EA038451B1 - 7-substituted 1-aryl-naphthyridine-3-carboxylic acid amides and use thereof - Google Patents

Abstract

The invention concerns novel 7-substituted 1-aryl-naphthyridine-3-carboxylic acid amides, methods for producing the same, intermediates and the use thereof for producing compounds of the invention, the use of the compounds of the invention for producing medicaments for the treatment and/or prevention of diseases, especially for the treatment and/or prevention of cardiovascular diseases and/or kidney diseases.

Description

The invention relates to new 7-substituted 1-aryl-naphthyridine-3-amides of carboxylic acids, methods for their preparation, their use alone or in combinations for the treatment and / or prevention of diseases, as well as their use for the manufacture of drugs for the treatment and / or prevention of diseases, in particular for the treatment and / or prevention of cardiovascular diseases and / or kidney diseases.

Muscarinic receptors are membrane constant receptors that, as an endogenous ligand, bind the acetylcholine (ACh) mediator (acetylcholine receptors) and can also be activated by muscarin. These G-protein coupled receptors are present in five subtypes (M1-M5), which are expressed in almost all tissues in the human body. They are present in both the central and peripheral nervous systems, as well as in many organs of the autonomic nervous system.

The M2 type (M2R) is predominantly expressed in the heart. At the cellular level, stimulation of the M2R agonist acetylcholine causes inhibition of adenyl cyclase and activation of the inwardly rectified potassium channel (IKACh channel, GIRK: G protein activated inwardly rectifying K + channel; also Kir3.x). This increases the permeability of potassium, which leads to hyperpolarization of muscle cells. In accordance with this, cells become less depolarized, which leads to negative chronotropic and dromotropic effects, which reduces the heart rate. M2R is a major mediator of the parasympathetic control of cardiac function, which is controlled by the vagus nerve. In this case, the right vagus nerve through the sinus nodes reduces the heart rate, the left vagus nerve through the atrioventricular nodes (AB-nodes) predominantly increases the atrioventricular conduction time. Overall, compared to the sympathetic nerve, the influence of the vagus nerve on resting heart rate is stronger. Thus, the effect of M2R stimulation is opposite to that of beta-adrenergic stimulation.

The activation of the M2 receptor by an endogenous agonist acetylcholine, as well as a synthetic analogue such as carbachol, oxotremorine-M or iperoxo (Schrage et al., Biochem. Pharmacol. 2014, 90 (3), 307-319), is carried out by combining the agonist with the so-called the orthosteric site of the interlacing of the receptor and thus released a change in the conformation of the receptor or stabilization of the active conformation of the receptor. The classical agonists of the muscarinic receptor of natural origin, in addition to the endogenous agonist acetylcholine (ACh), include various plant alkaloids such as arecoline, muscarine, and pilocarpine (Neubig et al., Pharmacol Rev., 2003, 55, 597-606). Orthosteric sites of interlacing of all muscarinic acetylcholine receptors are evolutionarily strongly preserved and show a high homology of sequences and structures between different subtypes. Therefore, many of the known agonists are nonselective towards various subtypes of muscarinic acetylcholine receptors (Kruse et al., Mol Pharmacol., 2013, 84 (4), 528540). M2R, in addition to an orthosteric weave site, also displays an allosteric weave site (Gregory et al., Current Neuropharmacol., 2007, 5 (3), 157-167). The oldest known allosteric modulator is gallamine (Clark and Mitchelson, Br. J. Pharmac, 1976, 55, 323-331).

Allosteric modulators differ significantly from classical, orthosteric ligands. The allosteric modulator itself has no direct effect on receptor activation. By using an allosteric modulator compound, modulation of the compound's affinity and / or the efficacy of orthosteric agonists is more likely to occur. The effect of an allosteric modulator can develop only in the presence of an endogenous ligand. This implies the spatial and temporal specificity of the allosteric effect (Conn et al., Nat. Rev. Drug Disc., 2009, 8, 41-54; Conn et al., Nat. Rev. Drug. Disc, 2014, 13, 692- 708). In addition, the effect of an allosteric modulator is self-limiting if it stabilizes the agonist compound at high concentrations. This again results in a favorable reliable pharmacological profile compared to agonists, since toxic effects are conditionally limited to receptor activation (Christopoulos, Mol. Pharmacol., 2014, 86, 463-478).

Called cooperativity, the interaction of an allosteric and orthosteric ligand with respect to affinity and intrinsic activity is determined by two ligands. In the case of a positive allosteric modulator M2R, the effects of ACh (orthosteric ligand) are enhanced (positive cooperativity). Based on their ability to modulate receptor conformations in the presence of an orthosteric ligand, allosteric ligands can induce fine tuning of pharmacological effects (Wang et al., J. Pharmacol. Exp. Therap., 2009, 331, 340-348). On this basis, in the case of a positive allosteric modulator M2R, a preferred action profile, a reduced risk of side effects and insertion for the development of subtype-selective ligands are expected compared to full agonists.

About positive allosteric M4R and M2R-ligand LY2119620 (3-amino-5-chloro-Ncyclopropyl-4-methyl-6- [2- (4-methylpiperazin-1-yl) -2-oxoethoxy] thieno [2,3-b ] puridin-2-carboxyamide) is evidenced by the crystal structure in a complex with M2R. The allosteric junction of the M2R is adjacent but clearly separated from the orthosteric junction and, compared to other muscarinic receptor subtypes, shows little stabilization or shows more sequence differences (Kruse et al., Nature, 2013, 504, 101-106). LY2119620 described

- 1 038451 as a non-selective M2R / M4R positive allosteric modulator (Croy et al., Molecular

Pharmacology, July 2014, 86, 1, 106-115; Schober et al., Molecular Pharmacology, July 2014, 86, 1, 116-123).

