (m, 1H), 3.91-3.80 (m, 1H) , 2.17 (br. s, 3H), 1.85 (d, 3H).

Example 63 (+/-)-4-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-phenylbutanoic acid (racemate)

- 152 040284

HATU (250 mg , 658 µmol) and DIPEA (230 µl, 1.3 mmol) and the mixture was stirred for 30 min at RT. Then (+/-)-4-amino-3-phenylbutanoic acid-hydrochloride (142 mg, 658 µmol, CAS-RN 3060-41-1, commercially available) dissolved in DMF (1 ml) was added and the mixture was stirred overnight at 60°C. After cooling to RT, the mixture was purified by preparative HPLC (Method 22). 206 mg (96% pure, 90% thor.) of the title compound were obtained.

LC-MS (Method 1): Rt = 1.85 min; MS (ESIpos): m/z = 503/505 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 2.065 (1.35), 2.073 (6.33), 2.085 (1.59), 2.573 (1.56), 2.590 (2.18), 2.613 (2.18), 2.724 (2.06 ), 2.738 (2.28), 2.763 (1.51), 2.778 (1.45), 3.390 (0.91), 3.399 (1.09), 3.405 (0.95), 3.413 (1.61), 3.428 (1.05), 3.436 (0.89), 3.573 (0.84 ), 3.593 (0.91), 3.607 (1.10), 3.619 (0.64), 3.752 (0.68), 3.770 (0.95), 3.791 (0.87), 3.804 (0.73), 7.224 (1.76), 7.241 (1.64), 7.260 (0.79 ), 7.278 (1.07), 7.298 (2.13), 7.318 (6.13), 7.337 (12.61), 7.353 (1.88), 7.358 (1.04), 7.490 (1.44), 7.501 (4.52), 7.508 (4.98), 7.519 (16.00 ), 7.526 (7.90), 7.530 (5.64), 7.534 (4.95), 7.541 (1.29), 7.835 (2.04), 7.840 (1.87), 7.857 (3.22), 7.862 (2.99), 7.929 (6.06), 7.951 (3.77 ), 8.803 (1.31), 8.820 (1.87), 8.832 (1.28).

Separation of enantiomers.

The title target compound (200 mg) was separated into its enantiomers by chiral phase preparative SLC (see Examples 64 and 65) [column: Daicel Chiralpak AD-H, 5 μm, 250 mm x 20 mm; flow: 80 ml/min; detection: 210 nm; temperature: 40°C; sample injection: 1 ml; eluent: 70% carbon dioxide/30% isopropanol; duration of action 70 min, isocratic].

Example 64 (-)-4-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-phenylbutanoic acid (enantiomer 1)

The separation of the enantiomers described in Example 63 gave 73 mg (98% pure, ee value 100%) of the title compound as the previously eluted enantiomer.

[a] _D20 = -26.3°, 589 nm, c = 0.32 ^g /100 ml, methanol.

LC-MS (Method 1): Rt = 1.87 min; MS (ESIpos): m/z = 503/505 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (0.76), 0.008 (0.75), 2.084 (1.66), 2.573 (1.59), 2.590 (2.19), 2.613 (2.18), 2.724 (2.14) ), 2.730 (1.00), 2.738 (2.33), 2.764 (1.55), 2.778 (1.45), 3.392 (0.98), 3.399 (1.13), 3.406 (1.03), 3.414 (1.66), 3.429 (1.09), 3.437 (0.91 ), 3.561 (0.61), 3.573 (0.90), 3.594 (0.99), 3.607 (1.16), 3.620 (0.66), 3.753 (0.71), 3.772 (1.02), 3.792 (0.90), 3.803 (0.77), 7.208 (1.11 ), 7.224 (1.97), 7.241 (1.77), 7.260 (0.84), 7.279 (1.22), 7.298 (2.49), 7.318 (6.59), 7.334 (13.17), 7.353 (1.90), 7.359 (1.00), 7.477 (0.79 ), 7.480 (0.87), 7.489 (1.74), 7.492 (1.94), 7.503 (5.07), 7.510 (5.62), 7.520 (16.00), 7.527 (7.93), 7.532 (5.62), 7.535 (4.55), 7.543 (1.04 ), 7.837 (2.19), 7.842 (1.93), 7.860 (3.35), 7.865 (2.92), 7.930 (5.95), 7.953 (3.66), 8.806 (1.46), 8.818 (1.95), 8.834 (1.25).

Example 65 (+)-4-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-phenylbutanoic acid (enantiomer 2)

The separation of enantiomers described in Example 63 gave the prepurified title compound as the later eluting enantiomer and further purified by preparative HPLC (Method 21). 65 mg (94% pure, ee value 100%) of the title compound were obtained.

[a] _D20 = +26.4°, 589 nm ^, c = 0.35 g/100 mL, methanol.

LC-MS (Method 2): Rt = 0.98 min; MS (ESIpos): m/z = 503/505 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 2.083 (1.85), 2.572 (1.51), 2.723 (2.01), 2.738 (2.17), 2.763 (1.41), 2.777 (1.34), 3.391 (0.92 ), 3.399 (1.09), 3.413 (1.64), 3.427 (1.16), 3.436 (0.96), 3.574 (0.97), 3.593 (1.09), 3.606 (1.27), 3.752 (0.72), 3.770 (1.09), 3.791 (1.03 ), 7.224 (1.64), 7.241 (1.57), 7.298 (1.72), 7.318 (5.68), 7.336 (13.29), 7.352 (2.78), 7.491 (1.18), 7.503 (3.89), 7.510 (4.60), 7.521 (16.00 ), 7.837 (1.86), 7.842 (1.88), 7.860 (3.04), 7.865 (3.10), 7.930 (5.11), 7.953 (3.46), 8.806 (1.26), 8.822 (2.18), 8.834 (1.62).

Example 66 (+/-)-4-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-(4-chlorophenyl)butanoic acid (racemate)

HATU (250 mg , 658 µmol) and DIPEA (230 µl, 1.3 mmol) and the mixture was stirred for 30 min at RT. Then add (+/-)-4- 153 040284 amino-3-(4-chlorophenyl)butanoic acid (140 mg, 658 µmol, CAS-RN 1134-47-0, commercially available) dissolved in DMF (2 ml) and the mixture was stirred for 3 hours at 60°C. After cooling to RT, the mixture in citric acid solution (50 ml) was added and shaken. The precipitate formed was filtered off, washed twice with 5 ml of water, respectively, and purified by preparative HPLC (Method

15). 97 mg (100% pure, 41% thor.) of the title compound were obtained.

LC-MS (Method 2): Rt = 1.09 min; MS (ESIpos): m/z = 537/539 [M+H]+.

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 2.086 (5.51), 2.568 (0.68), 2.608 (0.91), 2.725 (0.88), 2.738 (0.98), 2.764 (0.66), 7.380 (16.00) , 7.505 (2.07), 7.513 (1.89), 7.524 (5.04), 7.529 (4.78), 7.532 (4.20), 7.536 (3.04), 7.540 (2.40), 7.836 (0.74), 7.841 (0.74), 7.859 (1.17) , 7.864 (1.18), 7.932 (2.34), 7.955 (1.50), 8.826 (0.91).

1H-NMR (400 MHz, DMSO-d6): δ [ppm] = 12.03 (br. s, 1H), 8.82 (t, 1H), 7.94 (d, 1H), 7.85 (dd, 1H), 7.65-7.46 (m, 6H), 7.38 (s, 4H), 3.79 (br. s, 1H), 3.66-3.52 (m, 1H), 3.47-3.34 (m, 1H), 2.75 (dd, 1H), 2.63-2.55 (m, 1H, partially hidden), 2.20-2.02 (br. m, 3H).

Separation of enantiomers.

The title target compound (70 mg) was dissolved in a mixture of ethanol (2 ml) and isohexane (3 ml) and separated into enantiomers by chiral phase preparative HPLC (see Examples 67 and 68) [column: Daicel Chiralpak ID, 5 µm, 250 mm x 20 mm; flow: 15 ml/min; temperature: 30°C; sample injection: 0.25 ml; eluent: 82% isohexane/15% ethanol + 0.2% acetic acid; duration of action 22.5 min, isocratic].

Example 67 (+)-4-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-(4-chlorophenyl)butanoic acid (enantiomer 1)

The separation of enantiomers described in Example 66 gave the prepurified title compound as the previously eluted enantiomer and was further purified by preparative HPLC (Method 15). 28 mg (98% pure, ee value 99%) of the title compound were obtained.

[a] _D20 = +40.9°, 589 nm ^, c = 0.33 g/100 mL, chloroform.

LC-MS (Method 1): Rt = 1.95 min; MS (ESIpos): m/z = 537/539 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 2.583 (0.89), 2.606 (0.88), 2.723 (0.84), 2.737 (0.93), 7.378 (16.00), 7.504 (1.93), 7.512 (1.74) ), 7.523 (4.86), 7.528 (4.43), 7.532 (3.55), 7.536 (2.58), 7.540 (2.07), 7.836 (0.71), 7.858 (1.10), 7.863 (1.07), 7.931 (2.34), 7.954 (1.48 ).

1H-NMR (400 MHz, DMSO-d6): δ [ppm] = 12.17 (br. s, 1H), 8.82 (t, 1H), 7.94 (d, 1H), 7.85 (dd, 1H), 7.65-7.46 (m, 6H), 7.38 (s, 4H), 3.79 (br. s, 1H), 3.67-3.52 (m, 1H), 3.47-3.32 (m, 1H), 2.75 (dd, 1H), 2.63-2.54 (m, 1H), 2.12 (br. s, 3H).

Example 6 8. (-)-4-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-(4-chlorophenyl)butanoic acid (enantiomer 2).

The separation of enantiomers described in Example 66 gave the prepurified title compound as the later eluted enantiomer and further purified by preparative HPLC (Method 15). 30 mg (100% pure, ee value 94%) of the title compound were obtained.

[a] _D20 = -39.8°, 589 nm ^, c = 0.33 g/100 ml, chloroform.

LC-MS (Method 1): Rt = 1.95 min; MS (ESIpos): m/z = 537/539 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 2.583 (0.90), 2.607 (0.87), 2.723 (0.84), 2.738 (0.93), 7.379 (16.00), 7.505 (2.05), 7.513 (1.93) , 7.524 (5.10), 7.529 (4.75), 7.532 (3.91), 7.536 (2.87), 7.540 (2.25), 7.837 (0.77), 7.842 (0.73), 7.859 (1.19), 7.864 (1.14), 7.932 (2.42) , 7.955 (1.51), 8.825 (0.85).

1H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 8.82 (t, 1H), 7.94 (d, 1H), 7.85 (dd, 1H), 7.69-7.43 (m, 6H), 7.38 ( s, 4H), 3.80 (br. s, 1H), 3.65-3.53 (m, 1H), 3.48-3.35 (m, 1H), 2.75 (dd, 1H), 2.63-2.55 (m, 1H), 2.11 ( br. s, 3H).

Example 69 (+/-)-4-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-(2-chlorophenyl)butanoic acid

To a solution of (+/-)-tert-butyl-4-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-(2chlorophenyl)butanoate (527 mg, 887 µmol, example 182A) in dichloromethane (14 ml) was added TFA (6.8 ml, 89 mmol) and the mixture was stirred for 2 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 22). 340 mg (98% pure, 70% thor.) of the title compound were obtained.

- 154 040284

LC-MS (Method 2): R _t = 1.02 min; MS (ESIpos): m/z = 537/539 [M+H]+.

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.150 (0.40), -0.008 (3.25), 0.008 (3.06), 2.073 (8.11), 2.142 (8.84), 2.192 (0.44), 2.327 ( 0.65) 1.55), 7.428 (4.71), 7.431 (4.62), 7.447 (3.77), 7.451 (1.85), 2.645 (1.30), 2.664 (1.84), 2.674 (0.80), 2.685 (1.31), 2.779 (1.23), 2.15) 8.95), 7.512 (6.82), 7.521 (14.80), 7.527 (16.00), 7.530 (14.59), 7.534 (10.78), 7.538 (7.36) 2.95), 7.855 (4.93), 7.860 (4.75), 7.929 (9.28), 7.952 (5.83), 8.832 (1.79), 8.847 (3.52), 8.862 (1.73).

Separation of enantiomers.

The title target compound (200 mg) was dissolved in acetonitrile (18 ml) and separated into enantiomers by preparative chiral phase SLC (see examples 70 and 71) [column: Daicel Chiralpak AD, 5 μm, 250 mm x 20 mm; flow: 80 ml/min; detection: 210 nm; temperature: 40°C; sample injection: 0.3 ml; eluent: 80% carbon dioxide / 20% methanol; duration of action 12 min, isocratic].

Example 70 (+)-4-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-(2-chlorophenyl)butanoic acid (enantiomer 1)

Separation of enantiomers as described in Example 69 gave 44 mg (100% pure, ee value 100%) of the title compound as the previously eluted enantiomer.

[a] _D20 = +16.8°, 589 nm, c = 0.40 g/100 mL ^, methanol.

LC-MS (Method 1): R _t = 1.92 min; MS (ESIpos): m/z = 537/539 [M+H]+.

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 2.143 (8.97), 2.327 (0.46), 2.631 (0.98), 2.649 (1.09), 2.670 (3.05), 2.689 (2.67), 2.709 (2.71) , 2.725 (2.59), 2.749 (1.00), 2.765 (0.95), 3.311 (1.98), 3.711 (1.24), 3.813 (0.94), 3.929 (1.51), 3.945 (1.95), 3.963 (1.23), 7.243 (1.30) 7.261 (3.01), 7.280 (2.15), 7.332 (1.87), 7.350 (3.13), 7.368 (1.51), 7.427 (4.71), 7.447 (3.84), 7.475 (0.85), 7.501 (7.67), 7.508 (8.77) , 7.520 (14.62), 7.527 (16.00), 7.656 (1.05), 7.831 (3.10), 7.836 (2.78), 7.853 (4.62), 7.858 (4.42), 7.928 (8.78), 7.950 (5.48) .

Example 71 (-)-4-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-(2-chlorophenyl)butanoic acid (enantiomer 2)

Separation of the enantiomers as described in Example 69 gave 61 mg (98% pure, ee value 98%) of the title compound as the later eluted enantiomer.

[a] _D20 = -18.1°, 589 nm, c = 0.37 ^g /100 ml, methanol.

LC-MS (Method 1): R _t = 1.92 min; MS (ESIpos): m/z = 537/539 [M+H]+.

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.284 (2.85), 2.144 (9.37), 2.193 (0.50), 2.523 (0.75), 2.646 (1.24), 2.665 (1.48), 2.686 (3.35) , 2.705 (3.37), 2.723 (3.22), 2.740 (3.43), 2.764 (1.30), 2.780 (1.21) , 3.953(2.12), 3.970(1.36), 3.988(0.46),7.246(1.35), 7.264(3.13), 7.282(2.27), 7.334(2.01), 7.353(3.31), 7.371(1.64), 7.429(4.72) , 7.431 (4.62) , 7.546 (2.45), 7.663 (0.98), 7.832 (3.10), 7.837 (2.83), 7.854 (4.76), 7.859 (4.58), 7.929 (8.85), 7.952 (5.65), 8.835 (1.83), 8.849 (3.57) , 8.864 (1.82), 12.186 (1.34).

Example 72 (+/-)-4-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino }-3-(3-chlorophenyl)butanoic acid (racemate)

To a solution of (+/-)-tert-butyl-4-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-(3chlorophenyl)butanoate (220 mg, 370 µmol, example 183A) in dichloromethane (6.0 ml) was added TFA (2.9 ml, 37 mmol) and the mixture was stirred for 2 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 22). 93 mg (96% pure, 45% thor.) of the title compound were obtained.

LC-MS (Method 1): R _t = 1.95 min; MS (ESIpos): m/z = 537/539 [M+H]+.

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: -0.008 (0.62), 0.008 (0.73), 1.513 (4.18), 2.073 (1.21), 2.592 (1.53), 2.615 (1.62), 2.632 ( 2.44), 2.655 (2.46), 2.739 (2.29), 2.753 (2.58), 2.779 (1.63), 2.793 (1.51), 3.381 (0.92) 1.00), 3.570 (0.82), 3.582 (1.22), 3.595 (0.96), 3.603 (1.23), 3.615 (1.57), 3.628 (0.98), 3.781 (1.47), 3.799 (1.84), 3.805 (1.82), 3.814 ( 1.83) 3.822 (1.95)

- 155 040284 (3.60) 7.330 (5.17) 7.334 (3.33) 7.339 (4.65) 7.357 (3.12) 7.376 (1.02) 7.408 (5.29) 7.412 (3.39) 7.486 (0.77) ), 7.492 (1.48), 7.497 (1.47), 7.502 (4.59), 7.510 (4.68), 7.521 (16.00), 7.528 (7.86), 7.532 (5.84), 7.536 (5.32), 7.543 (1.39), 7.836 (1.84 ), 7.841 (1.74), 7.858 (2.85), 7.864 (2.81), 7.930 (6.11), 7.952 (3.87), 8.805 (1.47), 8.816 (1.89), 8.822 (1.94), 8.833 (1.42).

Separation of enantiomers.

The title target compound (220 mg) was dissolved in ethanol (2 ml) and separated into enantiomers by chiral phase preparative HPLC (see Examples 73 and 74) [column: Daicel Chiralpak AZ-H, 5 µm, 250 mm x 20 mm; flow: 20 ml/min; detection: 220 nm; temperature: 23°C; sample injection: 0.05 ml; eluent: 70% heptane/30% ethanol + 0.2% TFA; isocratic].

Example 73 4-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-(3-chlorophenyl)butanoic acid (enantiomer 1)

Separation of enantiomers as described in Example 72 gave 8 mg (90% pure, 81% ee) of the title compound as the previously eluted enantiomer.

LC-MS (Method 1): Rt = 1.93 min; MS (ESIpos): m/z = 537/539 [M+H] ⁺ .

1H-NMR (500 MHz, DMSO-d ₆ ) δ [ppm]: 0.844 (0.61), 0.858 (0.64), 1.090 (0.69), 1.104 (1.06), 1.118 (0.89), 1.148 (3.99), 1.163 (6.78 ), 1.177 (3.40), 1.233 (1.25), 1.257 (0.74), 2.067 (1.52), 2.600 (1.45), 2.618 (1.68), 2.632 (2.25), 2.650 (2.00), 2.745 (2.35), 2.756 (2.36 ), 2.777 (1.59), 2.788 (1.38), 2.906 (1.53), 2.920 (2.35), 2.931 (2.19), 2.945 (1.21), 3.407 (2.39), 3.587 (2.01), 3.612 (2.20), 3.730 (0.92 ), 3.744 (0.92), 3.790 (1.71), 3.804 (2.25), 3.848 (1.30), 7.298 (2.88), 7.316 (2.92), 7.330 (5.58), 7.341 (4.20), 7.356 (3.37), 7.371 (1.43 ), 7.408 (6.05), 7.509 (6.59), 7.523 (16.00), 7.842 (2.44), 7.859 (3.28), 7.933 (4.45), 7.951 (3.14), 8.823 (2.93).

Example 74 4-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-(3-chlorophenyl)butanoic acid (enantiomer 2)

Separation of the enantiomers as described in Example 72 gave 8 mg (90% pure, ee value 77%) of the title compound as the later eluted enantiomer.

LC-MS (Method 1): Rt = 1.93 min; MS (ESIpos): m/z = 537 [M+H] ⁺ .

1H-NMR (500 MHz, DMSO-d6) δ [ppm]: 0.845 (0.64), 0.859 (0.80), 1.090 (1.19), 1.104 (2.22), 1.118 (1.23), 1.148 (1.87), 1.162 (3.65) , 1.177 (1.89), 1.233 (1.16), 1.246 (0.80), 1.258 (0.76), 2.073 (1.36), 2.602 (1.97), 2.620 (2.14), 2.634 (3.02), 2.652 (2.87), 2.746 (2.92) , 2.757(3.08), 2.778(2.10), 2.790(1.89),2.925(0.79), 2.935(0.77), 3.380(0.71), 3.391(1.40), 3.398(1.64), 3.409(2.39), 3.420(1.66) . . . , 7.530 (14.69), 7.536 (11.79), 7.546 (2.42), 7.849 (2.50), 7.853 (2.45), 7.867 (3.55), 7.871 (3.43), 7.940 (6.73), 7.957 (4.55) , 8.826 (2.80), 8.831 (2.86), 8 .840 (2.11).

Example 75 (+/-)-4-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-(2-methylphenyl)butanoic acid (racemate)

To a solution of (+/-)-tert-butyl-4-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-(2methylphenyl)butanoate (750 mg, 1.31 mmol, example 184A) in dichloromethane (21 ml) was added TFA (10 ml,

130 mmol) and the mixture was stirred for 2 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 22). 574 mg (98% pure, 83% thor.) of the title compound were obtained.

LC-MS (Method 1): R _t = 1.91 min; MS (ESIpos): m/z = 517/519 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.195 (0.56), 1.211 (0.57), 2.072 (1.53), 2.118 (2.44), 2.398 (16.00), 2.580 (0.92), 2.602 (0.93) , 2.620 (1.80), 2.641 (1.77), 2.701 (1.65), 2.715 (1.71), 2.740 (1.10), 2.754 (0.97), 3.475 (0.88), (0.96), 3.803 (0.96), (0.88), 7.348 (2.62), (4.36), 7.533 (8.00),

3.491 (0.99), 3.504 (0.98), 3.714 (0.80), 3.729 (1.18), 3.755 (1.42), 3.771 (1.22), 3.785 7.087 (0.69), 7.105 (1.83), 7.122 (1.72), 7.151 (3.03), 7.171 (2.05), 7.193 (1.76), 7.210 7.366 (2.04), 7.490 (1.38), 7.505 (4.13), 7.511 (3.27), 7.516 (2.22), 7.522 (7.34), 7.528 7.535 (7.96), 7.539 (5.03), 7.543 (3.79), 7.552 (1.44), 7.841 (1.92), 7.846 (1.73), 7.864

(2.88), 7.869 (2.73), 7.940 (5.41), 7.962 (3.45), 8.855 (1.14), 8.871 (1.89), 8.883 (1.04).

Separation of enantiomers.

The title target compound (750 mg) was separated into its enantiomers by chiral phase preparative SLC (see Examples 76 and 77) [column: Daicel Chiralpak AD-H, 5 μm, 250 mm

- 156 040284 x 20 mm; flow: 80 ml/min; detection: 210 nm; temperature: 40°C; sample injection: 0.2 ml; eluent: 85% carbon dioxide/15% ethanol; isocratic].

Example 76 (-)-4-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-(2-methylphenyl)butanoic acid (enantiomer 1)

The separation of the enantiomers described in Example 75 gave the title compound as the previously eluted enantiomer. 188 mg (98% pure, ee value 100%) of the title compound were obtained.

[a] _D20 = -23.3°, 589 nm, c = 0.29 ^g /100 ml, methanol.

LC-MS (Method 2): R _t = 1.08 min; MS (ESIpos): m/z = 517/519 [M+H]+.

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: -0.008 (0.53), 0.008 (0.42), 1.031 (1.36), 1.046 (1.36), 1.285 (0.75), 2.072 (0.86), 2.116 ( 2.61), 2.396 (16.00), 2.522 (0.65), 2.579 (0.93), 2.600 (0.96), 2.618 (1.83), 2.640 (1.77), 2.700 (1.69) 0.98), 3.471 (0.96), 3.487 (1.07), 3.502 (1.06), 3.516 (0.67), 3.712 (0.84), 3.727 (1.25), 3.753 (1.51), 3.769 (1.30), 3.783 (1.01), 3.800 ( 0.98) 2.08), 7.475 (0.58), 7.488 (1.59), 7.502 (4.47), 7.508 (3.75), 7.520 (7.82), 7.530 (8.17), 7.532 (8.13) 2.01), 7.842 (1.81), 7.859 (2.92), 7.864 (2.77), 7.936 (5.33), 7.959 (3.38), 8.849 (1.23), 8.865 (1.95), 8.877 (1.07), 12.073 (1.54).

Example 77 (+)-4-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-(2-methylphenyl)butanoic acid (enantiomer 2)

The separation of the enantiomers described in Example 75 gave the title compound as the later eluted enantiomer. 179 mg (98% pure, ee value 97%) of the title compound were obtained.

[a] _D20 = +24.8°, 589 nm, c = 0.38 g ^/ 100 mL, methanol.

LC-MS (Method 2): R _t = 1.08 min; MS (ESIpos): m/z = 517/519 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: -0.008 (0.42), 1.030 (1.22), 1.046 (1.23), 1.284 (0.59), 2.073 (0.85), 2.116 (2.44), 2.396 ( 16.00), 2.523 (0.47), 2.578 (0.91), 2.599 (0.93), 2.617 (1.82), 2.639 (1.78), 2.699 (1.65), 2.712 (1.74), 2.738 (1.11), 2.752 (0.99), 0.90), 3.487 (1.01), 3.501 (1.01), 3.516 (0.66), 3.711 (0.78), 3.726 (1.17), 3.752 (1.41), 3.768 (1.22), 3.782 (0.97), 3.800 (0.96), 0.46), 7.086 (0.66),7.104 (1.82), 7.122 (1.73), 7.150 (2.98), 7.170 (2.01), 7.192 (1.74), 7.210 (0.87), 7.346 (2.67), 7.365 (2.07), 0.48), 7.488 (1.38), 7.493 (1.00), 7.502 (4.10), 7.509 (3.35), 7.521 (7.50), 7.529 (7.78), 7.532 (7.90), 7.536 (5.27), 7.548 (1.38), 0.60), 7.837 (1.93), 7.843 (1.74), 7.860 (2.90), 7.865 (2.79), 7.936 (5.20), 7.959 (3.34), 8.849 (1.15), 8.865 (1.90), 8.877 (1.05), 2.06).

Example 7 8. (+/-)-4-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-(2,6-dichlorophenyl)butanoic acid (racemate)

To a solution of (+/-)-tert-butyl-4-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-(2,6dichlorophenyl)butanoate (140 mg , 223 µmol, example 185A) in dichloromethane (3.6 ml) was added TFA (1.7 ml, 22 mmol) and the mixture was stirred for 2 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 22). 103 mg (97% pure, 78% thor.) of the title compound were obtained.

LC-MS (Method 1): R _t = 1.96 min; MS (ESIpos): m/z = 571/573/575 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (1.34), 0.008 (1.24), 1.194 (0.98), 1.211 (0.93), 1.491 (1.86), 2.073 (1.44), 2.170 (7.32 ), 2.881 (1.47), 2.898 (1.68), 2.921 (4.94), 2.937 (4.87), 2.948 (4.80), 2.968 (4.74), 2.987 (1.53), 3.008 (1.61), 3.628 (1.72), 3.801 (1.46 ), 4.118 (1.23), 4.414 (1.41), 4.430 (1.84), 4.450 (1.22), 7.266 (1.46), 7.286 (2.89), 7.307 (1.90), 7.424 (3.69), 7.444 (3.01), 7.464 (4.75 ), 7.488 (5.02), 7.495 (2.42), 7.504 (8.15), 7.511 (7.06), 7.515 (4.09), 7.523 (15.90), 7.530 (16.00), 7.533 (14.69), 7.537 (10.88), 7.541 (8.23 ), 7.550 (2.61), 7.838 (4.04), 7.843 (3.56), 7.860 (6.03), 7.866 (5.58), 7.933 (10.89), 7.956 (6.77), 8.914 (1.97), 8.929 (3.71), 8.944 (1.94 ).

Separation of enantiomers.

The title title compound (80 mg) was dissolved in 17 ml of a mixture of methanol acetonitrile and separated into enantiomers by chiral phase preparative SLC (see examples 79 and 80) [column: Daicel Chiralpak AD-H, 5 µm, 250 mm x 20 mm ; flow: 80 ml/min; detection: 210 nm; temperature: 40°C; sample injection: 3 ml; eluent: 70% carbon dioxide/30% isopropanol; isocratic].

- 157 040284

Example 79 4-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-(2,6-dichlorophenyl)butanoic acid (enantiomer 1)

Separation of the enantiomers as described in Example 78 gave the title compound as the previously eluted enantiomer and was further purified by preparative HPLC (Method 21). 22 mg (98% pure, ee value 96%) of the title compound were obtained.

LC-MS (Method 2): Rt = 1.04 min; MS (ESIpos): m/z = 571/573/575 [M+H]+.

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 2.073 (0.63), 2.168 (7.87), 2.314 (0.56), 2.327 (0.72), 2.366 (0.53), 2.670 (0.66), 2.710 (0.43 ), 2.879 (1.34), 2.896 (1.55), 2.919 (4.81), 2.936 (4.87), 2.945 (4.79), 2.966 (4.59), 2.985 (1.43), 3.006 (1.44), 3.814 (1.32), 4.119 (1.35 ), 4.409 (1.91), 4.428 (2.43), 4.446 (1.78), 4.716 (0.73), 7.267 (1.34), 7.287 (2.87), 7.307 (1.97), 7.424 (3.51), 7.444 (2.89), 7.465 (4.64 ), 7.485 (4.08), 7.505 (7.47), 7.511 (6.25), 7.524 (16.00), 7.531 (15.93), 7.740 (0.43), 7.840 (3.42), 7.846 (3.16), 7.863 (5.30), 7.868 (5.12 ), 7.934 (9.44), 7.956 (5.90), 8.914 (2.03), 8.929 (3.94), 8.943 (2.10).

Example 80 4-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-(2,6-dichlorophenyl)butanoic acid (enantiomer 2)

Separation of the enantiomers as described in Example 78 gave the title compound as a later eluting enantiomer and further purified by preparative HPLC (Method 21). 30 mg (98% pure, ee value 95%) of the title compound were obtained.

LC-MS (Method 2): Rt = 1.04 min; MS (ESIpos): m/z = 571/573/575 [M+H]+.

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: -0.008 (2.08), 0.008 (1.82), 2.168 (7.58), 2.327 (0.87), 2.366 (0.54), 2.669 (0.80), 2.710 ( 0.55), 2.879 (1.42), 2.896 (1.69), 2.919 (4.96), 2.936 (4.95), 2.945 (4.83),2.966 (4.71), 2.985 (1.53), 3.006 (1.57), 3.814 (1.27), 4.118 ( 1.41), 4.411 (2.21), 4.428 (2.71), 7.267 (1.35), 7.286 (2.83), 7.307 (1.96), 7.424 (3.66), 7.444 (2.99), 7.464 (4.84), 7.484 (4.25), 7.70), 7.511 (6.69), 7.524 (16.00), 7.530 (15.92), 7.549 (2.71), 7.723 (0.46), 7.839 (3.81), 7.845 (3.49), 7.862 (5.78), 7.867 (5.47), 10.51), 7.956 (6.50), 8.913 (2.01), 8.928 (3.84), 8.943 (2.01).

Example 81 (+/-)-4-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-(3-methoxyphenyl)butanoic acid (racemate)

To a solution of (+/-)-tert-butyl-4-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-(3methoxyphenyl)butanoate (220 mg, 373 µmol, example 186A) in dichloromethane (6.1 ml) was added TFA (2.9 ml, 37 mmol) and the mixture was stirred for 2 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 22). 145 mg (99% pure, 72% thor.) of the title compound were obtained.

LC-MS (Method 1): R _t = 1.83 min; MS (ESIpos): m/z = 533/535 [M+H]+.

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.517 (0.61), 2.073 (1.41), 2.100 (1.94), 2.566 (1.54), 2.583 (2.22), 2.606 (2.20), 2.706 (2.11) , 2.721 (2.33), 2.746 (1.54), 2.760 (1.42), 3.365 (0.91), 3.372 (1.03), 3.387 (1.66), 3.402 (1.10), 3.409 (0.94), 3.558 (0.75), 3.571 (1.09) . , 6.782 (1.71) . , 7.857 (3.16), 7.863 (3.14), 7.931 (6.42), 7.954 (4.05), 8.795 (1.39), 8.811 (2.08), 8.823 (1.41).

Separation of enantiomers.

The title title compound (120 mg) was dissolved in 4 ml ethanol-heptane and separated into enantiomers by chiral phase preparative HPLC (see Examples 82 and 83) [column: Daicel Chiralpak AZ-H, 5 µm, 250 mm x 20 mm; flow: 20 ml/min; detection: 220 nm; temperature: 40°C; sample injection: 0.5 ml; eluent: 70% heptane/30% ethanol + 0.2% TFA; isocratic, duration of action 8.5 min].

Example 82 (+)-4-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-(3-methoxyphenyl)butanoic acid (enantiomer 1)

The separation of the enantiomers described in Example 81 gave the title compound as the previously eluted enantiomer. 29 mg (98% pure, ee value 100%) of the title compound were obtained.

[a] _D20 = +33.7°, 589 nm ^, c = 0.29 g/100 ml, chloroform.

- 158 040284

LC-MS (Method 1): R _t = 1.82 min; MS (ESIpos): m/z = 533/535 [M+H]+.

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: -0.008 (2.93), 0.008 (1.70), 1.038 (0.98), 1.056 (1.91), 1.073 (0.96), 1.207 (1.03), 1.234 ( 0.68), 2.073 (1.46), 2.101 (1.94), 2.523 (1.89), 2.564 (1.66), 2.581 (2.19), 2.604 (2.10), 2.705 (2.08), 2.719 (2.22), 2.744 (1.47), 3.362 (0.95), 3.369 (1.04), 3.384 (1.62), 3.400 (1.09), 3.407 (0.99), 3.414 (0.68), 3.432 (1.09), 3.449 (1.04), 3.556 (0.81), 3.568 ( 1.12) 1.72), 6.804 (1.72), 6.894 (6.53), 6.898 (7.12), 6.915 (3.02), 7.210 (2.14), 7.230 (3.25), 7.250 (1.51),7.489 (1.68), 7.502 (4.67), 7.521 (16.00), 7.528 (7.49), 7.532 (5.66), 7.535 (4.90), 7.834 (2.12), 7.839 (1.91), 7.856 (3.12), 7.862 (2.88), 7.930 (5.97), 3.71), 8.792 (1.44), 8.809 (1.99), 8.821 (1.30).

Example 83 (-)-4-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-(3-methoxyphenyl)butanoic acid (enantiomer 2)

The separation of the enantiomers described in Example 81 gave the title compound as the later eluted enantiomer. 35 mg (98% pure, ee value 94%) of the title compound were obtained.

[a] _D20 = -25.8°, 589 nm, c = 0.32 g ^/ 100 ml, chloroform.

LC-MS (Method 1): Rt = 1.82 min; MS (ESIpos): m/z = 533/535 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (1.83), 0.008 (1.04), 0.840 (6.59), 0.858 (16.00), 0.875 (5.02), 1.242 (11.36), 1.247 (11.78) ), 1.258 (4.11), 1.267 (2.90), 1.279 (2.40), 1.297 (1.03), 2.097 (1.48), 2.564 (1.22), 2.581 (1.75), 2.604 (1.74), 2.705 (1.69), 2.719 (1.84 ), 2.744 (1.23), 2.759 (1.12), 3.363 (1.03), 3.370 (1.15), 3.385 (1.76), 3.399 (1.49), 3.407 (1.48), 3.422 (1.43), 3.432 (1.64), 3.450 (2.18 ), 3.467 (2.38), 3.535 (1.05), 3.544 (0.97), 3.556 (1.11), 3.569 (1.26), 3.583 (1.06), 3.589 (1.19), 3.602 (1.33), 3.759 (0.90), 6.781 (1.30 ), 6.804 (1.36), 6.894 (5.26), 6.898 (5.93), 6.916 (2.49), 7.210 (1.76), 7.230 (2.71), 7.250 (1.26), 7.488 (1.02), 7.491 (1.05), 7.501 (3.41 ), 7.509 (3.48), 7.520 (12.89), 7.527 (5.81), 7.532 (4.48), 7.535 (3.98), 7.832 (1.68), 7.838 (1.49), 7.855 (2.55), 7.860 (2.38), 7.929 (5.01 ), 7.952 (3.16), 8.792 (1.07), 8.808 (1.58), 8.820 (1.05).

Example 84 (+/-)-4-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-(3-chloropyridin-2yl)-3-methylbutanoic acid (racemate) ci^^ ^N o n ₃ cX A

O ^ NH ^Br ^ ^ ^CH s XX ⁿ he

To a solution of (+/-)-tert-butyl-4-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-(3chloropyridin-2-yl)-3 -methylbutanoate (650 mg, 1.07 mmol, example 187A) in dichloromethane (7.2 ml) TFA (1.6 ml, 21 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 adsorbed into dichloromethane and purified by flash column chromatography (100 g Biotage Snap-Cartridge KP-Sil, cyclohexane/ethyl acetate 8:2, Isolera One). 202 mg (98% pure, 34% thor.) of the title compound were obtained.

LC-MS (Method 1): R _t = 1.94 min; MS (ESIpos): m/z = 552/554 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 1.685 (12.85), 2.073 (1.34), 2.163 (16.00), 2.518 (0.84), 2.523 (0.61), 2.762 (2.25), 2.803 (2.54) ), 3.285 (2.17), 3.326 (1.94), 4.000 (0.48), 4.016 (0.55), 4.034 (0.81), 4.049 (0.77), 4.110 (0.87), 4.124 (0.93), 4.143 (0.67), 4.158 (0.63 ), 4.347 (0.43), 7.287 (2.15), 7.298 (2.17), 7.307 (2.26), 7.318 (2.32), 7.490 (1.13), 7.505 (3.27), 7.511 (2.48), 7.517 (1.62), 7.522 (5.09 ), 7.530 (2.23), 7.536 (6.91), 7.545 (2.41), 7.552 (1.07), 7.555 (1.18), 7.707 (3.35), 7.712 (3.56), 7.830 (2.30), 7.834 (2.42), 7.839 (1.78 ), 7.844 (1.60), 7.850 (2.27), 7.853 (2.19), 7.861 (2.59), 7.867 (2.41), 7.933 (4.39), 7.955 (2.76), 8.459 (2.26), 8.463 (2.29), 8.471 (2.29 ), 8.474 (2.11), 8.678 (0.85), 8.693 (1.78), 8.709 (0.84).

Separation of enantiomers.

The title target compound (175 mg) was dissolved in 5 ml of isopropanol and separated into enantiomers by chiral phase preparative HPLC (see Examples 85 and 86) [column:

YMC Chiralart Amylose SA, 5µm, 250mm x 30mm; flow: 30 ml/min; detection: 220 nm; temperature: 30°C; sample injection: 0.35 ml; eluent: 70% heptane / 30% isopropanol + 0.2% TFA; isocratic, duration of action 14.5 min].

Example 85 (-)-4-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-(3-chloropyridin-2yl)-3-methylbutanoic acid (enantiomer 1 ).

Separation of the enantiomers as described in Example 84 gave the prepurified title compound as the previously eluted enantiomer and was further purified by preparative HPLC (Method 20). Received 69 mg (98% pure, ee-value 99%) indicated

- 159 040284 in connection header.

[a]D ²⁰ = -29.1°, 589 nm, c = 0.31 g/100 ml, chloroform.

LC-MS (Method 2): R _t = 1.02 min; MS (ESIpos): m/z = 552/554 [M+H]+.

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.008 (0.71), 1.686 (13.36), 2.164 (16.00), 2.763 (2.29), 2.804 (2.60), 3.286 (2.29), 3.326 (2.03) , 4.001 (0.42), 4.017 (0.49), 4.034 (0.77), 4.050 (0.72), 4.111 (0.77), 4.125 (0.81), 4.144 (0.50), 4.159 (0.44), 7.287 (1.99), 7.298 (2.04) . . , 8.460 (2.14), 8.463 (2.18), 8.471 (2.15), 8.475 (2.02), 8.679 (0.93), 8.695 (1.93), 8.710 (0.89).

Example 86 (+)-4-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-(3-chloropyridin-2yl)-3-methylbutanoic acid (enantiomer 2 ).

Separation of the enantiomers as described in Example 84 gave the prepurified title compound as the later eluted enantiomer and further purified by preparative HPLC (Method 20). 73 mg (98% pure, ee value 99%) of the title compound were obtained.

[a] _D20 = +30.4°, 589 nm ^, c = 0.34 g/100 ml, chloroform.

LC-MS (Method 2): R _t = 1.02 min; MS (ESIpos): m/z = 552/554 [M+H]+.

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.687 (13.49), 2.165 (16.00), 2.764 (2.32), 2.804 (2.63), 3.286 (2.32), 3.327 (2.05), 4.002 (0.44) , 4.017 (0.51), 4.035 (0.80), 4.050 (0.75), 4.112 (0.80), 4.126 (0.85), 4.145 (0.53), 4.160 (0.46), 7.287 (1.94), 7.299 (2.01), 7.307 (2.08) , 7.319(2.11), 7.492(1.19), 7.506(3.59),7.512(2.74), 7.525(5.63), 7.537(7.08), 7.556(1.33), 7.710(3.50), 7.715(3.73), 7.831(2.13) . , 8.464 (2.24), 8.472 (2.13), 8.475 (2.11), 8.681 (0.95), 8.696 (1.97), 8.711 (0.92).

Example 87 (+/-)-4-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-(2-chloro-6-fluorophenyl)butanoic acid (racemate )

To a solution of (+/-)-tert-butyl-4-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-(2chloro-6-fluorophenyl)butanoate ( 110 mg, 180 μmol, example 188A) in dichloromethane (2.9 ml) was added TFA (1.4 ml, 21 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 adsorbed into dichloromethane and purified by preparative HPLC (Method 22). 48 mg (94% pure, 45% thor.) of the title compound were obtained.

Separation of enantiomers.

The title title compound (45 mg) was dissolved in a mixture of 2 ml of isopropanol and 1 ml of heptane and separated into enantiomers by chiral phase preparative HPLC (see examples 88 and 89) [column: YMC Chiralart Amylose SA, 5 μm, 250 mm x 30 mm; flow: 30 ml/min; detection: 220 nm; temperature: 35°C; sample injection: 1.0 ml; eluent: 50% heptane/50% isopropanol + 0.2% acetic acid; isocratic, duration of action 15 minutes].

LC-MS (Method 1): Rt = 1.90 min; MS (ESIpos): m/z = 555/557 [M+H]+.

1H-NMR (600 MHz, DMSO-d6) δ [ppm]: 0.005 (0.97), 2.143 (1.80), 2.614 (0.67), 2.642 (0.71), 2.735 (1.39), 2.747 (1.46), 2.760 (1.05) , 2.772 (0.93), 3.715 (1.03), 4.092 (1.28), 7.179 (1.36), 7.189 (1.47), 7.203 (1.20), 7.302 (3.61), 7.476 (0.76), 7.479 (0.91), 7.481 (1.01) . , 7.519 (12.20), 7.528 (13.47), 7.530 (16.00), 7.537 (2.27), 7.541 (2.72), 7.545 (1.44), 7.839 (3.12), 7.843 (2.91), 7.854 (4.11), 7.858 (3.81) , 7.927 (1.63), 7.930 (8.57), 7.945 (6.15), 9.021 (2.03).

Example 88 (-)-4-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-(2-chloro-6-fluorophenyl)butanoic acid (enantiomer 1) .

Method A

The separation of enantiomers described in Example 87 gave the prepurified title compound as the previously eluted enantiomer. 17 mg (98% pure, ee value 100%) of the title compound were obtained.

LC-MS (Method 1): R _t = 1.91 min; MS (ESIpos): m/z = 555 [M+H]+.

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (3.47), 0.008 (3.66), 2.154 (5.55), 2.709 (0.71), 2.749 (1.00), 2.799 (1.62), 2.814 (1.64 ), 2.835 (0.89), 3.314 (3.08), 3.747 (1.19), 3.873 (0.79), 4.109 (1.36), 7.175

- 160 040284 (1.30), 7.187 (1.80), 7.199 (1.84), 7.209 (1.55), 7.227 (1.49), 7.318 (5.52), 7.476 (0.85), 7.488 (1.94), 7.491 (2.00), 7.501 (6.32) ), 7.509 (5.74), 7.521 (16.00), 7.526 (15.04), 7.530 (11.76), 7.534 (9.53), 7.537 (7.36), 7.546 (2.01), 7.837 (3.01), 7.842 (2.69), 7.860 (4.62 ), 7.865 (4.27), 7.931 (8.32), 7.953 (5.14), 8.940 (1.44), 8.955 (2.61), 8.968 (1.41).

Method B

To a solution of (-)-tert-butyl-4-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-(2chloro-6-fluorophenyl)butanoate (1.83 g , 2.99 mmol, example 189A) in dichloromethane (15 ml) was added TFA (5.1 ml, 66 mmol) and the mixture was left for 4 h at RT. The mixture was then concentrated and mixed several times with dichloromethane and re-concentrated. The residue was dissolved in acetonitrile (9 ml) and purified by preparative HPLC (Method 16). 1.55 g (100% pure, ee-value 99%, 93% th. y.) of the title compound was obtained.

[a]D ²⁰ = -40.1°, 589 nm, c = 0.48 g/100 ml, methanol.

LC-MS (Method 2): Rt = 1.02 min; MS (ESIpos): m/z = 555/557 [M+H]+.

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: -0.008 (4.94), 0.008 (2.48), 2.073 (0.51), 2.153 (5.66), 2.327 (0.54), 2.366 (0.42), 2.523 ( 2.16), 2.669 (0.60), 2.709 (0.68), 2.774 (1.05), 2.804 (2.40), 2.820 (2.36) 0.89), 4.094 (1.31), 4.112 (1.61), 7.178 (1.12), 7.189 (1.95), 7.202 (1.90), 7.211 (1.52), 7.229 (1.52), 7.319 (5.49), 7.477 (1.27), 2.48) 4.86), 7.866 (4.40), 7.931 (8.73), 7.954 (5.30), 8.928 (1.89), 8.943 (3.44), 8.958 (1.69), 12.223 (0.44).

Example 89 (+)-4-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-(2-chloro-6-fluorophenyl)butanoic acid (enantiomer 2) .

Method A

The separation of the enantiomers described in Example 87 gave the title compound as the later eluted enantiomer. 16 mg (98% pure, ee value 99%) of the title compound were obtained.

LC-MS (Method 1): R _t = 1.91 min; MS (ESIpos): m/z = 555/557 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (3.94), 0.008 (3.80), 1.234 (0.72), 2.154 (5.67), 2.523 (1.40), 2.669 (0.59), 2.709 (0.81 ), 2.805 (1.47), 3.312 (3.14), 3.744 (1.07), 3.877 (0.86), 4.108 (1.32), 7.174 (0.95), 7.186 (1.80), 7.199 (1.82), 7.208 (1.52), 7.226 (1.46 ), 7.317 (5.76), 7.476 (0.85), 7.487 (1.93), 7.491 (2.01), 7.501 (6.44), 7.509 (5.74), 7.521 (16.00), 7.525 (15.01), 7.529 (11.89), 7.533 (9.55 ), 7.537 (7.67), 7.545 (2.01), 7.837 (3.09), 7.842 (2.90), 7.859 (4.69), 7.864 (4.64), 7.930 (9.07), 7.952 (5.56), 8.962 (2.38).

Method B

To a solution of (+)-tert-butyl-4-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-(2chloro-6-fluorophenyl)butanoate (1.79 g , 2.93 mmol, example 190A) in dichloromethane (15 ml) was added TFA (5.0 ml, 64 mmol) and the mixture was left for 4 h at RT. The mixture was then concentrated and mixed several times with dichloromethane and re-concentrated. The residue was dissolved in acetonitrile (9 ml) and purified by preparative HPLC (Method 16). 1.47 g (100% pure, ee-value 99%, 90% th. y.) of the title compound was obtained.