M2R, as a component of the autonomic nervous system, plays an important role in the pathogenesis and progression of cardiovascular diseases. Autonomic imbalance is characterized by parasympathetic weakening (weakening of the vagus nerve) and the dominance of the sympathetic nervous system is closely associated with increased morbidity and mortality. The clinical and prognostic significance of autonomic imbalance is well documented in various diseases of the cardiovascular system, including heart failure, cardiac arrhythmias, ischemia / reperfusion (I / R), hypertension (He et al., Br. J. Pharmacol. 2014, Epub) and chronic kidney disease (Ranpuria et al., Nephrol. Dial. Transplant. 2008, 23 (2), 444-4499). In patients with comorbidities such as diabetes, autonomic imbalance can increase morbidity and mortality (Vinik et al., Diabet Med., 2011, 28 (6), 643-651). Dysfunctions of baroreceptor reflexes, such as hypertensive crisis or instability of high blood pressure, often accompany the acute phase of ischemic or hemorrhagic paralysis as a sign of impaired autonomic nervous system (Sykora et al., Stroke, 2009, 40 (12), 678-682).

The often observed comorbidity between cardiovascular and mental illness, as between heart failure and depression, is likely based on common pathomechanisms that are accompanied by autonomic imbalance (Halaris et al., Mod Trends., 2013, 28, 144-161). Chronic stress shifts the homeostatic balance of the autonomic nervous system. Reduced parasympathicotonia leads to a pro-inflammatory state, and the regulation of mediators, in particular serotonergic transmission, deteriorates. Other mental disorders are also associated with autonomic dysregulation, such as attention deficit / hyperactivity disorder (ADHS), which are characterized by disinhibition, lack of emotional self-control, inattention and hyperactivity (Rash and Aguirre-Camacho, Atten Defic Hyperact Disord., 2012, 4 (4), 167-177).

Therefore, the enhancement of parasympathetic activity by a positive allosteric modulator, including the expected anti-inflammatory effects, an increase in nitrogen monoxide (NO) content, regulation of the redox state, improvement of mitochondrial function and calcium regulation, may represent a new principle in the treatment of diseases of the cardiovascular system. There are many indications for considering modulation of parasympathetic activity as a potential treatment target for chronic heart failure. Stimulation of the vagus nerve in dogs that have suffered myocardial infarction was able to significantly reduce the incidence of new cases and sudden cardiac deaths, as well as reduce mortality in rats with chronic heart failure (De Ferrari, J. Cardiovasc. Transl. Res., 2014, 7 (3 ), 310-320). In a dog model with heart failure (LVEF 35%) with an implanted vagus nerve stimulator, it was possible to prove that in the treatment group, compared with the control group, there was a significant improvement in left ventricular ejection fraction (LVEF) and a decrease in end-diastolic and diastolic volume (LVESV; LVEDV). as well as a significant reduction in heart rate within 3 months. The described effect of VNS was in addition to the administration of beta-blockers (De Ferrari, J. Cardiovasc. Transl. Res., 2014, 7 (3), 310-320). Plasma levels for TNF-α and IL-6, as well as their myocardial protein expression, can be lowered in this animal model by stimulation of the vagus nerve, suggesting that strengthening the parasympathetic nervous system, in addition to affecting LV reconstruction, also has a positive effect on proinflammatory cytokine.

In the meantime, based on experimental preclinical data, conducted the first clinical trials for vagal stimulation in patients with chronic heart failure, as already described in the treatment of epilepsy and depression. The effect of strengthening the parasympathetic nervous system by direct stimulation of the vagus nerve (VNS) was established in a non-random study of 32 patients with left ventricular (LV) systolic dysfunction, with results indicating that stimulation of the vagus nerve has a positive effect on quality of life, ability to tolerate exercise and LV reconstruction (De Ferrari GM et al., Eur. Heart J., 2011, 32, 847-855). In addition to standard treatment, the multicentric feasibility study ANTHEM-HF tested the reliability, compatibility and efficacy of vagus nerve stimulation in patients with chronic stable, symptomatic heart failure with reduced ejection fraction (HFrEF) (Premchand RK et al., J. Card Fail. 2014,20 (11) 808-816). Continuous vagal stimulation used in this study resulted in improvements in ejection fraction, heart rate instability, NYHA grade, and quality of life. In contrast, the first clinical studies with placebo control group NECTAR-HF showed no significant effect of vagus nerve stimulation on HF cardiac function in patients after 6 months (Zannad et al., Eur. Heart J., 2015, 36 (7), 425-433), could only improve the quality of life. INOVATE-HF studies with 650 HF patients failed to show the effect of this treatment in terms of mortality and hospitalization. (Gold et al., J. Am. Coll. Cardiol., 2016, Mar 29. pii: S0735-1097 (16) 32404-4. Doi:

- 2 038451

10.1016 / j.jacc.2016.03.525). The quality of life and walking distance could be significantly improved.

In addition to the risk of infection and the potential risks of surgery, therapy with electrostimulation of the vagus nerve is limited to side effects such as dysphonia, cough, and pain in the mouth and throat (Premchand RK et al., J. Card. Fail., 2014, 20 (11) , 808-816). Medicinal strengthening of the parasympathetic nervous system through direct action on the M2R may represent a new treatment option.

Atrial fibrillation is the most common, persistent heart rhythm disorder that increases with age (Chen et al., Circ. Res., 2014, 114 (9), 1500-1515). Atrial fibrillation and heart failure are often associated and exacerbated. Thus, atrial fibrillation increases with clinical severity of heart failure (Maisel and Stevenson, Am. J. Cardiol., 2003, 91, (suppl) 2D-8D). Clinical evidence suggests that patients in whom heart failure accompanies atrial fibrillation has a poor prognosis. Both mortality (general mortality, sudden death and cardiac failure) and mortality (hospitalization) were significantly increased in this group of patients.

During atrial fibrillation therapy, two treatment strategies are distinguished: the so-called heart rate control with setting and, if possible, normalizing the ventricular rate within atrial fibrillation and the so-called rhythm control, which contains measures to establish or maintain sinus rhythm. Effective treatment consists of a combination of non-drug as well as medical or invasive methods (Levalter T., Fortbildungsprogramm Pharmazie, 2011, 5, 106-127).

For pharmacological control of the rhythm after cardiac defibrillation, beta-blockers, class I and class III antiarrhythmics are used in accordance with the underlying heart disease and according to the limitations of left ventricular pumping function. Patients with continuous atrial fibrillation, as well as asymptomatic (most often older patients) patients with persistent or paroxysmal atrial fibrillation, often only choose to control the frequency of contractions while maintaining atrial fibrillation as treatment. Primarily, drugs are used that affect the refractory period or the volume of AV nodes. This effect can in principle be achieved by stimulating the M2R, which physiologically plays a major role in this place, for example, using a positive allosteric modulator. Beta-blockers, digitalis, calcium antagonists, and in some cases amiodarone are still available, which are individually taken, taking into account the lifestyle, underlying heart disease or possible concomitant diseases. However, in particular, in patients with reduced left ventricular pumping function and more severe form of heart failure, the possibilities of drug therapy are limited. Calcium antagonists are contraindicated in this group of patients. Recent studies have shown that digoxin therapy leads to increased mortality in patients with atrial fibrillation (Leong-Sit and Tang, Curr. Opin. Cardiol., 2015, Epub). A meta-analysis has shown the lack of efficacy of beta-blockers in patients with atrial fibrillation and heart failure (Leong-Sit and Tang, Curr. Opin. Cardiol., 2015, Epub). Therefore, the medical need for new effective and reliable therapies to control the heart rate is high enough. This could be achieved with M2R drug stimulation.

It is an object of the present invention to identify and provide novel substances which are potent, positively allosteric modulators of the muscarinic M2 receptor and which are useful for the treatment and / or prevention of, in particular, cardiovascular diseases and / or kidney diseases.

1-Benzyl-substituted 4-oxo-1,4-dihydroquinoline-3-carboxylic acids as allosteric modulators of the M1 muscarinic receptor for the treatment of neurodegenerative diseases such as Alzheimer's disease and schizophrenia are described in (Scammells et al., ACS Chem. Neurosci., 2013, 4 (7), 1026-1048; Mistry et al., J. Med. Chem. 2013, 56, 5151-5172.). Also from EP 0945435 B1 pyridone carboxylic acid derivatives are known which also have antibacterial activity. In WO 2002/085886-A2, WO 2003/050107-A1 and WO 2005/026145-A2, derivatives of 7-piperidino-substituted quinolone carboxylic acid are presented, as well as in WO 2005/026165-A1 and WO 2005/049602-A1 various derivatives of 7-pyrrolidine-substituted quinolone carboxylic acid, as well as in EP 1650192-A1 special derivatives of 7-azetidinylquinolone carboxylic acid with antimicrobial / antibacterial activity are described. Quinolone derivatives are known from WO 2005/009971-A1 and JP 2005012561 which can be used as platelet aggregation blockers. WO 2015/189560-A1 describes 1,4-dihydroquinoline derivatives as NPRC agonists for the treatment of cardiovascular diseases. Quinolone carboxylic acid derivatives as MCT modulators are described in WO 2016/081464-A1, in particular for the treatment of tumor diseases and inflammatory processes.

- 3 038451

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

in which X is halogen,

R ¹ means hydrogen, or means -NR4R ⁵ , where R ⁴ means hydrogen, methyl, (C ₂ -C ₄ ) alkyl or (C ₃ -C ₆ ) cycloalkyl, and (C ₂ -C ₄ ) alkyl may be substituted by hydroxyl or up to three times fluorine, and

R ⁵ means (C ₁ -C ₆ ) alkyl, (C ₃ -C ₆ ) cycloalkyl, 3-6-membered saturated heterocyclyl or (C ₁ -C ₄ ) alkylsulfonyl, wherein (C ₁ -C ₆ ) alkyl, (C ₃ -C ₆ ) cycloalkyl and 3-6-membered saturated heterocyclyl can be substituted up to three times, the same or differently, with methyl, difluoromethyl, trifluoromethyl, hydroxyl, hydroxycarbonyl, oxo, methoxy, difluoromethoxy, trifluoromethoxy, cyano and further up to four times with fluorine , or

R ⁴ and R ⁵ together with the nitrogen atom to which they are attached form a saturated or partially unsaturated 3-6 membered monocyclic or 6-10 membered bicyclic heterocycle, which may contain one or two additional, identical or different heteroatoms from the series N , O, S, SO and / or SO2 as a ring member, wherein the 3-6 membered monocyclic and 6-10 membered bicyclic heterocycle, respectively, may be substituted with 1-5 substituents independently selected from the group (C1-C4 ) alkyl, difluoromethyl, trifluoromethyl, hydroxyl, hydroxycarbonyl, oxo, (C1-C3) alkoxy, difluoromethoxy, trifluoromethoxy, cyano, (C1-C3) alkoxycarbonyl, aminocarbonyl, mono (C1-C3) alkylaminocarbonyloxy, -NHC (= O) ^14A , -CH2NHC (= O) R ^14B , OC (= O) R ¹⁵ , and then up to four times with fluorine, where (C ₁ -C ₄ ) alkyl can be substituted once or twice, equally or differently, with hydroxyl, ( C ₁ -C ₃ ) alkoxy and up to four times fluorine,