[a] _D20 = +38.0°, 589 nm, c = 0.51 g ^/ 100 mL, methanol.

LC-MS (Method 2): R _t = 1.02 min; MS (ESIpos): m/z = 555/557 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 2.065 (0.41), 2.147 (5.69), 2.319 (0.45), 2.661 (0.44), 2.702 (0.53), 2.753 (0.97), 2.797 (2.33 ), 2.813 (2.38), 2.836 (1.06), 2.852 (0.86), 3.740 (1.43), 3.869 (0.97), 4.086 (1.28), 4.104 (1.61), 5.746 (0.44), 7.170 (1.01), 7.182 (1.87 ), 7.194 (1.84), 7.204 (1.52), 7.221 (1.56), 7.312 (5.74), 7.469 (0.80), 7.484 (1.96), 7.495 (6.27), 7.502 (5.58), 7.514 (16.00), 7.518 (15.07 ), 7.526 (9.10), 7.538 (1.91), 7.831 (3.13), 7.836 (2.84), 7.854 (4.76), 7.859 (4.60), 7.924 (8.90), 7.947 (5.47), 8.921 (1.79), 8.936 (3.47 ), 8.951 (1.73).

Example 90 (+/-)-4-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-(4-methylphenyl)butanoic acid (racemate)

To a solution of (+/-)-tert-butyl-4-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-(4methylphenyl)butanoate (110 mg, 192 µmol, example 191A) in dichloromethane (3.1 ml) was added TFA (1.5 ml, 19 mmol) and the mixture was stirred for 2 h at RT. The mixture was then concentrated and mixed several times with dichloromethane and re-concentrated. The residue was purified by preparative

- 161 040284

HPLC (Method 22). 98 mg (98% pure, 97% theoretical) of the title compound were obtained.

LC-MS (Method 1): Rt = 1.95 min; MS (ESIpos): m/z = 517/519 [M+H]+.

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (1.65), 0.008 (1.37), 2.072 (1.21), 2.130 (2.31), 2.259 (16.00), 2.569 (2.41), 2.694 ( 2.27), 2.708 (2.62), 2.733 (1.79), 2.747 (1.64), 3.354 (1.01), 3.369 (1.50), 3.384 (1.08), 3.588 (1.02) 5.01), 7.134 (7.42), 7.210 (9.62), 7.230 (6.30), 7.477 (0.60), 7.489 (1.53), 7.492 (1.47), 7.498 (1.78) 10.92), 7.522 (12.64), 7.527 (11.67), 7.531 (9.46), 7.535 (7.34), 7.539 (5.85), 7.547 (1.72) 3.25), 7.929 (7.08), 7.951 (4.47), 8.786 (1.42), 8.800 (2.36), 8.815 (1.44).

Separation of enantiomers.

The title title compound (70 mg) was dissolved in acetonitrile (2 ml) and ethanol (1 ml) and separated into enantiomers by chiral phase preparative HPLC (see Examples 91 and 92) [column: Daicel Chiralpak IF, 5 μm, 250 mm x 20 mm; flow: 20 ml/min; detection: 220 nm; temperature: 23°C; sample injection: 0.08 ml; eluent: 70% heptane/30% ethanol + 0.2% TFA; isocratic].

Example 91 (+)-4-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-(4-methylphenyl)butanoic acid (enantiomer 1)

The separation of the enantiomers described in Example 90 gave the title compound as the previously eluted enantiomer. 35 mg (98% pure, ee value 100%) of the title compound were obtained.

[a] _D20 = +44.9°, 589 nm ^, c = 0.25 g/100 ml, chloroform.

LC-MS (Method 1): Rt = 1.93 min; MS (ESIpos): m/z = 517/519 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 2.134 (2.36), 2.259 (16.00), 2.569 (2.40), 2.694 (2.27), 2.708 (2.65), 2.734 (1.74), 2.748 (1.62) , 2.814 (0.62), 3.354 (0.99), 3.369 (1.51), 3.384 (1.07), 3.589 (0.93), 3.684 (0.89), 3.723 (0.74), 7.115 (4.97), 7.135 (7.41), 7.211 (9.48) . . , 8.816 (1.48).

Example 92 (-)-4-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-(4-methylphenyl)butanoic acid (enantiomer 2)

The separation of the enantiomers described in Example 90 gave the title compound as the later eluted enantiomer. 32 mg (98% pure, ee value 97%) of the title compound were obtained.

[a] _D20 = -39.1°, 589 nm ^, c = 0.27 g/100 ml, chloroform.

LC-MS (Method 1): Rt= 1.93 min; MS (ESIpos): m/z = 517/519 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (0.83), 2.132 (2.34), 2.259 (16.00), 2.569 (2.38), 2.694 (2.21), 2.708 (2.59), 2.733 (1.71 ), 2.747 (1.62), 3.354 (0.97), 3.368 (1.46), 3.383 (1.04), 3.588 (0.93), 3.683 (0.61), 3.723 (0.76), 7.114 (5.04), 7.134 (7.42), 7.210 (9.44 ), 7.230 (6.18), 7.489 (1.44), 7.493 (1.47), 7.503 (5.14), 7.511 (4.63), 7.523 (12.42), 7.527 (11.59), 7.531 (9.52), 7.535 (7.23), 7.539 (5.67 ), 7.547 (1.67), 7.835 (2.11), 7.840 (1.98), 7.857 (3.28), 7.862 (3.18), 7.929 (6.98), 7.952 (4.34), 8.787 (1.42), 8.801 (2.34), 8.815 (1.44 ).

Example 93 (+/-)-4-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-(3-methylphenyl)butanoic acid (racemate)

To a solution of (+/-)-tert-butyl-4-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-(3methylphenyl)butanoate (100 mg, 174 µmol, example 192A) in dichloromethane (2.8 ml) was added TFA (1.3 ml, 17 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 22). 90 mg (98% pure, 98% thor.) of the title compound were obtained.

LC-MS (Method 1): Rt = 1.94 min; MS (ESIpos): m/z = 517/519 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (1.53), 0.008 (1.08), 2.073 (0.88), 2.110 (1.56), 2.267 (16.00), 2.572 (1.71), 2.595 (1.70 ), 2.705 (1.63), 2.719 (1.79), 2.744 (1.20), 2.759 (1.12), 3.356 (0.74), 3.370 (1.19), 3.385 (0.80), 3.393 (0.68), 3.594 (0.83), 3.725 (0.73 ), 7.025 (1.29), 7.043 (1.52), 7.115 (1.56), 7.138 (4.98), 7.184 (2.01), 7.202 (2.80), 7.221 (1.07), 7.490 (0.94), 7.493 (1.09), 7.503 (3.35 ), 7.511 (3.25), 7.522

- 162 040284 (10.48) 7.525 (9.73) 7.530 (5.87) 7.534 (4.51) 7.537 (3.92) 7.545 (0.98) 7.839 (1.47) 7.844 (1.38) 7.861 (2.28) ), 7.932 (4.64), 7.954 (2.89), 8.789 (1.02), 8.804 (1.57), 8.817 (1.00).

Separation of enantiomers.

The title target compound (70 mg) was dissolved in acetonitrile (1 ml) and ethanol (1 ml) and separated into enantiomers by chiral phase preparative HPLC (see Examples 94 and 95) [column: Daicel Chiralpak IF, 5 μm, 250 mm x 20 mm; flow: 20 ml/min; detection: 220 nm; temperature: 23°C; sample injection: 0.05 ml; eluent: 70% heptane / 30% ethanol + 0.2% TFA; isocratic].

Example 94 4-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-(3-methylphenyl)butanoic acid (enantiomer 1)

The separation of the enantiomers described in Example 93 gave the title compound as the previously eluted enantiomer. 13 mg (98% pure, ee value 100%) of the title compound were obtained.

LC-MS (Method 1): Rt = 1.93 min; MS (ESIpos): m/z = 517/519 [M+H]+.

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 2.109 (1.50), 2.267 (16.00), 2.572 (1.68), 2.595 (1.66), 2.705 (1.59), 2.719 (1.76), 2.745 (1.18) , 2.759 (1.11), 3.355 (0.72), 3.370 (1.16), 3.385 (0.79), 3.594 (0.84), 3.724 (0.77), 7.025 (1.25), 7.043 (1.50), 7.115 (1.50), 7.138 (4.89) , 7.184(2.00), 7.202(2.79), 7.221(1.06),7.489(0.88), 7.492(1.04), 7.502(3.30), 7.510(3.15), 7.521(10.42), 7.524(9.62), 7.529(5.84) . , 8.803 (1.52), 8.816 (1.00).

Example 95 4-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-(3-methylphenyl)butanoic acid (enantiomer 2)

The separation of the enantiomers described in Example 93 gave the title compound as the later eluted enantiomer. 21 mg (98% pure, ee value 98%) of the title compound were obtained.

LC-MS (Method 1): R _t = 1.93 min; MS (ESIpos): m/z = 517/519 [M+H]+.

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 2.109 (1.56), 2.268 (16.00), 2.573 (1.67), 2.596 (1.67), 2.705 (1.58), 2.720 (1.76), 2.745 (1.17 ), 2.759 (1.11), 3.356 (0.73), 3.371 (1.19), 3.385 (0.81), 3.393 (0.69), 3.581 (0.76), 3.595 (0.86), 3.724 (0.78), 3.741 (0.79), 7.025 (1.28 ), 7.043 (1.55), 7.115 (1.52), 7.138 (5.00), 7.184 (1.98), 7.202 (2.76), 7.221 (1.06), 7.489 (0.87), 7.492 (1.06), 7.502 (3.29), 7.510 (3.10 ), 7.521 (10.40), 7.524 (10.04), 7.529 (6.10), 7.533 (4.63), 7.536 (4.10), 7.544 (1.01), 7.837 (1.46), 7.843 (1.38), 7.860 (2.24), 7.865 (2.23 ), 7.931 (4.71), 7.954 (2.93), 8.788 (1.01), 8.803 (1.56), 8.816 (1.01).

Example 96 (+/-)-4-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-(2-methoxyphenyl)butanoic acid (racemate)

To a solution of (+/-)-tert-butyl-4-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-(2methoxyphenyl)butanoate (4.50 g, 7.63 mmol, example 193A) in dichloromethane (52 ml) was added TFA (12 ml, 150 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 adsorbed into dichloromethane and purified by flash column chromatography (100 g Biotage SnapCartridge KP-Sil, cyclohexane/ethyl acetate 8:2, Isolera One). 3.71 g (91% pure, 83% th. y.) of the title compound was obtained.

LC-MS (Method 1): R _t = 1.88 min; MS (ESIpos): m/z = 533/535 [M+H]+.

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 1.157 (1.09), 1.174 (2.15), 1.192 (1.09), 1.229 (0.95), 1.910 (0.47), 1.988 (4.22), 2.136 (10.90 ), 2.614 (0.49), 2.632 (0.53), 2.654 (4.30), 2.662 (4.68), 2.673 (5.14), 2.677 (5.09), 2.701 (0.49), 3.171 (16.00), 3.632 (0.75), 3.645 (1.57 ), 3.660 (1.69), 3.676 (1.97), 3.689 (1.60), 3.714 (1.94), 3.732 (2.38), 3.748 (1.77), 3.765 (0.90), 3.785 (1.99), 3.831 (1.42), 3.849 (0.62 ), 3.965 (1.62), 4.021 (1.00), 4.039 (1.01), 6.896 (2.08), 6.915 (4.52), 6.933 (2.59), 6.975 (4.42), 6.996 (5.33), 7.196 (2.20), 7.215 (3.50 ), 7.237 (5.11), 7.256 (3.76), 7.476 (0.67), 7.488 (1.83), 7.501 (6.30), 7.509 (5.32), 7.521 (14.60), 7.526 (14.79), 7.687 (2.41), 7.832 (3.07 ), 7.837 (2.72), 7.854 (4.66), 7.860 (4.45), 7.928 (8.53), 7.950 (5.31), 8.737 (1.87), 8.751 (3.56), 8.765 (1.87).

Separation of enantiomers.

The title target compound (705 mg, 100% pure, from another test) was dissolved in a mixture of methanol and acetonitrile (25 mL) and separated into enantiomers by

- 163 040284 preparative SLC on chiral phase (see examples 97 and 98) [column: Daicel Chiralpak AD-H, 5 µm,

250 mm x 20 mm; flow: 80 ml/min; detection: 210 nm; temperature: 40°C; sample injection: 0.50 ml; eluent: 70% carbon dioxide / 30% isopropanol; isocratic].

Example 97 (-)-4-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-(2methoxyphenyl)butanoic acid (enantiomer 1)

The separation of the enantiomers described in Example 96 gave the title compound as the previously eluted enantiomer. 269 mg (100% pure, ee value 100%) of the title compound were obtained.

[a] _D20 = -16.9°, 589 nm, c = 0.35 ^g /100 ml, methanol.

LC-MS (Method 1): Rt = 1.87 min; MS (ESIpos): m/z = 533/535 [M+H]+.

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.030 (0.91), 1.045 (0.92), 2.132 (4.61), 2.649 (1.95), 2.657 (2.08), 2.668 (2.36), 2.673 (2.28) 3.640 (0.71), 3.654 (0.75), 3.670 (0.90), 3.709 (0.87), 3.727 (1.06), 3.742 (0.78), 3.779 (0.81), 3.800 (16.00), 3.810 (1.41), 6.893 (0.92) , 6.912 (1.98), 6.931 (1.13), 6.974 (1.95), 6.995 (2.36), 7.191 (0.90), 7.195 (0.95), 7.214 (1.50), 7.234 (2.59), 7.252 (1.72), 7.256 (1.33) . , 7.680 (0.94), 7.828 (1.30), 7.834 (1.13), 7.850 (2.02), 7.856 (1.84), 7.924 (3.70), 7.946 (2.35), 8.732 (0.81), 8.746 (1.51), 8.760 (0.78) , 12.043 (1.22).

Example 9 8. (+)-4-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-(2-methoxyphenyl)butanoic acid (enantiomer 2).

The separation of the enantiomers described in Example 96 gave the title compound as the later eluted enantiomer. 253 mg (100% pure, ee value 100%) of the title compound were obtained.

[a] _D20 = +18.1°, 589 nm, c = 0.37 g ^/ 100 mL, methanol.

LC-MS (Method 1): Rt = 1.87 min; MS (ESIpos): m/z = 533/535 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 2.073 (1.06), 2.132 (4.23), 2.648 (1.75), 2.657 (1.88), 2.667 (2.13), 2.673 (2.12), 3.670 (0.82) 3.709 (0.79), 3.727 (0.97), 3.800 (16.00), 6.895 (0.85), 6.912 (1.73), 6.914 (1.83), 6.931 (1.02), 6.933 (1.02), 6.976 (1.80), 6.995 (2.17) 7.191 (0.81), 7.195 (0.95), 7.215 (1.42), 7.234 (2.38), 7.237 (1.73), 7.252 (1.59), 7.256 (1.29), 7.485 (0.72), 7.499 (2.50), 7.507 (2.26) , 7.519 (6.59), 7.523 (6.36), 7.527 (4.56), 7.531 (3.65), 7.535 (3.04), 7.543 (0.82), 7.680 (0.87), 7.828 (1.33), 7.834 (1.18), 7.851 (2.04) , 7.856 (1.96), 7.924 (3.80), 7.946 (2.41), 8.748 (1.34), 12.046 (0.84).

Example 99 (+/-)-4-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-[2-(trifluoromethoxy)phenyl]butanoic acid (racemate)

To a solution of (+/-)-tert-butyl-4-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-[2(trifluoromethoxy)phenyl]butanoate ( 350 mg, 98% pure, 533 µmol, example 194A) in dichloromethane (3.8 ml) was added TFA (820 µl, 11 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 16). 241 mg (98% pure, 75% thor.) of the title compound were obtained.

LC-MS (Method 2): Rt = 1.06 min; MS (ESIpos): m/z = 587/589 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 2.126 (4.63), 2.328 (0.57), 2.585 (1.54), 2.604 (1.66), 2.625 (2.64), 2.643 (2.55), 2.669 (0.52) , 2.747 (2.51), 2.762 (2.75), 2.787 (1.77), 2.802 (1.67), 3.643 (1.24) . , 7.598 (3.69) , 8.884 (1.99).

Separation of enantiomers.

The title target compound (210 mg) was dissolved in ethanol (5 ml) and separated into enantiomers by chiral phase preparative HPLC (see examples 100 and 101) [column: Daicel Chiralcel OX-H, 5 µm, 250 mm x 20 mm; flow: 15 ml/min; detection: 220 nm; temperature: 30°C; sample injection: 0.15 ml; eluent: 85% heptane/15% ethanol; duration of action 11 min, isocratic]. Later, the enantiomer to be eluted was purified one more time under the same conditions. The combined target fractions were suitably concentrated and the residue was then lyophilized.

Example 100 (-)-4-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-[2-(trifluoromethoxy- 164 040284 si)phenyl]butanoic acid ( enantiomer 1).

Separation of the enantiomers as described in Example 99 gave the title compound as the previously eluted enantiomer. 87 mg (98% pure, ee value 99%) of the title compound were obtained.

[a]D ²⁰ = -20.0°, 589 nm, c = 0.25 g/100 ml, methanol.

LC-MS (Method 2): Rt = 1.08 min; MS (ESIpos): m/z = 587/589 [M+H]+.

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (1.23), 0.008 (1.04), 2.125 (4.52), 2.327 (0.45), 2.523 (1.23), 2.585 (1.75), 2.603 (1.88 ), 2.625 (2.85), 2.643 (2.74), 2.669 (0.49), 2.689 (3.20), 2.731 (3.78), 2.746 (2.66), 2.762 (2.95), 2.786 (1.95), 2.802 (1.83), 2.890 (4.64 ), 3.642 (1.26), 3.657 (2.09), 3.672 (1.71), 3.695 (0.78), 3.807 (4.36), 7.323 (1.73), 7.332 (2.60), 7.338 (2.78), 7.343 (3.32), 7.347 (2.98 ), 7.378 (6.83), 7.387 (5.84), 7.393 (5.69), 7.402 (5.04), 7.478 (0.93), 7.489 (2.33), 7.503 (7.47), 7.511 (6.32), 7.522 (16.00), 7.529 (15.26 ), 7.548 (2.47), 7.589 (3.95), 7.598 (3.72), 7.603 (3.77), 7.612 (3.43), 7.836 (3.30), 7.842 (3.04), 7.859 (5.11), 7.864 (4.91), 7.933 (9.89 ), 7.955 (6.62), 8.857 (1.92), 8.870 (3.75), 8.884 (1.99).

Example 101 (+)-4-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-[2-(trifluoromethoxy)phenyl]butanoic acid (enantiomer 2)

Separation of the enantiomers as described in Example 99 gave 82 mg (98% pure, ee value 98%) of the title compound as the later eluted enantiomer.

[a] _D20 = +22.8°, 589 nm, c = 0.35 g ^/ 100 mL, methanol.

LC-MS (Method 2): Rt = 1.08 min; MS (ESIpos): m/z = 587/589 [M+H]+.

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: -0.008 (1.25), 0.008 (1.39), 1.161 (0.66), 1.177 (0.65), 1.244 (1.05), 1.259 (1.29), 1.275 ( 0.74), 2.127 (4.52), 2.328 (0.47), 2.564 (0.42), 2.586 (1.73), 2.604 (1.83), 2.626 (2.78), 2.644 (2.70), 2.670 (0.56), 2.690 (4.00), 5.60) 2.89) 7.524 (16.00), 7.530 (15.63), 7.533 (14.30), 7.537 (10.49), 7.541 (8.03), 7.549 (2.55), 7.589 (3.94), 7.599 (3.70), 7.604 (3.78), 3.42), 7.837 (3.50), 7.843 (3.23), 7.860 (5.31), 7.865 (5.18), 7.934 (10.61), 7.956 (7.03), 8.872 (3.62), 8.886 (1.92).

Example 102 (+/-)-4-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-(pyridin-2-yl)butanoic acid (racemate)

To a solution of (+/-)-tert-butyl-4-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3(pyridin-2-yl)butanoate (600 mg, 1.07 mmol, example 195A) in dichloromethane (17 ml) was added TFA (8.2 ml, 110 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 22). 90 mg (428 mg, 98% pure, 78% theoretical yield) of the title compound were obtained.

LC-MS (Method 2): Rt = 0.80 min; MS (ESIneg): m/z = 504/506 [M+H]+.

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (2.12), 0.008 (1.81), 2.073 (0.81), 2.130 (5.34), 2.812 (0.58), 2.826 (0.71), 2.854 (2.56 ), 2.870 (3.13), 2.896 (2.33), 2.916 (0.60), 2.938 (0.66), 3.733 (1.84), 3.746 (1.91), 3.759 (0.84), 3.856 (0.67), 3.881 (1.38), 3.895 (1.37 ), 3.909 (0.97), 7.481 (0.70), 7.493 (1.88), 7.497 (2.00), 7.502 (2.63), 7.506 (6.48), 7.515 (5.92), 7.523 (15.59), 7.525 (16.00), 7.529 (15.81 ), 7.533 (11.80), 7.537 (7.95), 7.541 (6.53), 7.549 (2.08), 7.554 (1.06), 7.598 (1.98), 7.750 (1.84), 7.845 (3.15), 7.851 (2.83), 7.868 (4.80 ), 7.873 (4.55), 7.940 (9.37), 7.962 (5.85), 8.140 (1.50), 8.727 (2.88), 8.740 (2.68), 8.896 (1.70), 8.909 (2.72).

Separation of enantiomers.

The title target compound (400 mg) was dissolved in methanol (33 ml) and separated into enantiomers by preparative chiral phase SLC (see examples 103 and 104) [column: Daicel Chiralpak AD, 5 μm, 250 mm x 20 mm; flow: 80 ml/min; detection: 210 nm; temperature: 40°C; sample injection: 0.50 ml; eluent: 78% carbon dioxide / 22% isopropanol; isocratic].

Example 103 (-)-4-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-(pyridin-2-yl)butanoic acid (enantiomer 1)

The separation of enantiomers described in Example 102 gave the title compound as the previously eluted enantiomer. 116 mg (98% pure, ee value 100%) of the title compound were obtained.

- 165 040284

[a] _D20 = -26.1°, 589 nm, c = 0.38 ^g /100 ml, methanol.

LC-MS (Method 2): Rt = 0.80 min; MS (ESIneg): m/z = 504/506 [M+H]+.

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (1.17), 0.008 (1.18), 2.073 (0.99), 2.129 (4.97), 2.524 (1.11), 2.809 (0.67), 2.822 (0.84 ), 2.851 (2.87), 2.864 (3.16), 2.871 (3.04), 2.893 (2.57), 2.913 (0.72), 2.935 (0.80), 3.185 (2.38), 3.698 (2.11), 3.709 (2.99), 3.730 (1.89 ), 3.743 (2.02), 3.756 (0.91), 3.878 (1.35), 3.892 (1.30), 3.907 (1.00), 3.928 (0.48), 7.483 (0.61), 7.493 (1.72), 7.496 (1.89), 7.507 (6.03 ), 7.514 (5.84), 7.525 (16.00), 7.529 (15.78), 7.532 (11.69), 7.536 (7.83), 7.541 (6.61), 7.548 (2.10), 7.590 (1.92), 7.737 (1.76), 7.757 (1.84 ), 7.846 (3.09), 7.851 (2.89), 7.868 (4.74), 7.873 (4.67), 7.939 (9.18), 7.962 (5.68), 8.131 (1.56), 8.723 (2.98), 8.736 (2.90), 8.892 (1.71 ), 8.905 (2.63).

Example 104 (+)-4-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-(pyridin-2-yl)butanoic acid (enantiomer 2)

The separation of the enantiomers described in Example 102 gave the title compound as the later eluted enantiomer. 122 mg (98% pure, ee value 95%) of the title compound were obtained.

[a] _D20 = +23.1°, 589 nm, c = 0.33 g ^/ 100 mL, methanol.

LC-MS (Method 2): R _t = 0.80 min; MS (ESIneg): m/z = 504/506 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (1.06), 0.008 (1.29), 2.073 (0.85), 2.130 (4.93), 2.329 (0.40), 2.812 (0.71), 2.826 (0.83 ), 2.855 (2.89), 2.868 (3.23), 2.874 (3.13), 2.896 (2.56), 2.916 (0.72), 2.938 (0.77), 3.713 (3.01), 3.733 (1.91), 3.746 (2.07), 3.759 (0.91 ), 3.880 (1.32), 3.895 (1.32), 3.909 (0.97), 7.483 (0.78), 7.497 (2.06), 7.507 (6.21), 7.515 (6.03), 7.525 (16.00), 7.529 (15.65), 7.537 (7.59 ), 7.541 (6.26), 7.599 (1.99), 7.748 (1.90), 7.768 (1.91), 7.846 (3.11), 7.851 (2.82), 7.868 (4.67), 7.874 (4.50), 7.940 (9.06), 7.962 (5.53 ), 8.143 (1.66), 8.729 (3.09), 8.740 (2.92), 8.895 (1.76), 8.909 (2.62).

Example 105 (+/-)-4-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-[2-(trifluoromethyl)phenyl]butanoic acid (racemate)

To a solution of (+/-)-tert-butyl-4-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-[2(trifluoromethyl)phenyl]butanoate ( 1.00 g, 1.59 mmol, example 196A) in dichloromethane (15 ml) was added TFA (2.5 ml, 32 mmol) and the mixture was stirred overnight at RT. The mixture was then concentrated and mixed successively with dichloromethane several times and re-concentrated. The residue was purified by preparative HPLC (Method 20). The combined desired fractions were concentrated and the residue was dried in vacuo. 845 mg (98% pure, 91% thor.) of the title compound were obtained.

LC-MS (Method 1): R _t = 1.99 min; MS (ESIpos): m/z = 571/573 [M+H]+.

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (2.60), 0.008 (2.44), 2.112 (4.45), 2.328 (0.57), 2.606 (1.73), 2.622 (1.84), 2.646 (3.08 ), 2.662 (3.07), 2.737 (2.87), 2.755 (3.03), 2.777 (1.83), 2.795 (1.75), 3.715 (1.38), 3.787 (1.81), 3.804 (2.48), 3.819 (1.89), 3.898 (1.74 ), 7.448 (1.64), 7.468 (3.75), 7.487 (4.29), 7.501 (7.41), 7.508 (6.42), 7.520 (16.00), 7.526 (15.35), 7.668 (1.84), 7.686 (3.59), 7.712 (4.92 ), 7.732 (3.88), 7.776 (3.72), 7.796 (2.64), 7.826 (3.45), 7.832 (3.21), 7.849 (5.09), 7.854 (5.02), 7.926 (9.89), 7.948 (6.33), 8.856 (1.93 ), 8.871 (3.79), 8.885 (1.87).

1H-NMR (400 MHz, DMSO-d6): δ [ppm] = 12.20 (br. s, 1H), 8.87 (t, 2H), 7.93 (d, 1H), 7.84 (dd, 1H), 7.79 (d , 1H), 7.75-7.56 (m, 3H), 7.56-7.44 (m, 6H), 3.93-3.85 (br. m, 1H), 3.84-3.76 (m, 1H), 3.75-3.65 (br. m, 1H), 2.76 (dd, 1H), 2.64 (dd, 1H), 2.11 (br. s, 3H).

Separation of enantiomers.

The title title compound (750 mg) was dissolved in a 1:1 mixture of acetonitrile and methanol (60 ml) and separated into enantiomers by chiral phase preparative SLC (see Examples 106 and 107) [column: Chiralpak AD-H, 5 µm, 250 mm x 30 mm; flow: 100 ml/min; detection: 210 nm; temperature: 38°C; sample injection: 2.2 ml; eluent: 75% carbon dioxide/25% ethanol; duration of action 15.5 min, isocratic].

Example 106 (+)-4-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-[2-(trifluoromethyl)phenyl]butanoic acid (enantiomer 1)

Separation of enantiomers as described in Example 105 gave 363 mg (98% pure, ee value 100%) of the title compound as the previously eluted enantiomer.

[a] _D20 = +31.6°, 589 nm, c = 0.47 g ^/ 100 mL, methanol.

- 166 040284

The ethanol-containing residues were then removed by lyophilization.

LC-MS (Method 1): Rt = 2.00 min; MS (ESIpos): m/z = 571/573 [M+H]+.

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (1.38), 0.008 (1.00), 1.234 (0.45), 2.113 (4.47), 2.328 (0.49), 2.607 (1.66), 2.623 (1.82 ), 2.646 (2.93), 2.663 (2.93), 2.710 (0.52), 2.737 (2.83), 2.755 (2.99), 2.777 (1.82), 2.795 (1.69), 3.710 (1.21), 3.786 (1.68), 3.803 (2.20 ), 3.819 (1.64), 3.883 (1.19), 7.449 (1.73), 7.469 (3.93), 7.487 (4.52), 7.500 (7.72), 7.508 (6.99), 7.520 (16.00), 7.526 (15.16), 7.533 (10.45 ), 7.545 (2.74), 7.668 (1.89), 7.687 (3.63), 7.713 (4.86), 7.733 (3.86), 7.776 (3.76), 7.796 (2.57), 7.825 (3.46), 7.830 (3.27), 7.847 (5.01 ), 7.853 (4.91), 7.925 (9.61), 7.948 (6.13), 8.856 (2.04), 8.871 (3.74), 8.885 (1.85), 12.218 (3.06).

1H-NMR (400 MHz, DMSO-d6): δ [ppm] = 12.22 (br. s, 1H), 8.87 (t, 1H), 7.93 (d, 1H), 7.84 (dd, 1H), 7.79 (d , 1H), 7.75-7.56 (m, 3H), 7.56-7.43 (m, 6H), 3.95-3.85 (br. m, 1H), 3.85-3.76 (m, 1H), 3.75-3.65 (br. m, 1H), 2.76 (dd, 1H), 2.64 (dd, 1H), 2.11 (br. s, 3H).

Example 107 (-)-4-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-[2-(trifluoromethyl)phenyl]butanoic acid (enantiomer 2)

The separation of enantiomers described in Example 105 gave 357 mg (98% pure, ee value 99%) of the title compound as the later eluted enantiomer.

[a] _D20 = -27.3°, 589 nm, c = 0.46 ^g /100 ml, methanol.

The ethanol-containing residues were then removed by lyophilization.

LC-MS (Method 1): Rt = 2.00 min; MS (ESIpos): m/z = 571/573 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: -0.149 (0.67), -0.008 (7.44), 0.008 (5.88), 0.146 (0.72), 1.234 (0.59), 2.113 (4.41), 2.327 (0.78), 2.602 (1.69), 2.618 (1.67), 2.642 (2.92), 2.658 (2.90), 2.669 (1.08) (1.21) 7.525 (15.08), 7.533 (10.41), 7.545 (2.74), 7.667 (1.78), 7.686 (3.55), 7.712 (4.86), 7.732 (3.84), 7.774 (3.71), 7.794 (2.60), 7.825 (3.38), 7.830 (3.12), 7.847 (5.02), 7.852 (4.86), 7.924 (9.40), 7.947 (6.02), 8.867 (1.72), 8.882 (3.06), 12.220 (0.72).

1H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.22 (br. s, 1H), 8.88 (t, 1H), 7.93 (d, 1H), 7.84 (dd, 1H), 7.78 ( d, 1H), 7.76-7.58 (m, 3H), 7.56-7.43 (m, 6H), 3.95-3.85 (br. m, 1H), 3.84-3.76 (m, 1H), 3.75-3.64 (br. m , 1H), 2.76 (dd, 1H), 2.64 (dd, 1H), 2.11 (br. s, 3H).

Example 108 (+/-)-4-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-(3-methoxypyridin-2-yl)butanoic acid (racemate )

To a solution of (+/-)-tert-butyl-4-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)-carbonyl]amino}-3-(3methoxypyridin-2-yl)butanoate (1.70 g, 2.88 mmol, example 197A) in dichloromethane (47 ml) was added TFA (22 ml, 290 mmol) and the mixture was stirred overnight at RT. The mixture was then concentrated and mixed successively with dichloromethane several times and re-concentrated. The residue was purified by preparative HPLC (Method 22). 1.28 g (98% pure, 82% th. y.) of the title compound was obtained.

LC-MS (Method 1): Rt = 1.61 min; MS (ESIpos): m/z = 534/536 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (0.96), 0.008 (0.66), 2.189 (16.00), 2.607 (1.12), 2.622 (1.19), 2.648 (1.52), 2.662 (1.44) ), 2.880 (1.29), 2.902 (1.37), 2.921 (1.06), 2.942 (1.03), 3.170 (1.45), 3.342 (0.58), 3.709 (1.46), 3.722 (1.52), 3.957 (0.99), 3.972 (1.05 ), 3.978 (1.07), 3.994 (0.83), 7.224 (1.46), 7.236 (1.54), 7.245 (1.83), 7.257 (1.81), 7.384 (2.13), 7.403 (1.63), 7.477 (0.46), 7.489 (1.34 ), 7.504 (3.55), 7.510 (2.87), 7.522 (5.70), 7.536 (6.77), 7.553 (1.24), 7.763 (2.16), 7.836 (1.69), 7.842 (1.42), 7.858 (2.54), 7.864 (2.29 ), 7.930 (4.36), 7.952 (2.72), 8.116 (2.25), 8.119 (2.29), 8.128 (2.22), 8.130 (2.07), 8.730 (0.98), 8.745 (1.93), 8.760 (0.89), 11.987 (0.59 ).

Separation of enantiomers.

The title title compound (1.20 g) was dissolved in heat in 45 ml of a mixture of ethanol, heptane and dichloromethane and separated into enantiomers by chiral phase preparative HPLC (see Examples 109 and 110) [column: YMC Chiralart Amylose SA, 5 µm , 250 mm x 30 mm; flow: 50 ml/min; detection: 210 nm; temperature: 40°C; sample injection: 0.60 ml; eluent: 60% heptane / 40% isopropanol; isocratic; duration of action 7 minutes].

Example 109 (-)-4-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-(3-methoxypyridin2-yl)butanoic acid (enantiomer 1)

Separation of the enantiomers as described in Example 108 gave 526 mg (98% pure, ee-167 040284 value 99%) of the title compound as the previously eluted enantiomer.

[a] _D20 = -14.7°, 589 nm, c = 0.50 g ^/ 100 ml, chloroform.

LC-MS (Method 1): Rt = 1.60 min; MS (ESIpos): m/z = 534/536 [M+H]+.

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.031 (2.09), 1.047 (2.10), 2.191 (16.00), 2.606 (1.02), 2.621 (1.09), 2.647 (1.39), 2.661 (1.35) , 2.881 (1.17), 2.903 (1.24), 2.921 (0.95), 2.943 (0.95), 3.709 (1.37), 3.723 (1.44), 3.758 (0.43), 3.958 (0.90), 3.973 (1.01), 3.979 (1.04) 3.995 (0.80), 7.219 (1.72), 7.231 (1.77), 7.240 (2.16), 7.252 (2.17), 7.378 (2.43), 7.397 (1.90), 7.489 (1.26), 7.504 (3.55), 7.510 (2.76) . , 8.114 (2.39), 8.117 (2.44), 8.126 (2.44), 8.129 (2.34), 8.142 (1.51), 8.731 (0.91), 8.745 (1.87), 8.760 (0.87).

Example 110 (+)-4-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-(3-methoxypyridin-2-yl)butanoic acid (enantiomer 2) .

Separation of enantiomers as described in Example 108 gave the title compound prepurified (90% pure, 98% ee).

[a] _D20 = +12.3°, 589 nm, c = 0.49 g/100 ml ^, chloroform.

The prepurified title compound was then purified twice by preparative HPLC (Method 20) and further purified once by preparative HPLC [column: XBridge C18, 5 μm, 100 mm x 30 mm; flow: 80 ml/min; detection: 210 nm; temperature: 40°C; sample injection: 0.25 ml; eluent: 85% water/5% (acetonitrile/water 8:2) + 2% ammonia/5% acetonitrile → 75% water/5% (acetonitrile/water 8:2) + 2% ammonia/20% acetonitrile; duration of action 5 min]. 240 mg (98% pure) of the title compound were obtained.

LC-MS (Method 2): R _t = 0.84 min; MS (ESIpos): m/z = 534/536 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 1.754 (7.46), 2.189 (16.00), 2.577 (1.13), 2.592 (1.16), 2.617 (1.47), 2.632 (1.42), 2.836 (1.15) ), 2.856 (1.20), 2.876 (0.95), 2.897 (0.95), 3.308 (0.85), 3.711 (1.82), 3.947 (1.03), 3.968 (1.21), 3.983 (0.92), 7.215 (1.70), 7.227 (1.79 ), 7.236 (2.21), 7.248 (2.22), 7.373 (2.57), 7.393 (1.96), 7.488 (1.23), 7.503 (3.63), 7.509 (2.81), 7.522 (5.99), 7.535 (7.46), 7.552 (1.37 ), 7.761 (2.46), 7.834 (1.63), 7.839 (1.40), 7.857 (2.52), 7.862 (2.31), 7.928 (4.44), 7.950 (2.72), 8.113 (2.53), 8.123 (2.44), 8.804 (1.24 ).

Example 111 (+/-)-4-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-(2-chlorophenyl)2,2-dimethylbutanoic acid (racemate )

To a solution of (+/-)-tert-butyl-4-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-(2chlorophenyl)-2,2-dimethylbutanoate (330 mg, 531 µmol, Example 198A) in dichloromethane (10 mL) TFA (5 mL, 64.9 mmol) was added and the mixture was stirred overnight at RT. The mixture was then concentrated and mixed twice successively with dichloromethane and re-concentrated. The residue was purified by preparative HPLC (Method: Chromatorex C18, 10 µm, 125 x 30 mm, acetonitrile/water gradient with 0.01% TFA). 248 mg (99% pure, 82% thor.) of the title compound were obtained.

LC-MS (Method 7): R = 1.45 min; MS (ESIpos): m/z = 565/567 [M+H] ⁺ .

'H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (2.38), 0.008 (2.15), 1.099 (16.00), 1.115 (15.35), 1.919 (0.56), 2.073 (0.42), 2.327 ( 0.79), 2.366 (0.42), 2.523 (2.16), 2.670 (0.71), 3.661 (1.15), 3.936 (1.92), 4.098 (4.62), 7.270 (1.11), 7.365 (1.10), 7.433 (3.27), 3.05), 7.486 (13.79), 7.491 (13.00), 7.504 (3.35), 7.524 (2.60), 7.545 (1.69), 7.798 (1.45) 1.97).

1H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.55 (br. s, 1H), 8.75-8.62 (m, 1H), 7.90 (d, 1H), 7.81 (dd, 1H), 7.72-7.18 (m, 10H), 4.14-4.03 (m, 2H, partially obscured), 3.71-3.62 (m, 1H, partially obscured), 1.92 (br. s, 3H), 1.12 (s, 3H), 1.10 (s, 3H).

Separation of enantiomers.

The title title compound (212 mg) was dissolved in 25 ml of a mixture of methanol and acetonitrile and separated into enantiomers by preparative chiral phase SLC (see examples 112 and 113) [column: Daicel Chiralpak AD SFC, 5 μm, 250 mm x 20 mm; flow: 80 ml/min; detection: 210 nm; temperature: 40°C; sample injection: 1.50 ml; eluent: 70% carbon dioxide/30% ethanol; isocratic; duration of action 7 minutes].

- 168 040284

Example 112 4-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-(2-chlorophenyl)-2,2dimethylbutanoic acid (enantiomer 1)

Separation of enantiomers as described in Example 111 yielded 80 mg (99% pure, ee value

100%) of the title compound as the previously eluted enantiomer.

LC-MS (Method 2): R _t = 1.12 min; MS (ESIpos): m/z = 565/567 [M+H]+.

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: -0.008 (2.87), 0.008 (3.23), 1.099 (16.00), 1.115 (15.49), 1.937 (0.56), 2.327 (0.54), 2.366 ( 0.44), 2.523 (1.74), 2.670 (0.55), 2.710 (0.43), 3.663 (0.94), 4.098 (4.16), 7.272 (1.12), 7.366 (1.14), 7.433 (3.29), 7.453 (3.08), 7.485 14.05), 7.491 (13.77), 7.503 (4.00), 7.515 (1.29), 7.527 (2.52), 7.545 (1.78), 7.797 (1.48) 2.05), 12.562 (3.44).

1H-NMR (400 MHz, DMSO-d6): δ [ppm] = 12.56 (s, 1H), 8.73-8.64 (m, 1H), 7.90 (d, 1H), 7.81 (dd, 1H), 7.57-7.22 (m, 10H), 4.14-4.06 (m, 2H), 3.71-3.62 (m, 1H), 1.94 (br. s, 3H), 1.11 (s,3H), 1.10 (s,3H).

Example 113 4-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-(2-chlorophenyl)-2,2dimethylbutanoic acid (enantiomer 2)

The separation of enantiomers described in Example 111 gave 81 mg (99% pure, ee value 99%) of the title compound as the later eluted enantiomer.

LC-MS (Method 2): R _t = 1.12 min; MS (ESIpos): m/z = 565/567 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (2.88), 0.008 (2.30), 1.099 (16.00), 1.114 (15.33), 1.939 (0.59), 2.073 (0.45), 2.327 (0.48) ), 2.523 (1.54), 2.670 (0.41), 3.662 (0.94), 4.098 (4.20), 7.271 (1.12), 7.364 (1.11), 7.433 (3.21), 7.455 (2.99), 7.486 (14.01), 7.491 (13.51 ), 7.503 (4.03), 7.515 (1.35), 7.527 (2.61), 7.546 (1.84), 7.797 (1.44), 7.819 (2.27), 7.823 (2.23), 7.887 (4.73), 7.909 (2.96), 8.698 (1.95 ), 12.563 (1.12).

1H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.56 (br. s, 1H), 8.76-8.64 (m, 1H), 7.90 (d, 1H), 7.81 (dd, 1H), 7.57-7.21 (m, 10H), 4.14-4.04 (m, 2H), 3.72-3.61 (m, 1H), 1.94 (br. s, 3H), 1.11 (s, 3H), 1.10 (s, 3H).

Example 114 (+/-)-4-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-(2-chlorophenyl)-3methylbutanoic acid (racemate) jO o H ₃ cJ X N

O^NH

Br С Η з iОХ ^Ν chf

To a solution of (+/-)-tert-butyl-4-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)-carbonyl]amino}-3-(2chlorophenyl)-3-methylbutanoate ( 1.70 g, 87% pure, 2.43 mmol, example 199A) in dichloromethane (17 ml) was added TFA (3.7 ml, 49 mmol) and the mixture was stirred overnight at RT. The mixture was then concentrated and mixed successively with dichloromethane several times and re-concentrated. The residue was purified by preparative HPLC (Method 15). 1.06 g (98% pure, 77% th. y.) of the title compound was obtained.

LC-MS (Method 2): Rt = 1.06 min; MS (ESIpos): m/z = 517/519 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (2.48), 0.008 (1.95), 1.546 (0.42), 1.672 (16.00), 2.072 (1.61), 2.112 (1.69), 2.327 (0.51 ), 2.523 (1.63), 2.669 (0.51), 2.760 (4.48), 2.798 (5.03), 3.342 (3.72), 3.381 (3.37), 3.777 (1.67), 3.790 (1.85), 3.811 (2.05), 3.824 (1.90 ), 4.342 (1.91), 4.359 (2.08), 4.375 (1.90), 4.392 (1.78), 7.229 (0.83), 7.248 (2.29), 7.267 (2.18), 7.274 (2.24), 7.278 (2.34), 7.293 (2.82 ), 7.297 (2.96), 7.312 (1.36), 7.392 (2.60), 7.411 (2.11), 7.459 (3.52), 7.463 (3.53), 7.478 (3.27), 7.482 (3.14), 7.500 (5.81), 7.508 (5.01 ), 7.519 (12.10), 7.526 (11.50), 7.544 (2.31), 7.654 (0.63), 7.831 (2.64), 7.836 (2.49), 7.853 (4.11), 7.859 (4.10), 7.926 (7.99), 7.949 (5.13 ), 8.624 (1.72), 8.640 (2.91), 8.655 (1.76).

Example 115 (+)-4-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-(2-fluorophenyl)-3methylbutanoic acid (enantiomer 1)

To a solution of (+)-tert-butyl-4-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-(2fluorophenyl)-3-methylbutanoate (80 mg, 135 μmol, example 201A) in dichloromethane (2 ml) was added TFA (210 μl, 2.7 mmol) and the mixture was stirred overnight at RT. The mixture was then concentrated and mixed successively with dichloromethane several times and re-concentrated. The residue was purified by preparative HPLC (Method 16). Received 69 mg (98% purity, ee-value 100%,

93% theory out) specified in the connection header.

[a] _D20 = +31.5°, 589 nm, c = 0.31 g ^/ 100 mL, methanol.

LC-MS (Method 1): R _t = 1.92 min; MS (ESIpos): m/z = 535/537 [M+H] ⁺ .

1H-NMR (600 MHz, DMSO-d ₆ ) δ [ppm]: 1.590 (16.00), 2.076 (1.84), 2.158 (0.55), 2.652 (3.56), 2.677 (4.15), 2.968 (3.73), 2.993 (3.31 ), 3.668 (1.44), 3.677 (1.57), 3.690 (1.69), 3.699 (1.54), 4.067 (1.93), 4.079 (2.09), 4.089 (1.90), 4.101 (1.75), 7.118 (1.02), 7.140 (2.13 ), 7.153 (2.82), 7.292 (1.26), 7.350 (1.58), 7.364 (2.78), 7.376 (1.38), 7.486 (0.77), 7.494 (2.62), 7.500 (2.28), 7.505 (4.11), 7.508 (5.56 ), 7.521 (8.62), 7.533 (10.91), 7.545 (2.64), 7.843 (2.16), 7.847 (2.13), 7.858 (2.94), 7.861 (2.90), 7.936 (5.68), 7.951 (4.15), 8.715 (1.79 ), 8.726 (3.02), 8.736 (1.77).

1H-NMR (600 MHz, DMSO-d ₆ ): δ [ppm] = 8.73 (t, 1H), 7.94 (d, 1H), 7.85 (dd, 1H), 7.66 (br. s, 1H), 7.597. 46 (m, 5H), 7.36 (br. t, 1H), 7.29 (br. s, 1H), 7.19-7.09 (m, 2H), 4.08 (dd, 1H), 3.68 (dd, 1H), 2.98 ( d, 1H), 2.66 (d, 1H), 2.08 (br. s, 3H), 1.59 (s, 3H).

Example 116 (-)-4-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-(2-fluorophenyl)-3methylbutanoic acid (enantiomer 2)

To a solution of (-)-tert-butyl-4-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-(2fluorophenyl)-3-methylbutanoate (80 mg, 135 μmol, example 202A) in dichloromethane (2 ml) was added TFA (210 μl, 2.7 mmol) and the mixture was stirred overnight at RT. The mixture was then concentrated and mixed successively with dichloromethane several times and re-concentrated. The residue was purified by preparative HPLC (Method 16). 60 mg (98% pure, ee value 100%, 81% thor.) of the title compound were obtained.

[a] _D20 = -28.9°, 589 nm, c = 0.32 ^g /100 ml, methanol.

LC-MS (Method 1): R _t = 1.92 min; MS (ESIpos): m/z = 535/537 [M+H] ⁺ .