R ^14A and R ^14B independently represent (C ₁ -C ₃ ) alkyl or cyclopropyl,

R ¹⁵ is (C ₁ -C ₄ ) alkyl;

R ² means a group of formula r \ r ^6B \ / or * —L ¹ —Ag ^{2 zY 7} where * denotes the place of attachment of the amide group to the nitrogen atom,

R ^6A means hydrogen or (C ₁ -C ₄ ) alkyl,

R ^6B means hydrogen, (C ₁ -C ₄ ) alkyl, cyclopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, methoxymethyl or trifluoromethoxymethyl,

R ⁷ means (C ₁ -C ₆ ) alkyl or up to four times substituted by fluorine (C ₃ -C ₅ ) cycloalkyl, and (C ₁ -C ₆ ) alkyl may be substituted by amino, hydroxyl, (C ₁ -C ₆ ) alkoxy and up to five times with fluorine, where (C ₁ -C ₆ ) alkoxy may be substituted up to five times with fluorine,

L ¹ means a bond or a group of the formula -C (R ^8A R ^8B ) - (C (R ^9A R ^9B )) m-, where m is 0 or 1,

R ^8A is hydrogen or methyl,

R ^8B represents hydrogen, methyl, trifluoromethyl, pentafluoroethyl or trifluoromethoxymethyl,

R ^9A and R ^9B independently represent hydrogen or methyl,

Ar ² means phenyl, where phenyl can be substituted from one to three times, identically or differently, with fluorine, chlorine, (C ₁ -C ₃ ) alkyl, difluoromethoxymethyl, trifluoromethoxymethyl and / or trifluoromethyl, or means 5-10 membered monocyclic, a bicyclic or tricyclic carbocycle or heterocycle, which may contain one or two additional, identical or different heteroatoms from the series N, O, S, SO and / or SO2 as a ring member, wherein the 5-10 membered monocyclic, bicyclic or tricyclic carbocycle, or the heterocycle can be substituted up to three times, identically or differently, (C ₁ -C ₃ ) alkyl, trifluoromethyl, (C ₁ -C ₄ ) alkoxycarbonyl and further up to four times with fluorine,

Ar ¹ means a group of formula ***

where *** denotes the place of attachment to the nitrogen atom, R ^3A denotes fluorine, chlorine, trifluoromethyl or methyl, R ^3B denotes hydrogen or fluorine,

- 4 038451

R ^3C means hydrogen, fluorine, chlorine or methyl, or means a pyridine ring bonded to a carbon atom of the ring, and the pyridine ring can be substituted once or twice with fluorine, chlorine, cyano, methyl or trifluoromethyl, as well as their N-oxides, salts , solvates, salts of N-oxides and solvates of N-oxides and salts.

The compounds according to the invention are compounds of formula (I) and their salts, solvates and solvates of salts, compounds of the following named formulas and their salts, solvates and solvates of salts encompassed by formula (I), as well as those encompassed by formula (I), named in the following as exemplary compounds and their salts, solvates and solvates of salts, insofar as in the case of the compounds covered by formula (I) in the following, we are no longer talking about salts, solvates and solvates of salts.

The compounds according to the invention are also the N-oxides of the compounds of the formula (I) as well as their salts, solvates and salt solvates.

As salts within the scope of the present invention, preferred are the physiologically unquestionable salts of the invention, as well as salts which are themselves not suitable for pharmaceutical use, but which can be used, for example, for the isolation, purification or storage of the compounds of the invention.

A suitable pharmaceutically acceptable salt of the compounds of this invention may, for example, mean an acid addition salt of a compound of this invention with a basic nitrogen atom in the chain or ring, as an acid addition salt with an inorganic acid or mineral acid, for example, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfamic acid, pyrosulfuric acid, phosphoric acid or nitric acid, or with organic acids such as formic acid, acetic acid, acetoacetic acid, pyruvic acid, trifluoroacetic acid, propionic acid, hepanoic acid, hextoic acid , undecanoic acid, lauric acid, benzoic acid, salicylic acid, 2- (4-hydroxybenzoyl) benzoic acid, camphoric acid, cinnamic acid, cyclopentanepropionic acid, digluconic acid, 3-hydroxy-2-naphthoic acid, niacinic acid pitch tinic acid, 3-phenylpropionic acid, pivalic acid, 2-hydroxy-ethanesulfonic acid, itaconic acid, trifluoromethanesulfonic acid, dodecyl-sulfuric acid, ethanesulfonic acid, benzenesulfonic acid, paratoluenesulfonic acid, methanesulfonic acid citric acid, tartaric acid, stearic acid, lactic acid, oxalic acid, malonic acid, succinic acid, malic acid, adipic acid, alginic acid, maleic acid, fumaric acid, D-gluconic acid, mandelic acid, ascorbic acid, ascorbic acid glycerophosphoric acid, aspartic acid, sulfosalicylic or thiocyanic acid.