1H-NMR (600 MHz, DMSO-d ₆ ) δ [ppm]: 1.587 (16.00), 2.076 (0.93), 2.649 (3.54), 2.674 (4.12), 2.965 (3.72), 2.991 (3.30), 3.664 (2.15) ), 3.673 (2.30), 3.686 (2.47), 3.696 (2.30), 4.063 (1.95), 4.075 (2.10), 4.086 (1.90), 4.097 (1.75), 7.118 (1.05), 7.139 (2.16), 7.152 (2.84 ), 7.291 (1.29), 7.348 (1.60), 7.361 (2.79), 7.375 (1.39), 7.484 (0.86), 7.491 (2.60), 7.498 (2.40), 7.503 (4.00), 7.506 (5.30), 7.519 (8.77 ), 7.530 (11.64), 7.542 (2.44), 7.840 (2.20), 7.855 (2.98), 7.932 (5.50), 7.947 (4.00), 8.710 (1.80), 8.720 (3.02), 8.730 (1.73).

1H-NMR (600 MHz, DMSO-d ₆ ): δ [ppm] = 12.00 (br. s, 1H), 8.72 (t, 1H), 7.94 (d, 1H), 7.85 (d, 1H), 7.64 ( br. s, 1H), 7.56-7.47 (m, 5H), 7.36 (t, 1H), 7.28 (br. s, 1H), 7.19-7.09 (m, 2H), 4.08 (dd, 1H), 3.68 ( dd, 1H), 2.98 (d, 1H), 2.66 (d, 1H), 2.10 (br. s, 3H), 1.59 (s, 3H).

Example 117 (+/-)-4-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-methyl-3-(pyridin-2-yl)butanoic acid (racemate)

To a solution of (+/-)-tert-butyl-4-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3methyl-3-(pyridin-2-yl) butanoate (900 mg, 1.57 mmol, example 203A) in dichloromethane (20 ml) TFA (2.4 ml, 31 mmol) was added and the mixture was stirred overnight at RT. The mixture was then concentrated and mixed successively with dichloromethane several times and re-concentrated. The residue was purified by preparative HPLC (Method 16). 585 mg (98% pure, 71% thor.) of the title compound were obtained.

LC-MS (Method 1): R _t = 1.67 min; MS (ESIpos): m/z = 518/520 [M+H] ⁺ .

1H-NMR (600 MHz, DMSO-d6) δ [ppm]: 1.199 (0.59), 1.210 (0.60), 1.578 (16.00), 1.686 (0.78), 2.077 (2.22), 2.148 (2.50), 2.172 (1.84) , 2.503 (14.98), 2.735 (2.77), 2.762 (3.14), 3.099 (2.31), 3.125 (2.03), 3.765 (1.15), 3.774 (1.28), 3.787 (1.47), 3.797 (1.32), 3.973 (1.15) , 3.984 (1.24), 3.995 (1.04), 4.006 (0.93), 7.439 (1.01), 7.487 (0.64), 7.498 (2.33), 7.509 (3.62), 7.512 (4.88), 7.525 (6.71), 7.539 (3.97) . , 7.988 (0.95), 7.994 (0.98), 8.007 (0.53), 8.642 (1.83), 8.649 (1.81), 8.753 (1.14), 8.763 (2.10), 8.773 (1.14).

Separation of enantiomers.

The title target compound (530 mg) was dissolved in methanol (30 ml) and separated into enantiomers by chiral phase preparative SLC (see Examples 118 and 119) [column:

Chiralpak AD-H, 5 µm, 250 mm x 20 mm; flow: 50 ml/min; detection: 210 nm; temperature: 40°C; sample injection: 0.40 ml; eluent: 78% carbon dioxide/22% isopropanol; isocratic; duration of action 17 minutes].

- 170 040284

Example 118 (+)-4-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-methyl-3-(pyridin2-yl)butanoic acid (enantiomer 1) .

The separation of enantiomers described in Example 117 gave 202 mg (98% pure, ee value 100%) of the title compound as the previously eluted enantiomer.

[a]D ²⁰ = +17.8°, 589 nm, c = 0.34 g/100 ml, methanol.

LC-MS (Method 1): Rt = 1.68 min; MS (ESIpos): m/z = 518/520 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (1.63), 0.008 (1.38), 1.030 (2.31), 1.045 (2.33), 1.544 (16.00), 2.170 (15.68), 2.518 (1.12) ), 2.523 (0.86), 2.672 (3.09), 2.711 (3.64), 3.000 (3.08), 3.039 (2.56), 3.473 (1.48), 3.782 (0.75), (0.68), 7.208 (1.60), (1.76), 7.477 (0.66), (8.25), 7.543 (6.47), (1.73), 7.751 (2.38), (3.19), 7.934 (5.82),

3.797 (0.79), 3.816 (1.38), 3.830 (1.29), 3.873 (1.33), 3.888 (1.41), 3.906 (0.76), 3.921 7.210 (1.67), 7.220 (1.73), 7.222 (1.90), 7.226 (1.95), 7.228 (1.80), 7.238 (1.78), 7.241 7.486 (3.63), 7.488 (3.36), 7.499 (3.31), 7.504 (7.89), 7.517 (2.42), 7.522 (6.46), 7.539 7.548 (3.28), 7.552 (1.58), 7.558 (1.91), 7.564 (1.21), 7.701 (2.51), 7.732 (1.65), 7.736 7.756 (2.43), 7.771 (1.29), 7.775 (1.27), 7.835 (2.24), 7.841 (1.98), 7.858 (3.38), 7.863 7.956 (3.76), 8.527 (2.15), 8.529 (2.21), 8.539 (2.09), 8.541 (1.95), 8.628 (1.11), 8.644

(2.31), 8.659 (1.18), 11.953 (4.48).

1H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 11.95 (s, 1H), 8.64 (t, 1H), 8.53 (dd, 1H), 7.94 (d, 1H), 7.85 (dd, 1H), 7.75 (td, 1H), 7.70 (s, 1H), 7.57-7.46 (m, 6H), 7.22 (ddd, 1H), 3.89 (dd, 1H), 3.81 (dd, 1H), 3.02 (d , 1H), 2.69 (d, 1H), 2.17 (s, 3H), 1.54 (s, 3H).

Example 119 (-)-4-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-methyl-3-(pyridin2-yl)butanoic acid (enantiomer 2) .

Separation of the enantiomers as described in Example 117 gave 72 mg (98% pure, ee value 99%) of the title compound as the later eluted enantiomer.

[a] _D20 = -22.1°, 589 nm, c = 0.35 ^g /100 ml, methanol.

LC-MS (Method 1): Rt = 1.68 min; MS (ESIpos): m/z = 518/520 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: -0.008 (1.49), 0.008 (1.29), 1.542 (16.00), 2.171 (15.95), 2.523 (0.88), 2.673 (3.04), 2.712 ( 3.53), 2.995 (2.98), 3.034 (2.44), 3.786 (0.63), 3.801 (0.73), 3.819 (1.36), 3.834 (1.26), 3.870 (1.31) 0.62), 7.209 (1.73), 7.221 (1.94), 7.226 (1.93), 7.238 (1.79), 7.485 (3.48), 7.504 (8.08), 7.522 (6.48), 7.539 (8.24), 7.542 (6.57), 3.23) 2.01), 7.857 (3.39), 7.863 (3.19), 7.934 (6.13), 7.956 (3.87), 8.530 (2.34), 8.539 (2.30), 8.672 (1.37), 11.958 (0.90).

Example 120 (+/-)-4-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-(2-methoxyphenyl)-3-methylbutanoic acid (racemate )

To a solution of (+/-)-tert-butyl-4-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-(2methoxyphenyl)-3-methylbutanoate (100 mg, 98% pure, 162 µmol, example 204A) in dichloromethane (1.2 ml) TFA (250 µl, 3.2 mmol) was added and the mixture was stirred overnight at RT. The mixture was then concentrated and mixed successively with dichloromethane several times and re-concentrated. The residue was purified by preparative HPLC (Method 20). 84 mg (98% pure, 92% thor.) of the title compound were obtained.

LC-MS (Method 1): Rt = 1.97 min; MS (ESIpos): m/z = 547/549 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.572 (13.20), 2.072 (2.90), 2.655 (3.43), 2.691 (3.96), 3.072 (3.56), 3.109 (3.10), 3.691 (1.52) , 3.704 (1.64), 3.723 (1.81), 3.737 (1.66), 4.205 (1.34), 4.223 (1.47) , 6.977(2.51), 6.998(3.00), 7.188(1.45),7.208(2.41), 7.220(3.81), 7.239(3.02), 7.475(0.44), 7.486(1.36), 7.497(4.27), 7.505(4.46) , 7.516 (16.00), 7.660 (0.69), 7.825 (2.17), 7.831 (2.05), 7.848 (3.41), 7.853 (3.40), 7.919 (6.21), 7.941 (3.90), 8.480 (1.38), 8.496 (2.48) , 8.511 (1.39).

Example 121 (+)-4-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-(2-methoxyphenyl)3-methylbutanoic acid (enantiomer 1)

To a solution of (+)-tert-butyl-4-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-(2methoxyphenyl)-3-methylbutanoate (650 mg, 1.08 mmol, example 205A) in dichloromethane (16 ml) was added TFA (1.7 ml, 22 mmol) and the mixture was stirred overnight at RT. The mixture was then concentrated and mixed successively with dichloromethane several times and re-concentrated. Remainder

- 171 040284 was purified by preparative HPLC (Method 16). Received 398 mg (98% pure, ee-value

95%, 66% theoretical out) specified in the connection header.

[a]D ²⁰ = +30.0°, 589 nm, c = 0.44 g/100 ml, methanol.

LC-MS (Method 2): R _t = 1.04 min; MS (ESIpos): m/z = 547/549 [M+H] ⁺ .

1H-NMR (500 MHz, DMSO-d ₆ ) δ [ppm]: -0.007 (0.51), 1.254 (0.43), 1.577 (16.00), 2.071 (4.33), 2.080 (1.58), 2.664 (4.50), 2.693 ( 5.04), 3.080 (4.33), 3.109 (3.90), 3.702 (1.89), 3.712 (2.07), 3.728 (2.22),3.739 (1.98), 4.215 (1.45), 4.229 (1.60), 4.241 (1.51), 1.33) 3.60), 7.244 (3.13), 7.477 (0.76), 7.486 (1.89), 7.488 (1.64), 7.491 (1.52), 7.498 (5.02), 7.503 (4.86), 7.515 (11.97), 7.520 (11.66), 10.63), 7.536 (2.01), 7.674 (0.59), 7.828 (3.01), 7.833 (2.86), 7.846 (4.20) 2.97), 8.512 (1.75).

Example 122 (-)-4-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-(2-methoxyphenyl)3-methylbutanoic acid (enantiomer 2)

To a solution of (-)-tert-butyl-4-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-(2methoxyphenyl)-3-methylbutanoate (650 mg, 1.08 mmol, example 206A) in dichloromethane (16 ml) was added TFA (1.7 ml, 22 mmol) and the mixture was stirred overnight at RT. The mixture was then concentrated and mixed successively with dichloromethane several times and re-concentrated. The residue was purified by preparative HPLC (Method 16). 468 mg (98% pure, 99% ee, 78% thor.) of the title compound were obtained.

[a] _D20 = -35.6°, 589 nm, c = 0.43 ^g /100 ml, methanol.

LC-MS (Method 2): R _t = 1.04 min; MS (ESIpos): m/z = 547/549 [M+H] ⁺ .

1H-NMR (500 MHz, DMSO-d6) δ [ppm]: -0.007 (0.57), 1.575 (16.00), 2.071 (3.31), 2.663 (4.52), 2.692 (5.04), 3.079 (4.34), 3.108 (3.90 ), 3.700 (1.92), 3.711 (2.10), 3.726 (2.23), 3.737 (1.99), 4.213 (1.45), 4.227 (1.59), 4.239 (1.47), 4.253 (1.30), 6.873 (1.60), 6.888 (3.29 ), 6.903 (1.83), 6.979 (2.75), 6.995 (3.13), 7.191 (1.48), 7.206 (2.42), 7.225 (4.71), 7.228 (3.78), 7.241 (3.64), 7.243 (3.02), 7.471 (0.43 ), 7.476 (0.86), 7.485 (1.99), 7.487 (1.72), 7.490 (1.60), 7.497 (4.92), 7.502 (4.85), 7.514 (12.36), 7.519 (11.80), 7.524 (10.39), 7.535 (1.82 ), 7.673 (0.57), 7.827 (3.06), 7.831 (2.83), 7.845 (4.22), 7.849 (4.10), 7.921 (8.11), 7.939 (5.57), 8.485 (1.76), 8.497 (2.96), 8.510 (1.72 ).

Example 123 (+/-)-4-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-(5-fluoro-2-methoxyphenyl)butanoic acid (racemate )

To a solution of (+/-)-tert-butyl-4-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-(5fluoro-2-methoxyphenyl)butanoate ( 100 mg, 165 µmol, example 207A) in dichloromethane (1.5 ml) was added TFA (250 µl, 3.3 mmol) and the mixture was stirred for 16 h at RT. The mixture was then concentrated and mixed successively with dichloromethane several times and re-concentrated. The residue was purified by preparative HPLC (Method 20). 85 mg (98% pure, 92% thor.) of the title compound were obtained.

LC-MS (Method 2): Rt = 1.01 min; MS (ESIpos): m/z = 551/553 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 0.008 (1.91), 2.073 (0.62), 2.130 (10.47), 2.328 (0.42), 2.598 (0.87), 2.616 (0.89), 2.637 (3.99) ), 2.655 (6.87), 2.669 (4.44), 2.693 (0.99), 2.710 (1.01), 3.629 (0.89), 3.641 (1.93), 3.654 (1.67), 3.671 (2.33), 3.684 (1.55), 3.716 (0.77 ), 3.735 (1.75), 3.753 (2.34), 3.802 (2.87), 3.817 (1.90), 3.833 (1.57), 3.853 (0.85), 4.528 (0.50), 6.972 (1.13), 6.985 (1.67), 6.995 (5.05 ), 7.008 (6.28), 7.024 (2.40), 7.031 (2.66), 7.046 (0.67), 7.053 (0.86), 7.088 (2.87), 7.094 (2.60), 7.112 (2.95), 7.119 (2.50), 7.309 (0.53 ), 7.479 (0.71), 7.491 (1.84), 7.494 (1.88), 7.504 (6.38), 7.511 (5.58), 7.523 (16.00), 7.528 (15.38), 7.536 (9.41), 7.638 (1.59), 7.835 (3.16 ), 7.840 (2.92), 7.857 (4.89), 7.862 (4.72), 7.931 (8.83), 7.953 (5.66), 8.760 (1.91), 8.774 (3.65), 8.788 (1.89).

1H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 8.77 (t, 1H), 7.94 (d, 1H), 7.85 (dd, 1H), 7.64 (br. s, 1H), 7.567. 47 (m, 5H), 7.10 (dd, 1H), 7.07-6.95 (m, 2H), 3.86-3.71 (m, 2H), 3.79 (s, 3H), 3.70-3.60 (m, 1H), 2.73- 2.58 (m, 2H), 2.13 (br. s, 3H).

Example 124 (+)-4-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-(5-fluoro-2-methoxyphenyl)butanoic acid (enantiomer 1) .

To a solution of (+)-tert-butyl-4-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-(5fluoro-2-methoxyphenyl)butanoate (165 mg , 98% pure, 266 µmol, example 209A) in dichloromethane (1.9

- 172 040284 ml) TFA (410 μl, 5.3 mmol) was added and the mixture was stirred for 7 h at RT. The mixture was then concentrated and mixed successively with dichloromethane several times and re-concentrated. The residue was purified by preparative HPLC (Method 16). Received 134 mg (98% purity, 90% theory.

out, ee-value 99%) of the header compound.

[a] _D20 = +17.7°, 589 nm, c = 0.42 ^g /100 mL, methanol.

LC-MS (Method 1): Rt = 1.89 min; MS (ESIpos): m/z = 551/553 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.008 (0.86), 2.073 (0.59), 2.129 (10.14), 2.327 (0.46), 2.519 (2.04), 2.524 (1.96), 2.597 (0.90) , 2.615 (1.03), 2.636 (4.25), 2.654 (6.89), 2.669 (4.26), 2.692 (0.91), 2.709 (0.99), 3.628 (1.02), 3.640 (2.04), 3.653 (1.75), 3.670 (2.36) . , 6.995 (5.39), 7.008 (6.23), 7.023 (2.42), 7.031 (2.57), 7.046 (0.70), 7.053 (0.91), 7.087 (3.04), 7.094 (2.61), 7.111 (3.00), 7.118 (2.42) , 7.478 (1.26), 7.489 (2.54), 7.493 (2.59), 7.503 (7.04), 7.511 (6.33), 7.522 (16.00), 7.527 (14.82), 7.535 (8.46), 7.539 (6.67), 7.547 (1.77) 7.638 (1.44), 7.833 (3.28), 7.838 (2.91), 7.856 (4.92), 7.861 (4.52), 7.930 (8.60), 7.952 (5.46), 8.757 (2.10), 8.772 (3.68), 8.785 (1.80) .

1H-NMR (400 MHz, DMSO-d6): δ [ppm] = 8.77 (t, 1H), 7.94 (d, 1H), 7.85 (dd, 1H), 7.64 (br. s, 1H), 7.577.44 (m, 5H), 7.10 (dd, 1H), 7.07-6.93 (m, 2H), 3.88-3.70 (m, 2H), 3.78 (s, 3H), 3.66 (td, 1H), 2.73-2.57 (m , 2H), 2.13 (br. s, 3H).

Example 125 (-)-4-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-(5-fluoro-2-methoxyphenyl)butanoic acid (enantiomer 2) .

To a solution of (-)-tert-butyl-4-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-(5fluoro-2-methoxyphenyl)butanoate (160 mg , 98% pure, 258 µmol, example 208A) in dichloromethane (1.8 ml) was added TFA (400 µl, 5.2 mmol) and the mixture was stirred for 5 h at RT. The mixture was then concentrated and mixed successively with dichloromethane several times and re-concentrated. The residue was purified by preparative HPLC (Method 16). 116 mg (98% pure, 80% thor., ee-value 99%) of the title compound were obtained.

[a] _D20 = -17.5°, 589 nm, c = 0.36 ^g /100 ml, methanol.

LC-MS (Method 1): Rt = 1.90 min; MS (ESIpos): m/z = 551/553 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (1.05), 0.008 (0.98), 2.130 (10.36), 2.523 (1.05), 2.598 (0.88), (1.97), (2.21), (5.46),

2.616

3.654

3.802

7.008 (0.89), 2.637 (4.20), 2.655 (7.04), 2.669 (4.51), 2.693 (1.03), 2.709 (1.06), 3.629 (0.86), (1.64), 3.658 (1.64), 3.671 (2.35), 3.685 (1.54), 3.716 (0.68), 3.735 (1.69), 3.753 (2.26), (2.78), 3.817 (1.83), 3.822 (1.40), 3.833 (1.51), 3.853 (0.80), 6.972 (1.20), 6.985 ( 1.79), (6.55), 7.023 (2.45), 7.031 (2.75), 7.046 (0.67), 7.053 (0.91), 7.088 (3.00), 7.095 (2.67),

3.641

3.768

6.995

7.112 (3.09), 7.119 (2.62), 7.477 (0.74), 7.489 (1.89), 7.492 (1.85), 7.502 (6.44), 7.511 (5.82), 7.535 (9.42) 7.539 (7.62) 7.547 (2.13) 7.637 (1.48) 7.833 (3.40) 7.838 (3.11) 7.855 (5.24) 7.860 (5.04) 7.930 (9.35) 8.758 (1.97), 8.772 (3.76), 8.786 (1.91).

1H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 8.77 (t, 1H), 7.94 (d, 1H), 7.85 (dd, 1H), 7.64 (br. s, 1H), 7.567. 46 (m, 5H), 7.10 (dd, 1H), 7.06-6.95 (m, 2H), 3.88-3.70 (m, 2H), 3.79 (s, 3H), 3.70-3.62 (m, 1H), 2.72- 2.59 (m, 2H), 2.13 (br. s, 3H).

Example 126 (+/-)-4-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-(2-fluoro-6-methoxyphenyl)butanoic acid (racemate )

To a solution of (+/-)-tert-butyl-4-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-(2fluoro-6-methoxyphenyl)butanoate ( 60 mg, 98.8 µmol, example 210A) in dichloromethane (3.0 ml) was added TFA (610 µl, 7.9 mmol) and the mixture was left for 2.5 h at RT. The mixture was then concentrated and mixed successively with dichloromethane several times and re-concentrated. The residue was purified by preparative HPLC (Method 15). 45 mg (100% pure, 83% theoretical) of the title compound were obtained.

LC-MS (Method 1): Rt = 1.88 min; MS (ESIpos): m/z = 551/553 [M+H] ⁺ .

1H-NMR (500 MHz, DMSO-d6) δ [ppm]: -0.007 (0.41), 1.234 (0.69), 2.073 (0.73), 2.148 (5.32), 2.518 (0.50), 2.725 (5.08), 2.728 (5.40 ), 2.741 (7.14), 2.759 (0.52), 3.686 (1.01), 3.698 (1.78), 3.711 (2.24), 3.723 (2.60), 3.735 (1.48), 3.793 (1.56), 3.802 (3.24), 3.836 (1.69 ), 3.849 (1.18), 3.944 (0.75), 3.959 (1.78), 3.974 (2.07), 3.989 (1.39), 4.005 (0.54), 6.736 (2.56), 6.754 (3.94), 6.772 (2.67), 6.834 (4.16 ), 6.851 (4.48), 7.201 (0.98), 7.217 (2.10), 7.231 (2.01), 7.247 (0.83), 7.473 (0.54), 7.476 (0.65), 7.481 (1.15), 7.490 (2.67), 7.492 (2.31 ), 7.495 (2.26), 7.502 (5.32), 7.504 (5.21), 7.507 (6.24), 7.520 (14.64), 7.526 (16.00), 7.531 (15.46), 7.542

- 173 040284 (2.48), 7.683 (0.53), 7.837 (3.88), 7.842 (3.49), 7.855 (5.39), 7.860 (5.01), 7.929 (10.24), 7.947 (6.90), 8.818 (2.17), 8.830 (4.08) ), 8.842 (2.08).

1H-NMR (500 MHz, DMSO-d ₆ ): δ [ppm] = 12.05 (br. s, 1H), 8.83 (t, 1H), 7.94 (d, 1H), 7.85 (dd, 1H), 7.68 ( br. s, 1H), 7.55-7.46 (m, 5H), 7.27-7.17 (m, 1H), 6.84 (d, 1H), 6.75 (t, 1H), 4.02-3.92 (m, 1H), 3.87- 3.77 (m, 1H), 3.82 (s, 3H), 3.75-3.65 (m, 1H), 2.76-2.70 (m, 2H), 2.15 (br. s, 3H).

Example 127 (+)-4-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-(2-fluoro-6-methoxyphenyl)butanoic acid (enantiomer 1) .

To a solution of (+)-tert-butyl-4-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-(2fluoro-6-methoxyphenyl)butanoate (160 mg , 263 µmol, example 211A) in dichloromethane (8.0 ml) was added TFA (1.6 ml, 21 mmol) and the mixture was left for 24 h at RT. The mixture was then concentrated and mixed successively with dichloromethane several times and re-concentrated. The residue was purified by preparative HPLC (Method 15). 138 mg (100% pure, 95% th. ee, 99% ee) of the title compound were obtained.

[a] _D20 = +45.6°, 546 nm, c = 0.39 g ^/ 100 mL, methanol.

LC-MS (Method 1): Rt = 1.89 min; MS (ESIpos): m/z = 551/553 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 2.144 (5.94), 2.305 (0.40), 2.721 (5.05), 2.739 (6.25), 3.635 (1.06), 3.674 (1.38), 3.689 (1.90) . , 6.752 (3.05), 6.775 (2.11), 6.832 (3.38), 6.853 (3.76), 7.195 (0.82), 7.215 (1.83), 7.233 (1.81), 7.253 (0.71), 7.477 (0.57), 7.491 (1.63) . , 7.949 (4.31), 8.811 (1.60), 8.826 (3.15), 8.841 (1.57).

1H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.04 (br. s, 1H), 8.83 (t, 1H), 7.93 (d, 1H), 7.85 (dd, 1H), 7.70 ( br. s, 1H), 7.56-7.46 (m, 5H), 7.22 (dd, 1H), 6.84 (d, 1H), 6.75 (t, 1H), 4.03-3.91 (m, 1H), 3.82 (s, 3H), 3.873.65 (m, 2H), 2.73 (d, 2H), 2.14 (br. s, 3H).

Example 128 (-)-4-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-(2-fluoro-6-methoxyphenyl)butanoic acid (enantiomer 2) .

To a solution of (-)-tert-butyl-4-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-(2fluoro-6-methoxyphenyl)butanoate (180 mg , 296 µmol, example 212A) in dichloromethane (9.0 ml) was added TFA (1.8 ml, 24 mmol) and the mixture was left for 24 h at RT. The mixture was then concentrated and mixed successively with dichloromethane several times and re-concentrated. The residue was purified by preparative HPLC (Method 15). 163 mg (100% pure, 100% thor., 99% ee) of the title compound were obtained.

[a] _D20 = -39.2°, 546 nm, c = 0.39 ^g /100 ml, methanol.

LC-MS (Method 1): Rt = 1.89 min; MS (ESIpos): m/z = 551/553 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 2.144 (3.40), 2.720 (2.86), 2.739 (3.55), 3.674 (0.45), 3.689 (0.80), 3.706 (1.06), 3.722 (1.25) ), 3.736 (0.74), 3.781 (0.70), 3.801 (1.84), 3.818 (16.00), 3.853 (0.64), 3.932 (0.53), 3.950 (1.04), 3.969 (1.21), 3.988 (0.90), 4.007 (0.49 ), 6.730 (1.10), 6.752 (1.70), 6.775 (1.18), 6.832 (1.88), 6.853 (2.09), 7.195 (0.50), 7.215 (1.10), 7.234 (1.13), 7.253 (0.48), 7.491 (0.90 ), 7.501 (2.80), 7.509 (2.56), 7.521 (9.47), 7.835 (1.37), 7.840 (1.20), 7.858 (2.18), 7.863 (2.00), 7.927 (3.94), 7.949 (2.44), 8.812 (0.91 ), 8.827 (1.79), 8.841 (0.89).

1H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.12 (br. s, 1H), 8.83 (t, 1H), 7.94 (d, 1H), 7.85 (dd, 1H), 7.69 ( br. s, 1H), 7.57-7.46 (m, 5H), 7.22 (dd, 1H), 6.84 (d, 1H), 6.75 (t, 1H), 4.02-3.92 (m, 1H), 3.82 (s, 3H), 3.873.66 (m, 2H), 2.73 (d, 2H), 2.14 (br. s, 3H).

Example 129 (+/-)-4-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-(2-ethoxyphenyl)butanoic acid (racemate)

To a solution of (+/-)-tert-butyl-4-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-(2ethoxyphenyl)butanoate (40 mg, 98 % purity, 64.9 µmol, example 213A) in dichloromethane (460 µl) was added TFA (100 µl, 1.3 mmol) and the mixture was stirred for 3 days at RT. The mixture was then concentrated and mixed successively with dichloromethane several times and re-concentrated. The residue was purified by preparative HPLC (Method 16). 32 mg (98% pure, 88% thor.) of the title compound were obtained.

LC-MS (Method 1): Rt = 2.00 min; MS (ESIpos): m/z = 547/549 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: -0.008 (2.15), 0.008 (1.15), 1.357 (7.81), 1.374 (16.00), 1.392

- 174 040284 (7.54), 2.131 (7.94), 2.327 (0.46), 2.366 (0.53), 2.523 (2.32), 2.681 (6.13), 2.699 (6.24), 3.612 (0.81), 3.626 (1.44), 3.641 (1.57) ), 3.658 (1.87), 3.669 (2.00), 3.682 (1.94), 3.700 (2.04), 3.716 (1.35), 3.733 (0.46), 3.838 (1.13), 3.856 (1.63), 3.869 (1.52), 3.885 (1.39 ), 3.902 (0.63), 4.000 (0.43), 4.017 (1.07), 4.024 (1.46), 4.035 (1.99), 4.041 (3.68), 4.050 (3.25), 4.058 (3.67), 4.068 (2.95), 4.075 (1.71 ), 4.085 (1.07), 4.584 (0.53), 6.870 (1.82), 6.889 (3.70), 6.906 (2.12), 6.955 (3.54), 6.975 (4.16), 7.166 (1.80), 7.169 (2.03), 7.188 (2.95 ), 7.209 (4.78), 7.228 (3.16), 7.476 (0.97), 7.488 (1.95), 7.491 (2.08), 7.501 (5.51), 7.509 (5.16), 7.521 (13.33), 7.525 (12.65), 7.529 (9.54 ), 7.533 (7.34), 7.537 (5.94), 7.544 (1.76), 7.696 (1.94), 7.832 (2.65), 7.838 (2.40), 7.855 (3.99), 7.860 (3.78), 7.928 (7.02), 7.950 (4.45 ), 8.731 (1.63), 8.745 (2.66), 8.759 (1.55).

Example 130 (-)-4-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-(2-ethoxyphenyl)butanoic acid (enantiomer 1)

To a solution of (-)-tert-butyl-4-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-(2ethoxyphenyl)butanoate (60 mg, 98% pure , 97.4 µmol, example 214A) in dichloromethane (690 µl) was added TFA (150 µl, 1.9 mmol) and the mixture was stirred overnight at RT. TFA (150 μl, 1.9 mmol) was then added again and the mixture was stirred for an additional 4 h at RT. The mixture was then concentrated and mixed successively with dichloromethane several times and re-concentrated. The residue was purified by preparative HPLC (Method 16). 51 mg (98% pure, 94% thor., 99% ee) of the title compound were obtained.

[a] _D20 = -14.2°, 589 nm, c = 0.36 ^g /100 ml, methanol.

LC-MS (Method 1): R _t = 1.99 min; MS (ESIpos): m/z = 547/549 [M+H]+.

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 1.357 (7.63), 1.374 (16.00), 1.391 (7.66), 2.131 (8.54), 2.328 (0.54), 2.681 (6.29), 2.699 (6.56 ), 3.613 (0.64), 3.627 (1.35), 3.641 (1.48), 3.658 (1.79), 3.669 (2.00), 3.682 (1.92), 3.700 (2.09), 3.716 (1.39), 3.734 (0.44), 3.838 (1.12 ), 3.856 (1.61), 3.869 (1.48), 3.886 (1.40), 3.902 (0.57), 4.024 (1.19), 4.041 (3.49), 4.050 (3.11), 4.058 (3.57), 4.067 (2.94), 4.085 (1.01 ), 6.869 (1.84), 6.888 (4.01), 6.906 (2.25), 6.955 (3.76), 6.975 (4.49), 7.169 (1.94), 7.188 (3.05), 7.209 (4.91), 7.228 (3.30), 7.477 (0.56 ), 7.492 (1.58), 7.502 (5.44), 7.509 (4.75), 7.521 (13.88), 7.525 (13.53), 7.533 (7.90), 7.696 (2.14), 7.834 (2.65), 7.839 (2.42), 7.856 (4.12 ), 7.861 (3.96), 7.928 (7.59), 7.951 (4.75), 8.732 (1.55), 8.746 (2.79), 8.760 (1.62).

Example 131 (+)-4-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-(2-ethoxyphenyl)butanoic acid (enantiomer 2)

To a solution of (+)-tert-butyl-4-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-(2ethoxyphenyl)butanoate (50 mg, 98% pure , 81.2 µmol, example 215A) in dichloromethane (580 µl) was added TFA (130 µl, 1.6 mmol) and the mixture was stirred overnight at RT. Then again TFA (150 μl, 1.9 mmol) was added and the mixture was stirred for an additional 4 hours at RT. The mixture was then concentrated and mixed successively with dichloromethane several times and re-concentrated. The residue was purified by preparative HPLC (Method 16). 43 mg (100% pure, 97% th. ee, 96% ee) of the title compound were obtained.

[a] _D20 = +15.0°, 546 nm, c = 0.37 g ^/ 100 mL, methanol.

LC-MS (Method 1): R _t = 1.99 min; MS (ESIpos): m/z = 547/549 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.008 (1.19), 1.357 (7.49), 1.374 (16.00), 1.392 (7.67), 2.132 (7.97), 2.524 (1.23), 2.682 (6.05) , 2.699 (6.38), 3.613 (0.64), 3.627 (1.28), 3.641 (1.40), 3.659 (1.71), 3.669 (1.87), 3.683 (1.84), 3.700 (2.00), 3.716 (1.30), 3.734 (0.42) 3.838 (0.99), 3.856 (1.53), 3.870 (1.44), 3.886 (1.34), 3.903 (0.56), 4.018 (0.73), 4.024 (1.13), 4.035 (1.63), 4.042 (3.43), 4.051 (3.00) . , 7.189 (2.88), 7.209 (4.73), 7.228 (3.18), 7.477 (0.46), 7.492 (1.38), 7.502 (4.96), 7.510 (4.35) , 7.537 (6.06), 7.545 (1.75), 7.697 (1.92), 7.834 (2.42), 7.839 (2.25), 7.856 (3.82), 7.861 (3.77), 7.929 (7.09), 7.951 (4.49), 8.733 (1.45) , 8.747 (2.65), 8.760 (1.58).

Example 132 (+/-)-4-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-(5-fluoro-2-methoxyphenyl)-3-methylbutanoic acid (racemate)

To a solution of (+/-)-tert-butyl-4-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-(5fluoro-2-methoxyphenyl)-3 -methylbutanoate (80 mg, 98% pure, 126 µmol, example 216A) in dichloromethane (890 µl) TFA (190 µl, 2.5 mmol) was added and the mixture was stirred 3 h at RT. The mixture was then concentrated and mixed successively with dichloromethane several times and re-concentrated. The residue was purified by preparative HPLC (Method 16). Received 63 mg (98% pure, 87%

- 175 040284 theor. out) specified in the connection header.

LC-MS (Method 1): R _t = 1.96 min; MS (ESIpos): m/z = 565/567 [M+H]+.

1H-NMR (500 MHz, DMSO-d ₆ ) δ [ppm]: 1.545 (16.00), 2.072 (1.45), 2.630 (4.20), 2.660 (4.55), 3.118 (3.18), 3.148 (2.85), 3.645 (1.16) ), 3.662 (1.21), 3.787 (0.43), 3.991 (0.88), 4.262 (1.15), 6.980 (2.89), 6.985 (3.88), 7.001 (4.11), 7.006 (5.59), 7.025 (1.87), 7.480 (0.98 ), 7.489 (2.17), 7.502 (4.86), 7.506 (5.01), 7.519 (11.64), 7.525 (10.85), 7.529 (10.71), 7.832 (2.53), 7.836 (2.44), 7.850 (3.51), 7.854 (3.44 ), 7.928 (6.72), 7.946 (4.63), 8.529 (1.69), 8.542 (2.64), 8.554 (1.59).

1H-NMR (500 MHz, DMSO-d ₆ ): δ [ppm] = 11.80 (br. s, 1H), 8.54 (t, 1H), 7.94 (d, 1H), 7.84 (dd, 1H), 7.66 ( br. s, 1H), 7.56-7.46 (m, 5H), 7.06-6.94 (m, 3H), 4.33-4.21 (m, 1H), 3.85 (s, 3H), 3.69-3.59 (m, 1H), 3.13 (d, 1H), 2.64 (d, 1H), 2.09 (br. s, 3H), 1.55 (s, 3H).

Example 133 (+)-4-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-(5-fluoro-2-methoxyphenyl)-3-methylbutanoic acid ( enantiomer 1).

To a solution of (+)-tert-butyl-4-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-(5fluoro-2-methoxyphenyl)-3-methylbutanoate (350 mg, 98% pure, 552 µmol, example 217A) in dichloromethane (3.9 ml) was added TFA (850 µl, 11 mmol) and the mixture was stirred overnight at RT. The mixture was then concentrated and mixed successively with dichloromethane several times and re-concentrated. The residue was purified by preparative HPLC (Method 16). 256 mg (98% pure, 80% thor., 98% ee) of the title compound were obtained.

[a] _D20 = +14.2°, 589 nm ^, c = 0.35 g/100 mL, methanol.

LC-MS (Method 2): Rt = 1.04 min; MS (ESIpos): m/z = 565/567 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (2.29), 0.008 (1.82), 1.544 (16.00), 2.073 (1.83), 2.288 (0.43), 2.523 (1.02), 2.624 (4.25 ), 2.661 (4.92), 3.113 (3.61), 3.151 (3.22), 3.642 (2.21), 3.664 (2.55), 4.260 (1.06), 4.274 (1.01), 6.981 (3.74), 7.008 (7.08), 7.025 (2.13 ), 7.475 (0.68), 7.487 (1.66), 7.490 (1.82), 7.499 (5.60), 7.508 (5.27), 7.519 (15.60), 7.531 (7.16), 7.643 (0.46), 7.828 (2.57), 7.833 (2.30 ), 7.850 (3.95), 7.855 (3.70), 7.925 (7.40), 7.947 (4.69), 8.525 (1.67), 8.540 (2.68), 8.555 (1.57).

1H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 11.84 (br. s, 1H), 8.54 (t, 1H), 7.93 (d, 1H), 7.84 (dd, 1H), 7.64 ( br. s, 1H), 7.56-7.45 (m, 5H), 7.07-6.94 (m, 3H), 4.27 (br. dd, 1H), 3.85 (s, 3H), 3.65 (br. dd, 2H), 3.13 (d, 1H), 2.64 (d, 1H), 2.09 (br. s, 3H), 1.54 (s, 3H).

Example 134 (-)-4-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-(5-fluoro-2-methoxyphenyl)-3-methylbutanoic acid ( enantiomer 2).

To a solution of (-)-tert-butyl-4-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-(5fluoro-2-methoxyphenyl)-3-methylbutanoate (250 mg, 98% pure, 394 µmol, example 218A) in dichloromethane (2.8 ml) was added TFA (610 µl, 7.9 mmol) and the mixture was stirred overnight at RT. The mixture was then concentrated and mixed successively with dichloromethane several times and re-concentrated. The residue was purified by preparative HPLC (Method 16). 181 mg (98% pure, 80% thor., ee value 98%) of the title compound were obtained.

[a] _D20 = -28.5°, 589 nm, c = 0.35 ^g /100 ml, methanol.

LC-MS (Method 2): Rt = 1.04 min; MS (ESIpos): m/z = 565/567 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 1.544 (15.55), 2.073 (2.25), 2.327 (0.51), 2.624 (3.82), 2.661 (4.55), 3.113 (3.45), 3.151 (3.03 ), 3.641 (1.26), 3.665 (1.41), 3.787 (0.56), 4.028 (0.86), 4.259 (1.46), 6.981 (3.61), 7.008 (6.97), 7.024 (2.23), 7.500 (5.47), 7.508 (5.24 ), 7.519 (16.00), 7.639 (0.53), 7.829 (2.44), 7.834 (2.28), 7.851 (3.80), 7.856 (3.62), 7.925 (6.86), 7.948 (4.33), 8.525 (1.60), 8.541 (2.69 ), 8.556 (1.58).

1H-NMR (400 MHz, DMSO-d6): δ [ppm] = 11.86 (br. s, 1H), 8.54 (t, 1H), 7.93 (d, 1H), 7.84 (dd, 1H), 7.64 (br s, 1H), 7.56-7.46 (m, 5H), 7.06-6.96 (m, 3H), 4.31-4.22 (m, 1H), 3.85 (s, 3H), 3.70-3.60 (m, 1H), 3.13 (d, 1H), 2.64 (d, 1H), 2.09 (br. s, 3H), 1.54 (s, 3H).

Example 135 (+/-)-4-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-(3,5-difluoro-2methoxyphenyl)-3-methylbutanoic acid (racemate)

To a solution of (+/-)-tert-butyl-4-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-(3,5difluoro-2-methoxyphenyl) -3-methylbutanoate (80 mg, 98% pure, 123 µmol, example 219A) in dichloromethane (870 µl) TFA (190 µl, 2.5 mmol) was added and the mixture was stirred overnight at RT. The mixture was then concentrated and mixed successively with dichloromethane several times and re-concentrated. The residue was purified by preparative HPLC (Method 16). Got 57 mg

- 176 040284 (98% pure, 79% theoretical) of the title compound.

LC-MS (Method 2): R _t = 1.09 min; MS (ESIpos): m/z = 583/585 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: -0.008 (3.94), 0.008 (2.23), 1.159 (0.80), 1.175 (0.84), 1.194 (1.22), 1.205 (0.77), 1.211 ( 1.25), 1.222 (0.63), 1.433 (1.93), 1.546 (12.64), 2.073 (0.51), 2.159 (1.37), 2.327 (0.41), 2.518 (1.94), 2.523 (1.75), 2.637 (3.40) 4.00), 3.121 (2.77), 3.159 (2.42), 3.663 (1.46), 3.677 (1.53), 3.696 (1.70), 3.710 (1.52), 3.964 (16.00), 3.969 (15.16), 4.055 (1.34), 1.44), 4.087 (1.26),4.105 (1.11), 6.885 (1.74), 6.911 (1.64), 7.188 (0.80), 7.194 (0.85), 7.215 (1.30), 7.237 (0.78), 7.480 (0.73), 2.15), 7.506 (5.60), 7.512 (4.41), 7.524 (8.54), 7.537 (10.22), 7.556 (1.87), 7.840 (2.15), 7.846 (1.92) 6.09), 7.961 (3.88), 8.619 (1.48), 8.634 (2.53), 8.649 (1.32).

1H-NMR (400 MHz, DMSO-d6): δ [ppm] = 11.99 (br. s, 1H), 8.63 (t, 1H), 7.95 (d, 1H), 7.86 (dd, 1H), 7.63 (br s, 1H), 7.57-7.45 (m, 5H), 7.27-7.14 (m, 1H), 6.93-6.86 (m, 1H), 4.08 (dd, 1H), 3.97 (d, 3H), 3.69 (dd , 1H), 3.14 (d, 1H), 2.66 (d, 1H), 2.16 (br. s, 3H), 1.55 (s, 3H).

Example 136 (+)-4-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-(3,5-difluoro-2methoxyphenyl)-3-methylbutanoic acid ( enantiomer 1).

To a solution of (+)-tert-butyl-4-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-(3,5difluoro-2-methoxyphenyl)-3 -methylbutanoate (225 mg, 98% pure, 345 µmol, example 220A) in dichloromethane (2.4 ml) TFA (530 µl, 6.9 mmol) was added and the mixture was stirred overnight at RT. The mixture was then concentrated and mixed successively with dichloromethane several times and re-concentrated. The residue was purified by preparative HPLC (Method 16). 158 mg (98% pure, 77% thor., 93% ee) of the title compound were obtained.

[a] _D20 = +28.7°, 589 nm, c = 0.35 g ^/ 100 mL, methanol.

LC-MS (Method 1): R _t = 2.05 min; MS (ESIpos): m/z = 583/585 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (1.74), 0.007 (1.33), 1.547 (13.49), 2.073 (1.33), 2.159 (1.39), 2.637 (3.51), 2.676 (4.10 ), 3.121 (2.91), 3.159 (2.57), 3.663 (1.56), 3.677 (1.62), 3.696 (1.81), 3.710 (1.65), 3.964 (16.00), 3.969 (15.76), 4.055 (1.36), 4.072 (1.48 ), 4.088 (1.30), 4.105 (1.18), 6.885 (1.76), 6.912 (1.74), 7.193 (0.83), 7.215 (1.36), 7.237 (0.81), 7.479 (0.52), 7.492 (1.78), 7.506 (5.43 ), 7.512 (4.18), 7.524 (8.81), 7.537 (10.58), 7.555 (2.06), 7.841 (2.07), 7.846 (1.91), 7.863 (3.18), 7.868 (3.05), 7.939 (6.26), 7.961 (4.00 ), 8.619 (1.42), 8.635 (2.66), 8.650 (1.40).

1H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.00 (br. s, 1H), 8.63 (t, 1H), 7.95 (d, 1H), 7.86 (dd, 1H), 7.68 ( br. s, 1H), 7.57-7.46 (m, 5H), 7.27-7.17 (m, 1H), 6.90 (d, 1H), 4.08 (dd, 1H), 3.97 (d, 3H), 3.69 (dd, 1H), 3.14 (d, 1H), 2.66 (d, 1H), 2.16 (br. s, 3H), 1.55 (s, 3H).

Example 137 (-)-4-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-(3,5-difluoro-2methoxyphenyl)-3-methylbutanoic acid ( enantiomer 2).

To a solution of (-)-tert-butyl-4-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-(3,5difluoro-2-methoxyphenyl)-3 -methylbutanoate (225 mg, 98% pure, 345 µmol, example 221A) in dichloromethane (2.4 ml) TFA (530 µl, 6.9 mmol) was added and the mixture was stirred overnight at RT. The mixture was then concentrated and mixed successively with dichloromethane several times and re-concentrated. The residue was purified by preparative HPLC (Method 16). 159 mg (98% pure, 78% thor., 98% ee) of the title compound were obtained.

[a] _D20 = -31.6°, 589 nm, c = 0.45 ^g /100 ml, methanol.

LC-MS (Method 1): Rt = 2.05 min; MS (ESIpos): m/z = 583/585 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: -0.008 (0.48), 1.547 (12.71), 2.073 (0.80), 2.160 (1.28), 2.519 (0.84), 2.524 (0.68), 2.638 ( 3.41), 2.676 (3.97), 3.122 (2.77), 3.160 (2.46), 3.663 (1.63), 3.677 (1.66), 3.696 (1.80), 3.711 (1.64) 1.31), 4.073 (1.41), 4.089 (1.25), 4.106 (1.13), 6.886 (1.66), 6.913 (1.63), 7.187 (0.69), 7.194 (0.75), 7.216 (1.25), 7.237 (0.75), 0.69) 3.15), 7.869 (2.99), 7.940 (6.19), 7.962 (3.98), 8.620 (1.35), 8.636 (2.51), 8.651 (1.33).

1H-NMR (400 MHz, DMSO-d6): δ [ppm] = 11.99 (br. s, 1H), 8.64 (t, 1H), 7.95 (d, 1H), 7.86 (dd, 1H), 7.67 (br s, 1H), 7.57-7.46 (m, 5H), 7.26-7.17 (m, 1H), 6.90 (d, 1H), 4.08 (dd, 1H), 3.97 (d, 3H), 3.69 (dd, 1H ), 3.14 (d, 1H), 2.66 (d, 1H), 2.16 (br. s, 3H), 1.55 (s, 3H).

Example 138 (+/-)-4-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-(4-fluoro-2-methoxyphenyl)-3-methylbutanoic acid (racemate)

- 177 040284

To a solution of (+/-)-tert-butyl-4-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-(4fluoro-2-methoxyphenyl)-3 -methylbutanoate (80 mg, 98% pure, 126 µmol, example 222A) in dichloromethane (890 µl) TFA (190 µl, 2.5 mmol) was added and the mixture was stirred overnight at RT. The mixture was then concentrated and mixed successively with dichloromethane several times and re-concentrated. The residue was purified by preparative HPLC (Method 16). 43 mg (98% pure, 59% thor.) of the title compound were obtained.

LC-MS (Method 2): Rt = 1.06 min; MS (ESIpo): m/z = 565/567 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (2.84), 0.008 (2.39), 1.549 (14.23), 2.092 (1.63), 2.286 (0.61), 2.327 (0.44), 2.523 (1.26) ), 2.594 (4.23), 2.631 (4.77), 2.669 (0.42), 2.853 (0.52), 3.060 (4.14), 3.097 (3.69), 3.603 (3.87), 3.617 (4.23), 3.636 (4.36), 3.649 (4.02 ), 4.229 (1.86), 4.246 (2.03), 4.261 (1.86), 4.279 (1.71), 6.666 (1.05), 6.672 (1.20), 6.687 (2.07), 6.693 (2.22), 6.708 (1.18), 6.714 (1.17 ), 6.857 (2.08), 6.863 (2.11), 6.886 (2.19), 6.891 (2.05), 7.192 (2.56), 7.209 (3.14), 7.213 (3.09), 7.231 (2.42), 7.474 (0.64), 7.488 (1.81 ), 7.498 (5.53), 7.506 (5.27), 7.516 (16.00), 7.528 (7.27), 7.532 (6.20), 7.618 (0.43), 7.645 (0.44), 7.825 (2.60), 7.831 (2.39), 7.848 (4.02 ), 7.853 (3.90), 7.920 (7.70), 7.943 (4.84), 8.497 (1.71), 8.513 (2.89), 8.528 (1.62).

1H-NMR (400 MHz, DMSO-d6): δ [ppm] = 11.81 (br. s, 1H), 8.51 (t, 1H), 7.93 (d, 1H), 7.84 (dd, 1H), 7.66 (br s, 1H), 7.56-7.45 (m, 5H), 7.21 (dd, 1H), 6.87 (dd, 1H), 6.69 (td, 1H), 4.25 (dd, 1H), 3.86 (s, 3H), 3.63 (dd, 1h, partially hidden), 3.08 (d, 1H), 2.61 (d, 1H), 2.09 (br. s, 3H), 1.55 (s, 3H).

Example 139 (+)-4-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-(4-fluoro-2-methoxyphenyl)-3-methylbutanoic acid ( enantiomer 1).

To a solution of (+)-tert-butyl-4-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-(4fluoro-2-methoxyphenyl)-3-methylbutanoate (650 mg, 98% pure, 1.02 mmol, example 223A) in dichloromethane (7.3 ml) was added TFA (1.6 ml, 20 mmol) and the mixture was stirred overnight at RT. The mixture was then concentrated and mixed successively with dichloromethane several times and re-concentrated. The residue was purified by preparative HPLC (Method 16). 553 mg (98% pure, 94% thor. y., ee-value 98%) of the title compound were obtained.

[a] _D20 = +27.5°, 589 nm, c = 0.36 g ^/ 100 mL, methanol. LC-MS (Method 1): R _t = 1.98 min; MS (ESIpos): m/z = 565/567 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (1.57), 0.008 (1.42), 1.550 (14.64), 2.030 (0.71), 2.072 (4.01), 2.097 (1.69), 2.286 (0.55 ), 2.523 (0.91), 2.595 (4.29), 2.632 (4.86), 2.854 (0.49), 3.061 (4.19), 3.097 (3.74), 3.604 (2.68), 3.617 (3.05), 3.636 (3.50), 3.650 (3.52 ), 3.680 (2.03), 4.230 (1.90), 4.247 (2.09), 4.262 (1.92), 4.280 (1.77), 6.666 (1.07), 6.672 (1.23), 6.688 (2.13), 6.693 (2.28), 6.708 (1.21 ), 6.714 (1.21), 6.858 (2.13), 6.863 (2.17), 6.886 (2.19), 6.891 (2.11), 7.192 (2.56), 7.210 (3.18), 7.214 (3.14), 7.231 (2.45), 7.475 (0.59 ), 7.488 (1.77), 7.498 (5.58), 7.506 (5.27), 7.517 (16.00), 7.529 (7.63), 7.613 (0.45), 7.648 (0.45), 7.826 (2.59), 7.831 (2.43), 7.849 (4.03 ), 7.854 (3.96), 7.921 (7.64), 7.944 (4.84), 8.498 (1.71), 8.513 (2.95), 8.529 (1.67).

1H-NMR (400 MHz, DMSO-d6): δ [ppm] = 11.78 (br. s, 1H), 8.51 (t, 1H), 7.93 (d, 1H), 7.84 (dd, 1H), 7.65 (br s, 1H), 7.55-7.47 (m, 5H), 7.21 (dd, 1H), 6.87 (dd, 1H), 6.69 (td, 1H), 4.25 (dd, 1H), 3.86 (s, 3H), 3.63 (dd, 1h, partially hidden), 3.08 (d, 1H), 2.61 (d, 1H), 2.10 (br. s, 3H), 1.55 (s, 3H).

Example 140 (-)-4-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-(4-fluoro-2-methoxyphenyl)-3-methylbutanoic acid ( enantiomer 2).

To a solution of (-)-tert-butyl-4-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-(4fluoro-2-methoxyphenyl)-3-methylbutanoate (680 mg, 98% pure, 1.07 mmol, example 224A) in dichloromethane (7.6 ml) was added TFA (1.7 ml, 21 mmol) and the mixture was stirred overnight at RT. The mixture was then concentrated and mixed successively with dichloromethane several times and re-concentrated. The residue was purified by preparative HPLC (Method 16). 568 mg (98% pure, 92% th. ee, 98% ee) of the title compound were obtained.

[a] _D20 = -27.0°, 589 nm, c = 0.46 ^g /100 ml, methanol.

LC-MS (Method 1): Rt = 1.98 min; MS (ESIpos): m/z = 565/567 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.008 (1.45), 1.549 (14.11), 2.073 (1.75), 2.094 (1.73), 2.287

(0.48), 2.523 (1.72), 2.595 (4.05), 2.632 (4.55), 2.854 (0.41), 3.061 (4.00), 3.097 (3.53), 3.604 (1.78), 3.617 (1.92), 3.636 (2.06), 3.650 (1.85), 4.043 (0.45), 4.230 (2.75), 4.248 (2.96), 4.263 (2.80), 4.280 (2.63), 6.672 (1.25), 6.688 (2.10), 6.693 (2.21), 6.708 (1.18), 6.714 (1.15), 6.858 (2.08), 6.863 (2.13), 6.886 (2.16), 6.891 (2.01), 7.192 (2.48), 7.210 (3.10), 7.213 (3.05), 7.231 (2.29), 7.477 (0.75), 7.489 (2.14), 7.500 (5.94), 7.508 (5.81), 7.518 (16.00), 7.618 (0.47), 7.646 (0.47), 7.828 (2.57), 7.833 (2.38), 7.851 (3.89), 7.856 (3.74), 7.923

(7.25), 7.945 (4.55), 8.499 (1.80), 8.515 (2.91), 8.530 (1.64).

1H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 11.78 (br. s, 1H), 8.51 (t, 1H), 7.93 (d, 1H), 7.84 (dd, 1H), 7.65 ( br. s, 1H), 7.56-7.46 (m, 5H), 7.21 (dd, 1H), 6.87 (dd, 1H), 6.69 (td, 1H), 4.26 (dd, 1H), 3.86 (s, 3H) , 3.63 (dd, 1h, partially hidden), 3.08 (d, 1H), 2.61 (d, 1H), 2.09 (br. s, 3H), 1.55 (s, 3H).

Example 141 (+/-)-4-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-2,2-difluoro-3-(2methoxyphenyl)butanoic acid (racemate )

- 178 040284

To a solution from a mixture of (+/-)-ethyl-4-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-2,2difluoro-3-(2-methoxyphenyl)butanoate and (+/-)-methyl-4-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-2,2-difluoro-3-(2-methoxyphenyl)butanoate ( 40 mg, approx 67 µmol, example 225A) in THF (1 ml) was added with water (70 µl) and lithium hydroxide (3.2 mg, 134 µm) and the mixture was stirred for 1 h at RT. Lithium hydroxide (4.8 mg, 200 μm) was then added again and the mixture was stirred for another hour at RT. The mixture was then mixed with 1M hydrochloric acid (350 µl, 330 µmol) and prepurified by preparative HPLC (Chromatorex C18, 10 µm, 125 x 30 mm, acetonitrile/water gradient with 0.01% TFA). The pooled target fractions were concentrated, the residue was lyophilized and again purified by preparative HPLC (Chromatorex C18, 10 µm, 125 x 30 mm, acetonitrile/water gradient with 0.01% TFA). The combined target fractions were concentrated and the residue was lyophilized. 13 mg (95% pure, 31% thor.) of the title compound were obtained.

LC-MS (Method 1): Rt = 1.77 min; MS (ESIpos): m/z = 569/571 [M+H] ⁺ .

1H-NMR (600 MHz, DMSO-d6) δ [ppm]: 0.005 (1.53), 1.112 (0.69), 1.162 (0.52), 1.174 (0.86), 1.186 (0.42), 1.383 (0.49), 1.468 (1.69) , 2.019 (1.58), 2.386 (0.55), 2.517 (1.58), 2.520 (1.52), 2.523 (1.23) , 4.479 (0.96), 4.491 (0.98), 4.504 (0.95), 6.976 (0.78), 6.988 (1.48), 7.001 (0.92), 7.016 (2.53), 7.030 (2.72), 7.287 (0.81), 7.300 (1.34) . , 7.824 (1.91), 7.828 (1.84), 7.839 (2.64), 7.842 (2.58), 7.910 (5.19), 7.925 (3.69), 8.872 (1.42), 8.882 (2.72), 8.891 (1.42).

1H-NMR (600 MHz, DMSO-d6): δ [ppm] = 14.69 (br. s, 1H), 8.88 (t, 1H), 7.92 (d, 1H), 7.83 (dd, 1H), 7.63 (br . s, 1H), 7.54-7.46 (m, 5H), 7.38 (d, 1H), 7.30 (t, 1H), 7.02 (d, 1H), 6.99 (t, 1H), 4.54-4.45 (m, 1H ), 4.01-3.91 (m, 2H), 3.75 (s, 3H), 2.02 (br. s, 3H).

Example 142 (+/-)-4-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-(2-fluoro-6-methoxyphenyl)-3-methylbutanoic acid (racemate)

To a solution of (+/-)-tert-butyl-4-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-(2fluoro-6-methoxyphenyl)-3 -methylbutanoate (40 mg, 84% pure, 54 µmol, example 226A) in dichloromethane (800 µl) TFA (83 µl, 1.1 mmol) was added and the mixture was left overnight at RT. The mixture was then concentrated and mixed successively with dichloromethane several times and re-concentrated. The residue was purified by preparative HPLC (Method 15). The combined desired fractions were concentrated and the residue was dried in vacuo. 30 mg (90% pure, 90% thor.) of the title compound were obtained.

LC-MS (Method 1): Rt = 1.96 min; MS (ESIpos): m/z = 565/567 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 11.67 (br. s, 1H), 8.68 (t, 1H), 7.94 (d, 1H), 7.85 (dd, 1H), 7.64 ( br. s, 1H), 7.56-7.46 (m, 5H), 7.26-7.14 (m, 1H), 6.83 (d, 1H), 6.67 (dd, 1H), 4.17 (dd, 1H), 3.83 (s, 3H), 3.67 (dd, 1H), 3.33 (d, 1H), 2.48 (d, 1H, partially hidden), 2.12 (s, 3H), 1.69 (d, 3H).

Example 143 (+)-4-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-(2-fluoro-6-methoxyphenyl)-3-methylbutanoic acid ( enantiomer 1).

To a solution of (+)-tert-butyl-4-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-(2fluoro-6-methoxyphenyl)-3-methylbutanoate (66 mg, 87% pure, 91.8 µmol, example 228A) in dichloromethane (1.4 ml) was added TFA (140 µl, 1.8 mmol) and the mixture was left for 3 days at RT. The mixture was then concentrated and mixed successively with dichloromethane several times and re-concentrated. The residue was purified by preparative HPLC (Method 15). 56 mg (85% pure, 92% thor. y., >99% ee) of the title compound were obtained.

[a] _D20 = +13.8°, 589 nm, c = 0.39 g ^/ 100 mL, methanol.

- 179 040284

LC-MS (Method 1): Rt = 2.07 min; MS (ESIpos): m/z = 565/567 [M+H]+.

1H-NMR (400 MHz, DMSO-d6): δ [ppm] = 8.67 (t, 1H), 7.94 (d, 1H), 7.85 (dd, 1H), 7.64 (br. s, 1H), 7.567.47 (m, 5H), 7.25-7.15 (m, 1H), 6.83 (d, 1H), 6.67 (dd, 1H), 4.17 (br. dd, 1H), 3.83 (s, 3H), 3.67 (br. dd , 1H), 3.33 (d, 1H), 2.50 (d, 1H, partially hidden), 2.12 (br. s, 3H), 1.69 (d, 3H).

Example 144 (-)-4-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-(2-fluoro-6-methoxyphenyl)-3-methylbutanoic acid ( enantiomer 2).

To a solution of (-)-tert-butyl-4-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-(2fluoro-6-methoxyphenyl)-3-methylbutanoate (51 mg, 82.1 µmol, example 227A) in dichloromethane (1.2 ml) TFA (130 µl, 1.6 mmol) was added and the mixture was left overnight at RT. The mixture was then concentrated and mixed successively several times with dichloromethane and reconcentrated. The residue was purified by preparative HPLC (Method 15). 45 mg (100% pure, 96% thor., 96% ee) of the title compound were obtained.

[a] _D20 = -13.4°, 589 nm, c = ^0.37 g/100 ml, methanol.

LC-MS (Method 1): R _t = 2.07 min; MS (ESIpos): m/z = 565/567 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 8.68 (t, 1H), 7.94 (d, 1H), 7.85 (dd, 1H), 7.64 (br. s, 1H), 7.577. 47 (m, 5H), 7.24-7.15 (m, 1H), 6.83 (d, 1H), 6.67 (dd, 1H), 4.17 (dd, 1H), 3.83 (s, 3H), 3.67 (dd, 1H) , 3.33 (d, 1H), 2.50 (d, 1H, partially hidden), 2.12 (br. s, 3H), 1.69 (d, 3H).

Example 145 (+/-)-4-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-(2-chlorophenyl)valeric acid (racemate 1)

To a solution of (+/-)-tert-butyl-4-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-(2chlorophenyl)pentanoate (109 mg, 179 µmol, example 230A, Racemat 1) in dichloromethane (4.1 ml) was added with TFA (410 µl, 5.4 mmol) and the mixture was left for 16 h at RT. The mixture was then concentrated and mixed successively with dichloromethane several times and re-concentrated. The residue was purified by preparative HPLC (Method 17). The combined target fractions were concentrated and the residue was lyophilized in acetonitrile/water. 82 mg (100% pure, 83% thor.) of the title compound were obtained.

LC-MS (Method 1): R _t = 1.98 min; MS (ESIpos): m/z = 551/553 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.008 (1.20), 1.237 (13.23), 1.254 (13.14), 1.908 (0.66), 2.073 (0.72), 2.273 (1.13), 2.311 (0.99) , 2.327 (0.85), 2.366 (0.56), 2.698 (1.30), 2.710 (0.55), 2.720 (1.29) . . , 7.853 (3.43), 7.929 (5.38), 7.952 (3.55), 8.767 (1.35).

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 12.06 (br. s, 1H), 8.77 (br. s, 1H), 7.94 (d, 1H), 7.84 (d, 1H), 7.677 .15 (m, 10H), 4.78-4.54 (m, 1H), 3.86-3.69 (m, 1H), 2.87-2.63 (m, 2H), 2.44-1.69 (br. m, 3H), 1.25 (d, 3H).

Separation of enantiomers.

The title target compound (75 mg) purified by preparative HPLC was separated into enantiomers in the chiral phase (see Examples 146 and 147) [column: Daicel Chiralpak AD-H, 5 μm, 250 mm x 20 mm; flow: 40 ml/min; detection: 220 nm; sample injection: 0.25 ml; eluent: 70% heptane/30% ethanol; isocratic]. The combined target fractions were concentrated and the residue was lyophilized in acetonitrile/water.

Example 146 (-)-4-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-(2-chlorophenyl)valeric acid (enantiomer 1)

The separation of enantiomers described in Example 145 gave 38 mg (100% pure, ee value 99%) of the title compound as the previously eluted enantiomer.

[a] _D20 = -8.3°, 589 nm, c ⁼ 0.32 g/100 ml, methanol.

LC-MS (Method 1): Rt = 1.97 min; MS (ESIpos): m/z = 551/553 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: -0.008 (2.19), 0.008 (2.01), 1.240 (12.95), 1.256 (12.80), 1.897 (0.65), 2.274 (1.13), 2.312 ( 0.98), 2.328 (1.02), 2.366 (0.61), 2.670 (0.51), 2.707 (1.20), 2.728 (1.12), 2.747 (3.94), 2.772 (6.13), 2.786 (4.84), 2.813 (1.43), 1.08) 2.03)

- 180 040284 (5.43), 7.954 (3.52), 8.741 (1.31).

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.74 (br. s, 1H), 7.94 (d, 1H), 7.85 (d, 1H), 7.77-7..13 (m, 10H ),

4.76-4.62 (m, 1H), 3.85-3.72 (m, 1H), 2.88-2.64 (m, 2H), 2.39-1.74 (br. m, 3H), 1.25 (d,3H).

Example 147 (+)-4-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-(2-chlorophenyl)valeric acid (enantiomer 2)

The separation of enantiomers described in Example 145 gave 38 mg (100% pure, ee value 99%) of the title compound as the later eluted enantiomer.

[a] _D20 = +12.0°, 589 nm, c = 0.33 ^g /100 mL, methanol.

LC-MS (Method 1): Rt = 1.97 min; MS (ESIpos): m/z = 551/553 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (2.22), 0.008 (1.95), 1.239 (13.31), 1.256 (13.07), 1.901 (0.65), 2.272 (1.16), 2.311 (0.98) ), 2.328 (1.06), 2.366 (0.64), 2.670 (0.56), 2.706 (1.25), 2.728 (1.14), 2.747 (4.02), 2.772 (6.21), 2.786 (4.89), 2.813 (1.47), 2.826 (1.10 ), 3.762 (1.35), 3.783 (2.64), 3.796 (2.83), 3.817 (1.32), 4.370 (1.38), 4.661 (1.70), 4.681 (2.69), 4.698 (2.64), 4.719 (1.54), 7.352 (1.99 ), 7.422 (2.29), 7.480 (1.20), 7.492 (2.87), 7.508 (9.04), 7.514 (10.65), 7.525 (16.00), 7.538 (13.81), 7.835 (2.29), 7.857 (3.41), 7.931 (5.41 ), 7.953 (3.58), 8.743 (1.32).

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.74 (br. s, 1H), 7.94 (d, 1H), 7.85 (d, 1H), 7.78-7.11 (m, 10H), 4.76 -4.62 (m, 1H), 3.86-3.69 (m, 1H), 2.87-2.61 (m, 2H), 2.39-1.71 (br. m, 3H), 1.25 (d, 3H).

Example 148 (+/-)-4-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-(2-chlorophenyl)valeric acid (racemate 2)

To a solution of (+/-)-tert-butyl-4-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-(2chlorophenyl)pentanoate (143 mg, 236 µmol, example 231 A, racemate 2, uncorrected purity) in dichloromethane (5.4 ml) was added TFA (550 µl, 7.1 mmol) and the mixture was left for 16 h at RT. The mixture was then concentrated and mixed successively with dichloromethane several times and re-concentrated. The residue was purified by preparative HPLC (Method 17). The combined target fractions were concentrated and the residue was lyophilized in acetonitrile/water. 111 mg (100% pure, 86% thor.) of the title compound were obtained.

LC-MS (Method 1): Rt = 2.08 min; MS (ESIpos): m/z = 551/553 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.008 (2.38), 1.120 (15.15), 1.136 (15.18), 2.287 (11.03), 2.366 (0.80), 2.523 (1.59), 2.670 (0.67) , 2.710 (0.58), 2.794 (0.75), 2.835 (2.56), 2.863 (6.52), 2.875 (5.06), 2.903 (1.42), 2.915 (0.86), 3.755 (1.32), 3.774 (2.51), 3.791 (2.41) . . , 7.712 (1.08), 7.871 (5.30), 7.876 (4.76), 7.893 (7.73), 7.898 (7.35), 7.976 (12.07), 7.998 (7.91), 8.918 (0.82), 12.022 (0.72).

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 12.02 (br. s, 1H), 8.92 (br. s, 1H), 7.98 (d, 1H), 7.89 (dd, 1H), 7.71 ( br. s, 1H), 7.62-7.41 (m, 7H), 7.41-7.23 (m, 2H), 4.58-4.34 (m, 1H), 3.90-3.69 (m, 1H), 2.95-2.74 (m, 2H ), 2.29 (br. s, 3H), 1.13 (d, 3H).

Separation of enantiomers.

The title target compound (100 mg) was dissolved in ethanol (5 ml) and separated into enantiomers by chiral phase preparative HPLC (see examples 149 and 150) [column: YMC Chiralart Amylose SA, 5 μm, 250 mm x 30 mm ; flow: 30 ml/min; detection: 220 nm; temperature: 50°C; sample injection: 0.4 ml; eluent: 50% heptane/50% ethanol; duration of action 9 min, isocratic]. The combined target fractions were concentrated and the residue was lyophilized in acetonitrile/water.

Example 149 (-)-4-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-(2-chlorophenyl)valeric acid (enantiomer 3)

Separation of the enantiomers as described in Example 148 gave 51 mg (98% pure, 99% ee) of the title compound as the previously eluted enantiomer.

[a] _D20 = -43.1°, 589 nm, c = ^0.31 g/100 ml, methanol.

LC-MS (Method 1): Rt = 2.09 min; MS (ESIpos): m/z = 551/553 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.120 (15.75), 1.136 (16.00), 1.234 (1.04), 1.906 (5.70), 2.287 (11.95), 2.366 (0.59), 2.670 (0.51) , 2.709 (0.50), 2.796 (0.79), 2.836 (2.62), 2.863 (6.36), 2.875 (5.02), 2.903 (1.40), 3.757 (1.40), 3.775 (2.72), 3.791 (2.60), 4.482 (2.49) . , 7.541 (14.31), 7.556 (5.31), 7.584 (14.44), 7.600 (7.51), 7.708 (1.13), 7.870 (4.75), 7.875 (4.52), 7.893 (6.97), 7.897 (6.98) , 7.997 (7.40), 8.915 (0.92), 12.023 (0.72).

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 12.02 (br. s, 1H), 8.92 (br. s, 1H), 7.98 (d, 1H), 7.88 (dd, 1H), 7.71 (br. s, 1H), 7.62-7.42 (m, 7H), 7.41-7.23 (m, 2H), 4.56-4.43 (m, 1H), 3.84-3.73 (m, 1H), 2.94-2.75 (m, 2H), 2.29 (br. s, 3H), 1.13 (d, 3H).

Example 150 (+)-4-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-(2-chlorophenyl)valeric acid (enantiomer 4)

- 181 040284

The separation of enantiomers described in Example 148 gave 50 mg (100% pure, ee value 99%) of the title compound as the later eluted enantiomer.

[a] _D20 = +44.8°, 589 nm, c = 0.34 g ^/ 100 mL, methanol.

LC-MS (Method 1): R _t = 2.09 min; MS (ESIpos): m/z = 551/553 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 1.121 (15.53), 1.137 (15.76), 1.234 (0.98), 1.911 (3.31), 2.288 (11.97), 2.366 (0.64), 2.670 (0.42 ), 2.710 (0.50), 2.805 (0.74), 2.845 (2.61), 2.869 (6.06), 2.908 (1.29), 3.779 (2.66), 3.795 (2.57), 4.487 (2.46), 4.505 (2.45), 7.287 (2.85 ), 7.344 (2.57), 7.362 (4.10), 7.379 (2.37), 7.444 (6.97), 7.459 (8.99), 7.476 (5.05), 7.488 (1.97), 7.507 (4.50), 7.523 (16.00), 7.543 (14.48 ), 7.557 (5.51), 7.563 (4.31), 7.583 (13.32), 7.585 (14.36), 7.601 (7.69), 7.605 (6.62), 7.707 (1.19), 7.871 (5.03), 7.876 (4.79), 7.894 (7.43 ), 7.899 (7.37), 7.976 (11.53), 7.999 (7.62), 8.896 (1.08), 12.013 (1.09).

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 12.01 (br. s, 1H), 8.90 (br. s, 1H), 7.99 (d, 1H), 7.89 (dd, 1H), 7.71 ( br. s, 1H), 7.63-7.42 (m, 7H), 7.40-7.22 (m, 2H), 4.57-4.41 (m, 1H), 3.85-3.72 (m, 1H), 2.96-2.74 (m, 2H ), 2.29 (br. s, 3H), 1.13 (d, 3H).

Example 151 (+/-)-5-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-4-(2-chlorophenyl)valeric acid (racemate)

To a solution of (+/-)-tert-butyl-5-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-4-(2chlorophenyl)pentanoate (1.40 g, 2.30 mmol, example 232A) in dichloromethane (16 ml) was added TFA (3.5 ml, 46 mmol) and the mixture was stirred for 7 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 19). 1.17 g (98% pure, 90% th. y.) of the title compound was obtained.

LC-MS (Method 1): Rt = 1.97 min; MS (ESIpos): m/z = 551/553 [M+H]+.

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: -0.008 (0.75), 1.805 (0.47), 1.824 (0.99), 1.847 (1.30), 1.870 (0.70), 2.034 (0.64), 2.054 ( 2.58), 2.073 (10.29), 2.089 (2.87), 2.100 (2.84), 2.141 (4.96), 2.170 (1.18), 3.688 (1.28), 3.707 (1.72), 3.720 (2.05), 7.249 (0.90), 1.95), 7.286 (1.35), 7.358 (1.18), 7.376 (2.11),7.394 (1.10), 7.438 (3.36), 7.440 (3.41), 7.458 (2.79), 7.460 (2.78), 7.500 (6.51), 4.47) 1.29), 8.855 (2.54), 8.870 (1.23).

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 11.99 (br. s, 1H), 8.86 (t, 1H), 7.94 (d, 1H), 7.85 (dd, 1H), 7.69 (br. s, 1H), 7.56-7.48 (m, 6H), 7.45 (dd, 1H), 7.38 (br. t, 1H), 7.27 (br. t, 1H), 3.87-3.49 (m, 3H), 2.22- 2.02 (m, 6H), 1.92-1.71 (m, 1h).

Separation of enantiomers.

The title title compound (1.0 g) was dissolved in a 1:1 mixture of acetonitrile and methanol (100 ml) and separated into enantiomers by chiral phase preparative SLC (see Examples 152 and 153) [column: Daicel Chiralpak AD-H , 5 µm, 250 mm x 30 mm; flow: 100 ml/min; detection: 210 nm; temperature: 38°C; sample injection: 0.6 ml; eluent: 68% carbon dioxide/32% methanol; duration of action 14 min, isocratic]. The combined target fractions were concentrated, and the residue was dried in vacuo.

Example 152 (-)-5-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-4-(2-chlorophenyl)valeric acid (enantiomer 1)

The separation of enantiomers described in Example 151 gave 518 mg (98% pure, ee value 98%) of the title compound as the previously eluted enantiomer. Die Substanz was then lyophilized.

[a] _D20 = -11.1°, 589 nm, c = 0.37 ^g /100 ml, methanol.

LC-MS (Method 1): R _t = 1.98 min; MS (ESIpos): m/z = 551/553 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (1.55), 0.008 (1.55), 1.031 (0.68), 1.046 (0.70), 1.234 (0.66), 1.284 (1.07), 1.804 (0.44 ), 1.823 (0.94), 1.846 (1.23), 1.869 (0.68), 2.033 (0.59), 2.053 (2.43), 2.088 (2.71), 2.099 (2.69), 2.140 (4.66), 2.170 (1.18), 2.366 (0.81 ), 2.710 (0.85), 3.536 (0.42), 3.619 (1.01), 3.719 (1.42), 7.248 (0.88), 7.267 (1.86), 7.286 (1.34), 7.358 (1.16), 7.375 (2.06), 7.394 (1.09 ), 7.437 (3.50), 7.440 (3.33), 7.457 (2.89), 7.499 (6.46), 7.507 (4.44), 7.519 (16.00), 7.530 (5.52), 7.693 (0.46), 7.829 (2.23), 7.834 (1.99 ), 7.851 (3.31), 7.856 (3.20), 7.927 (6.22), 7.949 (3.92), 8.839 (1.23), 8.854 (2.39), 8.868 (1.16), 12.043 (1.79).

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 12.05 (br. s, 1H), 8.85 (t, 1H), 7.94 (d, 1H), 7.84 (dd, 1H), 7.69 (br. s, 1H), 7.56-7.47 (m, 6H), 7.45 (dd, 1H), 7.38 (br. t, 1H), 7.27 (br. t, 1H), 3.83-3.53 (m, 3H), 2.22- 2.00 (m,

- 182 040284

6H), 1.92-1.74 (m, 1H).

Example 153 (+)-5-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-4-(2-chlorophenyl)valeric acid (enantiomer 2)

The separation of enantiomers described in Example 151 gave 496 mg (98% pure, ee value 97%) of the title compound as the later eluted enantiomer. Die Substanz was then lyophilized.

[a] _D20 = +16.5°, 589 nm, c = 0.44 g/100 ml, methanol LC-MS ( ^Method 1): Rt = 1.98 min; MS (ESIpos): m/z = 551/553 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (0.95), 0.008 (0.81), 1.234 (0.60), 1.285 (0.86), 1.805 (0.48), 1.824 (1.03), 1.847 (1.34 ), 1.870 (0.74), 2.034 (0.66), 2.044 (0.81), 2.054 (2.62), 2.074 (2.15), 2.089 (2.92), 2.100 (2.92), 2.141 (5.04), 2.171 (1.25), 2.523 (0.48 ), 3.621 (1.09), 3.687 (0.58), 3.707 (1.13), 3.721 (1.56), 3.732 (1.34), 7.248 (0.92), 7.267 (1.98), 7.285 (1.39), 7.357 (1.22), 7.376 (2.16 ), 7.394 (1.15), 7.437 (3.50), 7.440 (3.25), 7.457 (2.93), 7.460 (2.67), 7.477 (0.67), 7.489 (1.92), 7.499 (6.75), 7.507 (4.65), 7.519 (16.00 ), 7.530 (5.84), 7.692 (0.46), 7.828 (2.25), 7.834 (1.98), 7.851 (3.36), 7.856 (3.13), 7.927 (6.00), 7.949 (3.83), 8.840 (1.33), 8.855 (2.61 ), 8.869 (1.26), 12.045 (1.75).

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 12.05 (br. s, 1H), 8.85 (t, 1H), 7.94 (d, 1H), 7.84 (dd, 1H), 7.69 (br. s, 1H), 7.55-7.48 (m, 6H), 7.45 (dd, 1H), 7.38 (br. t, 1H), 7.27 (br. t, 1H), 3.83-3.55 (m, 3H), 2.22- 2.01 (m, 6H), 1.91-1.77 (m, 1H).

Example 154 (+/-)-5-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-4-(2-chlorophenyl)-4methylvaleric acid (racemate)

To a solution of (+/-)-tert-butyl-5-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-4-(2chlorophenyl)-4-methylpentanoate (80 mg, 129 µmol, example 233A) in dichloromethane (911 µl) was added TFA (198 µl, 2.57 mmol) and the mixture was stirred for 7 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 16). The combined desired fractions were concentrated and the residue was dried in vacuo. 68 mg (98% pure, 92% thor.) of the title compound were obtained.

LC-MS (Method 2): Rt = 1.07 min; MS (ESIpos): m/z = 565/567 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 0.008 (1.35), 1.382 (0.70), 1.521 (16.00), 1.725 (0.83), 1.737 (0.96), 1.754 (1.30), 1.765 (1.99) ), 1.776 (1.15), 1.793 (1.58), 1.805 (1.47), 1.889 (1.36), 1.901 (1.55), 1.923 (1.80), 1.934 (1.86), 1.952 (0.95), 1.964 (1.39), 2.006 (1.79 ), 2.018 (1.52), 2.036 (2.12), 2.046 (2.66), 2.056 (1.85), 2.074 (2.33), 2.086 (2.02), 2.312 (0.43), 2.327 (0.54), 2.366 (0.43), 2.523 (1.26 ), 2.648 (0.89), 2.660 (1.12), 2.679 (1.55), 2.690 (1.43), 2.710 (1.15), 2.722 (0.71), 3.670 (1.74), 3.683 (1.89), 3.704 (2.07), 3.717 (1.88 ), 4.342 (2.29), 4.359 (2.49), 4.375 (2.34), 4.393 (2.19), 7.261 (0.91), 7.278 (2.37), 7.302 (2.68), 7.325 (3.06), 7.341 (1.52), 7.414 (4.36 ), 7.417 (4.44), 7.432 (4.91), 7.446 (2.34), 7.473 (0.77), 7.489 (1.89), 7.499 (6.18), 7.506 (5.65), 7.518 (14.98), 7.522 (13.05), 7.665 (0.52 ), 7.828 (2.74), 7.833 (2.49), 7.850 (4.25), 7.855 (4.03), 7.924 (7.73), 7.946 (4.92), 8.623 (1.86), 8.638 (3.12), 8.653 (1.90).

Separation of enantiomers.

The title target compound (55 mg) was dissolved in methanol (10 ml) and separated into enantiomers by chiral phase preparative SLC (see examples 155 and 156) [column: Daicel Chiralpak AD SFC, 5 μm, 250 mm x 20 mm ; flow: 80 ml/min; detection: 210 nm; temperature: 40°C; sample injection: 0.5 ml; eluent: 80% carbon dioxide/20% ethanol; duration of action 18 min, isocratic]. The combined desired fractions were concentrated and the residue was dried in vacuo.

Example 155 (-)-5-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-4-(2-chlorophenyl)-4methylvaleric acid (enantiomer 1)

The separation of enantiomers described in Example 154 gave 17 mg (98% pure, ee value 100%) of the title compound as the previously eluted enantiomer.

[a] _D20 = -38.2°, 589 nm, c = 0.27 ^g /100 ml, methanol.

LC-MS (Method 1): Rt = 2.01 min; MS (ESIpos): m/z = 565/567 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 1.234 (1.04), 1.520 (16.00), 1.721 (0.73), 1.732 (0.85), 1.750 (1.20), 1.760 (1.83), 1.770 (1.10) ), 1.788 (1.39), 1.800 (1.29), 1.889 (1.23), 1.901 (1.42), 1.923 (1.74), 1.933 (1.83), 1.952 (0.95), 1.964 (1.36), 2.001 (1.61), 2.013 (1.39 ), 2.031 (1.96), 2.040 (2.43), 2.069 (1.99), 2.080 (1.89), 2.310 (0.50), 2.328 (0.54), 2.366 (1.55), 2.643 (0.85), 2.655 (1.01), 2.675 (1.74 ), 2.709 (2.15), 3.313 (12.37), 3.670 (1.67), 3.682 (1.83), 3.703 (1.96), 3.716 (1.80), 4.341 (1.89), 4.358 (2.08), 4.374 (1.89), 4.392

- 183 040284 (1.74), 7.259 (1.01), 7.277 (2.52), 7.301 (2.81), 7.324 (3.22), 7.340 (1.48), 7.417 (4.42), 7.432 (4.70), 7.446 (2.56), 7.473 (0.88) ), 7.488 (2.02), 7.498 (6.28), 7.505 (5.78), 7.516 (14.93), 7.521 (13.32), 7.654 (0.54), 7.825 (2.65), 7.830 (2.52), 7.848 (4.07), 7.853 (4.04 ), 7.922 (7.57), 7.945 (4.83), 8.631 (1.77), 8.646 (3.00), 8.661 (1.70).

Example 156 (+)-5-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-4-(2-chlorophenyl)-4methylvaleric acid (enantiomer 2)

Separation of the enantiomers as described in Example 154 gave 17 mg (98% pure, ee value 100%) of the title compound as the later eluted enantiomer.

[a]D ²⁰ = +40.0°, 589 nm, c = 0.27 g/100 ml, methanol.

LC-MS (Method 1): Rt = 2.01 min; MS (ESIpos): m/z = 565/567 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 1.235 (0.76), 1.520 (16.00), 1.719 (0.74), 1.730 (0.82), 1.758 (1.74), 1.786 (1.33), 1.797 (1.22 ), 1.889 (1.19), 1.900 (1.38), 1.931 (1.86), 1.963 (1.32), 1.999 (1.58), 2.011 (1.36), 2.039 (2.39), 2.067 (1.93), 2.078 (1.94), 2.309 (0.52 ), 2.327 (0.73), 2.653 (1.00), 2.672 (1.91), 2.709 (0.93), 3.669 (1.69), 3.682 (1.82), 3.702 (1.98), 3.715 (1.82), 4.341 (1.87), 4.357 (2.07 ), 4.374 (1.90), 4.391 (1.75), 7.260 (1.10), 7.277 (2.64), 7.300 (2.91), 7.324 (3.28), 7.340 (1.53), 7.417 (4.54), 7.432 (4.81), 7.472 (0.95 ), 7.497 (6.67), 7.505 (6.14), 7.516 (15.64), 7.670 (0.59), 7.825 (2.88), 7.830 (2.70), 7.847 (4.40), 7.852 (4.24), 7.922 (8.20), 7.945 (5.18 ), 8.635 (1.78), 8.649 (3.02), 8.664 (1.67).

Example 157 (+/-)-5-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-4-(2-chloro-6-fluorophenyl)valeric acid (racemate )

To a solution of (+/-)-tert-butyl-5-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-4-(2chloro-6-fluorophenyl)pentanoate ( 550 mg, 879 µmol, example 236A) in dichloromethane (8.3 ml) was added TFA (1.4 ml, 18 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 16). The combined desired fractions were concentrated and the residue was dried in vacuo. 499 mg (98% pure, 98% theoretical) of the title compound were obtained.

LC-MS (Method 2): Rt = 1.04 min; MS (ESIpos): m/z = 569/571 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.008 (1.37), 1.965 (0.62), 2.073 (2.03), 2.085 (2.50), 2.110 (2.88), 2.121 (2.94), 2.159 (8.08) , 3.749 (1.78), 4.366 (0.42), 7.191 (0.74), 7.205 (1.11), 7.215 (1.29), 7.227 (1.07), 7.242 (1.01), 7.332 (4.41), 7.480 (0.49), 7.492 (1.47) , 7.503 (4.44) , 8.928 (1.23), 8.942 (2.23).

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 8.94 (t, 1H), 7.94 (d, 1H), 7.85 (dd, 1H), 7.72 (br. s, 1H), 7.567.47 ( m, 5H), 7.38-7.28 (m, 2H), 7.26-7.16 (m, 1H), 3.91-3.68 (m, 3H), 2.25-1.88 (m, 7H).

Separation of enantiomers.

The title title compound (440 mg) was dissolved in 40 ml of a 1:1 mixture of methanol and acetonitrile and separated into enantiomers by preparative chiral phase SLC (see Examples 158 and 159) [column: Daicel Chiralpak AD-H, 5 µm, 250 mm x 30 mm; flow: 100 ml/min; detection: 210 nm; temperature: 38°C; sample injection: 1.2 ml; eluent: 68% carbon dioxide/32% isopropanol; duration of action 16 min, isocratic]. The combined desired fractions were concentrated and the residue was dried in vacuo.

Example 158 (-)-5-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-4-(2-chloro-6-fluorophenyl)valeric acid (enantiomer 1) .

The separation of enantiomers described in Example 157 gave 221 mg (98% pure, ee value 94%) of the title compound as the previously eluted enantiomer. Die Substanz was then lyophilized.

[a] _D20 = -28.1°, 589 nm, c = 0.35 ^g /100 ml, methanol.

LC-MS (Method 2): Rt = 1.04 min; MS (ESIpos): m/z = 569/571 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (1.87), 0.008 (1.61), 1.030 (0.60), 1.046 (0.64), 1.966 (0.58), 2.084 (2.34), 2.109 (2.76 ), 2.119 (2.78), 2.158 (7.85), 2.524 (1.21), 3.748 (1.70), 7.190 (0.73), 7.204 (1.10), 7.214 (1.26), 7.227 (1.07), 7.242 (1.02), 7.331 (4.34 ), 7.478 (0.51), 7.491 (1.46), 7.501 (4.44), 7.509 (4.32), 7.521 (16.00), 7.527 (7.90), 7.532 (6.22), 7.535 (5.69), 7.836 (2.58), 7.841 (2.27 ), 7.858 (3.86), 7.864 (3.65), 7.931 (6.90), 7.953 (4.31), 8.926 (1.23), 8.940 (2.16), 12.075 (0.53).

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 12.08 (br. s, 1H), 8.94 (t, 1H), 7.94 (d, 1H), 7.85 (dd, 1H), 7.72

- 184 040284 (br. s, 1H), 7.56-7.46 (m, 5H), 7.37-7.28 (m, 2H), 7.27-7.17 (m, 1H), 3.94-3.66 (m, 3H), 2.23-1.89 (m, 7H).

Example 159 (+)-5-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-4-(2-chloro-6-fluorophenyl)valeric acid (enantiomer 2) .

The separation of enantiomers described in Example 157 gave 192 mg (98% pure, ee value 94%) of the title compound as the later eluted enantiomer. Die Substanz was then lyophilized.

[a] _D20 = +38.2°, 589 nm, c = 0.36 ^g /100 mL, methanol.

LC-MS (Method 2): Rt = 1.04 min; MS (ESIpos): m/z = 569/571 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.008 (1.41), 1.030 (0.64), 1.045 (0.68), 1.235 (0.53), 1.974 (0.64), 2.083 (2.36), 2.108 (2.73) , 2.120 (2.76), 2.157 (7.76), 2.328 (0.54), 2.670 (0.42), 3.749 (1.71) . , 8.940 (2.16), 12.061 (0.45).

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 12.06 (br. s, 1H), 8.94 (t, 1H), 7.94 (d, 1H), 7.85 (dd, 1H), 7.70 (br. s, 1H), 7.56-7.46 (m, 5H), 7.38-7.29 (m, 2H), 7.27-7..17 (m, 1H), 3.93-3.66 (m, 3H), 2.22-1.91 (m, 7H).

Example 160 (+/-)-5-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-4-(2-methylphenyl)valeric acid (racemate)

To a solution of (+/-)-tert-butyl-5-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-4-(2methylphenyl)pentanoate (75 mg, 98 % purity, 125 µmol, example 237A) in dichloromethane (890 µl) was added TFA (190 µl, 2.5 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 16). The combined desired fractions were concentrated and the residue was dried in vacuo. Received 53 mg (98% pure, 77% theoretical. output.) specified in the title compound.

LC-MS (Method 1): Rt = 2.00 min; MS (ESIpos): m/z = 531/533 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: -0.008 (2.21), 0.008 (1.47), 1.777 (0.46), 1.793 (0.92), 1.818 (1.16), 1.837 (0.65), 2.026 ( 0.86), 2.044 (1.56), 2.053 (1.38), 2.073 (7.16), 2.082 (4.15), 2.107 (3.35), 2.331 (16.00), 2.523 (0.68), 3.320 (1.12), 3.338 (1.22), 0.50), 3.478 (1.02), 3.490 (1.29), 3.510 (1.62), 3.524 (1.69), 3.540 (1.39), 3.714 (2.22), 3.733 (2.42), 3.749 (2.03), 3.765 (1.75), 1.14), 3.864 (0.50),7.095 (0.75), 7.113 (2.01), 7.131 (1.76), 7.167 (3.35), 7.184 (1.90), 7.194 (1.17), 7.214 (1.95), 7.232 (1.07), 3.11), 7.323 (2.15), 7.477 (0.44), 7.491 (1.29), 7.501 (4.06), 7.509 (3.74), 7.521 (12.71) 1.81), 7.857 (3.08), 7.862 (2.94), 7.933 (5.59), 7.955 (3.59), 8.827 (1.27), 8.842 (1.97), 8.856 (1.25).

Example 161 (-)-5-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-4-(2-methylphenyl)valeric acid (enantiomer 1)

To a solution of (-)-tert-butyl-5-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-4-(2methylphenyl)pentanoate (110 mg, 187 µmol, example 238A) in dichloromethane (1.3 ml) was added TFA (290 μl, 3.7 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 16). The combined desired fractions were concentrated and the residue was dried in vacuo. 85 mg (98% pure, 99% ee, 84% thor.) of the title compound were obtained.

[a] _D20 = -14.4°, 589 nm, c = 0.36 ^g /100 ml, methanol.

LC-MS (Method 2): Rt = 1.05 min; MS (ESIpos): m/z = 531/533 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 0.008 (0.72), 1.762 (0.40), 1.778 (0.57), 1.793 (1.03), 1.817 (1.22), 1.837 (0.68), 2.026 (1.10 ), 2.045 (1.96), 2.054 (1.92), 2.073 (7.90), 2.082 (4.58), 2.100 (3.49), 2.107 (3.68), 2.283 (0.50), 2.299 (0.90), 2.331 (16.00), 2.523 (1.16 ), 3.320 (1.18), 3.338 (1.22), 3.367 (0.40), 3.478 (0.84), 3.490 (1.08), 3.510 (1.29), 3.524 (1.25), 3.539 (0.76), 3.715 (0.95), 3.733 (1.43 ), 3.750 (1.25), 3.766 (1.11), 3.785 (0.63), 7.095 (0.90), 7.113 (2.15), 7.131 (1.88), 7.167 (3.49), 7.184 (2.07), 7.194 (1.30), 7.213 (2.03 ), 7.231 (1.10), 7.304 (3.20), 7.323 (2.18), 7.478 (0.88), 7.491 (2.00), 7.501 (4.88), 7.509 (4.69), 7.521 (13.16), 7.533 (5.93), 7.686 (0.65 ), 7.834 (2.17), 7.840 (1.93), 7.857 (3.18), 7.862 (2.93), 7.933 (5.55), 7.955 (3.53), 8.827 (1.43), 8.841 (2.07), 8.855 (1.26).

- 185 040284

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 11.98 (br. s, 1H), 8.84 (t, 1H), 7.94 (d, 1H), 7.85 (dd, 1H), 7.69 (br. s, 1H), 7.56-7.45 (m, 5H), 7.34-7.28 (m, 1H), 7.26-7.06 (m, 3H), 3.81-3.69 (m, 1H), 3.56-3.46 (m, 1H),

3.39-3.26 (m, 1H), 2.33 (s, 3H), 2.18-1.98 (m, 6H), 1.87-1.74 (m, 1H).

Example 162 (+)-5-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-4-(2-methylphenyl)valeric acid (enantiomer 2)

To a solution of (+)-tert-butyl-5-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-4-(2methylphenyl)pentanoate (110 mg, 187 µmol, example 239A) in dichloromethane (1.3 ml) was added TFA (290 μl, 3.7 mmol) and the mixture was stirred overnight at RT. TFA (140 μl, 1.9 mmol) was then added again and the mixture was stirred one more 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 16). The combined desired fractions were concentrated and the residue was dried in vacuo. 88 mg (98% pure, ee value 99, 86% theoretical yield of the title compound) were obtained.