In addition, another suitable pharmaceutically acceptable salt of the acidic compound of this invention is an alkali metal salt such as sodium or potassium salt, an alkaline earth metal salt such as a calcium, magnesium or strontium salt, or an aluminum or zinc or ammonium salt, which is derived from ammonia or an organic primary, secondary or tertiary amine with 1-20 carbon atoms, such as ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, diethylaminoethanol, trimethaninebenzylamino arginine, lysine, 1,2-ethylenediamine, N-methylpiperidine, N-methylglucamine, N, N-dimethylglucamine, N-ethylglucamine, 1,6-hexanediamine, glucosamine, sarcosine, serinol, 2-amino-1,3-propanediol, 3-amino-1,2-propanediol, 4-amino-1,2,3-butanetriol, or a salt with a quaternary ammonium ion with 1-20 carbon atoms, such as tetramethylammonium, tetraethylammonium, tetra (n-propyl) ammonium nium, tetra (n-butyl) ammonium, N-benzyl-N, N, Ntrimethylammonium, choline or benzalkonium.

It is further known to a person skilled in the art that acid addition salts of the claimed compounds can be prepared by replacing the compounds with the corresponding inorganic or organic acids by several known methods. Alternatively, alkali and alkaline earth metal salts of the acidic compounds of the invention can be prepared by substituting the compounds of the invention with appropriate bases using known methods.

The present invention includes all possible salts of the compounds of this invention as separate salts or mixtures of these salts in any ratio.

If in this text, in particular in the experimental part, for the synthesis of intermediates and examples of this invention are named compounds in the form of salts with the corresponding base or salt, then the exact stoichiometric composition of the salt form, which was obtained using the corresponding method of preparation and / or purification, in most cases unknown. Unless otherwise indicated, additions to chemical names or structural formulas that refer to a salt, such as hydrochloride, trifluoroacetate, sodium salt or x HCl, x CF3COOH, x Na ⁺ denote a salt form, the stoichiometry of this salt is not indicated. This applies to those cases in which the intermediate products of the synthesis or compounds of the examples or their salts were obtained using the described methods of preparation or purification in the form of solvates, for example in the form of hydrates.

In the context of the invention, solvates are those forms of the compounds according to the invention which, in the solid or liquid state, form a complex with solvent molecules. Hydrates are a special form of solvates that reconcile with water. Hydrates are preferred solvates in the context of the present invention.

The compounds according to the invention, depending on their structure, can exist in different 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 atropic isomers). Therefore, the present invention contains enantiomers and diastereoisomers and mixtures thereof. From such mixtures of enantiomers and / or diastereoisomers, stereoisomeric single components can be isolated in a known manner. For this, a chromatographic method is preferably used, in particular HPLC chromatography of achiral or chiral separation phases. In the case of using a carboxylic acid as an intermediate or final product, it is also possible, alternatively, to carry out a resolution via the diastereoisometric salt with chiral amine bases.

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

Enantiomer 1 (area percent) - Enantiomer 2 (area percent)

Enantiomer 1 (area percent) + Enantiomer 2 (area percent) x 100%.

Since the compounds according to the invention can occur in tautomeric forms, the present invention contains all tautomeric forms.

The present invention also contains all suitable isotopic variations of the compounds of the invention. An isotopic variant of a compound according to the invention is here understood as a compound in which at least one atom within the compound according to the invention is changed to another atom with the same serial number, but with a different atomic mass with a common or naturally occurring atomic mass predominantly in nature (unnatural component) ... The expression “unnatural component” should be understood to mean components of such an isotope that are present in a greater amount than those common in nature. Used in this context, the abundance of isotopes in nature is described in Isotopic Compositions of the Elements 1997, Pure Appl. Chem., 70 (1), 217-235, 1998. Examples of isotopes that can be included in the compound according to the invention are such as hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine and iodine, such as 2H (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 a compound according to the invention, such as, in particular, those in which one or more radioactive isotopes are attached, can be useful, for example, to study the mechanism of action or distribution of biologically active substance in the body; because of the relatively easy preparation and detection, compounds marked with ³ H or ¹⁴ C isotopes are suitable for this. Based on this, the introduction of isotopes, such as deuterium, can lead to certain therapeutic benefits 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, can also represent a preferred embodiment of the present invention. In view of the treatment and / or prevention of the disorders indicated herein, isotopic variants of the compounds of general formula (I) preferably contain deuterium (deuterium-containing compounds of general formula (I)). Isotopic variants of general formula (I), in which one or more radioactive isotopes, such as ³ H or ¹⁴ C, are embedded, are used, for example, in studies on the distribution of drugs and / or substrate. Because of their easy incorporation and detectability, these isotopes are particularly preferred. ^{Positron-emitting isotopes such as 18} F or ⁿ C can be incorporated into the compound of general formula (I). These isotopic variants of compounds of formula (I) are suitable for use in in vivo medical imaging. Compounds of general formula (I) containing deuterium or ¹³ C can be used in preclinical and clinical studies in mass spectrometric analyzes (HJ Leis et al., Curr. Org. Chem., 1998, 2, 131). Isotopic variants of the compounds according to the invention can also be obtained by conventional methods known to the person skilled in the art, for example, by the methods described below and further demonstrated in the described examples of execution by the methods, while using the corresponding isotopic modifications of the reagents and / or starting compounds.