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

LC-MS (Method 2): Rt = 1.05 min; MS (ESIpos): m/z = 531/533 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.008 (0.97), 1.778 (0.45), 1.793 (0.92), 1.818 (1.14), 1.837 (0.65), 2.026 (0.83), 2.044 (1.53) , 2.053 (1.37), 2.073 (7.18), 2.082 (4.17), 2.107 (3.40), 2.331 (16.00), 2.523 (0.69), 3.320 (1.07), 3.338 (1.15), 3.366 (0.40) 3.490 (1.00), 3.510 (1.23), 3.524 (1.22), 3.539 (0.77), 3.714 (0.92), 3.733 (1.43), 3.750 (1.28), 3.766 (1.19), 3.785 (0.75), 7.095 (0.76) , 7.113 (2.03) , 7.488 (1.24), 7.491 (1.42), 7.501 (4.18), 7.509 (3.98), 7.521 (12.74), 7.532 (5.63), 7.535 (4.82) , 7.839 (1.87), 7.857 (3.22), 7.862 (3.01), 7.933 (5.66), 7.955 (3.64), 8.827 (1.30), 8.841 (1.98), 8.855 (1.22).

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 12.01 (br. s, 1H), 8.84 (t, 1H), 7.94 (d, 1H), 7.85 (dd, 1H), 7.69 (br. s, 1H), 7.55-7.47 (m, 5H), 7.35-7.28 (m, 1H), 7.25-7.08 (m, 3H), 3.80-3.69 (m, 1H), 3.56-3.45 (m, 1H), 3.39-3.27 (m, 1H), 2.33 (s, 3H), 2.19-2.00 (m, 6H), 1.86-1.74 (m, 1H).

Example 163 (+/-)-5-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-4-(2-chloro-5-fluorophenyl)valeric acid (racemate )

GT

Ο^ΝΗ O n z TT 4% ^N tQ

To a solution of (+/-)-tert-butyl-5-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-4-(2chloro-5-fluorophenyl)pentanoate ( 60 mg, 95.9 µmol, example 240A) in dichloromethane (680 µl) was added with TFA (150 µl, 1.9 mmol) and the mixture was stirred overnight at RT. Then added again

TFA (150 μl, 1.9 mmol) and the mixture was stirred 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 16). The combined desired fractions were concentrated and the residue was dried in vacuo. 48 mg (98% pure, 86% thor.) of the title compound were obtained.

LC-MS (Method 1): R _t = 2.00 min; MS (ESIpos): m/z = 569/571 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.819 (1.01), 1.839 (1.23), 2.031 (0.98), 2.062 (2.52), 2.088 (2.22), 2.101 (2.02), 2.110 (2.52) , 2.140 (8.20), 2.158 (2.61), 2.181 (0.91), 3.612 (1.09), 3.739 (2.47), 4.055 (1.13), 7.119 (0.79), 7.139 (1.42), 7.409 (1.76), 7.416 (1.87) . , 7.838 (2.11), 7.855 (3.52), 7.860 (3.44), 7.930 (6.44), 7.952 (4.06), 8.847 (1.27), 8.862 (2.54), 8.876 (1.24).

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.86 (t, 1H), 7.94 (d, 1H), 7.85 (dd, 1H), 7.66 (br. s, 1H), 7.567.47 (m, 6H), 7.43 (dd, 1H), 7.18-7.09 (m, 1H), 3.79-3.55 (m, 3H), 2.22-1.99 (m, 6H), 1.88-1.76 (m, 1H).

Example 164 (-)-5-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-4-(2-chloro-5-fluorophenyl)valeric acid (enantiomer 1) .

To a solution of (-)-tert-butyl-5-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-4-(2chloro-5-fluorophenyl)pentanoate (1.56 g , 86% pure, 2.14 mmol, example 241A) in dichloromethane (15 ml) was added TFA (3.3 ml, 43 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 twice by preparative HPLC (Method 16). The combined desired fractions were concentrated and the residue was dried in vacuo. Received 949 mg (98% purity, 99% ee value, 76% thor.)

- 186 040284 header connection.

[a] _D20 = -22.2°, 589 nm, c = 0.42 ^g /100 ml, methanol.

LC-MS (Method 1): Rt = 1.97 min; MS (ESIpos): m/z = 569/571 [M+H]+.

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: -0.008 (2.07), 1.797 (0.50), 1.819 (1.05), 1.840 (1.25), 1.861 (0.74), 2.018 (0.76), 2.031 ( 1.01), 2.050 (1.19), 2.061 (2.61), 2.073 (0.72), 2.088 (2.28), 2.101 (2.05), 2.110 (2.52), 2.140 (8.45), 2.158 (2.74), 2.181 (0.93), 2.198 ( 0.44), 3.615 (1.02), 3.738 (2.40), 7.119 (0.79), 7.139 (1.41), 7.154 (0.82), 7.408 (1.88), 7.416 (1.91), 7.434 (1.91), 7.441 (1.83), 2.72) 5.99), 7.950 (3.83), 8.845 (1.32), 8.860 (2.66), 8.874 (1.26), 12.066 (1.15).

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 12.07 (br. s, 1H), 8.86 (t, 1H), 7.94 (d, 1H), 7.85 (dd, 1H), 7.66 (br s, 1H), 7.55-7.47 (m, 6H), 7.42 (dd, 1H), 7.18-7.09 (m, 1H), 3.82-3.55 (m, 3H), 2.21-1.98 (m, 6H), 1.91 -1.76 (m, 1H).

Example 165 (+)-5-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-4-(2-chloro-5-fluorophenyl)valeric acid (enantiomer 2) .

To a solution of (+)-tert-butyl-5-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-4-(2chloro-5-fluorophenyl)pentanoate (1.26 g , 98% pure, 1.97 mmol, example 242A) in dichloromethane (14 ml) was added TFA (3.0 ml, 39 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 16). The combined desired fractions were concentrated and the residue was dried in vacuo. 1.03 g (98% pure, ee value 95%, 89% th. y.) of the title compound was obtained.

[a] _D20 = +20.1°, 589 nm, c = 0.38 ^g /100 mL, methanol.

LC-MS (Method 1): Rt = 1.97 min; MS (ESIpos): m/z = 569/571 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (2.01), 0.008 (1.76), 1.796 (0.49), 1.819 (1.03), 1.828 (0.64), 1.840 (1.24), 1.861 (0.71 ), 2.018 (0.76), 2.031 (1.00), 2.049 (1.19), 2.061 (2.63), 2.073 (0.82), 2.088 (2.31), 2.101 (2.07), 2.110 (2.51), 2.140 (8.28), 2.158 (2.73 ), 2.181 (0.94), 2.198 (0.45), 2.523 (0.64), 3.616 (1.00), 3.738 (2.38), 7.119 (0.77), 7.139 (1.37), 7.154 (0.82), 7.408 (1.85), 7.416 (1.90 ), 7.434 (1.90), 7.441 (1.82), 7.480 (2.76), 7.494 (3.67), 7.500 (5.17), 7.508 (4.41), 7.519 (16.00), 7.530 (5.70), 7.830 (2.31), 7.835 (2.07 ), 7.853 (3.49), 7.858 (3.30), 7.928 (6.23), 7.950 (3.98), 8.845 (1.30), 8.860 (2.64), 8.874 (1.26), 12.067 (1.03).

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 12.07 (br. s, 1H), 8.86 (t, 1H), 7.94 (d, 1H), 7.85 (dd, 1H), 7.66 (br s, 1H), 7.56-7.47 (m, 6H), 7.42 (dd, 1H), 7.18-7.10 (m, 1H), 3.83-3.54 (m, 3H), 2.22-1.99 (m, 6H), 1.90 -1.76 (m, 1H).

Example 166 (+/-)-5-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-4-(2-methoxyphenyl)valeric acid (racemate)

H3 _% +J

Ο^ΝΗ Oh

Vg N s ^N chf

To a solution of (+/-)-tert-butyl-5-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-4-(2methoxyphenyl)pentanoate (40 mg, 98 % purity, 64.9 µmol, example 243A) in dichloromethane (460 µl) was added TFA (100 µl, 1.3 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 16). The combined desired fractions were concentrated and the residue was dried in vacuo. 35 mg (98% pure, 96% theoretical) of the title compound were obtained.

LC-MS (Method 1): Rt = 1.96 min; MS (ESIpos): m/z = 547/549 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.195 (0.72), 1.212 (0.73), 1.776 (0.74), 1.802 (1.20), 1.816 (1.27), 1.853 (0.50), 1.985 (1.24) , 2.004 (1.49), 2.016 (2.88), 2.049 (4.81), 2.075 (3.56), 2.092 (1.80), 2.146 (7.88), 2.328 (0.67), 2.367 (0.76), 2.670 (0.44), 2.731 (1.81) , 2.890 (2.22), 3.401 (1.49), 3.620 (0.86) . , 7.492 (2.11), 7.502 (5.02), 7.510 (5.09), 7.522 (16.00), 7.707 (1.77), 7.832 (2.38), 7.838 (2.30) , 7.950 (4.12), 8.757 (1.62), 8.772 (2.96), 8.786 (1.60).

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 8.77 (br. t, 1H), 7.94 (d, 1H), 7.85 (dd, 1H), 7.71 (br. s, 1H), 7.57- 7.46 (m, 5H), 7.27-7.18 (m, 2H), 7.02-6.89 (m, 2H), 3.78 (s, 3H), 3.77-3.60 (m, 2H), 3.46-3.34 (m, 1H), 2.19-1.94 (m, 6H), 1.88-1.73 (m, 1H).

- 187 040284

Example 167 (-)-5-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-4-(2-methoxyphenyl)valeric acid (enantiomer 1)

To a solution of (-)-tert-butyl-5-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-4-(2-methoxyphenyl)pentanoate (60 mg, 98 % purity, 97.4 µmol, example 244A) in dichloromethane (690 µl) was added TFA (150 µl, 1.9 mmol) and the mixture was stirred overnight at RT. Then again TFA (150 μl, 1.9 mmol) was added and the mixture was stirred for an additional 3 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 16). The combined target fractions were concentrated and the residue was lyophilized. 51 mg (98% pure, ee value 97, 93% thor.) of the title compound were obtained.

[a]D ²⁰ = -12.6°, 589 nm, c = 0.37 g/100 ml, methanol.

LC-MS (Method 2): R _t = 1.05 min; MS (ESIpos): m/z = 547/549 [M+H]+.

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (1.92), 0.008 (1.56), 1.776 (0.63), 1.801 (1.03), 1.815 (1.14), 1.829 (0.88), 1.839 (0.64 ), 1.853 (0.42), 1.984 (3.49), 2.048 (4.43), 2.074 (3.42), 2.092 (1.49), 2.114 (0.77), 3.620 (1.26), 3.634 (1.77), 3.652 (2.54), 3.667 (3.19 ), 3.756 (2.77), 3.953 (0.59), 6.927 (1.56), 6.945 (1.81), 7.219 (3.06), 7.227 (3.89), 7.239 (1.91), 7.246 (0.94), 1.997 (1.05), 2.004 (1.10 ), 2.016 (2.66), 2.043 (0.98), 2.145 (7.48), 2.523 (1.02), 3.399 (1.46), 3.599 (3.10), 3.682 (2.34), 3.703 (2.65), 3.719 (3.18), 3.739 (3.49 ), 6.964 (2.06), 6.979 (3.60), 6.998 (4.19), 7.200 (3.28), 7.477 (0.49), 7.490 (1.47), 7.500 (4.51), 7.508 (4.29), 7.520 (16.00), 7.531 (6.55 ), 7.705 (1.50), 7.829 (2.44), 7.834 (2.20), 7.851 (3.77), 7.856 (3.62), 7.926 (6.85), 7.948 (4.37), 8.755 (1.48), 8.770 (2.95), 8.784 (1.47 ).

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 12.00 (br. s, 1H), 8.77 (t, 1H), 7.93 (d, 1H), 7.85 (dd, 1H), 7.71 (br. s, 1H), 7.55-7.46 (m, 5H), 7.27-7.18 (m, 2H), 7.01-6.91 (m, 2H), 3.78 (s, 3H), 3.77-3.61 (m, 2H), 3.46- 3.33 (m, 1H), 2.19-1.95 (m, 6H), 1.87-1.74 (m, 1H).

Example 168 (+)-5-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-4-(2-methoxyphenyl)valeric acid (enantiomer 2).

To a solution of (+)-tert-butyl-5-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-4-(2-methoxyphenyl)pentanoate (55 mg, 98 % purity, 89.3 µmol, example 245A) in dichloromethane (630 µl) was added TFA (140 µl, 1.8 mmol) and the mixture was stirred overnight at RT. TFA (140 µl, 1.8 mmol) was then added again and the mixture was stirred for an additional 4 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 16). The combined target fractions were concentrated and the residue was lyophilized. 46 mg (98% pure, ee value 99, 92% thor.) of the title compound were obtained.

[a] _D20 = +14.1°, 589 nm, c = 0.35 ^g /100 mL, methanol.

LC-MS (Method 2): R _t = 1.05 min; MS (ESIpos): m/z = 547/549 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (0.42), 1.802 (0.63), 1.815 (0.70), 1.828 (0.53), 1.984 (0.57), 1.997 (0.64), 2.004 (0.65 ), 2.016 (1.63), 2.043 (2.14), 2.048 (2.70), 2.074 (2.10), 2.092 (0.92), 2.114 (0.59), 2.145 (4.55), 2.524 (0.53), 3.400 (1.05), 3.431 (0.60 ), 3.619 (2.56), 3.633 (2.25), 3.652 (2.13), 3.667 (2.07), 3.682 (1.32), 3.703 (1.21), 3.719 (1.35), 3.739 (1.22), 3.756 (0.91), 3.776 (16.00 ), 6.927 (0.96), 6.946 (2.13), 6.964 (1.26), 6.979 (2.22), 6.998 (2.60), 7.200 (1.12), 7.219 (1.89), 7.227 (2.40), 7.239 (1.18), 7.246 (2.03 ), 7.490 (0.90), 7.500 (2.81), 7.508 (2.70), 7.520 (9.88), 7.527 (5.03), 7.531 (4.00), 7.534 (3.68), 7.704 (0.90), 7.829 (1.57), 7.834 (1.40 ), 7.851 (2.41), 7.856 (2.30), 7.926 (4.33), 7.948 (2.78), 8.755 (0.91), 8.770 (1.80), 8.784 (0.90).

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 11.97 (br. s, 1H), 8.77 (t, 1H), 7.93 (d, 1H), 7.85 (dd, 1H), 7.70 (br. s, 1H), 7.56-7.44 (m, 5H), 7.26-7.18 (m, 2H), 7.02-6.91 (m, 2H), 3.78 (s, 3H), 3.76-3.61 (m, 2H), 3.45- 3.35 (m, 1H), 2.20-1.94 (m, 6H), 1.87-1.73 (m, 1H).

Example 169 (+/-)-5-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-4-(2-chloro-5-fluorophenyl)-4-methylvaleric acid (racemate)

To a solution of (+/-)-tert-butyl-5-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-4-(2chloro-5-fluorophenyl)-4 -methylpentanoate (40 mg, 72% pure, 45.0 µmol, example 246A) in dichloromethane (320 µl) was added with TFA (69 µl, 900 µmol) and the mixture was stirred 48 h at RT. TFA (69 μl, 900 μmol) was then added again and the mixture was stirred for an additional 24 h at RT. After that the mixture

- 188 040284 concentrated and mixed several times with dichloromethane and re-concentrated. The residue was purified by preparative HPLC (Method 15). The combined target fractions were concentrated and the residue was mixed with ethyl acetate and saturated 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 dried in vacuo. 25 mg (98% pure, 93% thor.) of the title compound were obtained.

LC-MS (Method 2): Rt = 1.09 min; MS (ESIpos): m/z = 583/585 [M+H]+.

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 1.233 (0.75), 1.334 (0.50), 1.475 (16.00), 1.555 (0.62), 1.592 (1.31), 1.617 (0.98), 1.853 (0.95 ), 1.877 (1.37), 1.914 (1.56), 1.951 (1.24), 2.146 (2.24), 2.259 (0.40), 2.327 (0.62), 2.366 (0.44), 2.669 (0.59), 2.710 (0.42), 3.327 (4.51 ), 3.698 (1.25), 4.301 (1.03), 7.119 (1.15), 7.139 (2.08), 7.160 (1.25), 7.217 (2.04), 7.246 (2.10), 7.445 (1.49), 7.468 (1.99), 7.484 (2.99 ), 7.499 (6.68), 7.504 (5.17), 7.518 (9.57), 7.532 (11.52), 7.644 (0.86), 7.820 (2.62), 7.825 (2.41), 7.842 (3.95), 7.847 (3.88), 7.921 (7.11 ), 7.943 (4.62), 9.110 (0.51).

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 9.11 (br. s, 1H), 7.93 (d, 1H), 7.84 (dd, 1H), 7.64 (br. s, 1H), 7.57 -7.42 (m, 6H), 7.23 (br. d, 1H), 7.18-7.07 (m, 1H), 4.39-4.25 (m, 1H), 3.77-3.62 (m, 1H), 2.49-2.40 (m, 1H, partially hidden), 2.15 (br. s, 3H), 2.02-1.79 (m, 2H), 1.67-1.52 (m, 1H), 1.47 (s, 3H).

Example 170 (-)-5-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-4-(2-chloro-5-fluorophenyl)-4-methylvaleric acid ( enantiomer 1).

To a solution of (-)-tert-butyl-5-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-4-(2chloro-5-fluorophenyl)-4-methylpentanoate (60 mg, 93.8 µmol, example 247A) in dichloromethane (690 µl) was added TFA (72 µl, 940 µmol) and the mixture was left 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 16). The combined target fractions were concentrated and the residue was mixed with ethyl acetate and saturated 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. 48 mg (98% pure, 86% thor.) of the title compound were obtained.

[a] _D20 = -10.4°, 589 nm, c = ^0.25 g/100 ml, methanol.

LC-MS (Method 1): R _t = 2.05 min; MS (ESIpos): m/z = 583/585 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.463 (16.00), 1.744 (1.05), 1.761 (1.23), 1.776 (0.90), 1.998 (1.25), 2.016 (1.10), 2.165 (5.53) , 2.332 (1.41), 2.353 (1.27), 2.366 (1.37), 2.670 (0.74), 2.710 (0.64), 3.736 (0.94), 4.244 (0.86), 7.101 (1.05), 7.108 (1.30), 7.127 (2.15) , 7.141(1.37), 7.149(1.42), 7.256(1.82),7.281(1.92), 7.435(1.75), 7.450(2.12), 7.457(2.03), 7.471(2.15), 7.485(2.13), 7.500(7.01) . .

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 9.45 (br. s, 1H), 7.93 (d, 1H), 7.83 (dd, 1H), 7.65 (br. s, 1H), 7.58 -7.41 (m, 6H), 7.27 (br. d, 1H), 7.16-7.08 (m, 1H), 4.24 (br. s, 1H), 3.74 (br. s, 1H), 2.42-2.29 (m, 1H), 2.17 (br. s, 3H), 2.07-1.93 (m, 1H), 1.83-1.68 (m, 1H), 1.46 (s, 3H), 1.55-1.43 (m, 1H).

Example 171 (+)-5-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-4-(2-chloro-5-fluorophenyl)-4-methylvaleric acid ( enantiomer 2).

To a solution of (+)-tert-butyl-5-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-4-(2chloro-5-fluorophenyl)-4-methylpentanoate (80 mg, 125 µmol, example 248A) in dichloromethane (920 µl) TFA (96 µl, 1.3 mmol) was added and the mixture was left 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 16). The combined target fractions were concentrated and the residue was mixed with ethyl acetate and saturated 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. 68 mg (98% pure, 91% theoretical) of the title compound were obtained.

[a] _D20 = +14.5°, 589 nm ^, c = 0.25 g/100 mL, methanol.

LC-MS (Method 1): Rt = 2.05 min; MS (ESIpos): m/z = 583/585 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.149 (0.46), 0.147 (0.46), 1.462 (16.00), 1.743 (1.16), 1.761 (1.28), 2.007 (1.21), 2.168 (6.38 ), 2.327 (1.98), 2.366 (1.39), 2.669 (1.02), 2.689 (2.41), 2.710 (0.78), 2.731 (0.91), 2.890 (0.88), 3.731 (0.89), 4.213 (0.83), 7.109 (1.31 ), 7.128 (2.20), 7.142 (1.34), 7.148 (1.37), 7.261 (1.83), 7.286 (1.85), 7.435 (1.90), 7.450 (2.20), 7.457 (2.12), 7.472 (2.30), 7.485 (2.25 ), 7.500 (7.08), 7.518 (7.99), 7.539 (9.68), 7.558 (2.92), 7.656 (3.56), 7.816 (2.46), 7.821 (2.36), 7.838 (3.76), 7.843 (3.65), 7.919 (6.25 ), 7.941 (4.07), 9.524 (0.41).

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 9.52 (br. s, 1H), 7.93 (d, 1H), 7.83 (dd, 1H), 7.66 (br. s, 1H),

- 189 040284

7.57-7.42 (m, 6H), 7.27 (br. d, 1H), 7.16-7.09 (m, 1H), 4.22 (br. s, 1H), 3.73 (br. s, 1H), 2.40-2.27 (m , 1H), 2.17 (br. s, 3H), 2.07-1.95 (m, 1H), 1.83-1.70 (m, 1H), 1.49 (m, 1H), 1.46 (s, 3H).

Example 172 (+/-)-5-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-4-(2-chloro-3,6-difluorophenyl)valeric acid (racemate)

To a solution of (+/-)-tert-butyl-5-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-4-(2-chloro-3,6-difluorophenyl )pentanoate (100 mg, 155 µmol, example 249A) in dichloromethane (1.1 ml) TFA (120 µl, 1.6 mmol) was added and the mixture was left for 5 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 16). The combined target fractions were concentrated and the residue was lyophilized. 81 mg (96% pure, 85% thor.) of the title compound were obtained.

LC-MS (Method 2): Rt = 1.07 min; MS (ESIpos): m/z = 587/589 [M+H]+.

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (2.48), 0.008 (2.23), 1.366 (1.46), 1.374 (1.01), 1.989 (0.64), 2.077 (1.02), 2.090 (1.26 ), 2.096 (1.29), 2.111 (0.43), 2.524 (0.98), 3.761 (1.41), 3.801 (1.14), 7.270 (1.03), 7.329 (0.90), 7.406 (1.25), 7.415 (1.25), 7.482 (2.28 ), 2.153 (8.77), 2.187 (1.59), 2.209 (0.60), 2.225 (0.60), 7.281 (0.72), 7.294 (1.33), 7.304 (1.38), 7.318 (0.54), 7.495 (1.55), 7.505 (4.63 ), 7.513 (4.55), 7.524 (16.00), 7.535 (6.42), 7.538 (5.67), 7.844 (2.39), 7.849 (2.16), 7.866 (3.69), 7.871 (3.52), 7.938 (6.67), 7.960 (4.19 ), 8.942 (1.21), 8.956 (2.17).

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 8.96 (t, 1H), 7.95 (d, 1H), 7.86 (dd, 1H), 7.72 (br. s, 1H), 7.567.48 ( m, 5H), 7.45-7.37 (m, 1H), 7.35-7.25 (m, 1H), 3.95-3.68 (m, 3H), 2.26-1.92 (m, 7H).

Example 173 (-)-5-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-4-(2-chloro-3,6-difluorophenyl)valeric acid (enantiomer 1 ).

To a solution of (-)-tert-butyl-5-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-4-(2chloro-3,6-difluorophenyl)pentanoate ( 240 mg, 373 μmol, example 250A) in dichloromethane (2.7 ml) was added TFA (290 μl, 3.7 mmol) and the mixture was left for 2 days at RT. The mixture was then concentrated and mixed several times with dichloromethane and re-concentrated. The residue was adsorbed into acetonitrile and purified by preparative HPLC (Method 15). The combined target fractions were concentrated and the residue was lyophilized. 212 mg (100% pure, >95% ee value, 97% thor.) of the title compound were obtained.

[a] _D20 = -39.2°, 589 nm, c = 0.34 ^g /100 ml, methanol.

LC-MS (Method 1): Rt = 1.99 min; MS (ESIpos): m/z = 587/589 [M+H]+.

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 0.008 (1.93), 1.990 (0.67), 2.073 (3.12), 2.097 (1.31), 2.112 (2.29), 2.154 (9.13), 2.187 (1.62 ), 2.210 (0.58), 2.524 (0.76), 3.762 (1.50), 3.803 (1.22), 4.388 (0.53), 7.270 (0.59), 7.281 (0.72), 7.294 (1.36), 7.304 (1.41), 7.319 (1.05 ), 7.330 (0.90), 7.405 (1.27), 7.415 (1.22), 7.482 (0.54), 7.495 (1.55), 7.505 (4.66), 7.513 (4.50), 7.524 (16.00), 7.535 (6.51), 7.843 (2.34 ), 7.849 (2.11), 7.866 (3.63), 7.871 (3.44), 7.938 (6.46), 7.960 (4.05), 8.942 (1.26), 8.957 (2.25).

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 11.97 (br. s, 1H), 8.96 (t, 1H), 7.95 (d, 1H), 7.86 (dd, 1H), 7.72 (br s, 1H), 7.57-7.47 (m, 5H), 7.45-7.37 (m, 1H), 7.35-7.24 (m, 1H), 3.94-3.67 (m, 3H), 2.25-1.90 (m, 7H) .

Example 174 (+)-5-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-4-(2-chloro-3,6-difluorophenyl)valeric acid (enantiomer 2).

To a solution of (+)-tert-butyl-5-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-4-(2chloro-3,6-difluorophenyl)pentanoate ( 250 mg, 388 µmol, example 251A) in dichloromethane (2.9 ml) was added with TFA (300 µl, 3.9 mmol) and the mixture was left for 2 days at RT. The mixture was then concentrated and mixed several times with dichloromethane and re-concentrated. The residue was adsorbed into acetonitrile and purified by preparative HPLC (Method 15). The combined target fractions were concentrated and the residue was lyophilized. 217 mg (100% pure, ee value 98, 95% thor.) of the title compound were obtained.

[a] _D ²⁰ = +37.4°, 589 nm, c = 0.36 g/100 ml, methanol LC-MS (Method 1): R _t = 1.99 min; MS (ESIpos): m/z = 587/589 [M+H]+.

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (3.25), 0.008 (2.24), 1.990 (0.66), 2.073 (2.48), 2.097 (1.28), 2.111 (2.23), 2.153 (8.83 ), 2.186 (1.54), 2.209 (0.55), 2.524 (1.02), 3.740 (2.63), 7.270 (0.59), 7.281 (0.71), 7.294 (1.32), 7.304 (1.37), 7.319 (1.03), 7.329 (0.88 ), 7.405 (1.24), 7.415 (1.20), 7.494 (1.50), 7.504 (4.49), 7.512 (4.34), 7.523 (16.00), 7.535 (6.16), 7.842 (2.29), 7.847 (2.09), 7.864 (3.52 ), 7.870 (3.33), 7.936

- 190 040284 (6.38), 7.959 (3.98), 8.940 (1.22), 8.955 (2.16).

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 12.10 (br. s, 1H), 8.95 (t, 1H), 7.94 (d, 1H), 7.86 (dd, 1H), 7.72 (br s, 1H), 7.56-7.47 (m, 5H), 7.46-7.36 (m, 1H), 7.34-7.26 (m, 1H), 3.83-3.62 (m, 3H), 2.24-1.90 (m, 7H) .

Example 175 (+/-)-5-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-4-(2-fluorophenyl)valeric acid (racemate)

To a solution of (+/-)-tert-butyl-5-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-4-(2fluorophenyl)pentanoate (500 mg, 845 µmol, example 252A) in dichloromethane (6.2 ml) was added TFA (650 µl, 8.5 mmol) and the mixture was left overnight at RT. The mixture was then concentrated and mixed several times with dichloromethane and re-concentrated. The residue was adsorbed into acetonitrile and purified by preparative HPLC (Method 16). The combined target fractions were concentrated and the residue was lyophilized. The lyophilisate was mixed with ethyl acetate and saturated 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. 449 mg (98% pure, 97% theoretical) of the title compound were obtained.

LC-MS (Method 1): R _t = 1.90 min; MS (ESIpos): m/z = 535/537 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.788 (0.55), 1.805 (0.74), 1.814 (0.87), 1.828 (0.96), 1.839 (0.68), 1.850 (0.52), 2.033 (0.88) 2.045 (1.01), 2.060 (2.26), 2.069 (1.20), 2.086 (3.57), 2.094 (4.79), 2.117 (4.38), 2.134 (2.79), 2.155 (1.10), 3.347 (0.85), 3.359 (0.89) 3.368 (0.87), 3.637 (0.46), 3.651 (0.80), 3.670 (1.01), 3.684 (1.39), 3.697 (0.75), 3.735 (0.60), 3.753 (0.87), 3.771 (0.75), 7.144 (1.24) , 7.166 (1.93) , 7.419 (2.25), 7.438 (1.13), 7.490 (1.36), 7.502 (3.61), 7.510 (4.01), 7.520 (16.00), 7.834 (1.78), 7.839 (1.57), 7.857 (2.72), 7.861 (2.48) , 7.929 (5.01), 7.951 (3.11), 8.853 (1.26), 8.868 (2.06), 8.882 (1.09).

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 8.87 (t, 1H), 7.94 (d, 1H), 7.85 (dd, 1H), 7.68 (br. s, 1H), 7.557.46 ( m, 5H), 7.45-7.38 (m, 1H), 7.36-7.25 (m, 1H), 7.25-7.13 (m, 2H), 3.83-3.72 (m, 1H), 3.71-3.62 (m, 1H), 3.41-3.30 (m, 1H), 2.20-1.99 (m, 6H), 1.88-1.75 (m, 1H).

Separation of enantiomers.

The title target compound (400 mg) was dissolved in methanol (20 ml) and separated into enantiomers by chiral phase preparative SLC (see Examples 176 and 177) [column: Daicel Chiralpak AD, 5 μm, 250 mm x 20 mm; flow: 80 ml/min; detection: 210 nm; temperature: 40°C; sample injection: 1.0 ml; eluent: 21% ethanol/79% carbon dioxide; duration of action 13 min, isocratic]. The combined desired fractions were concentrated and the residue was dried in vacuo.

Example 176 (-)-5-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-4-(2-fluorophenyl)valeric acid (enantiomer 1)

Separation of enantiomers as described in Example 175 gave 128 mg (98% pure, ee value 96%) of the title compound as the previously eluted enantiomer.

[a] _D20 = -32.2°, 589 nm, c = 0.34 ^g /100 ml, methanol.

LC-MS (Method 2): R _t = 1.00 min; MS (ESIpos): m/z = 535/537 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (2.76), 0.008 (1.82), 1.785 (0.53), 1.812 (0.78), 1.826 (0.88), 1.847 (0.53), 2.030 (1.00 ), 2.056 (2.16), 2.073 (2.12), 2.083 (3.51), 2.092 (4.44), 2.114 (4.01), 2.131 (2.68), 2.523 (1.54), 3.530 (2.19), 3.634 (0.52), 3.648 (0.83 ), 3.667 (1.03), 3.681 (1.32), 3.695 (0.75), 3.732 (0.63), 3.750 (0.85), 7.144 (1.22), 7.165 (1.92), 7.189 (2.26), 7.206 (2.10), 7.225 (1.45 ), 7.285 (1.19), 7.302 (1.04), 7.399 (1.28), 7.418 (2.19), 7.436 (1.19), 7.486 (1.67), 7.499 (3.86), 7.506 (4.36), 7.517 (16.00), 7.527 (4.36 ), 7.828 (1.83), 7.833 (1.66), 7.850 (2.65), 7.855 (2.51), 7.924 (5.15), 7.946 (3.20), 8.848 (1.13), 8.863 (1.83), 8.877 (1.05), 12.048 (0.45 ).

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 12.05 (br. s, 1H), 8.86 (t, 1H), 7.93 (d, 1H), 7.84 (dd, 1H), 7.67 (br. s, 1H), 7.55-7.47 (m, 5H), 7.45-7.39 (m, 1H), 7.35-7.25 (m, 1H), 7.24-7.13 (m, 2H), 3.83-3.71 (m, 1H), 3.71-3.61 (m, 1H), 3.41-3.33 (m, 1H, partially hidden), 2.20-1.99 (m, 6H), 1.88-1.75 (m, 1H).

Example 177 (+)-5-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-4-(2-fluorophenyl)valeric acid (enantiomer 2)

The separation of enantiomers described in Example 175 gave 130 mg (98% pure, ee value 99%) of the title compound as the later eluted enantiomer.

[a] _D20 = +36.9°, 589 nm, c = 0.25 g ^/ 100 mL, methanol.

LC-MS (Method 2): Rt = 1.00 min; MS (ESIpos): m/z = 535/537 [M+H]+.

- 191 040284

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (1.11), 0.008 (1.01), 1.786 (0.50), 1.803 (0.70), 1.813 (0.78), 1.825 (0.90), 1.836 (0.61 ), 1.848 (0.49), 2.031 (0.80), 2.043 (0.93), 2.056 (1.99), 2.067 (1.12), 2.073 (1.31), 2.084 (3.28), 2.092 (4.41), 2.115 (3.90), 2.131 (2.64 ), 2.152 (1.05), 2.523 (0.46), 3.635 (0.44), 3.648 (0.75), 3.667 (0.96), 3.681 (1.32), 3.695 (0.72), 3.733 (0.56), 3.752 (0.80), 3.769 (0.71 ), 7.144 (1.09), 7.165 (1.77), 7.190 (2.21), 7.206 (2.04), 7.225 (1.44), 7.271 (0.66), 7.285 (1.15), 7.301 (1.12), 7.322 (0.46), 7.399 (1.13 ), 7.403 (1.14), 7.418 (2.04), 7.421 (1.92), 7.436 (1.02), 7.480 (0.55), 7.486 (1.15), 7.499 (3.30), 7.506 (3.66), 7.517 (16.00), 7.523 (5.91 ), 7.528 (4.35), 7.828 (1.76), 7.833 (1.58), 7.850 (2.67), 7.855 (2.52), 7.924 (5.27), 7.947 (3.33), 8.849 (1.12), 8.864 (1.90), 8.878 (1.07 ).

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 12.05 (br. s, 1H), 8.86 (t, 1H), 7.93 (d, 1H), 7.84 (dd, 1H), 7.67 (br. s, 1H), 7.54-7.48 (m, 5H), 7.45-7.39 (m, 1H), 7.36-7.26 (m, 1H), 7.24-7.12 (m, 2H), 3.82-3.71 (m, 1H), 3.71-3.61 (m, 1H), 3.42-3.33 (m, 1H, partially hidden), 2.22-1.98 (m, 6H), 1.89-1.75 (m, 1H).

Example 178 (+/-)-5-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-4-[2-(difluoromethoxy)phenyl]valeric acid (racemate)

To a solution of (+/-)-tert-butyl-5-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-4-[2(difluoromethoxy)phenyl]pentanoate ( 500 mg, 782 µmol, example 253A) in dichloromethane (5.7 ml) was added with TFA (600 µl, 7.8 mmol) and the mixture was left overnight at RT. The mixture was then concentrated and mixed several times with dichloromethane and re-concentrated. The residue was adsorbed into acetonitrile and purified by preparative HPLC (Method 16). The combined target fractions were concentrated and the residue was lyophilized. The lyophilisate was mixed with ethyl acetate and saturated 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. 238 mg (98% pure, 51% th. y.) of the title compound were obtained.

LC-MS (Method 1): R _t = 2.00 min; MS (ESIpos): m/z = 583/585 [M+H]+.

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.821 (0.58), 1.841 (1.12), 1.862 (1.43), 1.886 (0.90), 2.000 (0.42), 2.022 (1.00), 2.037 (3.07) , 2.067 (3.02), 2.077 (4.34), 2.095 (2.55), 2.124 (4.67), 2.146 (2.22), 3.378 (1.23), 3.397 (1.28), 3.636 (0.63), 3.651 (1.02), 3.669 (1.45) 3.684 (1.78), 3.698 (0.98), 3.733 (1.04), 3.751 (1.49), 3.768 (1.39), 3.783 (0.87), 3.803 (0.56), 4.624 (1.03), 6.992 (2.69), 7.158 (3.03) . , 7.448 (2.55), 7.452 (2.49), 7.481 (0.55), 7.494 (1.58), 7.504 (4.68), 7.512 (4.55), 7.523 (15.91) , 7.680 (0.71), 7.838 (2.34), 7.843 (2.22), 7.860 (3.62), 7.865 (3.62), 7.934 (6.72), 7.956 (4.28), 8.832 (1.55), 8.847 (2.98), 8.861 (1.52) .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 8.85 (t, 1H), 7.94 (d, 1H), 7.85 (dd, 1H), 7.68 (br. s, 1H), 7.567.48 ( m, 5H), 7.44 (dd, 1H), 7.38-7.23 (m, 2H), 7.21-6.97 (m, 2H), 3.82-3.72 (m, 1H), 3.71-3.60 (m, 1H), 3.453. 32 (m, 1H), 2.21-1.98 (m, 6H), 1.94-1.78 (m, 1H).

Separation of enantiomers.

The title target compound (230 mg) was dissolved in methanol (20 ml) and separated into enantiomers by chiral phase preparative SLC (see examples 179 and 180 [column: Daicel Chiralpak AD-H, 5 μm, 250 mm x 20 mm ;flow: 80 ml/min; detection: 210 nm; temperature: 40°C; injection: 1.0 ml; eluent: 25% isopropanol/75% carbon dioxide; duration 7 min, isocratic]. dried in vacuum.

Example 179 (-)-5-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-4-[2-(difluoromethoxy)phenyl]valeric acid (enantiomer 1)

Separation of enantiomers as described in Example 178 gave 60 mg (98% pure, ee value 99%) of the title compound as the previously eluted enantiomer.

[a] _D20 = -17.7°, 589 nm, c = 0.30 ^g /100 ml, methanol.

LC-MS (Method 2): Rt = 1.03 min; MS (ESIpos): m/z = 583/585 [M+H]+.

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: -0.008 (1.52), 0.008 (1.39), 1.030 (4.20), 1.045 (4.27), 1.819 (0.56), 1.840 (1.09), 1.860 ( 1.40), 1.884 (0.90), 1.999 (0.40), 2.020 (0.94), 2.035 (3.03), 2.065 (2.88), 2.075 (4.17), 2.094 (2.50), 2.123 (4.63), 2.145 (2.12), 3.375 ( 1.26), 3.394 (1.29), 3.523 (0.73), 3.634 (0.59), 3.648 (0.97), 3.666 (1.40), 3.682 (1.74), 3.696 (0.94) 1.36)

- 192 040284 (2.40), 7.345 (0.97), 7.363 (2.73), 7.428 (3.01), 7.432 (3.03), 7.447 (2.55), 7.451 (2.44), 7.477 (0.57), 7.490 (1.52), 7.500 (4.55) ), 7.508 (4.30), 7.520 (16.00), 7.530 (6.42), 7.677 (0.70), 7.831 (2.27), 7.836 (2.11), 7.853 (3.48), 7.859 (3.41), 7.929 (6.63), 7.951 (4.24 ), 8.826 (1.52), 8.841 (2.91), 8.855 (1.50), 12.015 (2.69).

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 12.02 (s, 1H), 8.84 (t, 1H), 7.94 (d, 1H), 7.85 (dd, 1H), 7.68 (br. s , 1H), 7.56-7.48 (m, 5H), 7.44 (dd, 1H), 7.38-7.23 (m, 2H), 7.19-6.98 (m, 2H), 3.82-3.72 (m, 1H), 3.71-3.61 (m, 1H), 3.43-3.34 (m, 1H), 2.20-1.97 (m, 6H), 1.92-1.76 (m, 1H).

Example 180 (+)-5-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-4-[2-(difluoromethoxy)phenyl]valeric acid (enantiomer 2)

Separation of the enantiomers as described in Example 178 gave 67 mg (98% pure, ee value 99%) of the title compound as the later eluted enantiomer.

[a] _D20 = +16.8°, 589 nm, c = 0.33 ^g /100 ml, methanol.

LC-MS (Method 2): Rt = 1.03 min; MS (ESIpos): m/z = 583/585 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (0.54), 1.839 (1.03), 1.859 (1.36), 1.883 (0.86), 2.020 (4.45), 3.374 (1.21), 3.394 (1.22 ), 3.633 (0.56), 3.648 (0.95), 3.747 (1.42), 3.766 (1.37), 3.779 (0.89), 3.800 (2.92), 7.177 (8.88), 7.243 (1.12), 7.260 (2.91), 7.278 (2.66 ), 7.428 (2.91), 7.431 (2.87), 7.447 (2.49), 7.477 (2.17), 0.008 (1.84), 1.030 (4.30), 1.045 (4.35), 1.819 (0.90), 2.035 (2.94), 2.075 (4.00 ), 2.093 (2.37), 2.122 (0.95), 3.666 (1.33), 3.681 (1.65), 3.696 (0.90), 3.730 (0.51), 4.325 (0.54), 4.336 (0.52), 6.991 (2.66), 7.156 (2.22 ), 7.310 (1.94), 7.328 (2.30), 7.344 (0.94), 7.362 (0.50), 7.490 (1.46), 7.500 (4.46), 7.508 (4.24), 7.520 (16.00), 7.531 (6.21), 7.677 (0.71 ), 7.831 (2.33), 7.836 (2.11), 7.853 (3.53), 7.859 (3.38), 7.928 (6.72), 7.951 (4.28), 8.826 (1.45), 8.841 (2.79), 8.855 (1.41), 12.014 (2.07 ).

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 12.01 (s, 1H), 8.84 (t, 1H), 7.94 (d, 1H), 7.85 (dd, 1H), 7.68 (br. s, 1H), 7.56-7.48 (m, 5H), 7.44 (dd, 1H), 7.38-7.22 (m, 2H), 7.20-6.96 (m, 2H), 3.83-3.71 (m, 1H), 3.71-3.60 ( m, 1H), 3.44-3.34 (m, 1H), 2.20-1.96 (m, 6H), 1.94-1.77 (m, 1H).

Example 181 (+/-)-5-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-4-(2,6-difluorophenyl)valeric acid (racemate)

To a solution of (+/-)-tert-butyl-5-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-4-(2,6difluorophenyl)pentanoate (500 mg , 820 μmol, example 254A) in dichloromethane (6.0 ml) was added TFA (630 μl, 8.2 mmol) and the mixture was left overnight at RT. The mixture was then concentrated and mixed several times with dichloromethane and re-concentrated. The residue was adsorbed into acetonitrile and purified by preparative HPLC (Method 16). The combined target fractions were concentrated and the residue was lyophilized. The lyophilisate was mixed with ethyl acetate and saturated 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. 442 mg (98% pure, 95% theoretical) of the title compound were obtained.

LC-MS (Method 1): Rt = 1.92 min; MS (ESIpos): m/z = 553/555 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (0.64), 0.008 (0.51), 1.886 (0.55), 1.901 (0.72), 1.916 (0.93), 1.927 (0.87), 1.958 (0.42 ), 2.061 (0.90), 2.074 (1.15), 2.092 (1.18), 2.112 (1.59), 2.127 (5.66), 2.144 (7.80), 3.521 (0.88), 3.721 (0.74), 3.740 (1.31), 3.754 (1.85 ), 3.769 (1.54), 3.788 (1.01), 3.809 (0.81), 7.056 (2.54), 7.078 (4.69), 7.101 (3.00), 7.333 (0.88), 7.352 (1.17), 7.369 (0.79), 7.483 (0.41 ), 7.493 (1.20), 7.505 (3.76), 7.512 (3.82), 7.523 (16.00), 7.534 (5.28), 7.842 (2.02), 7.847 (1.84), 7.864 (3.16), 7.869 (3.07), 7.934 (5.90 ), 7.956 (3.70), 8.942 (1.26), 8.957 (2.42), 8.971 (1.26).

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 8.96 (t, 1H), 7.94 (d, 1H), 7.86 (dd, 1H), 7.71 (br. s, 1H), 7.567.46 ( m, 5H), 7.40-7.29 (m, 1H), 7.08 (t, 2H), 3.86-3.68 (m, 2H), 3.58-3.46 (m, 1H), 2.22-2.03 (m, 6H), 1.981. 85(m, 1H).

Separation of enantiomers.

The title target compound (380 mg) was dissolved in methanol (20 ml) and separated into enantiomers by chiral phase preparative SLC (see Examples 182 and 183) [column: Daicel Chiralpak AD, 5 μm, 250 mm x 20 mm; flow: 80 ml/min; detection: 210 nm; temperature: 40°C; sample injection: 1.0 ml; eluent: 25% isopropanol/75% carbon dioxide; duration of action 10 min, isocratic]. The combined desired fractions were concentrated and the residue was dried in vacuo.

Example 182 (-)-5-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-4-(2,6-difluorophenyl- 193 040284 nyl)valeric acid (enantiomer 1).

The separation of enantiomers described in Example 181 gave the prepurified title compound as the previously eluted enantiomer (ee value 99%). Then purified by preparative HPLC (Method 14). The combined desired fractions were concentrated and the residue was dried in vacuo. Then one more time further purified by preparative HPLC (Method 18). 27 mg (98% pure) of further purified title compound was obtained.

[a] _D20 = -47.5°, 589 nm, c = ^0.31 g/100 ml, methanol.

LC-MS (Method 1): R _t = 1.92 min; MS (ESIpos): m/z = 553/555 [M+H]+.

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (3.36), 0.008 (3.27), 1.909 (0.80), 2.054 (0.74), 2.067 (0.89), 2.088 (1.10), 2.114 (4.71 ), 2.130 (4.70), 2.144 (4.68), 2.327 (0.54), 2.670 (0.59), 3.514 (0.89), 3.714 (0.65), 3.733 (1.16), 3.748 (1.58), 3.762 (1.27), 3.782 (0.91 ), 7.054 (2.15), 7.076 (4.00), 7.099 (2.52), 7.332 (0.78), 7.348 (1.00), 7.488 (1.07), 7.501 (3.22), 7.508 (3.48), 7.519 (16.00), 7.835 (1.80 ), 7.840 (1.66), 7.857 (2.81), 7.863 (2.74), 7.928 (5.21), 7.951 (3.25), 8.939 (1.07), 8.954 (1.99), 8.969 (1.07).

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 12.00 (br. s, 1H), 8.95 (t, 1H), 7.94 (d, 1H), 7.85 (dd, 1H), 7.70 (br. s, 1H), 7.56-7.45 (m, 5H), 7.41-7.25 (m, 1H), 7.08 (t, 2H), 3.88-3.67 (m, 2H), 3.51 (br. s, 1H), 2.24- 2.01 (m, 6H), 1.99-1.82 (m, 1H).

Example 183 (+)-5-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-4-(2,6-difluorophenyl)valeric acid (enantiomer 2)

The separation of enantiomers described in Example 181 gave the prepurified title compound as the later eluted enantiomer (ee value 99%). Then further purified by preparative HPLC (Method 14). The combined desired fractions were concentrated and the residue was dried in vacuo. 56 mg (98% pure) of further purified title compound was obtained.

[a] _D ²⁰ = +56.2°, 589 nm, c = 0.38 g/100 ml, methanol LC-MS (Method 2): R _t = 0.99 min; MS (ESIpos): m/z = 553/555 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.882 (0.61), 1.897 (0.80), 1.912 (1.00), 1.952 (0.41), 2.058 (1.06), 2.073 (2.93), 2.089 (1.45) , 2.124 (5.99), 2.140 (7.91), 3.517 (0.98), 3.703 (0.47), 3.717 (0.82) , 7.055 (2.46) , 7.836 (1.87) .

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 12.08 (br. s, 1H), 8.95 (t, 1H), 7.94 (d, 1H), 7.85 (dd, 1H), 7.70 (br . s, 1H), 7.56-7.46 (m, 5H), 7.41-7.29 (m, 1H), 7.08 (t, 2H), 3.87-3.67 (m, 2H), 3.52 (br. s, 1H), 2.21 -2.02 (m, 6H), 1.98-1.83 (m, 1H).

Example 184 (+/-)-5-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-4-(2-chloro-3-fluorophenyl)valeric acid (racemate )

To a solution of (+/-)-tert-butyl-5-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-4-(2chloro-3-fluorophenyl)pentanoate ( 100 mg, 160 μmol, example 255A) in dichloromethane (1.2 ml) was added with TFA (120 μl, 1.6 mmol) and the mixture was left for three days at RT. The mixture was then concentrated and mixed several times with dichloromethane and re-concentrated. The residue was adsorbed into acetonitrile and purified by preparative HPLC (Method 15). The combined target fractions were concentrated and the residue was lyophilized. 78 mg (100% pure, 86% thor.) of the title compound were obtained.

LC-MS (Method 1): R _t = 1.96 min; MS (ESIpos): m/z = 569/571 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.818 (0.64), 1.838 (1.05), 1.858 (1.38), 1.880 (0.81), 2.028 (0.44), 2.049 (0.90), 2.073 (2.99) , 2.085 (1.48), 2.098 (3.43), 2.110 (5.48), 2.140 (5.75), 2.176 (1.34),3.631 (1.74), 3.746 (1.83), 7.283 (0.98), 7.304 (2.11), 7.325 (1.39) . . , 8.869 (2.99), 8.883 (1.46).

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 12.09 (br. s, 1H), 8.87 (t, 1H), 7.94 (d, 1H), 7.85 (dd, 1H), 7.65 (br s, 1H), 7.56-7.47 (m, 5H), 7.46-7.35 (m, 2H), 7.34-7.26 (m, 1H), 3.87-3.35 (m, 3H, partially hidden), 2.23-194 040284

2.00 (m, 6H), 1.93-1.75 (m, 1H).

Example 185 (-)-5-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-4-(2-chloro-3-fluorophenyl)valeric acid (enantiomer 1)

To a solution of (-)-tert-butyl-5-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-4-(2chloro-3-fluorophenyl)pentanoate (275 mg , 439 μmol, example 256A) in dichloromethane (3.7 ml) was added TFA (740 μl, 9.7 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 adsorbed into acetonitrile and purified by preparative HPLC (Method 16). The combined target fractions were concentrated and the residue was lyophilized. 204 mg (100% pure, ee value 96%, 81% thor.) of the title compound were obtained.

[a] _D20 = -18.3°, 589 nm, c = 0.38 ^g /100 ml, methanol.

LC-MS (Method 1): R _t = 1.96 min; MS (ESIpos): m/z = 569/571 [M+H]+.

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 1.818 (0.61), 1.837 (1.07), 1.857 (1.36), 1.879 (0.84), 2.070 (2.64), 2.084 (1.42), 2.097 (3.39 ), 2.109 (5.38), 2.140 (5.93), 3.640 (1.33), 3.745 (1.77), 7.283 (1.02), 7.304 (2.13), 7.326 (1.43), 7.364 (1.63), 7.382 (3.24), 7.400 (1.44 ), 7.419 (1.73), 7.434 (1.48), 7.454 (0.60), 7.491 (1.75), 7.502 (4.64), 7.509 (4.71), 7.522 (16.00), 7.643 (0.42), 7.831 (2.09), 7.836 (2.04 ), 7.853 (3.22), 7.858 (3.21), 7.929 (5.64), 7.952 (3.62), 8.853 (1.50), 8.868 (2.89), 8.881 (1.45), 12.068 (0.80).

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 12.07 (br. s, 1H), 8.87 (t, 1H), 7.94 (d, 1H), 7.84 (dd, 1H), 7.64 (br s, 1H), 7.56-7.47 (m, 5H), 7.46-7.35 (m, 2H), 7.34-7.25 (m, 1H), 3.87-3.55 (m, 3H), 2.22-1.99 (m, 6H) , 1.92-1.76 (m, 1H).

Example 186 (+)-5-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-4-(2-chloro-3-fluorophenyl)valeric acid (enantiomer 2) .

To a solution of (+)-tert-butyl-5-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-4-(2chloro-3-fluorophenyl)pentanoate (290 mg , 463 μmol, example 257A) in dichloromethane (3.9 ml) was added TFA (790 μl, 10 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 adsorbed into acetonitrile and purified by preparative HPLC (Method 16). The combined target fractions were concentrated and the residue was lyophilized. 266 mg (100% pure, ee value 98%, 100% thor.) of the title compound were obtained.

[a] _D20 = +18.0°, 589 nm, c = 0.37 g ^/ 100 mL, methanol.

LC-MS (Method 1): R _t = 1.96 min; MS (ESIpos): m/z = 569/571 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.818 (0.65), 1.838 (1.11), 1.858 (1.42), 1.880 (0.84), 2.029 (0.40), 2.049 (0.92), 2.071 (2.77) , 2.085 (1.40), 2.099 (3.51), 2.110 (5.62), 2.141 (6.00), 2.176 (1.41) 7.364 (1.67), 7.382 (3.38), 7.401 (1.44), 7.419 (1.73), 7.434 (1.50), 7.454 (0.57), 7.479 (0.64), 7.492 (1.68), 7.503 (4.84), 7.510 (4.62) . , 8.870 (3.08), 8.884 (1.51).

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 12.10 (br. s, 1H), 8.87 (t, 1H), 7.94 (d, 1H), 7.85 (dd, 1H), 7.65 (br. s, 1H), 7.56-7.47 (m, 5H), 7.46-7.34 (m, 2H), 7.34-7.26 (m, 1H), 3.87-3.58 (m, 3H, partially hidden), 2.222.00 (m, 6H), 1.93-1.76 (m, 1H).

Example 187 (+/-)-N-[2-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-1-(2-chlorophenyl)ethyl]-N- methylglycine (racemate)

To a solution of (+/-)-tert-butyl-N-[2-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-1(2-chlorophenyl)ethyl] -N-methylglycinate (150 mg, 241 μmol, example 258A) in dichloromethane (1.8 ml) TFA (190 μl, 2.4 mmol) was added 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 adsorbed into acetonitrile and purified by preparative HPLC (Method 16). The combined target fractions were concentrated and the residue was lyophilized. The residue was then mixed with ethyl acetate and saturated sodium hydrogen carbonate solution (respectively 10 ml), shaken and the aqueous phase after phase separation was extracted twice with ethyl acetate (10 ml). The combined organic phases were dried over sodium sulfate, filtered and concentrated and the residue was lyophilized. 106 mg (98% pure, 76% thor.) of the title compound were obtained.

LC-MS (Method 1): R _t = 1.54 min; MS (ESIpos): m/z = 566/568 [M+H] ⁺ .

- 195 040284

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 2.089 (7.35), 2.644 (1.80), 4.062 (0.43), 4.161 (0.56), 5.018 (0.45), 7.434 (1.06), 7.454 (1.84) , 7.473 (1.43), 7.513 (16.00), 7.552 (1.61), 7.572 (1.18), 7.676 (0.54), 7.761 (0.86), 7.778 (0.78), 7.834 (1.30), 7.839 (1.23), 7.856 (2.01) , 7.861 (2.01), 7.926 (3.68), 7.948 (2.25), 8.881 (1.00).

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 8.88 (br. s, 1H), 7.93 (d, 1H), 7.85 (dd, 1H), 7.81-7.73 (m, 1H), 7.68 ( br. s, 1H), 7.56 (br. d, 1H), 7.53-7.40 (m, 7H), 5.02 (br. s, 1H), 4.12 (br. d, 2H), 3.70 (br. d, 2H ), 2.64 (br. s, 3H), 2.09 (s, 3H).

Separation of enantiomers.

The title target compound (70 mg) was dissolved in methanol (10 ml) and separated into enantiomers by chiral phase preparative SLC (see Examples 188 and 189) [column: Daicel Chiralpak AD, 5 μm, 250 mm x 20 mm; flow: 80 ml/min; detection: 210 nm; temperature: 40°C; sample injection: 1.0 ml; eluent: 25% isopropanol/75% carbon dioxide; duration of action 9 min, isocratic]. The combined desired fractions were concentrated and the residue was dried in vacuo.

Example 188 (-)-N-[2-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-1-(2-chlorophenyl)ethyl]-N-methylglycine ( enantiomer 1).

Separation of enantiomers as described in Example 187 yielded 22 mg (98% pure, ee value

99%) of the title compound as the previously eluted enantiomer.

[a] _D20 = -27.9°, 589 nm, c = 0.25 ^g /100 ml, methanol.

LC-MS (Method 2): R _t = 0.81 min; MS (ESIpos): m/z = 566/568 [M+H]+.

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: -0.008 (1.35), 0.008 (1.09), 2.152 (14.46), 2.327 (0.41), 2.362 (16.00), 2.523 (1.06), 3.149 ( 1.90), 3.191 (2.75), 3.353 (4.75), 3.396 (2.42), 3.827 (0.54), 3.979 (0.65), 4.631 (1.23), 4.648 (1.83) ), 7.366 (1.51), 7.384 (2.16), 7.400 (0.94), (3.68), 7.507 (3.24), 7.519 (8.83), 7.524 (8.36), (1.80), 7.600 (1.70), 7.742 (1.68), 7.827 (1.80),

7.310 (0.81), 7.325 (1.95), 7.329 (1.97), 7.344 (1.76), 7.348

7.465 (2.88), 7.468 (2.88), 7.485 (3.05), 7.488 (3.02), 7.500

7.532 (5.29), 7.544 (1.15), 7.577 (2.10), 7.581 (2.12), 7.596

7.832 (1.58), 7.849 (2.77), 7.854 (2.62), 7.923 (4.87), 7.945 (3.12), 8.726 (1.02), 8.741 (2.04), 8.755 (0.99).

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 12.19 (br. s, 1H), 8.74 (t, 1H), 7.93 (d, 1H), 7.84 (dd, 1H), 7.74 (br s, 1H), 7.59 (dd, 1H), 7.56-7.49 (m, 5H), 7.48 (dd, 1H), 7.38 (td, 1H), 7.33 (td, 1H), 4.65 (t, 1H), 3.98 (br. s,

1H), 3.83 (br. s, 1H), 3.37 (d, 1H, partially hidden), 3.17 (d, 2H), 2.36 (s, 3H), 2.15 (s, 3H).

Example 189 (+)-N-[2-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-1-(2-chlorophenyl)ethyl]-N-methylglycine ( enantiomer 2).

Separation of the enantiomers as described in Example 187 gave 19 mg (98% pure, ee value 99%) of the title compound as the later eluted enantiomer.

[a] _D20 = +27.1°, 589 nm, c = 0.25 g ^/ 100 mL, methanol.

LC-MS (Method 2): R _t = 0.81 min; MS (ESIpos): m/z = 566/568 [M+H]+.

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.008 (1.13), 2.152 (14.59), 2.327 (0.43), 2.362 (16.00), 3.149 (1.93), 3.191 (2.73), 3.353 (4.74) . . . , 7.923 (5.10), 7.945 (3.24), 8.727 (1.00), 8.741 (2.02), 8.756 (0.97).

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 12.15 (br. s, 1H), 8.74 (t, 1H), 7.93 (d, 1H), 7.84 (dd, 1H), 7.74 (br s, 1H), 7.59 (dd, 1H), 7.55-7.49 (m, 5H), 7.48 (dd, 1H), 7.38 (td, 1H), 7.33 (td, 1H), 4.65 (t, 1H), 3.98 (br. s, 1H), 3.82 (br. s, 1H), 3.37 (d, 1H, partially hidden), 3.17 (d, 1H), 2.36 (s, 3H), 2.15 (s, 3H).

Example 190 (+/-)-N-[2-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-1-(2-chlorophenyl)ethyl]glycine (racemate )

To a solution of (+/-)-tert-butyl-N-[2-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-1(2-chlorophenyl)ethyl] glycinate (150 mg, 246 μmol, example 259A) in dichloromethane (1.8 ml) TFA (190 μl, 2.5 mmol) was added 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 adsorbed into acetonitrile and purified by preparative HPLC (Method 16). The combined target fractions were concentrated and the residue was lyophilized. The residue was then mixed with ethyl acetate and a saturated solution of hydro-196 040284 sodium carbonate (respectively 10 ml), shaken and the aqueous phase after phase separation was extracted twice with ethyl acetate (10 ml). The combined organic phases were dried over sodium sulfate, filtered and concentrated and the residue was lyophilized. 52 mg (98% pure, 37% thor.) of the title compound were obtained.

LC-MS (Method 1): R _t = 1.47 min; MS (ESIpos): m/z = 552/554 [M+H]+.

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: -0.150 (0.75), 0.146 (0.72), 1.235 (1.11), 1.365 (0.81), 1.876 (0.72), 2.283 (16.00), 2.327 ( 2.01), 2.366 (1.42), 2.670 (1.90), 2.690 (1.92), 2.709 (1.64), 2.731 (2.26) 1.39), 4.302 (2.31), 7.289 (2.79), 7.306 (2.34), 7.345 (2.23), 7.362 (3.21), 7.419 (4.13), 7.438 (3.99), 7.510 (6.94), 7.529 (5.97), 7.41), 7.672 (2.59), 7.690 (2.51), 7.842 (2.51), 7.865 (3.43), 7.903 (3.51), 7.939 (4.32), 7.960 (2.70), 9.456 (1.23).

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 9.46 (br. s, 1H), 7.99-7.81 (m, 3H), 7.68 (br. d, 1H), 7.61-7.25 (m, 9H ), 4.30 (br. s, 1H), 3.67 (br. s, 1H), 3.54 (br. s, 1H), 2.84-2.60 (m, 2H), 2.28 (s, 3H).

Example 191 (+/-)-[2-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-1-(2-chlorophenyl)ethoxy]acetic acid (racemate)

Solution from (+/-)-ethyl-[2-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-1-(2-chlorophenyl)ethoxy]acetate (179 mg , 307 µmol, example 260A) in a mixture of THF (3 ml) and methanol (1 ml) was mixed with 1 M sodium hydroxide solution (1.2 ml, 1.2 mmol) with stirring and the mixture was left for 1.5 h at RT. The mixture was then mixed with TFA (97 μl, 1.3 mmol) and directly (without further processing) purified by preparative HPLC (Method 15). The combined target fractions were concentrated and the residue was lyophilized. 164 mg (100% pure, 96% theoretical) of the title compound were obtained.

LC-MS (Method 1): Rt = 1.97 min; MS (ESIpos): m/z = 553/555 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 2.217 (0.41), 2.263 (16.00), 3.910 (3.67), 3.951 (5.90), 4.039 (6.43), 4.080 (4.00), 5.166 (1.86 ), 5.180 (3.39), 5.194 (1.77), 7.376 (1.03), 7.391 (2.46), 7.395 (2.47), 7.409 (2.68), 7.414 (2.90), 7.421 (2.41), 7.437 (2.78), 7.455 (1.35 ), 7.493 (4.12), 7.496 (4.26), 7.516 (8.14), 7.536 (6.88), 7.558 (7.92), 7.579 (5.24), 7.599 (2.67), 7.824 (2.67), 7.851 (2.45), 7.856 (1.90 ), 7.874 (3.42), 7.879 (2.91), 7.949 (4.95), 7.971 (3.19), 8.946 (1.54), 8.960 (2.80), 8.974 (1.44).

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 12.66 (br. s, 1H), 8.96 (t, 1H), 7.96 (d, 1H), 7.87 (dd, 1H), 7.82 (br . s, 1H), 7.63-7.48 (m, 7H), 7.47-7.35 (m, 2H), 5.18 (t, 1H), 4.06 (d, 1H), 3.94 (d, 1H), 3.79 (br. s , 2H), 2.26 (s, 3H).

Example 192 (+)-[2-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-1-(2-chlorophenyl)ethoxy]acetic acid (enantiomer 1)

Solution from (+)-ethyl-[2-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-1-(2-chlorophenyl)ethoxy]acetate (415 mg, 713 µmol, example 261A) in THF (7.0 ml) and methanol (2.3 ml) at RT was mixed with 1 M sodium hydroxide solution (2.9 ml, 2.9 mmol) and left for 1.5 h at RT. The mixture was then mixed with trifluoroacetic acid (230 μl, 2.9 mmol) and purified directly (without further workup) by preparative HPLC (Method 17). The combined target fractions were concentrated and the residue was lyophilized. 308 mg (100% pure, 99% ee, 78% thor.) of the title compound were obtained.

[a] _D20 = +53.0°, 589 nm, c = 0.46 g/100 mL ^, methanol.

LC-MS (Method 2): Rt = 1.05 min; MS (ESIpos): m/z = 553/555 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (1.47), 2.263 (16.00), 3.783 (2.00), 3.904 (2.71), 3.945 (4.66), 4.035 (5.37), 4.076 (3.05 ), 5.163 (1.64), 5.177 (3.23), 5.191 (1.60), 7.371 (0.76), 7.375 (0.85), 7.390 (2.20), 7.394 (2.26), 7.408 (2.32), 7.413 (2.47), 7.421 (2.04 ), 7.437 (2.44), 7.440 (2.62), 7.455 (1.11), 7.492 (3.62), 7.496 (4.22), 7.514 (7.64), 7.533 (6.13), 7.556 (6.82), 7.560 (5.89), 7.580 (4.34 ), 7.599 (2.27), 7.603 (2.04), 7.822 (2.29), 7.847 (2.38), 7.853 (1.67), 7.870 (3.34), 7.875 (2.84), 7.946 (5.43), 7.968 (3.50), 8.977 (1.70 ), 12.693 (2.36).

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 12.69 (s, 1H), 8.98 (t, 1H), 7.95 (d, 1H), 7.86 (dd, 1H), 7.82 (br. s, 1H), 7.62-7.47 (m, 7H), 7.47-7.36 (m, 2H), 5.18 (t, 1H), 4.05 (d, 1H), 3.93 (d, 1H), 3.78 (br. s, 2H) , 2.26(s, 3H).

Example 193 (-)-[2-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-1-(2-chlorophenyl)ethoxy]acetic acid (enantiomer 2)

Solution from (-)-ethyl-[2-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-1-(2-chlorophenyl)ethoxy]acetate (390 mg, 670 µmol, example 262A) in THF (6.5 ml) and methanol (2.2 ml) at RT was mixed with 1 M sodium hydroxide solution (2.7 ml, 2.7 mmol) and left for 1.5 h at RT. The mixture was then mixed with trifluoroacetic acid (210 μl, 2.7 mmol) and purified directly (without further workup) by preparative HPLC (Method 17). The combined target fractions were concentrated and the residue was lyophilized. 307 mg (100% pure, ee value 99%, 83% thor.) of the title compound were obtained.

[a] _D20 = -54.3°, 589 nm, c = 0.44 ^g /100 ml, methanol.

LC-MS (Method 2): R _t = 1.05 min; MS (ESIpos): m/z = 553/555 [M+H]+.

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 0.008 (1.08), 2.263 (16.00), 3.783 (1.96), 3.905 (2.66), 3.946 (4.56), 4.036 (5.22), 4.077 (2.98 ), 5.163 (1.60), 5.177 (3.16), 5.191 (1.54), 7.371 (0.78), 7.376 (0.89), 7.390 (2.23), 7.395 (2.31), 7.409 (2.37), 7.414 (2.54), 7.422 (2.07 ), 7.437 (2.40), 7.440 (2.66), 7.455 (1.10), 7.492 (3.75), 7.496 (4.41), 7.514 (7.86), 7.534 (6.17), 7.556 (7.02), 7.560 (6.04), 7.580 (4.26 ), 7.599 (2.27), 7.603 (2.05), 7.822 (2.33), 7.848 (2.53), 7.853 (1.75), 7.870 (3.52), 7.875 (2.97), 7.946 (5.67), 7.968 (3.63), 8.961 (1.03 ), 8.975 (1.90), 8.989 (0.98), 12.693 (2.11).

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 12.69 (br. s, 1H), 8.97 (t, 1H), 7.95 (d, 1H), 7.86 (dd, 1H), 7.82 (br s, 1H), 7.62-7.48 (m, 7H), 7.47-7.36 (m, 2H), 5.18 (t, 1H), 4.05 (d, 1H), 3.93 (d, 1H), 3.78 (br. s , 2H), 2.26 (s, 3H).

Example 194 (+/-)-{[2-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-1-(2-chlorophenyl)ethyl]sulfanyl}acetic acid (racemate)

Solution from (+/-)-methyl-{[2-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-1-(2chlorophenyl)ethyl]sulfanyl}acetate (388 mg, 87% pure, 578 µmol, example 263A) in THF (4.9 ml) and methanol (2.5 ml) at RT was mixed with 1M sodium hydroxide solution (3.5 ml, 3.5 mmol) and stirred for 16 h at RT. The mixture was then directly (without further workup) purified by preparative HPLC (Method 19). The combined target fractions were concentrated and the residue was lyophilized. 310 mg (98% pure, 92% thor.) of the title compound were obtained.

LC-MS (Method 2): Rt = 1.06 min; MS (ESIpos): m/z = 569/571 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 2.073 (0.84), 2.147 (8.51), 3.201 (3.59), 3.239 (5.50), 3.357 (5.53), 3.395 (3.63), 3.986 (2.19) , 4.816 (1.34), 4.835 (2.38), 4.854 (1.22), 7.306 (0.88), 7.324 (2.07), 7.342 (1.55), 7.385 (1.44), 7.404 (2.33), 7.421 (1.11), 7.473 (3.71) . . .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 12.65 (br. s, 1H), 9.04 (t, 1H), 7.94 (d, 1H), 7.84 (dd, 1H), 7.78 (br. s, 1H), 7.62 (dd, 1H), 7.55-7.46 (m, 6H), 7.40 (t, 1H), 7.33 (t, 1H), 4.84 (t, 1H), 3.99 (br. s, 2H) , 3.37 (d, 1H), 3.22 (d, 1H), 2.15 (s, 3H).

Separation of enantiomers.

The title target compound (250 mg) was dissolved in methanol (15 ml) and separated into enantiomers by preparative SLC on a chiral phase (see examples 195 and 196) [column: Daicel AD-H, 5 μm, 250 mm x 20 mm ; flow: 80 ml/min; detection: 210 nm; temperature: 40°C; sample injection: 0.5 ml; eluent: 25% isopropanol/75% carbon dioxide; duration of action 13.2 min, isocratic]. The combined target fractions were concentrated and the residue was lyophilized.

Example 195 (+)-{[2-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-1-(2-chlorophenyl)ethyl]sulfanyl}acetic acid (enantiomer 1).

The separation of enantiomers described in Example 194 gave 110 mg (98% pure, ee value 99%) of the title compound as the previously eluted enantiomer.

[a] _D20 = +22.8°, 589 nm, c = 0.25 g ^/ 100 mL, methanol.

LC-MS (Method 1): R _t = 1.97 min; MS (ESIpos): m/z = 569/571 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: -0.008 (0.70), 1.030 (0.60), 1.046 (0.60), 2.059 (0.59), 2.073 (0.43), 2.145 (8.31), 2.523 ( 0.40), 3.199 (3.42), 3.236 (5.29), 3.353 (5.58), 3.391 (3.45), 3.582 (0.55), 3.983 (1.61), 4.812 (1.30), 4.831 (2.31), 4.850 (1.17), 7.305 ( 0.86) 16.00) 3.38), 9.025 (1.18), 9.040 (2.35), 9.054 (1.21).

- 198 040284

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 12.65 (br. s, 1H), 9.04 (t, 1H), 7.93 (d, 1H), 7.84 (dd, 1H), 7.77 (br s, 1H), 7.62 (d, 1H), 7.55-7.45 (m, 6H), 7.40 (t, 1H), 7.33 (t, 1H), 4.83 (t, 1H), 3.98 (br. s, 2H ), 3.37 (d, 1H),

3.22 (d, 1H), 2.15 (s, 3H).

Example 196 (-)-{[2-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-1-(2-chlorophenyl)ethyl]sulfanyl}acetic acid (enantiomer 2).

The separation of enantiomers described in Example 194 gave 70 mg (98% pure, ee value 99%) of the title compound as the later eluted enantiomer.

[a] _D20 = -25.4°, 589 nm, c = 0.28 ^g /100 ml, methanol.

LC-MS (Method 1): R _t = 1.97 min; MS (ESIpos): m/z = 569/571 [M+H]+.

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: -0.008 (1.20), 0.008 (0.96), 1.151 (0.48), 2.058 (0.42), 2.146 (8.57), 2.523 (0.60), 3.194 ( 3.65), 3.232 (5.76), 3.344 (6.61), 3.382 (3.69), 3.980 (1.60), 4.806 (1.31), 4.825 (2.35), 4.844 (1.18), 7.304 (0.87), 7.322 (2.08), 1.56) 16.00), 7.527 (5.22), 7.530 (4.79), 7.605 (2.60), 7.622 (2.20), 7.776 (0.56), 7.828 (2.40), 7.833 (1.99), 7.850 (3.49), 7.856 (3.13), 7.925 ( 5.97), 7.948 (3.77), 9.041 (1.14), 9.055 (2.19), 9.069 (1.09).

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 12.69 (br. s, 1H), 9.06 (t, 1H), 7.93 (d, 1H), 7.84 (dd, 1H), 7.78 (br . s, 1H), 7.61 (dd, 1H), 7.56-7.45 (m, 6H), 7.40 (t, 1H), 7.32 (t, 1H), 4.83 (t, 1H), 3.98 (br. s, 2H ), 3.36 (d, 1H), 3.22 (d, 1H), 2.15 (s, 3H).

Example 197 (+/-)-{[2-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-1-(2-chlorophenyl)ethyl]sulfonyl}acetic acid (racemate)

To a solution of (+/-)-methyl-{[2-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-1-(2chlorophenyl)ethyl]sulfonyl}acetate ( 50 mg, 93% pure, 75.5 µmol, example 264A) in THF (740 µl) and methanol (250 µl) was added 1M sodium hydroxide solution (300 µl, 300 µmol) and the mixture was left for 16 h at RT. The mixture was then directly (without further workup) purified by preparative HPLC (Method 17). The combined target fractions were concentrated and the residue was lyophilized. 40 mg (98% pure, 86% thor.) of the title compound were obtained.

LC-MS (Method 1): R _t = 1.86 min; MS (ESIpos): m/z = 601/603 [M+H] ⁺ .

'H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 9.23 (br. s, 1H), 7.92 (d, 1H), 7.83 (dd, 1H), 7.76-7.57 (m, 2H), 7.56-7.38 (m, 8H), 5.87 (t, 1H), 4.42-4.18 (m, 3H), 4.00-3.83 (m, 1H), 2.01 (br. s, 3H).

Separation of enantiomers.

The title title compound (35 mg) was dissolved in a mixture of ethanol (1 ml) and dichloromethane (2 ml) and separated into enantiomers by chiral phase preparative HPLC (see Examples 198 and 199) [column: Daicel Chiralpak IF, 5 µm, 250 mm x 20 mm; flow: 15 ml/min; detection: 220 nm; temperature: 35°C; sample injection: 0.50 ml; eluent: 60% heptane/40% (ethanol + 0.2% TFA); duration of action 12 min, isocratic]. The combined target fractions were concentrated and the residue was lyophilized.

Example 198 (+)-{[2-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-1-(2-chlorophenyl)ethyl]sulfonyl}acetic acid (enantiomer 1).

Separation of the enantiomers as described in Example 197 gave the prepurified title compound as the previously eluted enantiomer (ee value 99%). Then further purified by preparative HPLC (Method 18). The combined desired fractions were concentrated and the residue was dried in vacuo. 23 mg (95% pure, containing solvent laut 1H-NMR) of additionally purified title compound was obtained.

[a] _D20 = +17.2°, 589 nm, c = 0.25 g ^/ 100 mL, methanol.

LC-MS (Method 1): R _t = 1.78 min; MS (ESIpos): m/z = 601/603 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 9.32 (s, 1H), 7.91 (d, 1H), 7.83 (dd, 1H), 7.75 (d, 1H), 7.56-7.37 (m, 9H), 6.02-5.93 (m, 1H), 4.41-4.15 (m, 2H), 3.91 (d, 1H), 3.56 (d, 1H), 2.03 (br. s, 3H).

Example 199 {[2-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-1-(2-chlorophenyl)ethyl]sulfonyl}acetic acid (enantiomer 2)

The separation of enantiomers described in Example 197 gave the prepurified title compound as the later eluted enantiomer (ee value 99%). Then further purified by preparative HPLC (Method 18). United Target Fractions

- 199 040284 was concentrated and the residue was dried in vacuo. 23 mg (95% pure) of further purified title compound was obtained.

LC-MS (Method 1): R _t = 1.78 min; MS (ESIpos): m/z = 601/603 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 9.42-9.32 (m, 1H), 7.91 (d, 1H), 7.82 (dd, 1H), 7.75 (d, 1H), 7.567.31 ( m, 9H), 5.98 (dd, 1H), 4.44-4.28 (m, 1H), 4.26-4.14 (m, 1H), 3.87 (d, 1H), 3.52 (d, 1H), 2.04 (br. s, 3H).

Example 200 (+/-)-5-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-4-(6-chloro-2,3-difluorophenyl)valeric acid (racemate)

To a solution of (+/-)-tert-butyl-5-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-4-(6chloro-2,3-difluorophenyl) pentanoate (121 mg, 188 µmol, example 265A) in dichloromethane (1.6 ml) TFA (320 µl, 4.1 mmol) was added 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 adsorbed into acetonitrile and purified by preparative HPLC (Method 15). The combined target fractions were concentrated and the residue was lyophilized. 81 mg (100% pure, 73% theoretical) of the title compound were obtained.

LC-MS (Method 2): Rt = 1.05 min; MS (ESIpos): m/z = 587/589 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 0.008 (0.62), 1.988 (0.64), 2.073 (0.98), 2.084 (1.18), 2.103 (1.23), 2.121 (2.06), 2.156 (10.15 ), 2.183 (2.38), 2.206 (0.95), 2.524 (0.67), 3.730 (1.05), 3.766 (0.80), 3.814 (1.72), 7.350 (0.69), 7.373 (2.16), 7.384 (2.42), 7.406 (1.29 ), 7.426 (1.00), 7.491 (1.49), 7.502 (4.34), 7.510 (4.30), 7.521 (16.00), 7.532 (5.94), 7.838 (2.39), 7.844 (2.04), 7.861 (3.68), 7.866 (3.33 ), 7.933 (6.34), 7.955 (3.93), 8.940 (1.24), 8.954 (2.38), 8.968 (1.16).

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 12.10 (br. s, 1H), 8.95 (br. t, 1H), 7.94 (d, 1H), 7.86 (dd, 1H), 7.72 ( br. s, 1H), 7.57-7.46 (m, 5H), 7.46-7.32 (m, 2H), 3.96-3.61 (m, 3H), 2.27-1.85 (m, 7H).

Example 201 (-)-5-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-4-(6-chloro-2,3-difluorophenyl)valeric acid (enantiomer 1).

To a solution of (-)-tert-butyl-5-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-4-(6chloro-2,3-difluorophenyl)pentanoate ( 140 mg, 217 μmol, example 266A) in dichloromethane (3.8 ml) was added TFA (170 μl, 2.2 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 adsorbed into acetonitrile and purified by preparative HPLC (Method 14). The combined target fractions were concentrated and the residue was lyophilized. 93 mg (98% pure, 99% ee, 71% thor.) of the title compound were obtained.

[a] _D20 = -31.6°, 589 nm, c = ^0.25 g/100 ml, methanol.

LC-MS (Method 1): Rt = 2.08 min; MS (ESIpos): m/z = 587/569 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.991 (0.63), 2.071 (0.93), 2.083 (1.12), 2.102 (1.18), 2.118 (1.94), 2.156 (10.24), 2.179 (2.39) 3.730 (1.04), 3.766 (0.82), 3.813 (1.70), 7.372 (2.13), 7.384 (2.40), 7.405 (1.29), 7.426 (1.00), 7.491 (1.42), 7.502 (4.04), 7.509 (3.99) , 7.521 (16.00), 7.838 (2.18), 7.843 (2.00), 7.861 (3.31), 7.866 (3.21), 7.932 (5.89), 7.955 (3.64), 8.940 (1.16), 8.955 (2.24), 8.969 (1.13) .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 12.11 (br. s, 1H), 8.96 (t, 1H), 7.94 (d, 1H), 7.85 (dd, 1H), 7.72 (br. s, 1H), 7.55-7.46 (m, 5H), 7.46-7.33 (m, 2H), 3.92-3.63 (m, 3H), 2.28-1.82 (m, 7H).

Example 202 (+)-5-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-4-(6-chloro-2,3-difluorophenyl)valeric acid (enantiomer 2).

To a solution of (+)-tert-butyl-5-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-4-(6chloro-2,3-difluorophenyl)pentanoate ( 145 mg, 225 µmol, example 267A) in dichloromethane (4.0 ml) was added TFA (170 µl, 2.3 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 adsorbed into acetonitrile and purified by preparative HPLC (Method 14). The combined target fractions were concentrated and the residue was lyophilized. 94 mg (98% pure, 93% ee, 70% thor.) of the title compound were obtained.

[a] _D20 = +34.9°, 589 nm, c = 0.28 g ^/ 100 mL, methanol.

LC-MS (Method 1): R _t = 2.08 min; MS (ESIpos): m/z = 587/589 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.153 (0.91), 1.180 (0.64), 1.992 (0.63), 2.074 (0.95), 2.087 (1.14), 2.105 (1.16), 2.125 (1.89) , 2.156 (10.43), 2.188 (2.43), 2.210 (0.95), 3.731 (1.05), 3.768 (0.82), 3.815

- 200 040284 (1.72), 7.373 (2.18), 7.385 (2.46), 7.406 (1.30), 7.428 (1.04), 7.492 (1.55), 7.503 (4.33), 7.510 (4.32), 7.522 (16.00), 7.532 (6.01) ), 7.840 (2.40), 7.845 (2.15), 7.862 (3.65), 7.867 (3.48), 7.934 (6.44), 7.956 (3.98), 8.940 (1.22), 8.955 (2.34), 8.969 (1.15).

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 12.08 (br. s, 1H), 8.95 (t, 1H), 7.94 (d, 1H), 7.86 (dd, 1H), 7.72 (br. s, 1H), 7.55-7.47 (m, 5H), 7.45-7.33 (m, 2H), 3.93-3.62 (m, 3H), 2.28-1.87 (m, 7H).

Example 203 (+/-)-5-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-4-[2-(trifluoromethyl)phenyl]valeric acid (racemate)

To a solution of (+/-)-methyl-5-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-4-[2-(trifluoromethyl)phenyl]pentanoate (500 mg, 96% pure, 801 µmol, example 268A) in THF (7.8 ml) and methanol (2.6 ml) was added 1M sodium hydroxide solution (3.2 ml, 3.2 mmol) and the mixture was left for 16 h at RT. The mixture was then directly (without further workup) purified by preparative HPLC (Method 17). The combined target fractions were concentrated and the residue was lyophilized. 415 mg (98% pure, 87% theoretical) of the title compound were obtained.

LC-MS (Method 2): Rt = 1.09 min; MS (ESIpos): m/z = 585/587 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (3.38), 0.008 (2.76), 1.667 (1.46), 1.681 (1.85), 1.691 (2.53), 1.714 (2.17), 1.725 (1.83 ), 1.758 (0.78), 1.780 (1.28), 1.820 (5.23), 1.832 (2.78), 1.844 (2.63), 1.856 (1.82), 1.879 (0.92), 1.968 (1.06), 1.982 (1.59), 1.996 (1.85 ), 2.014 (1.74), 2.026 (2.03), 2.179 (5.86), 2.258 (0.88), 2.328 (0.58), 2.366 (0.51), 2.670 (0.56), 2.710 (0.46), 3.606 (1.44), 3.622 (1.90 ), 3.638 (2.00), 3.719 (1.35), 3.735 (2.21), 3.751 (2.00), 3.767 (1.50), 7.426 (1.77), 7.440 (3.06), 7.458 (2.01), 7.472 (1.21), 7.476 (1.17 ), 7.488 (3.64), 7.499 (5.24), 7.504 (11.48), 7.509 (8.35), 7.523 (13.20), 7.542 (16.00), 7.561 (4.59), 7.661 (1.58), 7.681 (7.35), 7.694 (15.24) ), 7.710 (6.12), 7.826 (4.03), 7.831 (3.77), 7.849 (6.03), 7.854 (5.92), 7.929 (10.87), 7.952 (7.22), 9.401 (2.02).

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 9.40 (br. s, 1H), 7.94 (d, 1H), 7.84 (dd, 1H), 7.80-7.58 (m, 4H), 7.57 -7.39 (m, 6H), 3.81-3.69 (m, 1H), 3.68-3.55 (m, 1H), 3.37-3.24 (m, 1H, hidden), 2.18 (br. s, 3H), 2.061.94 ( m, 1H), 1.91-1.75 (m, 2H), 1.74-1.60 (m, 1H).

Separation of enantiomers.

The title target compound (380 mg) was adsorbed in methanol (30 ml), filtered and separated into enantiomers by preparative SLC on a chiral phase (see examples 204 and 205) [column: Daicel Chiralcel AD-H, 5 μm, 250 mm x 20 mm; flow: 80 ml/min; sample injection: 0.50 ml; eluent: 25% isopropanol/75% carbon dioxide; duration of action 6 min, isocratic]. The combined target fractions were concentrated and the residue was lyophilized.

Example 204 (-)-5-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-4-[2-(trifluoromethyl)phenyl]valeric acid (enantiomer 1)

Separation of enantiomers as described in Example 203 gave 122 mg (98% pure, ee value 99%) of the title compound as the previously eluted enantiomer.

[a] _D20 = -21.3°, 589 nm, c = 0.29 ^g /100 ml, methanol.

LC-MS (Method 1): Rt = 2.11 min; MS (ESIpos): m/z = 585/587 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (1.59), 0.008 (1.00), 1.030 (1.73), 1.046 (1.73), 1.876 (2.12), 1.889 (2.92), 1.904 (2.98) ), 1.926 (2.60), 1.983 (1.27), 2.004 (2.14), 2.027 (2.52), 2.042 (1.42), 2.063 (2.62), 2.084 (1.71), 2.097 (1.99), 2.105 (2.02), 2.164 (4.49 ), 2.248 (0.63), 2.328 (0.41), 2.524 (1.71), 2.670 (0.40), 3.625 (1.75), 3.643 (2.03), 3.657 (2.01), 3.762 (2.00), 3.778 (1.81), 3.794 (1.41 ), 7.446 (1.79), 7.465 (3.56), 7.488 (4.35), 7.499 (5.24), 7.504 (8.90), 7.510 (7.19), 7.523 (13.11), 7.536 (16.00), 7.555 (3.03), 7.624 (0.60 ), 7.678 (2.04), 7.698 (4.60), 7.711 (6.35), 7.729 (8.88), 7.748 (2.18), 7.830 (3.68), 7.836 (3.32), 7.853 (5.27), 7.858 (4.94), 7.934 (9.75 ), 7.956 (6.33), 8.991 (2.64).

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 8.99 (br. t, 1H), 7.94 (d, 1H), 7.84 (dd, 1H), 7.78-7.57 (m, 4H), 7.57- 7.42 (m, 6H), 3.85-3.72 (m, 1H), 3.70-3.59 (m, 1H), 3.37-3.27 (m, 1H, partially hidden), 2.23-1.96 (m, 5H), 1.95-1.83 ( m, 2H).

Example 205 (+)-5-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-4-[2-(trifluoromethyl)phenyl]valeric acid (enantiomer 2)

The separation of enantiomers described in Example 203 gave 109 mg (98% pure, ee value 98%) of the title compound as the later eluted enantiomer.

[a] _D20 = +22.7°, 589 nm, c = 0.37 g ^/ 100 mL, methanol.

- 201 040284

LC-MS (Method 1): R _t = 2.11 min; MS (ESIpos): m/z = 585/587 [M+H]+.

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: -0.008 (0.81), 1.031 (3.90), 1.046 (3.97), 1.858 (0.66), 1.889 (1.78), 1.909 (2.85), 1.926 ( 2.61), 1.938 (1.68), 1.949 (2.14), 2.004 (1.36), 2.023 (2.06), 2.046 (2.38), 2.062 (1.51), 2.080 (2.49), 2.109 (1.99), 2.118 (2.20), 4.52), 2.250 (0.57), 3.631 (1.49), 3.648 (1.82), 3.664 (1.87), 3.766 (1.88), 3.774 (1.80), 3.782 (1.72), 3.799 (1.33), 7.450 (1.66), 3.74), 7.489 (4.62), 7.505 (8.38), 7.511 (6.77), 7.524 (12.77), 7.537 (16.00), 7.555 (3.12) 6.05), 7.734 (8.49), 7.755 (2.27), 7.832 (3.52), 7.837 (3.31), 7.854 (5.18), 7.859 (5.12), 7.935 (9.70), 7.957 (6.31), 8.942 (1.72) 3.21), 8.969 (1.68).

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 8.96 (t, 1H), 7.94 (d, 1H), 7.85 (dd, 1H), 7.78-7.58 (m, 4H), 7.577.43 ( m, 6H), 3.85-3.72 (m, 1H), 3.71-3.59 (m, 1H), 3.38-3.29 (m, 1H), 2.23-1.99 (m, 5H), 1.98-1.82 (m, 2H).

Example 206 (+/-)-5-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-4-(5-fluoro-2-methylphenyl)valeric acid (racemate )

To a solution of (+/-)-tert-butyl-5-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-4-(5fluoro-2-methylphenyl)pentanoate ( 122 mg, 202 µmol, example 269A) in dichloromethane (1.7 ml) was added with TFA (340 µl, 4.4 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 adsorbed into acetonitrile and purified by preparative HPLC (Method 15). The combined target fractions were concentrated and the residue was lyophilized. 91 mg (100% pure, 82% thor.) of the title compound were obtained.

LC-MS (Method 2): R _t = 1.05 min; MS (ESIpos): m/z = 549/551 [M+H]+.

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (0.76), 0.969 (0.40), 1.773 (0.79), 1.788 (0.99), 1.796 (1.02), 1.807 (1.15), 1.812 (1.15) ), 1.830 (0.89), 1.845 (0.48), 1.981 (0.45), 2.001 (1.09), 2.013 (1.39), 2.032 (1.49), 2.051 (1.65), 2.080 (5.67), 2.096 (8.09), 2.112 (4.66 ), 2.295 (14.18), 2.524 (0.71), 3.505 (0.93), 3.518 (1.31), 3.538 (1.41), 3.552 (1.61), 3.565 (0.95), 3.724 (0.98), 3.743 (1.45), 3.762 (1.27 ), 3.776 (1.15), 3.796 (0.69), 6.920 (0.96), 6.941 (1.82), 6.957 (1.03), 7.156 (2.15), 7.162 (2.21), 7.183 (2.42), 7.190 (4.02), 7.207 (2.52 ), 7.211 (2.39), 7.227 (1.87), 7.478 (0.56), 7.491 (1.66), 7.501 (4.98), 7.509 (4.71), 7.520 (16.00), 7.531 (7.07), 7.648 (0.56), 7.833 (2.49 ), 7.838 (2.35), 7.855 (3.81), 7.860 (3.73), 7.932 (6.89), 7.954 (4.42), 8.836 (1.61), 8.852 (2.38), 8.865 (1.56).

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 12.06 (br. s, 1H), 8.85 (t, 1H), 7.94 (d, 1H), 7.85 (dd, 1H), 7.65 (br s, 1H), 7.56-7.45 (m, 5H), 7.24-7.13 (m, 2H), 6.94 (td, 1H), 3.76 (td, 1H), 3.54 (td, 1H), 3.42-3.30 (1H , hidden), 2.30 (s, 3H), 2.16-1.96 (m, 6H), 1.87-1.73 (m, 1H).

Example 207 (-)-5-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-4-(5-fluoro-2-methylphenyl)valeric acid (enantiomer 1) .

To a solution of (-)-tert-butyl-5-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-4-(5fluoro-2-methylphenyl)pentanoate (112 mg , 185 μmol, example 270A) in dichloromethane (1.6 ml) was added TFA (310 μl, 4.1 mmol) and the mixture was left 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 17). The combined target fractions were concentrated and the residue was lyophilized. 95 mg (100% pure, ee 99, 93% thor.) of the title compound were obtained.

[a] _D20 = -20.0°, 589 nm, c = 0.34 g ^/ 100 ml, methanol.

LC-MS (Method 1): R _t = 1.98 min; MS (ESIpos): m/z = 549/551 [M+H]+.

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 0.008 (1.08), 1.769 (0.75), 1.784 (1.00), 1.792 (1.01), 1.807 (1.16), 1.822 (0.89), 1.841 (0.49 ), 1.976 (0.49), 1.996 (1.09), 2.009 (1.38), 2.028 (1.46), 2.036 (1.15), 2.046 (1.73), 2.073 (5.26), 2.089 (7.14), 2.105 (5.18), 2.294 (14.25 ), 3.503 (0.90), 3.516 (1.28), 3.537 (1.37), 3.550 (1.61), 3.564 (0.94), 3.724 (0.98), 3.742 (1.45), 3.762 (1.25), 3.775 (1.14), 3.796 (0.69 ), 6.918 (0.95), 6.939 (1.84), 6.954 (1.05), 7.154 (2.15), 7.160 (2.16), 7.181 (2.40), 7.188 (3.89), 7.205 (2.56), 7.209 (2.38), 7.226 (1.89 ), 7.477 (0.54), 7.490 (1.62), 7.500 (4.98), 7.508 (4.63), 7.520 (16.00), 7.531 (7.15), 7.647 (0.58), 7.832 (2.54), 7.837 (2.31), 7.854 (3.87 ), 7.859 (3.68), 7.931 (6.92), 7.953 (4.45), 8.838 (1.58), 8.853 (2.39), 8.866 (1.54).

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 12.11 (br. s, 1H), 8.85 (t, 1H), 7.94 (d, 1H), 7.85 (dd, 1H), 7.65 (br. s, 1H), 7.56-7.44 (m, 5H), 7.25-7.11 (m, 2H), 6.94 (td, 1H), 3.82-3.69 (m, 1H), 3.59-3.48 (m, 1H), 3.4- 3.3 (1H, hidden), 2.29 (s, 3H), 2.18-1.95 (m, 6H), 1.86-1.73 (m, 1H).

- 202 040284

Example 208 (+)-5-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-4-(5-fluoro-2-methylphenyl)valeric acid (enantiomer 2) .

To a solution of (+)-tert-butyl-5-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-4-(5fluoro-2-methylphenyl)pentanoate (110 mg , 182 µmol, example 271A) in dichloromethane (1.5 ml) was added TFA (310 µl, 4.0 mmol) and the mixture was left 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 17). The combined target fractions were concentrated and the residue was lyophilized. 93 mg (100% pure, 97% ee, 93% thor.) of the title compound were obtained.

[a] _D20 = +16.3°, 589 nm, c = 0.37 g ^/ 100 mL, methanol.