Isotopic variants of compounds of general formula (I), in general, can be obtained using methods known to the person skilled in the art, as shown in the schemes described here and / or in the examples, by replacing the reaction with an isotopic variant of the reaction, preferably a reaction containing deuterium. Depending on the desired site of deuterization, in some cases it is possible to incorporate deuterium from D2O either directly directly into compounds, or into reactions that can be used for synthesis

6,038,451 similar compounds (Esaki et al., Tempahedron, 2006, 62, 10954; Esaki et al., Chem. Eur. J., 2007, 13, 4052). Deuterium gas is also a useful reagent for incorporating deuterium into a molecule. A quick way to incorporate deuterium is catalytic deuterization of olefinic compounds (HJ Leis et al., Curr. Org. Chem., 1998, 2, 131; JR Morandi et al., J. Org. Chem., 1969, 34 (6), 1889 ) and acetylene compounds (NH Khan, J. Am. Chem. Soc., 1952, 74 (12), 3018; S. Chandrasekhar et al., Tetrahedron, 2011, 52, 3865). Metal catalysts (i.e., Pd, Pt and Rh) in the presence of deuterium gas can also be used to directly exchange hydrogen for deuterium in functionalized hydrocarbons (J.G. Atkinson et al., US-Patent 3,966,781). Various deuterium-containing synthesis reagents and components are commercially available from companies such as C / D / N Isotopes, Quebec, Canada; Cambridge Isotope Laboratories Inc., Andover, MA, USA; and CombiPhos Catalysts, Inc., Princeton, NY, USA. Other information regarding existing deuterium-hydrogen exchange technologies is found, for example, in Hanzlik et al., J. Org. Chem. 1990, 55, 39923997; R.P. Hanzlik et al., Biochem. Biophys. Res. Commun. 1989,160,844; P.J. Reider et al., J. Org. Chem. 1987, 52, 3326-3334; M. Jarman et al., Carcinogenesis, 1993,16 (4), 683-688; J. Atzrodt et al. Angew. Chem., Int. Ed. 2007, 46, 7744; K. Matoishi et al., 2000, J. Chem. Soc, Chem. Commun. 1519-1520; K. Kassahun et al., WO 2012/112363.

The term deuterium-containing compound of general formula (I) means a compound of general formula (I), in which one or more hydrogen atoms are replaced by one or more deuterium atoms, and in which the frequency of deuterium in each position of the compound of general formula (I) is higher than natural the repeatability of deuterium, which is approximately 0.015%. In particular, in the deuterium-containing compound of general formula (I), the frequency of deuterium in each of its positions is higher than 10, 20, 30, 40, 50, 60, 70 or 80%, preferably higher than 90, 95, 96 or 97%, still more preferably above 98 or 99% at this position or these positions. This means that the repeatability of deuterium in each of its positions does not depend on the repeatability of deuterium in another position of deuterium.

By selectively incorporating one or more deuterium atoms into the compound of general formula (I), the physicochemical properties can be changed (such as acidity [A. Streitwieser et al., J. Am. Chem. Soc., 1963, 55, 2759 ; CL Perrin et al., J. Am. Chem. Soc., 2007, 129, 4490], basicity [CL Perrin, et al., J. Am. Chem. Soc., 2003, 125, 15008; CL Perrin in Advances in Physical Organic Chemistry, 44, 144; CL Perrin et al., J. Am. Chem. Soc., 2005, 127, 9641], lipophilia [B. Testa et al., Int. J. Pharm., 1984, 19 (3), 271]) and / or the metabolic profile of the molecule and change the ratio of the main compound to metabolites or the amount of metabolites formed. Such changes can lead to certain therapeutic benefits and are therefore preferred under certain conditions. A decrease in metabolic rate and a change in metabolism, due to which the ratio of metabolites changes, is written in (DJ Kushner et al., Can. J. Physiol. Pharmacol., 1999, 77, 79; AE Mutlib et al., Toxicol. Appl. Pharmacol., 2000, 169, 102). These changes in exposure to the parent compound and metabolites can have important implications for the pharmacodynamics, compatibility and efficacy of the deuterium-containing compound of general formula (I). In some cases, with the help of a deuterium salt, the formation of undesirable or toxic metabolites is reduced or stopped and the formation of desirable metabolites is enhanced (for example, nevirapine: A. M. Sharma et al., Chem. Res. Toxicol., 2013, 26, 410; Uetrecht et al. ., Chemical Research in Toxicology, 2008, 21, 9, 1862; Efavirenz: AE Mutlib et al., Toxicol. Appl. Pharmacol., 2000, 169, 102). In some cases, the main effect of deuterization is to reduce the rate of systemic clearance. Because of this, the half-life of the compound is increased. Potential biological benefits include the ability to maintain a similar systemic exposure with a low maximum high concentration and an increased minimum concentration. Depending on the pharmacokinetic / pharmacodynamic relationship of the compound concerned, this may lead to minor side effects and increased efficacy. An example of this deuterium effect is indiplon (AJ Morales et al., Abstract 285, The 15 ^th North American Meeting of the International Society of Xenobiotics, San Diego, CA, 12.-16. October, 2008), ML-337 (CJ Wenthur et al., J. Med. Chem., 2013, 56, 5208) and odanacitib (K. Kassahun et al., WO 2012/112363). Other cases have been reported in which low metabolic rates lead to increased drug exposure without altering the rate of systemic clearance (eg, rofecoxib: F. Schneider et al., Arzneim. Forsch. Drug. Res., 2006, 56, 295; Telaprevir: F. Maltais et al., J. Med. Chem., 2009, 52, 7993). Deuterium drugs that exhibit these effects may have low dosage requirements (eg, few doses or low dosages to achieve the desired result) and / or result in low metabolite loads.

Compounds of general formula (I) can have many potential metabolic targets. In order to optimize the above-described effects on the physicochemical properties and the metabolic profile, deuterium-containing compounds of general formula (I) with a specific pattern of one or more deuterium-hydrogen exchanges can be selected. In particular, the deuterium atom / atoms of the deuterium-containing compounds of the general formula (I) are bonded to the carbon atom and / or stands / stand in the positions of the compounds of the general formula (I), which mean the positions of the action for enzymes

- 7 038451 metabolism, such as cytochrome P ₄₅₀ .