LC-MS (Method 1): R _t = 1.98 min; MS (ESIpos): m/z = 549/551 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.069 (0.42), 1.771 (0.79), 1.787 (1.01), 1.794 (1.04), 1.805 (1.19), 1.825 (0.92), 1.843 (0.50) , 1.979 (0.49), 1.998 (1.12), 2.012 (1.42), 2.030 (1.52), 2.049 (1.74) , 3.517 (1.27), 3.537 (1.36), 3.551 (1.60), 3.565 (0.93), 3.724 (0.97), 3.742 (1.47), 3.761 (1.28), 3.775 (1.15), 3.796 (0.67), 6.919 (1.00) , 6.939 (1.89), 6.956 (1.07), 7.155 (2.18), 7.161 (2.23), 7.189 (4.00), 7.206 (2.58), 7.226 (1.83), 7.476 (0.63), 7.490 (1.71), 7.500 (5.00) , 7.508 (4.64), 7.520 (16.00), 7.647 (0.60), 7.832 (2.38), 7.837 (2.20), 7.854 (3.59), 7.859 (3.49), 7.931 (6.51), 7.953 (4.17), 8.837 (1.60) , 8.851 (2.45), 8.865 (1.55).

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 12.08 (br. s, 1H), 8.85 (t, 1H), 7.94 (d, 1H), 7.85 (dd, 1H), 7.65 (br. s, 1H), 7.56-7.45 (m, 5H), 7.25-7.13 (m, 2H), 6.94 (td, 1H), 3.82-3.68 (m, 1H), 3.60-3.48 (m, 1H), 3.4- 3.3 (1H, hidden), 2.29 (s, 3H), 2.19-1.95 (m, 6H), 1.86-1.71 (m, 1H).

Example 209 (+/-)-5-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-4-[2-(trifluoromethoxy)phenyl]valeric acid (racemate)

To a solution of (+/-)-tert-butyl-5-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-4-[2(trifluoromethoxy)phenyl]pentanoate ( 250 mg, 380 µmol, example 272A) in dichloromethane (5.0 ml) was added TFA (290 µl, 3.8 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 adsorbed into acetonitrile and purified by preparative HPLC (Method 14). The combined target fractions were concentrated and the residue was lyophilized. 192 mg (98% pure, 82% thor.) of the title compound were obtained.

LC-MS (Method 1): Rt = 2.15 min; MS (ESIpos): m/z = 601/603 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.826 (1.37), 1.836 (1.46), 1.847 (1.91), 1.870 (1.28), 2.054 (2.96), 2.062 (2.63), 2.082 (10.68) , 2.109 (2.89), 2.146 (4.05), 2.525 (1.39), 3.412 (2.61), 3.627 (0.95) . , 7.437 (1.32) , 7.565 (3.86), 7.581 (2.94), 7.588 (2.71), 7.655 (0.64), 7.835 (3.21), 7.841 (2.87), 7.858 (4.67), 7.863 (4.30), 7.934 (8.58), 7.957 (5.43) , 8.864 (2.03), 8.879 (3.53), 8.893 (1.77).

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 12.07 (br. s, 1H), 8.88 (t, 1H), 7.94 (d, 1H), 7.85 (dd, 1H), 7.66 (br s, 1H), 7.60-7.46 (m, 6H), 7.45-7.31 (m, 3H), 3.86-3.56 (m, 2H), 3.48-3.33 (m, 1H, partially hidden), 2.251.97 (m , 6H), 1.91–1.76 (m, 1H).

Example 210 (+)-5-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-4-[2-(trifluoromethoxy)phenyl]valeric acid (enantiomer 1)

To a solution of (+)-tert-butyl-5-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-4-[2(trifluoromethoxy)phenyl]pentanoate (1.00 g , 1.52 mmol, example 273A) in dichloromethane (10 ml) was added TFA (1.2 ml, 15 mmol) and the mixture was left 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 19). The combined target fractions were concentrated and the residue was lyophilized. 782 mg (98% pure, 94% theoretical) of the title compound were obtained.

[a] _D20 = +20.8°, 589 nm, c = 0.30 g ^/ 100 mL, methanol.

LC-MS (Method 1): Rt = 2.08 min; MS (ESIpos): m/z = 601/603 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: -0.008 (1.23), 0.008 (1.09), 1.827 (1.38), 1.838 (1.41), 1.849 (1.97), 1.872 (1.34), 2.058 ( 2.52), 2.074 (4.27), 2.086 (11.66), 2.112 (2.61), 2.146 (3.88), 2.333 (0.49), 3.415

- 203 040284 (1.70), 3.429 (1.69), 3.628 (1.61), 3.643 (2.22), 3.661 (3.30), 3.677 (3.96), 3.692 (3.02), 3.703 (3.03), 3.720 (3.62), 3.738 (3.22) ), 3.754 (2.28), 3.772 (1.71), 7.341 (1.76), 7.360 (3.77), 7.381 (1.51), 7.400 (4.95), 7.410 (4.07), 7.419 (4.86), 7.437 (1.15), 7.479 (0.88 ), 7.490 (2.03), 7.504 (6.72), 7.511 (5.87), 7.524 (16.00), 7.529 (14.91), 7.536 (9.93), 7.548 (2.26), 7.566 (3.87), 7.582 (3.03), 7.589 (2.94 ), 7.658 (0.62), 7.837 (3.15), 7.842 (2.93), 7.859 (4.76), 7.864 (4.68), 7.935 (9.45), 7.958 (6.02), 8.862 (1.93), 8.877 (3.73), 8.891 (1.94 ).

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 12.11 (br. s, 1H), 8.88 (t, 1H), 7.94 (d, 1H), 7.85 (dd, 1H), 7.66 (br s, 1H), 7.60-7.47 (m, 6H), 7.45-7.31 (m, 3H), 3.79-3.61 (m, 2H), 3.47-3.37 (m, 1H), 2.24-1.99 (m, 6H) , 1.92-1.75 (m, 1H).

Example 211 (-)-5-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-4-[2-(trifluoromethoxy)phenyl]valeric acid (enantiomer 2)

To a solution of (-)-tert-butyl-5-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-4-[2(trifluoromethoxy)phenyl]pentanoate (1.00 g , 1.52 mmol, example 274A) in dichloromethane (9.4 ml) was added TFA (1.2 ml, 15 mmol) and the mixture was left 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 19). The combined target fractions were concentrated and the residue was lyophilized. 726 mg (98% pure, 78% thor.) of the title compound were obtained.

[a] _D20 = -18.6°, 589 nm, c = 0.34 ^g /100 ml, methanol.

LC-MS (Method 2): Rt = 1.10 min; MS (ESIpos): m/z = 601/603 [M+H]+.

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: -0.008 (2.09), 0.008 (1.21), 1.814 (0.89), 1.825 (1.42), 1.837 (1.47), 1.848 (1.95), 1.871 ( 1.29), 2.019 (0.40), 2.058 (2.85), 2.063 (2.58), 2.085 (11.46), 2.112 (2.86), 2.145 (3.97), 3.627 (0.89), 3.642 (1.34), 3.661 (2.18), 2.64) 3.12) 7.523 (16.00), 7.528 (14.76), 7.536 (9.48), 7.548 (2.27), 7.565 (3.91), 7.582 (2.98), 7.589 (2.80), 7.652 (0.61), 7.836 (3.23), 2.90), 7.858 (4.74), 7.864 (4.41), 7.934 (8.93), 7.957 (5.65), 8.861 (2.07), 8.875 (3.64), 8.889 (1.81).

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 12.06 (br. s, 1H), 8.88 (t, 1H), 7.94 (d, 1H), 7.85 (dd, 1H), 7.65 (br. s, 1H), 7.61-7.47 (m, 6H), 7.45-7.31 (m, 3H), 3.80-3.60 (m, 2H), 3.5-3.4 (1H, hidden), 2.24-2.00 (m, 6H), 1.91-1.76 (m, 1H).

Example 212 (+/-)-5-{[(6-Bromo-3-chloro-2-phenylquinolin-4-yl)carbonyl]amino}-4-(2-chlorophenyl)valeric acid (racemate)

To a solution of (+/-)-tert-butyl-5-{[(6-bromo-3-chloro-2-phenylquinolin-4-yl)carbonyl]amino}-4-(2chlorophenyl)pentanoate (150 mg, 239 µmol, example 275A) in dichloromethane (2.0 ml) was added TFA (370 µl, 4.8 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 14). The combined target fractions were concentrated and the residue was lyophilized. 100 mg (100% pure, 73% th. y.) of the title compound was obtained.

LC-MS (Method 1): R, = 2.08 min; MS (ESIpos): m/z = 571/573/575 [M+H] ⁺ .

'H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 9.13 (br. s, 1H), 8.01 (d, 1H), 7.96 (dd, 1H), 7.70-7.63 (m, 3H), 7.58-7.52 (m, 3H), 7.47 (dd, 2H), 7.37 (t, 1H), 7.31-7.20 (m, 1H), 3.80-3.52 (m, 3H), 2.15-1.92 (m, 3H), 1.901.77 (m, 1H).

Example 213 (-)-5-{[(6-Bromo-3-chloro-2-phenylquinolin-4-yl)carbonyl]amino}-4-(2-chlorophenyl)valeric acid (enantiomer 1)

To a solution of (-)-tert-butyl-5-{[(6-bromo-3-chloro-2-phenylquinolin-4-yl)carbonyl]amino}-4-(2chlorophenyl)pentanoate (715 mg, 1.14 mmol, example 276A) in dichloromethane (8.8 ml) was added TFA (1.9 ml, 25 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 dissolved in 6 ml of acetonitrile. 2 ml of this resulting crude product solution was purified by preparative HPLC (Method 17) and the combined target fractions were concentrated and the residue was lyophilized. 337 mg (100% pure, 52% theoretical yield, see Analysis section) of the first fraction of the title compound were obtained. A solid precipitated from the remaining solution of the crude product (4 ml), which, even after the addition of another 2 ml of acetonitrile, no longer went into solution. Therefore, after 3 hours at RT, the solid was filtered off, washed once with acetonitrile (1 ml) and dried in vacuo. Received 197

- 204 040284 mg (100% pure, 30% thor. yield) of the second batch of the title compound.

[a] _D20 = -10.6°, 589 nm, c = 0.36 ^g /100 ml, methanol.

LC-MS (Method 2): Rt = 1.09 min; MS (ESIpos): m/z = 571/573/575 [M+H]+.

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.365 (0.80), 1.832 (1.80), 1.857 (2.81), 1.880 (1.60), 1.901 (0.60), 2.050 (1.74), 2.063 (3.99) , 2.074 (3.56), 2.090 (7.57), 2.114 (4.60), 2.123 (3.87), 2.149 (2.58),2.171 (1.21), 3.615 (2.49), 3.714 (4.45), 3.726 (5.85), 7.257 (2.21) . , 7.536 (16.00), 7.545 (12.64), 7.662 (9.54), 7.667 (11.41), 7.676 (12.92), 7.942 (3.25), 7.947 (3.02), 7.965 (6.62), 7.969 (6.33) , 8.028 (5.08), 8.991 (2.69), 9.005 (5.23), 9.019 (2.56), 12.041 (0.92).

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 12.04 (br. s, 1H), 9.00 (t, 1H), 8.01 (d, 1H), 7.96 (dd, 1H), 7.717.64 ( m, 3H), 7.59-7.43 (m, 5H), 7.38 (t, 1H), 7.28 (t, 1H), 3.81-3.66 (m, 2H), 3.65-3.54 (m, 1H), 2.22-1.99 ( m,

3H), 1.93-1.75 (m, 1H).

Example 214 (+)-5-{[(6-Bromo-3-chloro-2-phenylquinolin-4-yl)carbonyl]amino}-4-(2-chlorophenyl)valeric acid (enantiomer 2)

To a solution of (+)-tert-butyl-5-{[(6-bromo-3-chloro-2-phenylquinolin-4-yl)carbonyl]amino}-4-(2chlorophenyl)pentanoate (735 mg, 1.17 mmol, example 277A) in dichloromethane (9.0 ml) was added TFA (2.0 ml, 26 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 adsorbed in 8 ml of acetonitrile. This mixture was sonicated at elevated temperature and then left for 3 hours at RT. The solid present was filtered off, washed twice with acetonitrile (respectively 1 ml) and dried in vacuo. 522 mg (100% pure, 78% thor.) of the title compound were obtained.

[a] _D20 = +11.7°, 589 nm, c = 0.53 g ^/ 100 mL, methanol.

LC-MS (Method 2): R _t = 1.09 min; MS (ESIpos): m/z = 571/573/575 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 1.365 (0.85), 1.832 (1.62), 1.847 (1.64), 1.858 (2.62), 1.880 (1.50), 1.901 (0.55), 2.050 (1.57 ), 2.063 (3.64), 2.074 (2.95), 2.080 (2.51), 2.090 (6.93), 2.100 (4.42), 2.114 (4.05), 2.123 (3.57), 2.149 (2.48), 2.159 (1.28), 2.171 (1.18 ), 3.616 (2.16), 3.713 (3.90), 3.726 (5.23), 7.255 (1.92), 7.258 (2.17), 7.277 (4.93), 7.293 (3.39), 7.296 (3.52), 7.361 (2.97), 7.380 (5.38 ), 7.398 (2.68), 7.449 (6.16), 7.452 (6.60), 7.469 (5.16), 7.472 (5.38), 7.500 (5.52), 7.520 (5.31), 7.530 (14.83), 7.536 (16.00), 7.547 (12.13 ), 7.555 (3.66), 7.571 (0.74), 7.653 (1.69), 7.661 (8.93), 7.667 (10.86), 7.676 (12.18), 7.685 (7.49), 7.942 (3.44), 7.947 (3.32), 7.965 (6.91 ), 7.970 (7.12), 8.006 (11.94), 8.028 (5.78), 8.990 (2.47), 9.005 (5.10), 9.019 (2.45), 12.042 (2.44).

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 12.04 (br. s, 1H), 9.00 (t, 1H), 8.01 (d, 1H), 7.96 (dd, 1H), 7.727.63 (m, 3H), 7.58-7.43 (m, 5H), 7.38 (t, 1H), 7.31-7.23 (m, 1H), 3.80-3.67 (m, 2H), 3.66-3.56 (m, 1H), 2.201 .98 (m, 3H), 1.92-1.78 (m, 1H).

Example 215 (+/-)-5-{[(6-Bromo-3-chloro-2-phenylquinolin-4-yl)carbonyl]amino}-4-[2-(trifluoromethyl)phenyl]valeric acid (racemate)

To a solution of (+/-)-tert-butyl-5-{[(6-bromo-3-chloro-2-phenylquinolin-4-yl)carbonyl]amino}-4-[2(trifluoromethyl)phenyl]pentanoate ( 80 mg, 121 µmol, example 280A) in dichloromethane (1.0 ml) was added with TFA (200 µl, 2.7 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 17). The pooled target fractions were concentrated and the residue was lyophilized. Received 57 mg (100% pure, 78% theoretical. yield.) specified in the title compound.

LC-MS (Method 1): R _t = 2.13 min; MS (ESIpos): m/z = 605/607 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 1.917 (1.64), 1.926 (1.70), 1.939 (3.77), 1.953 (2.29), 1.970 (3.17), 1.982 (1.57), 1.994 (2.62 ), 2.006 (1.90), 2.038 (1.64), 2.057 (2.56), 2.065 (1.57), 2.081 (2.75), 2.097 (1.35), 2.121 (1.21), 2.144 (1.04), 2.156 (1.46), 2.168 (1.72 ), 2.181 (1.71), 2.190 (1.70), 2.229 (0.47), 3.640 (0.79), 3.656 (1.32), 3.673 (2.34), 3.689 (2.73), 3.706 (1.75), 3.718 (1.78), 3.734 (2.68 ), 3.751 (2.16), 3.768 (1.32), 3.783 (0.71), 7.466 (2.15), 7.484 (4.72), 7.503 (2.97), 7.537 (14.63), 7.542 (16.00), 7.551 (11.33), 7.553 (11.19 ), 7.574 (0.99), 7.623 (3.21), 7.679 (8.09), 7.684 (9.17), 7.692 (9.95), 7.703 (6.72), 7.712 (5.60), 7.732 (9.29), 7.753 (11.58), 7.772 (3.08 ), 7.951 (3.64), 7.956 (3.38), 7.973 (6.89), 7.978 (6.87), 8.018 (11.35), 8.040 (5.77), 9.055 (2.33), 9.069 (4.61), 9.084 (2.26).

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 12.06 (br. s, 1H), 9.07 (t, 1H), 8.03 (d, 1H), 7.97 (dd, 1H), 7.81-205 040284

7.43 (m, 10H), 3.87-3.56 (m, 2H), 3.4-3.3 (1H, hidden), 2.26-1.82 (m, 4H).

Example 216 (-)-5-{[(6-Bromo-3-chloro-2-phenylquinolin-4-yl)carbonyl]amino}-4-[2-(trifluoromethyl)phenyl]valeric acid (enantiomer 1)

To a solution of (-)-tert-butyl-5-{[(6-bromo-3-chloro-2-phenylquinolin-4-yl)carbonyl]amino}-4-[2(trifluoromethyl)phenyl]pentanoate (85 mg , 128 μmol, example 281A) in dichloromethane (1.1 ml) was added TFA (220 μl, 2.8 mmol) and the mixture was left 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 17). The combined target fractions were concentrated and the residue was lyophilized. 62 mg (100% pure, 80% thor.) of the title compound were obtained.

[a] _D20 = -15.0°, 589 nm, c = 0.22 g ^/ 100 ml, methanol.

LC-MS (Method 1): Rt = 2.13 min; MS (ESIpos): m/z = 605/607 [M+H]+.

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 1.236 (1.00), 1.917 (1.50), 1.943 (3.67), 1.957 (2.00), 1.974 (3.20), 1.987 (1.36), 1.998 (2.60 ), 2.010 (1.91), 2.041 (1.57), 2.060 (2.55), 2.068 (1.50), 2.084 (2.74), 2.100 (1.29), 2.123 (1.22), 2.146 (0.98), 2.158 (1.36), 2.170 (1.63 ), 2.182 (1.54), 2.192 (1.54), 2.231 (0.45), 2.328 (0.46), 2.670 (0.50), 3.641 (0.73), 3.657 (1.19), 3.674 (2.22), 3.690 (2.57), 3.706 (1.64 ), 3.718 (1.67), 3.733 (2.53), 3.750 (2.02), 3.767 (1.19), 3.783 (0.62), 7.467 (2.09), 7.485 (4.66), 7.504 (2.87), 7.536 (14.83), 7.542 (16.00 ), 7.550 (10.71), 7.553 (11.29), 7.562 (3.32), 7.577 (0.86), 7.623 (3.10), 7.669 (1.40), 7.678 (8.29), 7.683 (9.37), 7.692 (9.37), 7.702 (6.59 ), 7.713 (5.25), 7.733 (9.14), 7.754 (11.35), 7.773 (2.88), 7.951 (3.80), 7.956 (3.60), 7.973 (7.06), 7.978 (7.33), 8.018 (12.32), 8.040 (6.20 ), 9.049 (2.26), 9.064 (4.63), 9.079 (2.22), 12.023 (2.74).

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 12.02 (br. s, 1H), 9.06 (t, 1H), 8.03 (d, 1H), 7.97 (dd, 1H), 7.817.44 (m, 10H), 3.82-3.60 (m, 2H), 3.4-3.3 (m, 1H, partially hidden), 2.26-1.85 (m, 4H).

Example 217 (+)-5-{[(6-Bromo-3-chloro-2-phenylquinolin-4-yl)carbonyl]amino}-4-[2-(trifluoromethyl)phenyl]valeric acid (enantiomer 2)

To a solution of (+)-tert-butyl-5-{[(6-bromo-3-chloro-2-phenylquinolin-4-yl)carbonyl]amino}-4-[2-(trifluoromethyl)phenyl]pentanoate (85 mg, 128 µmol, example 282A) in dichloromethane (1.1 ml) was added TFA (220 µl, 2.8 mmol) and the mixture was left 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 17). The combined target fractions were concentrated and the residue was lyophilized. 62 mg (100% pure, 80% thor.) of the title compound were obtained.

[a] _D20 = +14.3°, 589 nm, c = 0.43 ^g /100 mL, methanol.

LC-MS (Method 1): Rt = 2.13 min; MS (ESIpos): m/z = 605/607 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 1.235 (0.71), 1.917 (1.81), 1.941 (3.98), 1.955 (2.36), 1.972 (3.30), 1.984 (1.60), 1.995 (2.69 ), 2.007 (1.95), 2.039 (1.80), 2.058 (2.66), 2.082 (2.81), 2.098 (1.37), 2.122 (1.27), 2.145 (1.18), 2.158 (1.55), 2.169 (1.82), 2.181 (1.75 ), 2.191 (1.71), 2.328 (0.42), 3.640 (0.93), 3.655 (1.46), 3.673 (2.46), 3.689 (2.81), 3.706 (1.88), 3.718 (1.89), 3.734 (2.72), 3.750 (2.15 ), 3.767 (1.29), 7.466 (2.34), 7.485 (4.91), 7.503 (3.34), 7.536 (15.16), 7.542 (16.00), 7.550 (11.28), 7.553 (11.15), 7.562 (3.43), 7.575 (1.00 ), 7.623 (3.41), 7.678 (8.94), 7.684 (9.79), 7.692 (10.30), 7.702 (7.12), 7.712 (5.76), 7.732 (9.48), 7.753 (11.47), 7.772 (2.96), 7.950 (3.82 ), 7.956 (3.60), 7.973 (6.94), 7.978 (6.88), 8.018 (11.31), 8.040 (5.66), 9.052 (2.48), 9.067 (4.61), 9.081 (2.21), 12.038 (0.76).

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 12.04 (br. s, 1H), 9.07 (t, 1H), 8.03 (d, 1H), 7.97 (dd, 1H), 7.807.43 ( m, 10H), 3.81-3.60 (m, 2H), 3.4-3.3 (m, 1H, partially hidden), 2.26-1.86 (m, 4H).

Example 218 (+/-)-4-(2-Chlorophenyl)-5-{[(6-ethynyl-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}valeric acid (racemate)

To a solution of (+/-)-tert-butyl-4-(2-chlorophenyl)-5-{[(6-ethynyl-3-methyl-2-phenylquinolin-4yl)carbonyl]amino}pentanoate (130 mg, 235 µmol, example 283A) in dichloromethane (2.0 ml) was added TFA (400 µl, 5.2 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 17). The combined target fractions were concentrated and the residue was lyophilized. 69 mg (100% pure, 59% thor.) of the title compound were obtained.

LC-MS (Method 1): R _t = 1.88 min; MS (ESIpos): m/z = 497 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 1.801 (0.56), 1.822 (1.23), 1.844 (1.55), 1.867 (0.84), 2.028 (0.84), 2.048 (3.24), 2.082 (3.52 ), 2.098 (3.73), 2.126 (4.59), 2.144 (3.85), 2.168 (1.41), 3.611 (1.29), 3.670

- 206 040284 (0.59), 3.683 (0.89), 3.703 (1.37), 3.716 (1.78), 3.729 (1.06), 3.767 (1.15), 3.782 (0.98), 4.414 (6.20), 7.239 (1.05), 7.258 (2.20) ), 7.277 (1.56), 7.353 (1.29), 7.371 (2.26), 7.389 (1.23), 7.429 (3.77), 7.449 (3.09), 7.497 (6.68), 7.507 (4.98), 7.519 (16.00), 7.706 (2.76 ), 7.728 (3.22), 7.956 (4.41), 7.977 (3.77), 8.822 (1.51), 8.837 (2.81), 8.850 (1.42).

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 12.06 (br. s, 1H), 8.84 (t, 1H), 7.97 (d, 1H), 7.72 (d, 1H), 7.7-7.4 ( br. m, 1H), 7.56-7.47 (m, 6H), 7.44 (d, 1H), 7.37 (t, 1H), 7.26 (t, 1H), 4.41 (s, 1H), 3.90-3.47 (m, 3H), 2.31-1.99 (m, 6H), 1.94-1.61 (m, 1H).

Example 219 (-)-4-(2-Chlorophenyl)-5-{[(6-ethynyl-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}valeric acid (enantiomer 1)

To a solution of (-)-tert-butyl-4-(2-chlorophenyl)-5-{[(6-ethynyl-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}pentanoate (185 mg, 334 µmol, example 284A) in dichloromethane (2.8 ml) was added TFA (570 µl, 7.4 mmol) and the mixture was left 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 17). The combined target fractions were concentrated and the residue was lyophilized. 126 mg (100% pure, 76% thor.) of the title compound were obtained.

[a] _D20 = -20.3°, 589 nm, c = 0.41 ^g /100 ml, methanol.

LC-MS (Method 1): R _t = 1.88 min; MS (ESIpos): m/z = 497 [M+H]+.

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.802 (0.53), 1.823 (1.17), 1.845 (1.47), 1.867 (0.80), 2.050 (3.23), 2.085 (3.29), 2.100 (3.72) , 2.128 (4.42), 2.147 (3.44), 2.171 (1.30), 3.612 (1.21), 3.671 (0.55) , 4.414 (7.46), 7.238 (0.99), 7.258 (2.14),7.277 (1.51), 7.353 (1.23), 7.371 (2.17), 7.389 (1.18), 7.429 (3.88), 7.449 (3.19), 7.498 (6.54) , 7.507 (4.77), 7.519 (16.00), 7.706 (3.04), 7.728 (3.50), 7.956 (4.48), 7.978 (3.78), 8.821 (1.46), 8.835 (2.75), 8.849 (1.39), 12.049 (0.97) .

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 12.05 (br. s, 1H), 8.84 (t, 1H), 7.97 (d, 1H), 7.72 (d, 1H), 7.7-7.4 (br. m, 1H), 7.56-7.47 (m, 6H), 7.44 (d, 1H), 7.37 (t, 1H), 7.26 (t, 1H), 4.41 (s, 1H), 3.87-3.48 (m , 3H), 2.27-1.95 (m, 6H), 1.92-1.70 (m, 1H).

Example 220 (+)-4-(2-Chlorophenyl)-5-{[(6-ethynyl-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}valeric acid (enantiomer 2)

To a solution of (+)-tert-butyl-4-(2-chlorophenyl)-5-{[(6-ethynyl-3-methyl-2-phenylquinolin-4yl)carbonyl]amino}pentanoate (185 mg, 334 µmol, example 285A) in dichloromethane (2.8 ml) was added TFA (570 μl, 7.4 mmol) and the mixture was left 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 17). The combined target fractions were concentrated and the residue was lyophilized. 152 mg (100% pure, 91% thor.) of the title compound were obtained.

[a] _D20 = +20.2°, 589 nm ^, c = 0.32 g/100 mL, methanol.

LC-MS (Method 1): R _t = 1.88 min; MS (ESIpos): m/z = 497 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.802 (0.55), 1.823 (1.21), 1.845 (1.53), 1.868 (0.84), 2.030 (0.81), 2.038 (0.93), 2.051 (3.31) , 2.086 (3.46), 2.101 (3.94), 2.128 (4.59), 2.148 (3.59), 2.171 (1.36), 3.613 (1.28), 3.670 (0.59), 3.684 (0.90), 3.703 (1.37), 3.717 (1.79) . . , 8.820 (1.55), 8.835 (2.96), 8.849 (1.51).

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 12.04 (br. s, 1H), 8.83 (t, 1H), 7.97 (d, 1H), 7.72 (d, 1H), 7.7-7.4 (br. m, 1H), 7.57-7.47 (m, 6H), 7.44 (d, 1H), 7.37 (t, 1H), 7.26 (t, 1H), 4.41 (s, 1H), 3.88-3.53 (m , 3H), 2.25-1.96 (m, 6H), 1.93-1.71 (m, 1H).

Example 221 (+/-)-5-{[(6-Bromo-3-chloro-2-phenylquinolin-4-yl)carbonyl]amino}-4-(2-chloro-3,6difluorophenyl)valeric acid (racemate )

O. NH

To a solution of (+/-)-tert-butyl-5-{[(6-bromo-3-chloro-2-phenylquinolin-4-yl)carbonyl]amino}-4-(2chloro-3,6-difluorophenyl) pentanoate (65 mg, 98 µmol, example 286A) in dichloromethane (830 µl) TFA (170 µl, 2.2 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 17). The pooled target fractions were concentrated and the residue lyophilized

- 207 040284 Vali. 34 mg (100% pure, 56% thor.) of the title compound were obtained.

LC-MS (Method 1): Rt = 2.08 min; MS (ESIpos): m/z = 607/609/611 [M+H]+.

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.981 (1.03), 2.074 (1.54), 2.093 (1.50), 2.109 (3.76), 2.146 (8.52), 2.174 (2.16), 2.189 (1.98) , 2.212 (0.70), 2.695 (0.74), 3.755 (2.13), 3.774 (2.01), 3.819 (2.95) . . , 8.015 (12.42), 8.037 (5.55), 9.088 (2.21), 9.102 (4.20), 9.115 (2.13), 12.096 (8.00).

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 12.10 (s, 1H), 9.10 (t, 1H), 8.02 (d, 1H), 7.97 (dd, 1H), 7.73-7.63 (m, 3H), 7.57-7.51 (m, 3H), 7.41 (td, 1H), 7.30 (td, 1H), 3.95-3.67 (m, 3H), 2.27-2.05 (m, 3H), 2.04-1.89 (m, 1H).

Example 222 (-)-5-{[(6-Bromo-3-chloro-2-phenylquinolin-4-yl)carbonyl]amino}-4-(2-chloro-3,6-difluorophenyl)valeric acid (enantiomer 1).

To a solution of (-)-tert-butyl-5-{[(6-bromo-3-chloro-2-phenylquinolin-4-yl)carbonyl]amino}-4-(2-chloro3,6-difluorophenyl)pentanoate ( 45 mg, 68 µmol, example 287A) in dichloromethane (520 µl) was added with TFA (110 µl, 1.5 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 17). The combined target fractions were concentrated and the residue was lyophilized. 34 mg (100% pure, 82% thor.) of the title compound were obtained.

[a] _D20 = -33.3°, 589 nm, c = 0.38 ^g /100 ml, methanol.

LC-MS (Method 1): Rt = 2.08 min; MS (ESIpos): m/z = 607/609/611 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 1.235 (0.82), 1.980 (1.02), 2.093 (1.51), 2.109 (3.71), 2.146 (8.29), 2.189 (1.92), 2.212 (0.68 ), 3.753 (2.12), 3.775 (2.01), 3.819 (2.95), 7.268 (1.36), 7.279 (1.56), 7.292 (2.78), 7.303 (2.89), 7.317 (2.23), 7.329 (2.09), 7.382 (1.79 ), 7.393 (2.05), 7.404 (2.89), 7.415 (2.80), 7.426 (1.49), 7.437 (1.25), 7.522 (1.82), 7.531 (14.85), 7.538 (16.00), 7.546 (11.67), 7.548 (12.40 ), 7.569 (0.72), 7.649 (1.59), 7.658 (8.50), 7.663 (9.30), 7.672 (8.78), 7.681 (6.87), 7.694 (3.02), 7.956 (3.50), 7.961 (3.35), 7.978 (7.36 ), 7.984 (7.66), 8.015 (12.07), 8.037 (5.42), 9.088 (2.19), 9.102 (4.15), 9.116 (2.11), 12.097 (2.42).

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 12.10 (s, 1H), 9.10 (t, 1H), 8.02 (d, 1H), 7.97 (dd, 1H), 7.74-7.63 (m, 3H), 7.58-7.51 (m, 3H), 7.41 (td, 1H), 7.30 (td, 1H), 3.94-3.67 (m, 3H), 2.26-2.06 (m, 3H), 1.98 (br. s, 1H).

Example 223 (+)-5-{[(6-Bromo-3-chloro-2-phenylquinolin-4-yl)carbonyl]amino}-4-(2-chloro-3,6-difluorophenyl)valeric acid (enantiomer 2).

To a solution of (+)-tert-butyl-5-{[(6-bromo-3-chloro-2-phenylquinolin-4-yl)carbonyl]amino}-4-(2-chloro3,6-difluorophenyl)pentanoate ( 45 mg, 68 µmol, example 288A) in dichloromethane (520 µl) was added with TFA (110 µl, 1.5 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 17). The combined target fractions were concentrated and the residue was lyophilized. 29 mg (100% pure, 69% thor.) of the title compound were obtained.

[a] _D20 = +35.3°, 589 nm, c = 0.36 ^g /100 mL, methanol.

LC-MS (Method 1): Rt = 2.08 min; MS (ESIpos): m/z = 607/609/611 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (0.62), 1.235 (0.56), 1.977 (0.97), 2.108 (3.49), 2.142 (8.02), 2.186 (1.89), 2.209 (0.65 ), 3.750 (2.03), 3.774 (1.91), 3.817 (2.76), 7.267 (1.37), 7.278 (1.54), 7.291 (2.80), 7.302 (2.88), 7.317 (2.23), 7.328 (2.12), 7.381 (1.76 ), 7.393 (2.01), 7.403 (2.88), 7.414 (2.78), 7.425 (1.49), 7.436 (1.23), 7.522 (1.67), 7.531 (15.31), 7.537 (16.00), 7.547 (12.27), 7.555 (3.68 ), 7.569 (0.74), 7.648 (1.53), 7.657 (8.76), 7.662 (9.30), 7.672 (8.81), 7.681 (6.84), 7.693 (3.00), 7.956 (3.75), 7.961 (3.45), 7.978 (7.82 ), 7.983 (7.97), 8.015 (12.92), 8.037 (5.78), 9.088 (2.12), 9.102 (4.02), 9.116 (2.04), 12.106 (0.55).

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 12.11 (br. s, 1H), 9.10 (t, 1H), 8.02 (d, 1H), 7.97 (dd, 1H), 7.747.63 ( m, 3H), 7.58-7.50 (m, 3H), 7.41 (td, 1H), 7.30 (td, 1H), 3.94-3.67 (m, 3H), 2.25-2.06 (m, 3H), 1.98 (br. s, 1H).

Example 224 (+/-)-5-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-4-(pyridin-2-yl)valeric acid (racemate)

To a solution of (+/-)-tert-butyl-5-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-4(pyridin-2-yl)pentanoate (100 mg, 174 µmol, example 289A, uncorrected purity) in dichloromethane (750 µl) TFA (270 µl, 3.5 mmol) was added and the mixture was stirred for 7 h at RT. The mixture was then concentrated and mixed several times with dichloromethane and re-concentrated. The rest of the eye

- 208 040284 styles by preparative HPLC (Chromatorex C18 column, 10 µm, 125 x 30 mm; gradient 20% ^ 60% acetonitrile in 0.1% aqueous ammonia). The combined target fractions were concentrated and the residue was lyophilized. 46 mg (92% pure, 49% thor.) of the title compound were obtained.

LC-MS (Method 5): Rt = 0.99 min; MS (ESIpos): m/z = 518/520 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 1.107 (12.82), 1.737 (0.48), 1.882 (0.41), 1.905 (0.87), 1.914 (0.67), 1.924 (1.29), 1.938 (0.95 ), 1.945 (0.81), 1.967 (0.78), 1.982 (0.86), 1.988 (1.35), 1.995 (1.12), 2.000 (1.11), 2.011 (1.20), 2.021 (2.54), 2.047 (2.18), 2.059 (1.78 ), 2.067 (1.57), 2.079 (2.19), 2.102 (2.39), 2.108 (2.79), 2.125 (4.18), 2.147 (2.08), 2.518 (2.49), 2.523 (1.57), 2.539 (1.37), 3.202 (0.98 ), 3.619 (0.83), 3.638 (0.87), 3.652 (1.11), 3.794 (0.70), 7.247 (1.05), 7.263 (1.42), 7.276 (1.14), 7.312 (1.73), 7.331 (1.84), 7.472 (0.45 ), 7.475 (0.48), 7.481 (0.73), 7.485 (1.28), 7.487 (1.44), 7.498 (4.79), 7.506 (4.67), 7.516 (16.00), 7.518 (15.39), 7.523 (7.66), 7.528 (5.83 ), 7.532 (5.46), 7.539 (1.18), 7.737 (1.28), 7.752 (1.95), 7.772 (1.02), 7.829 (2.64), 7.834 (2.35), 7.851 (3.81), 7.856 (3.77), 7.922 (7.82 ), 7.944 (4.82), 8.579 (2.37), 8.589 (2.35), 8.796 (1.37), 8.811 (2.19), 8.825 (1.33), 12.041 (1.59).

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 12.04 (br. s, 1H), 8.81 (t, 1H), 8.58 (d, 1H), 7.93 (d, 1H), 7.84 (dd , 1H), 7.75 (t, 1H), 7.67 (br. s, 1H), 7.55-7.45 (m, 5H), 7.32 (d, 1H), 7.26 (t, 1H), 3.88-3.73 (m, 1H ), 3.71

3.55 (m, 1H), 3.27-3.13 (m, 1H), 2.23-1.86 (m, 7H).

Example 225 (+/-)-5-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-4-[2-fluoro-6-(trifluoromethyl)phenyl] valeric acid (racemate)

(+/-)-tert-Butyl-5-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-4-[2-fluoro-6-(trifluoromethyl)phenyl] pentanoatev (80 mg, 93% pure, 113 µmol, example 290A) was dissolved in dichloromethane (1.5 ml). TFA (850 μl, 11.28 mmol) was added at RT and the mixture was stirred 1 h at RT. The volatile components were then removed on a rotary evaporator. The residue was mixed three times with some toluene and again concentrated on a rotary evaporator. The residue was dissolved in a small amount of DMSO and purified by preparative HPLC (Method 28). The appropriate fractions were combined and concentrated in vacuo. The residue was dried in vacuo. 63 mg (100% pure, 93% thor.) of the title compound were obtained.

LC-MS (Method 1): Rt = 2.03 min; MS (ESIpos): m/z = 603/605 [M+H] ⁺ .

'H-NMR (400 MHz, DMSO-d6) δ [ppm]: 12.11 (br. s, 1H), 8.96 (t, 1H), 7.95 (d, 1H), 7.85 (dd, 1H), 7.757.46 (m, 9H), 3.95 (br. s, 1H), 3.72 (br. s, 1H), 3.31 (1H, latent, empirical), 2.25-1.98 (m, 7H).

Example 226 (+)-5-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-4-[2-fluoro-6-(trifluoromethyl)phenyl]valeric acid ( enantiomer 1).

tert-Butyl 5-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-4-[2-fluoro-6-(trifluoromethyl)phenyl]pentanoate (440mg, 667 µmol, example 291A, Enantiomer 1) was dissolved in dichloromethane (8.9 ml). TFA (5 ml, 66.7 mmol) was added at RT and the mixture was stirred 1 h at RT. The volatile components were then removed on a rotary evaporator. The residue was dissolved in a small amount of DMSO and purified by preparative HPLC (Method 29). The appropriate fractions were combined and concentrated in vacuo. The residue was dried in vacuo. 356 mg (98% pure, 87% thor.) of the title compound were obtained.

LC-MS (Method 1): Rt = 2.01 min; MS (ESIpos): m/z = 603/605 [M+H] ⁺ .

'H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 12.06 (br. s, 1H), 8.95 (t, 1H), 7.95 (d, 1H), 7.85 (dd, 1H), 7.787. 44 (m, 9H), 3.96 (br. s, 1H), 3.73 (br. s, 1H), 3.32 (1H, latent, experimental), 2.24-2.00 (m, 7H).

[a] _D20 = +45.6°, 589 nm ^, c = 0.415 g/100 mL, methanol.

Example 227 (-)-5-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-4-[2-fluoro-6-(trifluoromethyl)phenyl]valeric acid ( enantiomer 2).

tert-Butyl 5-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-4-[2-fluoro-6-(trifluoromethyl)phenyl]pentanoate (412 mg, 625 µmol, example 292A, Enantiomer 2) was dissolved in dichloromethane (8.3 ml). TFA (4.6 ml, 62.5 mmol) was added at RT and the mixture was stirred for 1 h at RT. The volatile components were then removed on a rotary evaporator. The residue was dissolved in a small amount of DMSO and purified by preparative HPLC (Method 29). The appropriate fractions were combined and concentrated in vacuo. The residue was dried in vacuo. 344 mg (98% pure, 89% thor.) of the title compound were obtained.

LC-MS (Method 1): Rt = 2.01 min; MS (ESIpos): m/z = 603/605 [M+H] ⁺ .

- 209 040284

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 12.06 (br. s, 1H), 8.95 (t, 1H), 7.95 (d, 1H), 7.85 (dd, 1H), 7.807.44 (m, 9H), 3.96 (br. s, 1H), 3.73 (br. s, 1H), 3.33 (1H, partially obscured, experimentally), 2.24-2.00 (m, 7H).

[a] _D20 = -45.6°, 589 nm, c = 0.38 ^g /100 ml, methanol.

Example 228 (+/-)-5-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-4-(2,3,5,6-tetrafluorophenyl)valeric acid (racemate)

(+/-)-tert-Butyl-5-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-4-(2,3,5,6-tetrafluorophenyl)pentanoate (25 mg, 38.7 µmol, example 293A) was dissolved in dichloromethane (520 µl). TFA (290 μl, 3.8 mmol) was added at RT and the mixture was stirred overnight at RT. The volatile components were then removed on a rotary evaporator. The residue was repeatedly mixed with some toluene and again concentrated on a rotary evaporator. The residue was dissolved in a small amount of DMSO and purified by preparative HPLC (Method 28). The combined desired fractions were concentrated and the residue was dried in vacuo. 17 mg (100% pure, 74% thor.) of the title compound were obtained.

LC-MS (Method 2): R _t = 1.04 min; MS (ESIpos): m/z = 589/591 [M+H] ⁺ .

'H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.13 (br. s, 1H), 8.98 (t, 1H), 7.95 (d, 1H), 7.86 (dd, 1H), 7.87 .6 (m, 2H), 7.58-7.46 (m, 5H), 3.87-3.77 (m, 2H), 3.61-3.51 (m, 1H), 2.27-2.04 (m, 6H), 2.00-1.90 (m, 1H).

Example 229 (-)-5-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-4-(2,3,5,6-tetrafluorophenyl)valeric acid (enantiomer 1).

tert-Butyl 5-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-4-(2,3,5,6-tetrafluorophenyl)pentanoate (265mg, 410µmol , example 294A, Enantiomer 1) was dissolved in dichloromethane (5.5 ml). TFA (3.1 ml, 41.0 mmol) was added at RT and the mixture was stirred overnight at RT. The volatile components were then removed on a rotary evaporator. The residue was repeatedly mixed with some toluene and again concentrated on a rotary evaporator. The residue was dissolved in a small amount of DMSO and purified by preparative HPLC (Method 28). The appropriate fractions were combined and concentrated in vacuo. The residue was dried in vacuo. 237 mg (98% pure, 96% thor.) of the title compound were obtained.

[a] _D20 = -50.9°, 589 nm, c = 0.45 ^g /100 ml, methanol.

LC-MS (Method 1): R _t = 1.99 min; MS (ESIpos): m/z = 589/591 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (2.12), 0.008 (1.97), 1.922 (0.60), 1.956 (1.02), 1.981 (0.92), 1.997 (0.53), 2.074 (1.06 ), 2.088 (1.41), 2.107 (1.34), 2.128 (1.19), 2.158 (6.34), 2.202 (3.94), 2.219 (5.66), 2.238 (2.23), 2.328 (0.54), 2.366 (0.44), 2.669 (0.47 ), 2.710 (0.41), 3.167 (0.95), 3.558 (1.10), 3.794 (2.43), 3.810 (3.34), 7.495 (1.52), 7.506 (4.54), 7.514 (4.40), 7.525 (16.00), 7.536 (6.45 ), 7.539 (5.76), 7.800 (1.00), 7.848 (2.66), 7.853 (2.35), 7.870 (3.85), 7.875 (3.72), 7.940 (7.13), 7.963 (4.44), 8.155 (0.67), 8.969 (1.31 ), 8.984 (2.59), 8.998 (1.30).

Example 230 (+)-5-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-4-(2,3,5,6-tetrafluorophenyl)valeric acid (enantiomer 2).

tert-Butyl 5-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-4-(2,3,5,6-tetrafluorophenyl)pentanoate (274mg, 99% purity, 420 µmol, example 295A, Enantiomer 2) was dissolved in dichloromethane (5.6 ml). TFA (3.2 ml, 42.0 mmol) was added at RT and the mixture was stirred overnight at RT. The volatiles were then removed on a rotary evaporator. The residue was repeatedly mixed with some toluene and again concentrated on a rotary evaporator. The residue was dissolved in a small amount of DMSO and purified by preparative HPLC (Method 28). The appropriate fractions were combined and concentrated in vacuo. The residue was dried in vacuo. 235 mg (99% pure, 94% theoretical) of the title compound were obtained.

[a] _D20 = +47.2°, 589 nm ^, c = 0.445 g/100 mL, methanol.

LC-MS (Method 1): R _t = 2.00 min; MS (ESIpos): m/z = 589/591 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: -0.008 (1.64), 0.008 (1.47), 1.923 (0.61), 1.957 (1.04), 1.981 (0.93), 1.998 (0.52), 2.056 ( 0.44), 2.075 (1.06), 2.089 (1.38), 2.107 (1.35), 2.126 (1.21), 2.159 (6.40), 2.202 (3.92), 2.219 (5.62), 2.238 (2.22), 2.329 (0.43), 3.559 ( 1.10) 2.55), 7.853 (2.31), 7.870 (3.72), 7.875 (3.60), 7.941 (6.90), 7.963 (4.29), 8.969 (1.33), 8.984 (2.61), 8.998 (1.28), 12.153 (0.46).

Example 231 (+/-)-5-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-4-(2,3,5-trifluorophenyl)valeric acid (racemate )

- 210 040284

(+/-)-tert-Butyl-5-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-4-(2,3,5-trifluorophenyl)pentanoate (25 mg, 39.8 µmol, example 296A) was dissolved in dichloromethane (530 µl). TFA (40 μl, 3.1 mmol) was added at RT and the mixture was stirred for 1 h at RT. Since the exercise was not complete (HPLC control), additional portions of trifluoroacetic acid were added (total 230 μl). The mixture was further stirred until starting material was detected by HPLC (4 hours). The volatile components were then removed on a rotary evaporator. The residue was repeatedly mixed with some toluene and again concentrated on a rotary evaporator. The residue was dissolved in a small amount of DMSO and purified by preparative HPLC (Method 28). The combined desired fractions were concentrated and the residue was dried in vacuo. 20 mg (100% pure, 88% thor.) of the title compound were obtained.

LC-MS (Method 2): Rt = 1.02 min; MS (ESIpos): m/z = 571/573 [M+H]+.

1H-NMR (400 MHz, DMSO-d6): δ [ppm] = 12.10 (br. s, 1H), 8.89 (t, 1H), 7.94 (d, 1H), 7.85 (dd, 1H), 7.81-7.56 (br. s, 1H), 7.56-7.46 (m, 5H), 7.46-7.35 (m, 1H), 7.27-7.20 (m, 1H), 3.84-3.66 (m, 2H), 3.50-3.37 (m, 1H), 2.24-1.98 (m, 6H), 1.88-1.77 (m, 1H).

Example 232 5-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-4-(2,3,5-trifluorophenyl)valeric acid (enantiomer 1)

tert-Butyl 5-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-4-(2,3,5-trifluorophenyl)pentanoate (38 mg, 60.2 µmol, example 297A, Enantiomer 1) was dissolved in dichloromethane (800 μl). TFA (450 μl) was added at RT and the mixture was stirred overnight at RT. The volatile components were then removed on a rotary evaporator. The residue was repeatedly mixed with some toluene and again concentrated on a rotary evaporator. The residue was dissolved in a small amount of DMSO and purified by preparative HPLC (Method 28). The combined target fractions were concentrated in vacuo and the residue was dried in vacuo. 29 mg (100% pure, 84% thor.) of the title compound were obtained.

LC-MS (Method 2): Rt = 1.04 min; MS (ESIpos): m/z = 571/573 [M+H]+.

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 0.008 (2.16), 1.798 (0.71), 1.834 (1.03), 1.849 (0.83), 1.872 (0.53), 2.018 (1.07), 2.031 (1.34 ), 2.051 (1.41), 2.073 (9.44), 2.082 (1.24), 2.124 (4.71), 2.145 (7.02), 2.327 (0.68), 2.366 (0.51), 2.670 (0.61), 2.709 (0.50), 3.428 (1.17 ), 3.682 (0.83), 3.703 (1.26), 3.716 (1.82), 3.729 (1.15), 3.763 (0.91), 7.223 (1.35), 7.411 (1.03), 7.494 (1.56), 7.504 (4.57), 7.512 (4.41 ), 7.523 (16.00), 7.534 (6.76), 7.837 (2.19), 7.842 (2.04), 7.859 (3.36), 7.864 (3.29), 7.933 (6.54), 7.956 (4.15), 8.875 (1.32), 8.890 (2.48 ), 8.903 (1.37), 12.092 (0.68).

Example 233 5-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-4-(2,3,5-trifluorophenyl)valeric acid (enantiomer 2)

tert-Butyl 5-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-4-(2,3,5-trifluorophenyl)pentanoate (40 mg, 62.8 µmol, example 298A, Enantiomer 2) was dissolved in dichloromethane (840 µl). Trifluoroacetic acid (470 μl) was added at RT and the mixture was stirred overnight at RT. The volatile components were then removed on a rotary evaporator. The residue was repeatedly mixed with some toluene and again concentrated on a rotary evaporator. The residue was dissolved in a small amount of DMSO and purified by preparative HPLC (Method 28). The combined target fractions were concentrated in vacuo and the residue was dried in vacuo. 25 mg (100% pure, 70% thor.) of the title compound were obtained.

LC-MS (Method 1): Rt = 1.97 min; MS (ESIpos): m/z = 571/573 [M+H]+.

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: -0.149 (1.73), -0.008 (16.00), 0.008 (15.95), 0.146 (1.73), 1.825 (0.98), 2.022 (1.21), 2.041 (1.17), 2.060 (1.31), 2.117 (3.50), 2.140 (3.50), 2.327 (1.77), 2.366 (1.82), 2.670 (1.96) (1.35), 7.395 (1.07), 7.503 (4.34), 7.511 (4.10), 7.523 (14.23) (4.10), 8.908 (2.10).

Example 234 (+/-)-5-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-4-(2,3,6-trichlorophenyl)valeric acid (racemate )

- 211 040284 (+/-)-tert-Butyl-5- {[(6-bromo-3 -methyl-2-phenylquinolin-4-yl)carbonyl] amino} -4-(2,3,6-trichlorophenyl) pentanoate (80 mg, 118 µmol, example 299A) was dissolved in dichloromethane (1.6 ml). Added on CT

TFA (880 µl, 11.8 mmol) and the mixture was stirred for 2 h at RT. The volatiles were removed on a rotary evaporator and the residue was dried in vacuo. The crude product was then dissolved in a small amount of DMSO and purified by preparative HPLC (Method 29). The combined target fractions were concentrated in vacuo and the residue was dried in vacuo. 66 mg (100% pure, 90% thor.) of the title compound were obtained.

LC-MS (Method 1): R _t = 2.14 min; MS (ESIpos): m/z = 619/621/623 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6): δ [ppm] = 12.11 (br. s, 1H), 8.99-8.87 (m, 1H), 7.95 (dd, 1H), 7.89-7.83 (m, 1H) , 7.82-7.64 (m, 1H), 7.64-7.57 (m, 1H), 7.56-7.46 (m, 6H), 4.20-4.00 (m, 2H), 3.94-3.79 (m, 1H), 2.352.03 ( m, 7H).

Example 235 (+)-5-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-4-(2,3,6-trichlorophenyl)valeric acid (enantiomer 1) .

tert-Butyl 5-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-4-(2,3,6-trichlorophenyl)pentanoate (227mg, 95% pure, 319 µmol, example 300A, enantiomer 1) was dissolved in dichloromethane (2.7 ml). TFA (2.4 ml) was added at RT and the mixture was stirred for 2 h at RT. The volatile components were then removed on a rotary evaporator. The residue was mixed twice with some toluene and again concentrated on a rotary evaporator. The residue was dissolved in a small amount of DMSO and purified by preparative HPLC (Method 30). The combined target fractions were concentrated in vacuo and the residue was dried in vacuo. 148 mg (96% pure, 73% thor.) of the title compound were obtained.

[a] _D20 = +34.1°, 589 nm, c = 0.44 g ^/ 100 mL, methanol.

LC-MS (Method 2): R _t = 1.11 min; MS (ESIpos): m/z = 619/621/623 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 2.073 (8.70), 2.095 (2.02), 2.108 (2.74), 2.128 (3.53), 2.153 (5.13), 2.164 (4.58), 2.180 (9.66 ), 2.212 (1.42), 2.237 (0.76), 2.283 (1.22), 2.311 (1.53), 2.328 (1.16), 2.670 (0.67), 3.832 (0.83), 3.850 (1.05), 3.863 (1.16), 3.876 (1.10 ), 4.087 (1.55), 4.111 (1.70), 4.141 (0.81), 7.476 (1.72), 7.504 (5.34), 7.509 (4.33), 7.513 (4.34), 7.528 (16.00), 7.551 (5.39), 7.586 (2.11 ), 7.593 (2.25), 7.607 (1.58), 7.695 (0.45), 7.741 (0.47), 7.840 (1.67), 7.846 (2.40), 7.863 (2.55), 7.868 (3.83), 7.874 (2.07), 7.935 (4.34 ), 7.940 (3.94), 7.957 (2.78), 7.963 (2.48), 8.927 (1.77), 8.940 (2.09), 12.107 (1.53).

Example 236 (-)-5-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-4-(2,3,6-trichlorophenyl)valeric acid (enantiomer 2) .

tert-Butyl 5-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-4-(2,3,6-trichlorophenyl)pentanoate (280mg, 99% pure, 410 µmol, Example 301A, Enantiomer 2) was dissolved in dichloromethane (3.5 ml). TFA (3.1 ml) was added at RT and the mixture was stirred 2 h at RT. The volatile components were then removed on a rotary evaporator. The residue was mixed twice with some toluene and again concentrated on a rotary evaporator. The residue was dissolved in a small amount of DMSO and purified by preparative HPLC (Method 31). The combined target fractions were concentrated in vacuo and the residue was dried in vacuo. 214 mg (100% pure, 84% th. y.) of the title compound were obtained.

[a] _D20 = -33.9°, 589 nm, c = 0.19 ^g /100 ml, methanol.

LC-MS (Method 2): R _t = 1.11 min; MS (ESIpos): m/z = 619/621/623 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.149 (0.76), -0.008 (6.72), 0.008 (7.91), 0.146 (0.78), 2.073 (5.46), 2.082 (1.42), 2.095 ( 2.02), 2.108 (2.66), 2.128 (3.53), 2.153 (5.18), 2.164 (4.61), 2.180 (9.99), 2.212 (1.38), 2.237 (0.78) 1.49), 2.366 (0.71), 2.670 (1.10), 2.710 (0.64), 3.832 (0.80), 3.863 (1.17), 4.088 (1.56), 4.111 (1.77), 4.140 (0.85), 7.476 (1.77), 5.32) 1.40), 7.863 (2.73), 7.869 (4.03), 7.875 (2.13), 7.935 (4.52), 7.940 (4.06), 7.957 (2.87), 7.963 (2.48), 8.926 (1.83), 8.940 (2.27), 1.05).

Example 237 (+/-)-6-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-5-(2-chlorophenyl)hexanoic acid (racemate)

- 212 040284

To a solution of (+/-)-tert-butyl-6-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-5-(2chlorophenyl)hexanoate (100 mg, 161 µmol, example 302A) in dichloromethane (1.2 ml) was added TFA (120 µl, 1.6 mmol) and the mixture was left for three 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 15). The combined target fractions were concentrated and the residue was lyophilized. 73 mg (100% pure, 80% thor.) of the title compound were obtained.

LC-MS (Method 1): Rt = 2.02 min; MS (ESIpos): m/z = 565/567 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 11.97 (br. s, 1H), 8.85 (t, 1H), 7.94 (d, 1H), 7.85 (dd, 1H), 7.72 (br. s, 1H), 7.56-7.42 (m, 7H), 7.37 (t, 1H), 7.26 (t, 1H), 3.80-3.35 (m, 3H, partially hidden), 2.27-2.06 (m, 5H), 1.87 -1.72 (m, 1H), 1.70-1.57 (m, 1H), 1.53-1.25 (m, 2H).

Example 238 (-)-6-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-5-(2-chlorophenyl)hexanoic acid (enantiomer 1)

To a solution of tert-butyl 6-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-5-(2-chlorophenyl)hexanoate (460 mg, 740 µmol, Example 303A , Enantiomer 1) in dichloromethane (6.2 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 16). The combined target fractions were concentrated and the residue was lyophilized. 367 mg (100% pure, 88% thor.) of the title compound were obtained.

[a] _D20 = -12.4°, 589 nm, c = ^0.37 g/100 ml, methanol.

LC-MS (Method 1): Rt = 2.03 min; MS (ESIpos): m/z = 565/567 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.326 (0.41), 1.339 (0.80), 1.358 (1.09), 1.370 (1.18), 1.384 (1.22), 1.398 (0.94), 1.422 (0.87) , 1.438 (1.19), 1.449 (1.18), 1.457 (1.11), 1.464 (1.30), 1.481 (1.04), 1.497 (0.61), 1.594 (0.46), 1.628 (1.23), 1.640 (1.09), 1.652 (1.32) . . , 7.254 (2.76), 7.273 (1.90), 7.349 (1.67), 7.368 (3.04), 7.386 (1.62), 7.432 (4.96), 7.452 (4.08),7.486 (5.02), 7.502 (8.76), 7.508 (6.18) , 7.521 (16.00), 7.525 (15.01), 7.723 (0.62), 7.835 (2.89), 7.840 (2.55), 7.857 (4.35), 7.862 (4.06), 7.932 (8.15), 7.954 (5.11), 8.834 (1.76) , 8.849 (3.52), 8.863 (1.67).

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 11.95 (br. s, 1H), 8.85 (t, 1H), 7.94 (d, 1H), 7.85 (dd, 1H), 7.72 (br. s, 1H), 7.56-7.42 (m, 7H), 7.37 (t, 1H), 7.26 (t, 1H), 3.77-3.51 (m, 3H, partially hidden), 2.25-2.09 (m, 5H), 1.85 -1.73 (m, 1H), 1.71-1.56 (m, 1H), 1.53-1.25 (m, 2H).

Example 239 (+)-6-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-5-(2-chlorophenyl)hexanoic acid (enantiomer 2)

To a solution of tert-butyl 6-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-5-(2-chlorophenyl)hexanoate (415 mg, 667 µmol, Example 304A , Enantiomer 2) in dichloromethane (5.6 ml) was added with TFA (11.1 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 16). The combined target fractions were concentrated and the residue was lyophilized. 367 mg (100% pure, 88% thor.) of the title compound were obtained.

[a] _D20 = +13.6°, 589 nm, c = 0.44 ^g /100 mL, methanol.

LC-MS (Method 1): Rt = 2.03 min; MS (ESIpos): m/z = 565/567 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 0.008 (1.03), 1.337 (0.89), 1.356 (1.15), 1.369 (1.22), 1.382 (1.24), 1.396 (0.97), 1.421 (0.94 ), 1.436 (1.25), 1.447 (1.20), 1.455 (1.14), 1.462 (1.28), 1.480 (1.00), 1.495 (0.57), 1.592 (0.56), 1.626 (1.26), 1.640 (1.11), 1.650 (1.31 ), 1.662 (0.99), 1.687 (0.45), 1.741 (0.75), 1.754 (1.29), 1.768 (1.40), 1.780 (1.32), 1.814 (0.72), 2.149 (6.09), 2.185 (4.76), 2.204 (7.72 ), 2.222 (3.48), 2.248 (0.41), 3.547 (0.97), 3.584 (1.69), 3.698 (2.95), 7.234 (1.33), 7.253 (2.63), 7.272 (1.78), 7.349 (1.71), 7.368 (2.91 ), 7.386 (1.57), 7.431 (4.72), 7.451 (3.97), 7.485 (5.40), 7.501 (8.92), 7.508 (6.68), 7.520 (16.00), 7.532 (7.56), 7.699 (0.61), 7.834 (2.92 ), 7.839 (2.51), 7.856 (4.20), 7.861 (3.76), 7.930 (7.74), 7.952 (4.78), 8.832 (1.79), 8.847 (3.30), 8.860 (1.53).

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 11.95 (br. s, 1H), 8.85 (t, 2H), 7.94 (d, 1H), 7.85 (dd, 1H), 7.72 (br. s, 1H), 7.56-7.42 (m, 7H), 7.37 (t, 1H), 7.25 (t, 1H), 3.78-3.50 (m, 3H), 2.24-2.09 (m, 5H), 1.85-1.71 ( m, 1H), 1.70-1.57 (m, 1H), 1.54-1.27 (m, 2H).

- 213 040284

Example 240 (+/-)-6-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-5-(2-chlorophenyl)-5methylhexanoic acid (racemate)

To a solution of (+/-)-tert-butyl-6-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-5-(2chlorophenyl)-5-methylhexanoate (866 mg, 1.36 mmol, uncorrected purity, first mixed fraction from example 305A) in dichloromethane (10 ml) was added with TFA (1.0 ml, 14 mmol) and the mixture was left 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 16). Three fractions were concentrated. After vacuum drying, the first fraction gave 189 mg (100% pure) of the first batch of dechlorinated product ((+/-)-6-{[(6-bromo-3-methyl-2-phenylquinolin4-yl)carbonyl]amino}- 5-methyl-5-phenylhexanoic acid, see example 243). From the third fraction, 282 mg (96% pure) of the first batch of the title compound were obtained. The middle fraction was again purified by preparative HPLC (Method 26). Concentration of the appropriate desired fractions and drying in vacuo gave 61 mg (100% pure) of the second batch of dechlorinated product ((+/-)-6-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl ]amino}-5-methyl-5-phenylhexanoic acid, see example 243). In addition, 67 mg (100% pure, see Analysis section) of a second batch of the title compound was obtained.

LC-MS (Method 1): Rt = 2.12 min; MS (ESIpos): m/z = 579/581 [M+H]+.

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.008 (2.57), 1.047 (0.92), 1.066 (1.29), 1.079 (1.36), 1.098 (1.09), 1.110 (0.75), 1.315 (1.08) 1.335 (1.35), 1.347 (1.37), 1.366 (1.11), 1.391 (1.30), 1.529 (16.00), 1.600 (1.04), 1.611 (1.11), 1.633 (1.91), 1.644 (1.75), 1.666 (1.15) . . , 5.754 (8.27), 7.242 (1.04), 7.260 (2.63), 7.279 (2.41), 7.292 (2.38), 7.310 (3.20), 7.327 (1.59), 7.413 (3.43), 7.432 (6.46), 7.451 (3.16) 7.474 (0.83), 7.486 (2.00), 7.500 (6.53), 7.507 (5.67), 7.518 (14.80), 7.524 (13.14), 7.680 (0.60), 7.829 (2.76), 7.833 (2.56), 7.851 (4.25) , 7.856 (4.03), 7.925 (7.72), 7.947 (4.86), 8.590 (1.85), 8.605 (3.26), 8.619 (1.86).

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 12.01 (br. s, 1H), 8.62 (t, 1H), 7.93 (d, 1H), 7.84 (dd, 1H), 7.67 (br. s, 1H), 7.56-7.39 (m, 7H), 7.35-7.21 (m, 2H), 4.31 (dd, 1H), 3.69 (dd, 1H), 2.47-2.35 (m, 1H), 2.24-2.02 ( m, 5H), 1.64 (td, 1H), 1.53 (s, 3H), 1.43–1.25 (m, 1H), 1.15–0.99 (m, 1H).

Separation of enantiomers.

The title target compound (247 mg) was dissolved in methanol (15 ml) and separated into enantiomers by chiral phase preparative SLC (see Examples 241 and 242) [column: Daicel Chiralcel IC, 5 μm, 250 mm x 20 mm; flow: 80 ml/min; sample injection: 0.30 ml; eluent: 25% ethanol/75% carbon dioxide; duration of action 19 min, isocratic]. The combined target fractions were concentrated and the corresponding residue was dried in vacuo.

Example 241 (-)-6-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-5-(2-chlorophenyl)-5methylhexanoic acid (enantiomer 1)

Separation of enantiomers as described in Example 240 gave 66 mg (95% pure, >99% ee) of the title compound as the previously eluted enantiomer.

[a] _D20 = -27.7°, 589 nm, c = 0.35 ^g /100 ml, methanol.

LC-MS (Method 1): Rt = 2.13 min; MS (ESIpos): m/z = 579/581 [M+H]+.

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.048 (0.93), 1.065 (1.23), 1.077 (1.29), 1.095 (1.07), 1.233 (0.55), 1.314 (1.06), 1.332 (1.34) 1.345 (1.33), 1.363 (1.09), 1.390 (1.60), 1.527 (16.00), 1.601 (1.01), 1.610 (1.08), 1.633 (1.83), 1.642 (1.71), 1.665 (1.04), 2.133 (4.41) , 2.151 (5.76), 2.278 (0.54), 2.391 (1.00), 2.414 (1.60), 2.422 (1.59), 2.447 (0.93), 3.667 (1.35), 3.679 (1.46), 3.700 (1.57), 3.712 (1.44) . , 7.343 (0.60) , 7.826 (2.64), 7.848 (4.09), 7.923 (6.70), 7.945 (4.28), 8.596 (1.73), 8.610 (3.12), 8.624 (1.78).

Example 242 (+)-6-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-5-(2-chlorophenyl)-5methylhexanoic acid (enantiomer 2)

Separation of enantiomers as described in Example 240 gave 60 mg (100% pure, >99% ee) of the title compound as the later eluted enantiomer.

- 214 040284

[a] _D20 = +25.7°, 589 nm, c = 0.35 g ^/ 100 mL, methanol.

LC-MS (Method 1): R _t = 2.12 min; MS (ESIpos): m/z = 579/581 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (2.05), 0.008 (1.72), 1.077 (1.24), 1.113 (0.92), 1.232 (0.71), 1.332 (1.25), 1.527 (16.00 ), 1.611 (1.06), 1.633 (1.68), 1.664 (0.94), 2.149 (4.91), 2.277 (0.62), 2.327 (0.64), 2.387 (1.03), 2.414 (1.57), 2.443 (0.98), 2.670 (0.47 ), 3.540 (1.21), 3.668 (1.34), 3.680 (1.37), 3.701 (1.51), 4.288 (1.61), 4.305 (1.81), 4.322 (1.67), 4.338 (1.52), 7.241 (1.12), 7.259 (2.88 ), 7.278 (2.66), 7.291 (2.48), 7.308 (3.45), 7.326 (1.62), 7.411 (3.37), 7.431 (6.32), 7.451 (3.15), 7.472 (1.00), 7.484 (2.24), 7.498 (6.98 ), 7.505 (5.98), 7.516 (14.63), 7.523 (13.31), 7.667 (0.64), 7.825 (3.06), 7.830 (2.78), 7.848 (4.56), 7.853 (4.27), 7.923 (8.71), 7.945 (5.48 ), 8.600 (1.77), 8.615 (2.99), 8.630 (1.66).

Example 243 (+/-)-6-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-5-methyl-5-phenylhexanoic acid (racemate)

As described in Example 240, 189 mg (100% pure, see Analytics) of the first batch of the title compound and 61 mg (100% pure) of the second batch of the title compound were obtained.

LC-MS (Method 1): R _t = 2.07 min; MS (ESIpos): m/z = 545/547 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: -0.150 (0.16), 0.007 (1.24), 0.146 (0.16), 1.141 (0.62), 1.160 (0.85), 1.173 (0.93), 1.192 ( 0.80), 1.204 (0.51), 1.334 (0.82), 1.353 (1.06), 1.366 (1.17), 1.391 (16.00), 1.529 (0.36), 1.586 (0.62), 1.597 (0.70), 1.619 (1.29), 1.23), 1.651 (0.85), 1.661 (0.68), 1.774 (0.75), 1.784 (0.82), 1.806 (1.18), 1.816 (1.12), 1.838 (0.58), 2.085 (1.70), 2.118 (4.12), 6.68) 1.97), 3.584 (1.97), 3.655 (1.18), 3.833 (1.50), 3.850 (1.59), 3.866 (1.33), 3.883 (1.21), 3.964 (0.23) 0.88), 7.213 (2.20), 7.231 (1.49), 7.325 (2.43), 7.344 (4.84), 7.363 (2.95), 7.412 (6.54), 7.431 (4.28), 7.473 (0.54), 7.485 (1.44), 4.46), 7.507 (3.68), 7.518 (8.57), 7.528 (8.40), 7.570 (0.34), 7.588 (0.28), 7.667 (0.57) 2.81), 7.928 (5.42), 7.950 (3.54), 8 .598 (1.29), 8.613 (2.28), 8.628 (1.26).

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 11.97 (br. s, 1H), 8.61 (t, 1H), 7.94 (d, 1H), 7.84 (dd, 1H), 7.67 (br. s, 1H), 7.59-7.46 (m, 5H), 7.45-7.39 (m, 2H), 7.34 (t, 2H), 7.22 (t, 1H), 3.86 (dd, 1H), 3.56 (dd, 1H) , 2.251.98 (m, 5H), 1.81 (td, 1H), 1.62 (td, 1H), 1.45–1.29 (m, 1H), 1.39 (s, 3H), 1.25–1.09 (m, 1H).

Separation of enantiomers.

The title target compound (160 mg) was dissolved in methanol (20 ml) and separated into enantiomers by chiral phase preparative SLC (see Examples 244 and 245) [column: Daicel Chiralpak AD, 250 mm x 20 mm; flow: 80 ml/min; sample injection: 0.50 ml; eluent: 12% ethanol/88% carbon dioxide; duration of action 22 min, isocratic]. The combined target fractions were concentrated and the corresponding residue was dried in vacuo.

Example 244 (-)-6-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-5-methyl-5-phenylhexanoic acid (enantiomer 1)

The separation of enantiomers described in Example 243 gave 56 mg (100% pure, ee value 99%) of the title compound as the previously eluted enantiomer.

[a] _D20 = -18.7°, 589 nm, c = 0.40 ^g /100 ml, methanol.

LC-MS (Method 1): R _t = 2.07 min; MS (ESIpos): m/z = 545/547 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: -0.008 (1.29), 0.008 (1.06), 1.030 (0.82), 1.045 (0.85), 1.140 (0.68), 1.160 (0.92), 1.172 ( 1.00), 1.191 (0.83), 1.333 (0.83), 1.352 (1.07), 1.390 (16.00), 1.585 (0.67), 1.597 (0.76), 1.618 (1.35), 1.629 (1.28), 1.650 (0.90), 1.661 ( 0.71), 1.773 (0.78), 1.782 (0.87), 1.805 (1.23), 1.814 (1.18), 1.837 (0.61), 1.846 (0.52), 2.072 (1.18), 2.115 (4.26), 2.133 (6.73), 2.152 3.32) 1.12), 7.196 (1.02), 7.213 (2.47), 7.231 (1.65), 7.324 (2.71), 7.344 (5.30), 7.363 (3.21), 7.412 (6.82),7.431 (4.23), 7.472 (0.60), 1.69), 7.499 (5.05), 7.506 (4.13), 7.517 (9.35), 7.527 (9.32), 7.545 (1.74), 7.669 (0.66), 7.826 (2.19), 7.831 (1.97), 7.848 (3.28), 3.08), 7.927 (6.46), 7.949 (4.33), 8.602 (1.35), 8.617 (2.32), 8.632 (1.27).

Example 245 (+)-6-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-5-methyl-5-phenylhexanoic acid (enantiomer 2)

The separation of enantiomers described in Example 243 gave 35 mg (100% pure, ee value 94%) of the title compound as the later eluted enantiomer.

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[a]D ²⁰ = +18.0°, 589 nm, c = 0.35 g/100 ml, methanol.

LC-MS (Method 1): Rt = 2.07 min; MS (ESIpos): m/z = 545/547 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.141 (0.68), 1.161 (0.94), 1.173 (1.04), 1.192 (0.85), 1.334 (0.85), 1.353 (1.12), 1.391 (16.00) , 1.587 (0.64), 1.597 (0.75), 1.619 (1.37), 1.629 (1.29), 1.651 (0.91), 1.662 (0.72), 1.784 (0.88), 1.806 (1.25), 1.816 (1.20), 1.839 (0.64) , 2.118 (4.31), 2.137 (6.84), 2.155 (3.37), 2.731 (0.94), 2.890 (1.03), 3.537 (1.19), 3.551 (1.22), 3.571 (1.40), 3.585 (1.31) . , 7.432 (4.22), 7.473 (0.59), 7.485 (1.59), 7.500 (4.92), 7.506 (4.04), 7.518 (9.53), 7.528 (9.42) , 7.849 (3.18), 7.854 (3.09), 7.927 (6.17), 7.949 (4.02), 8.598 (1.37), 8.613 (2.42), 8.628 (1.31), 11.939 (1.52).

Example 246 1-[2-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-1-(2-methoxyphenyl)ethyl]pyrrolidine-3-carboxylic acid

HATU (125 mg , 329 µmol) and DIPEA (110 µl, 660 µmol) and the mixture was stirred for 30 min at RT. Then 1-[2-amino-1-(2methoxyphenyl)ethyl]pyrrolidine-3-carboxylic acid (102 mg, 85% pure, 329 µmol, CAS-RN 886363-84-4, commercially available) dissolved in DMF ( 1 ml) and the mixture was stirred for 3 h at 60°C. The mixture was then mixed with ethyl acetate and water (respectively 20 ml) and shaken. After phase separation, the aqueous phase was extracted twice with ethyl acetate (20 ml). The combined organic phases were washed with saturated aqueous sodium chloride, dried over sodium sulfate, filtered and concentrated. Upon concentration, a solid precipitated out, which was filtered off. The filtrate was concentrated and the residue was adsorbed into dichloromethane and previously purified by flash column chromatography (50 g Biotage Snap-Cartridge KP-Sil, 85:15 cyclohexane/ethyl acetate, Isolera One). The combined target fractions were concentrated and the residue was further purified by preparative HPLC (Method 16). Then again further purified by preparative HPLC (Method 22). Then again further purified by preparative HPLC (Method 25). 4 mg (90% pure, 3% thor.) of the title compound were obtained.

LC-MS (Method 2): R _t = 0.80 & 0.82 min; MS (ESIpos): m/z = 588/590 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.236 (0.85), 1.886 (1.62), 1.899 (1.67), 2.167 (12.14), 2.183 (2.43), 2.256 (0.64), 2.328 (0.71) , 2.366 (0.76), 2.403 (0.48), 2.421 (0.53), 2.451 (0.74), 2.569 (2.03), 2.589 (1.30), 2.637 (0.52), 2.670 (0.72), 2.710 (0.41), 2.765 (2.17) , 2.774 (4.88), 2.834 (1.19), 2.872 (0.89), 2.905 (1.19), 2.939 (2.25), 2.958 (5.33), 3.724 (0.92), 3.783 (16.00), 3.910 (0.82), 4.181 (1.03) , 4.195 (1.76),4.208 (0.91), 4.256 (0.68), 6.928 (1.16), 6.947 (2.36), 6.965 (1.35), 7.003 (2.11), 7.023 (2.44), 7.232 (1.32),7.250 (2.08) , 7.270 (0.95), 7.337 (0.85), 7.354 (1.91), 7.370 (1.78), 7.385 (0.70), 7.474 (0.63), 7.487 (1.71), 7.501 (4.65), 7.506 (4.14), 7.520 (8.73) , 7.531 (9.03), 7.795 (1.46), 7.836 (2.96), 7.860 (3.31), 7.926 (4.22), 7.948 (2.61), 8.584 (1.09), 8.599 (1.48), 8.614 (0.99).

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 T-helper cells

DMEM Medium Needle in Dulbecco's modification

DMSO dimethyl sulfoxide

DP ROI2 receptor (prostaglandin D2 receptor, type 2)

ECso half maximum effective concentration

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Em Emission EP PGE2 receptor (prostaglandin E2 receptor) Ex excitation Fa. Firm (supplier) FCS fetal calf serum FP POP2a receptor HEPES 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid IC50 half-maximal inhibitory concentration IP PGI2 receptor (prostacyclin receptor) Lit. literary source MES 2-(A-morpholino)ethanesulfonic acid Pen/Strep penicil in/streptomycin PGD2 Prostaglandin D2 PGE2 Prostaglandin E2 PGF2a Prostaglandin F2a PGI2 Prostaglandin 12 TC tissue culture TP Thromboxane A2 receptor Tris Tris(hydroxymethyl)aminomethane vol./rev. volume to volume ratio (solution) wt./wt. mass to mass ratio (solution)

B-1. In vitro-Test for blocking human FP receptor activity.

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 plates (Greiner, TC Platte, black with clear bottom) and incubated at 33°C, 5% CO ₂ for 24 h. 5% CO ₂ for 24 hours. 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 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).

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Note. No. FPreceptor activity IC50 [µmol/L] 1 0.13 2 0.16 3 0.27 4 0.031 5 0.037 6 0.032 7 0.024 8 0.13 9 0.0072 10 0.32 eleven 0.47 34 0.13 35 0.19 36 0.81 37 0.16 38 0.047 39 0.14 40 0.034 41 0.13 42 0.12 43 0.14 44 0.19 45 0.60 46 0.23 47 0.043 48 0.033 49 0.069 50 0.079 51 0.042 52 0.071 53 0.18 54 0.50 55 0.078 56 0.021 57 0.21 58 0.0097 59 0.39 60 0.12 61 0.23 62 0.043 63 0.34 64 0.34

Note. No. FPreceptor activity IC50 [µmol/L] 12 0.18 13 0.094 14 0.053 15 0.19 16 0.17 17 0.26 18 0.12 19 0.15 20 0.097 21 0.17 22 0.076 65 0.22 66 0.50 67 0.37 68 >1.0 69 0.048 70 0.032 71 0.036 72 0.045 73 0.086 74 0.079 75 0.069 76 0.023 77 0.085 78 0.10 79 0.14 80 0.051 81 0.19 82 0.22 83 0.28 84 0.016 85 0.016 86 0.24 87 0.023 88 0.019 89 0.027 90 0.47 91 0.46 92 0.32 93 0.080 94 0.096 95 0.084

Table 1

Note. No. FPreceptor activity IC50 [µmol/L] 23 0.53 24 0.58 25 >1.0 26 0.044 27 0.053 28 0.10 29 0.14 thirty 0.34 31 0.068 32 0.15 33 0.19 96 0.023 97 0.12 98 0.0090 99 0.028 100 0.020 101 0.032 102 0.46 103 0.29 104 >1.0 105 0.092 106 0.28 107 0.051 108 0.078 109 0.075 BY 0.075 111 0.089 112 0.092 113 0.062 114 0.018 115 0.031 116 0.074 117 0.24 118 0.28 119 0.15 120 0.030 121 0.010 122 0.46 123 0.011 124 0.0053 125 0.097 126 0.039

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127 0.025 128 ο,ιι 129 0.13 130 0.32 131 0.099 132 0.032 133 0.047 134 0.80 135 0.013 136 0.013 137 0.44 138 0.042 139 0.028 140 >1.0 141 0.024 142 0.015 143 0.0068 144 0.13 145 0.049 146 >1.0 147 >1.0 148 0.042 149 >1.0 150 0.96 151 0.0078 152 0.0079 153 0.0090 154 0.015 155 0.060 156 0.0080 157 0.0037

158 0.0035 159 0.024 160 0.013 161 0.0082 162 0.033 163 0.0087 164 0.015 165 0.0066 166 0.0061 167 0.026 168 0.0036 169 0.026 170 θ,ιι 171 0.011 172 0.0032 173 0.0011 174 0.019 175 0.015 176 0.012 177 0.019 178 0.0065 179 0.0041 180 0.0082 181 0.0092 182 0.0072 183 0.023 184 0.0077 185 0.0039 186 0.017 187 0.036 188 0.054

189 0.062 190 0.067 191 0.10 192 0.042 193 0.15 194 0.0079 195 0.0080 196 0.012 197 0.021 198 0.40 199 0.025 200 0.0036 201 0.0012 202 0.0062 203 0.0076 204 0.0037 205 0.022 206 0.013 207 0.010 208 0.011 209 0.0018 210 0.0061 211 0.0017 212 0.0066 213 0.0028 214 0.0044 215 0.0054 216 0.0050 217 0.019 218 0.013 219 0.010

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220 0.0080 221 0.0024 222 0.00096 223 0.012 224 0.10 225 0.0047 226 0.10 227 0.0016 228 0.0042 229 0.0027 230 0.049 231 0.022 232 0.0088 233 0.025 234 0.0072 235 0.032 236 0.0020 237 0.0052 238 0.0043 239 0.010 240 0.024 241 0.068 242 0.016 243 0.031 244 0.020 245 0.063 246 0.094 247 0.0072 248 0.013 249 0.0028 250 0.017

251 0.015 252 0.014

B-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 modified Tris-HCl buffer, 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,

- 220 040284 which were experiential 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 EP1 receptor binding.

For this test, human recombinant prostanoid EP1 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 #268110). 14 μg of the membrane was incubated with 1 nm [ ³ H]-PGF2 for 60 minutes 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].

B-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 modified MES/KOH buffer, 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°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.: 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 modified MES buffer, 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 IP receptor binding inhibition.

For this test, human recombinant prostanoid IP receptors were used, which were expressed in HEK293 cells, in modified HEPES buffer, pH 6.0. This test has already been proposed (Eurofins Panlabs, catalog #268600). 15 μg of the membrane was incubated with 5 nm of [ 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 mcg meme

- 221 040284 branes 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].

B-11. In vitro test for DP agonism and α-incompatibility.

To characterize the test substance for DP agonism and α-incompatibility, PGD2-induced calcium flux was used in DP-expressed CHEM1 cells (millipores, HTS091C): 3000 cells in 25 µl of complete medium [DMEM, 4.5 g/l glucose, 10% inactivated at elevated temperature FCS, 1% 100x non-essential amino acids, 10 mM HEPES, 0.25 mg/mL geneticin (G418), 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 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 (2 x EC ₅₀ , final concentration) of PGD2 in e.g. calcium-free Tyrode/2 mM CaCl ₂ solution and determine the calcium flux by measuring fluorescence at Ex. 470 nm/Em. 525 nm in 120 s. [Lit.: 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 HEPES, 0.25 mg/mL geneticin (G418), 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 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 (2 x EC ₅₀ , final concentration) of PGE2 in, for example, calcium-free Tyrode/2 mM CaCl ₂ solution and determine the calcium flux by measuring fluorescence at Ex. 470 nm/Em. 525 nm in 120 s. [Lit.: 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: 5093-5096].

B-13. In vitro test for EP2 agonism and α-incompatibility.

PGE2-induced calcium flux in EP2-expressed CHEM9 cells (millipores, HTS185C) was used to characterize the test substance for EP2 agonism and -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 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 Na

- 222 040284

HCO 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 (2 x EC ₅₀ , final concentration) of PGE2 in, for example, calcium-free Tyrode/2 mM CaCl ₂ solution and determine the calcium flux by measuring fluorescence at Ex. 470 nm/Em. 525 nm in 120 s. [Lit.: C. R. Kennedy et al. (1999) Nat. Med. 5:217-220; S. Narumiya and GA Fitzgerald (2001) J. Clin. Invest. 108:25-30; N. Yang et al. (2003) J. Clin. Invest. Ill: 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 (splice 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 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 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 (2 x EC ₅₀ , final concentration) of PGE2 in e.g. calcium-free Tyrode/2 mM CaCl2 solution and determine the calcium flux by measuring fluorescence at Ex. 470 nm/Em. 525 nm in 120 s. [Ref.: M. Kotani et al. (1995) Mol. Pharmacol. 48:869-879; M. Kotani et al. (1997) Genomics 40: 425-434; T. Kunikata et al. (2005) Nat. Immunol. 6:524-531; S. Narumiya and GA Fitzgerald (2001) J. Clin. Invest. 108:25-30; F. Ushikubi et al. (1998) Nature 395: 281-284].

B-15. In vitro test for EP4 agonism and -incompatibility.

PGE2-induced calcium flux in EP4-expressed CHEM1 cells (millipores, HTS142C) was used to characterize the test substance for EP4 agonism and -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 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 MgCl2, 4.8 mm NaHCO ₃ , 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 nm/Em. 525 nm 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 (2 x EC ₅₀ , final concentration) of PGE2 in, for example, calcium-free Tyrode/2 mM CaCl ₂ solution and determine the calcium flux by measuring fluorescence at Ex. 470 nm/Em. 525 nm in 120 s. [Lit.: 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/ 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

- 223 040284 was carefully prepared in DMSO at various concentrations (initial concentration 10 mM, dilution factor 3.16) as a dose-effect curve and pre-diluted 1:50 with, for example, 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 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, activate the IP receptor in FLIPR Tetra® by adding 20 μl ~106 nm (2 x EC ₅₀ , final concentration) of iloprost in, for example, calcium-free Tyrode/2 mM CaCl ₂ solution and determine the calcium flux by measuring fluorescence at Ex. 470 nm/Em. 525 nm in 120 s. [Lit.: S. Narumiya et al. (1999) Physiol. Rev. 79:1193-1226; T. Murata et al. (1997) Nature 388: 678682; Y Cheng et al. (2002) Science 296: 539-541; CH 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 α-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 hours. 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 NaHCO ₃ , 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. The cells were then incubated at 37°C/5% CO ₂ for 10 min. To determine TP incompatibility, activate the TP receptor in FLIPR Tetra® by adding 20 μl ~88 nm (2 x EC ₅₀ , final concentration) U46619 in, for example, calcium-free Tyrode/2 mM CaCl ₂ solution and determine the calcium flux by measuring fluorescence at Ex. 470 nm/Em. 525 nm in 120 s. [Lit.: S. Ali et al. (1993) J. Biol. Chem. 268: 17397-17403; K. Hanasaki et al. (1989) Biochem. Pharmacol. 38: 2967-2976; M. Hirata et al. (1991) Nature 349: 617-620].

B-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)]. Lung tissue, in particular, is affected by 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 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 (forcible

- 224 040284 224 040284 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 silicate instillation or therapeutically after 3-14 days and continue for 3-12 weeks . At the end of the study, bronchoalveolar lavage is performed to determine the content of cells and pro-inflammatory and fibrosing markers, as well as a measurement of lung function and a histological assessment of pulmonary fibrosis.

B-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 (by force-feeding, addition to food or drinking water, using an osmotic mini-pump, subcutaneous or intraperitoneal injection, or inhalation) begins on the day of the first installation of DQ12-quartz or one day later and continues 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 fibrosing markers.

B-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. CCl4 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 CCl4 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 administration of the compound of formula (I) began 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.

B-22. Animal model of unilateral ureteral obstruction (UOM) in 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 C57Bl6J 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 of the control group (SHAM) with a visible operation, only an opening of the abdominal cavity was performed, 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 assessment of renal tissues.

B-23. Silica-induced pulmonary fibrosis in mice. Therapeutic chronic 30-day study with an FP antagonist.

Adult female C57Bl6J 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. Kon

- 225 040284 the untreated trol 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 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, 75 x 4.6 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 c < 0.05 was considered significant.

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 untreated, 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 thread. 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:

Paw Response Threshold (β) = ——

Xf is the value (in logarithmic units) of the last used Frey threads;

k is the table value for the positive/negative response sample (see Chaplan et al., J. Neurosci. Meth. 1994, 53, 56-63, appendix 1, p. 62);

δ is the average difference (in logarithmic 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 Dosage (mg/kg) Dosage volume drug base Note. Day of Treatment/Frequency 1 Fluprosten ol -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 Fluprosten ol -0.15 20 µl 10%DMSObPBS IPL day 0, T = 0 Note. 153 90 5 ml/kg DMSO/PEG400/H2O (10/60/30) PO Zx, T = -2, 8, 22 h 3 Fluprosten ol - 1.5 20 µl 10%DMSObPBS IPL day 0, T = 0 Medicinal base / 5 ml/kg DMSO/PEG400/H _2Q (10/60/30) PO Zx, T = -2, 8, 22 h 4 Fluprosten ol - 1.5 20 µl 10%DMSObPBS IPL day 0, T = 0 Note. 153 90 5 ml/kg DMSO/PEG400/H2O (10/60/30) PO Zx, T = -2, 8, 22 h

IPL: intraplantar injection; PO: oral.

- 226 040284

To evaluate the analgesic effect of an FP antagonist on fluprostenol-induced mechanical sensitivity, the test substance from Example 153 (90 mg/kg) was administered 2 hours before and 8 hours, and 22 hours after fluprostenol administration. Ipsilateral and contralateral 50% hindlimb response thresholds are measured before fluprostenol administration and 0.5, 2, 6 and 24 hours after administration. In the 1.5 mg/kg fluprostenol group, the increase in oral administration from Example 153 (90 mg/kg) 50% hindlimb response threshold at 0.5 h after fluprostenol administration is significant compared to drug-treated animals. In the 0.15 mg/kg fluprostenol group, the increase in oral administration from Example 153 (90 mg/kg) 50% hind limb response threshold is significant compared to animals treated with the drug base 24 hours after fluprostenol administration (see Table 2).

Table 2. 50% Hind Limb Response Threshold (r)

Time (h) Group 1 Group 2 Group 3 Group 4 „50% hindlimb response threshold“ Average value SEM Average value SEM Average value SEM Average value SEM BL (baseline) 4.674 0.9985 4.421 0.9326 4.35 0.9245 4.215 0.9664 0.5 0.975 0.2096 2.65 0.8343 0.229 0.1135 0.728 0.2598 2 1.164 0.3284 2.403 0.8626 0.536 0.2116 0.716 0.2451 6 0.732 0.1917 1.89 0.8388 0.936 0.2443 1.57 0.5395 24 0.816 0.17 3.245 0.8173 1.225 0.3563 1.683 0.7927

C. Examples of pharmaceutical compositions.

Compounds according to the invention can be converted in the following way into pharmaceutical preparations.

Pills.

Composition: 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.

Preparation: A mixture of a compound according to the invention, lactose and starch is granulated with a 5% (m/m) 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.

Composition: 1000 mg of the 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.

Preparation: Rhodigel is made into a suspension in ethanol, the suspension is added to the compound according to the invention. Water is added while stirring. Finally, the swollen Rhodigel is stirred for about 6 hours.

Orally administered solutions.

Composition: 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.

Preparation: 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.

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 (8)

CLAIM 1. Compound of formula (I) ABOUT in which Ar means phenyl or pyridyl, and phenyl can be substituted up to four times and pyridyl once, 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 fluorine (C ₁ -C ₂ )alkoxy, or moreover, two substituents of the phenyl group, if connected to adjacent ring atoms, can be connected to each other so that together they form a methylenedioxy group, Y means a bond or a group of formula # ¹ -X-(CR ^10A R ^10B ) _k -# ² or 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, -CH2-, -O-, -S(=O)m- or -N(R ¹¹ )-, where m is 0 or 2, and R ¹¹ means hydrogen or methyl, R ^10A and R ^10B are independently hydrogen, fluorine or methyl, k is 1, 2 or 3, R ¹ means halogen or ethynyl, R ² , R ³ and R ⁴ are independently hydrogen, R ⁵ means halogen or (C ₁ -C ₄ )αkyl, R ⁶ means phenyl, R ^7A and R ^7B are independently hydrogen or methyl, R ⁸ means hydrogen, fluorine, methyl, ethyl or hydroxy, R ⁹ means hydrogen, as well as their salts. 2. The compound of formula (I) according to claim 1, in which Ar is phenyl or 2-pyridyl, where the phenyl may be substituted up to four times with fluorine, or up to three times, equally or differently, with fluorine, chlorine, methyl, trifluoromethyl, methoxy, difluoromethoxy, trifluoromethoxy, or ethoxy, or where two substituents on the phenyl group, if they are connected to adjacent ring atoms, they can be so connected to each other that together they form a methylenedioxy group, and moreover, 2-pyridyl can be substituted once by chlorine or methoxy, 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 -CH2-, -O-, -S(=O) _m - or -N(R ¹¹ )-, where m means 0 or 2 and R ¹¹ means hydrogen or methyl, R ^10A and R ^10B are independently hydrogen, fluorine or methyl, k is 1, 2 or 3, R ¹ means bromine or ethynyl, R ² means hydrogen, R ³ and R ⁴ are hydrogen, R ⁵ means chlorine or methyl, and R ⁶ means phenyl, - 228 040284 R ^7A means hydrogen or methyl, R ^7B means hydrogen, R ⁸ means hydrogen, fluorine, methyl, ethyl or hydroxy, R ⁹ means hydrogen, as well as their salts. 3. The compound of formula (I) according to claim 1 or 2, in which Ar is phenyl, where phenyl may be substituted up to four times with fluorine or up to three times, equally or differently, with fluorine, chlorine, methyl, trifluoromethyl, methoxy, difluoromethoxy or trifluoromethoxy, Y means a group of the formula # ¹ -(CH2)n-# 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, 2 or 3, R ¹ means bromine or ethynyl, R ² , R ³ and R ⁴ are respectively hydrogen, R ⁵ means chlorine or methyl, and R ⁶ means phenyl, R ^7A and R ^7B are respectively hydrogen, R ⁸ means hydrogen or methyl, R ⁹ means hydrogen, as well as their salts. 4. The compound of formula (I) according to one of claims 1 to 3, in which Ar is phenyl, where phenyl may be substituted up to four times with fluorine or up to three times, equally or differently, with fluorine, chlorine, methyl, trifluoromethyl or trifluoromethoxy, Y means a group of the formula # ¹ -CH2CH2 - # 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 or ethynyl, R ² , R ³ , R ⁴ are respectively hydrogen, R ⁵ means methyl or chlorine, R ⁶ means phenyl, R ^7A , R ^7B , R ⁸ and R ⁹ are respectively hydrogen and their salts. 5. A process for the preparation of a compound of formula (I) as defined in one of claims 1 to 4, characterized in that the compound of formula (II) in which R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ have the meanings given in paragraphs 1-4, in the first stage [A] upon activation of the carboxylic acid function is reacted with an amine compound of formula (III-A) or (III-B) Oh Oh ^x r ⁹ (lll-A) ⁴ r ⁹ (Ill-B) in which R ^7A , R ^7B , R ⁸ , R ⁹ and Ar have the meanings given in paragraphs 1-4, and T means the protective group of esters, which is (C ₁ -C ₄ )alkyl, and in the next step [B] separating the residue T of the ester of the compound of formula (IV) obtained in step [A] after reaction with the amine compound (III-B) - 229 040284 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 meanings given in paragraphs 1-4, and T means a protective group of complex ethers, which is (C1-C ₄ )alkyl, and thus obtain the compounds of formula (I) 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 meanings given in paragraphs 1-4. 6. Process according to claim 5, characterized in that the compounds of formula (I) are additionally converted with appropriate bases or acids into their salts. 7. An active substance having FP receptor antagonist properties, which is a compound of formula (I) as defined in one of claims 1 to 4. 8. 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 4, in combination with one or more inert, non-toxic, pharmaceutically acceptable excipients.