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

Alkyl itself and the alk and alkyl particles in alkoxy, alkylsulfonyl, alkylaminocarbonyloxy and alkoxycarbonyl denote a linear or branched alkyl radical, usually with 1-6, preferably 1-4 or 1-3 carbon atoms, for example and preferably denotes methyl, ethyl, n-propyl, isopropyl, tert-butyl, isobutyl (2-methyl-prop-1-yl), n-pentyl, and n-hexyl.

Alkoxy, for example and preferably, means methoxy, ethoxy, n-propoxy, isopropoxy, tert-butoxy, n-pentoxy and n-hexoxy.

Alkylaminocarbonyloxy means an alkylaminocarbonyloxy radical with one or two (independently selected) alkyl substituents. (Cl-C ₃ ) Alkylaminocarbonyloxy means, for example, a monoalkylaminocarbonyloxy residue with 1-3 carbon atoms or a dialkylaminocarbonyloxy residue with 1-3 carbon atoms per alkyl substituent, respectively. For example, methylaminocarbonyloxy, ethylaminocarbonyloxy, n-propylaminocarbonyloxy, isopropylaminocarbonyloxy, tert-butylaminocarbonyloxy, n-pentylaminocarbonyloxy, n-hexylaminocarbonyloxy, N, N-dimethylaminocarbonyloxy, N, N-dimethylaminocarbonyloxy, N-dimethylaminocarbonyloxy N-methyl-N-n-propylaminocarbonyloxy, N-isopropyl-N-n-propylaminocarbonyloxy, N-tert-butyl-N-methylaminocarbonyl, N-ethyl-N-n-pentylaminocarbonyl and N-n-hexyl-N-methylaminocarbonyloxy.

Alkylsulfonyl in the context of the invention means a straight or branched chain alkyl radical with 1-4 carbon atoms bonded by a sulfonyl group. For example, methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl, n-butylsulfonyl and tert-butylsulfonyl are to be mentioned as preferred.

Alkoxycarbonyl, for example and preferably, means methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl and tert-butoxycarbonyl.

A carbocycle in the context of the invention means a mono-, poly- or spirocyclic, preferably mono- or bicyclic saturated carbocycle with 3-6 ring atoms. A monocyclic, saturated carbocycle is called synonymously cycloalkyl. For example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, spiro [2.3] hexyl, spiro [2.4] heptyl, spiro [2.5] octyl, bicyclo [1.1.1] pentyl , bicyclo [2.2.1] heptyl, bicyclo [2.2.2] octyl, tricyclo [3.3.1.13,7] decyl.

Preferably means monocyclic cycloalkyl with 3-5 carbon atoms. For example and preferably cyclopropyl, cyclobutyl, cyclopentyl, bicyclo [2.2.1] heptyl, or bicyclo [1.1.1] pent-1 -yl should be mentioned.

Heterocyclyl means mono-, poly- or spirocyclic, preferably mono-, bi- or spirocyclic, non-aromatic heterocyclic radical, usually with 3-10 ring atoms and containing up to 3, preferably up to 2 heteroatoms and / or hetero groups from the series N, O , S, SO, SO ₂ . Bicyclic spirocyclic heterocyclic residues within the meaning of this invention are to be encompassed by the definition of a bicyclic heterocycle. Heterocyclic residues can be saturated or partially unsaturated. Preferred are 4-6 membered monocyclic saturated heterocyclic radicals with one nitrogen atom, such as radicals with another heteroatom from the series N or O, as well as 6-7 membered bi- or spirocyclic saturated heterocyclic radicals with one nitrogen atom. For example, the following should be named as preferred: azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, oxazolidinyl, imidazolidinyl, morpholinyl, tetrahydropyrimidine, azabicyclo [3.1.0] hexyl, azaspiro [2.4] heptyl or 2-oxa-6 ]azaspit -il.

Halogen means fluorine, chlorine, bromine and iodine, preferably fluorine and chlorine.

In a formula for a group where R ¹ , R ² , Ar ^1, or L ^{1 is} , the end point of the line on which the # 1 symbol is located; *, ** and *** does not mean a carbon atom or, for example, not a CH ₂ group, but a component of a compound with a correspondingly designated atom to which R1, R ² , Ar ¹ or L ¹ are bonded.

If the residues in the compounds according to the invention are substituted, they may, unless otherwise indicated, be substituted singly or repeatedly. Within the framework of the present invention, it is valid for all residues that occur several times that their meaning is independent of each other. If the residues in the compounds according to the invention are substituted, they may, unless otherwise indicated, be substituted singly or repeatedly. Substitution with one or two or three identical or different substituents is preferred.

In the present invention, such a concept as treatment or treatment includes restraining, slowing down, delaying, alleviating, weakening, reducing, reducing, suppressing, restraining or curing a disease, ailment, disease, damage or disorder related to health, development, course or the progression of such a condition and / or symptoms of such a condition. At the same time, the concept of therapy is synonymous with the concept of treatment.

The terms prevention or prophylaxis within the framework of this invention can be used as synonyms and mean the prevention or reduction of the risk of acquiring, receiving, experiencing or having a disease, ailment, disease, damage or disorder associated with health, development, course or progression of such a condition. and / or symptoms of such a condition.

Treatment or prevention of illness, illness, disease, injury, or health related disorder may be complete or partial.

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

X means fluorine, chlorine or bromine,

R ¹ means hydrogen, or means NR ⁴ R ⁵ , where R ⁴ means hydrogen, methyl or ethyl and R ⁵ means (C ₁ -C ₃ ) alkyl, up to four times substituted with fluorine, and (C ₁ -C ₃ ) alkyl can be substituted with hydroxyl, or

R ⁴ and R ⁵ together with the nitrogen atom to which they are attached form a saturated 4-6 membered monocyclic or 6-9 membered bicyclic heterocycle, which may contain one or two additional, identical or different heteroatoms from the series N and / or O as a ring member, wherein the 4-6 membered monocyclic and 6-9 membered bicyclic heterocycle, respectively, may be substituted with 1-4 substituents independently selected from the group (C ₁ -C ₄ ) alkyl, difluoromethyl, trifluoromethyl, hydroxyl, oxo, (C ₁ -C ₃ ) alkoxy, difluoromethoxy, trifluoromethoxy, (C ₁ -C ₃ ) alkoxycarbonyl, (C ₁ -C ₃ ) alkylaminocarbonyloxy, -OC (= O) R ¹⁵ , and then up to four times with fluorine where (C ₁ -C ₄ ) alkyl may be substituted once or twice, identically or differently, with hydroxyl, (C ₁ -C ₃ ) alkoxy and up to four times with fluorine,

R ¹⁵ is (C ₁ -C ₄ ) alkyl;

R ² means a group of the formula

where * denotes the place of attachment of the amide group to the nitrogen atom,

R ^6A means hydrogen or (C ₁ -C ₄ ) alkyl,

R ^6B means methyl, ethyl, isopropyl, cyclopropyl, monofluoromethyl, difluoromethyl, or trifluoromethyl,

R ⁷ means (C ₁ -C ₄ ) alkyl, up to five times substituted with fluorine, (C ₃ -C ₅ ) cycloalkyl, up to four times substituted with fluorine, methoxymethyl or trifluoromethoxymethyl,

L ¹ means a bond or a group of the formula -CR ^8A R ^8B -, where R ^8A is hydrogen,

R ^8B represents hydrogen, methyl, trifluoromethyl, pentafluoroethyl or trifluoromethoxymethyl,

Ar ² means phenyl, where phenyl may be substituted one to three times, the same or differently, with fluorine or chlorine, or means a 5-7 membered bicyclic carbocycle or a 5-6 membered monocyclic heterocycle which contains a nitrogen atom as a ring member , wherein 5-7 membered bicyclic carbocycle or 5-6 membered monocyclic heterocycle, respectively, may be substituted by (C ₁ -C ₄ ) alkoxycarbonyl and further up to four times with fluorine,

Ar ¹ means a group of the formula

where *** denotes the place of attachment to the nitrogen atom,

R ^3A means fluorine, chlorine, trifluoromethyl or methyl,

R ^3B means hydrogen or fluorine,

R ^3C means hydrogen, fluorine, chlorine or methyl, or means a pyridine ring bonded to a carbon atom of the ring, the pyridine ring being substituted once or twice by fluorine, chlorine or cyano, as well as their salts, solvates and salt solvates.

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

X means fluorine, chlorine or bromine,

R ¹ means NR4R ⁵ , where R ⁴ means methyl or ethyl, and

R ⁵ means methyl, 2-hydroxyethyl or 2-hydroxypropyl,

- 9 038451 or means a heterocycle of the formula attached to a nitrogen atom

where ** denotes the place of attachment to the remainder of the molecule,

R ¹⁰ is fluorine, methyl, hydroxyl, hydroxymethyl, methoxycarbonyl or acetyloxy, p is the number 0, 1 or 2, and in the case when substituents R ¹⁰ occur repeatedly, their meanings can be the same or different, respectively,

Y ¹ represents -NH-, -N (CH ₃ ) - or -O-,

R ² means a group of the formula

where * denotes the place of attachment of the amide group to the nitrogen atom,

R ^6A means hydrogen, methyl or ethyl,

R ^6B means methyl, ethyl, trifluoromethyl, isopropyl or cyclopropyl,

R ⁷ means methyl, ethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, isopropyl, isobutyl, methoxymethyl, trifluoro-methoxymethyl or cyclopropyl,

R ¹¹ means hydrogen,

R ¹² means methoxycarbonyl,

R ¹³ means hydrogen or tert-butoxycarbonyl,

L ¹ means a bond or a group of the formula -CR ^8A R ^8B -, where R ^8A is hydrogen,

R ^8B is hydrogen, methyl or trifluoromethyl,

Ar ² means phenyl, and phenyl may be substituted once or twice, identically or differently, with fluorine or chlorine,

Ar ¹ means a group of the formula

where *** denotes the place of attachment to the nitrogen atom,

R ^3A means fluorine or chlorine, and

R ^3C means hydrogen or fluorine, as well as their salts, solvates and salt solvates.

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

X means fluorine,

R ¹ means a heterocycle of the formula attached to a nitrogen atom

where ** denotes the place of attachment to the remainder of the molecule, R ² denotes a group of the formula

where * denotes the place of attachment of the amide group to the nitrogen atom,

- 10 038451

R ^7A means trifluoromethyl, ethyl or cyclopropyl,

R ^7B means methyl or ethyl,

R ^7C means trifluoromethyl or pentafluoroethyl,

Ar ¹ means a group of the formula

where *** denotes the place of attachment to the nitrogen atom, as well as their salts, solvates and solvates of salts.

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

X means fluorine,

R ¹ means a heterocycle of the formula attached to a nitrogen atom

where * * denotes the place of attachment to the remainder of the molecule, R ² denotes a group of the formula

* denotes the place of attachment of the amide group to the nitrogen atom, denotes a group of the formula where

Ar ¹

where *** denotes the place of attachment to the nitrogen atom, as well as their salts, solvates and solvates of salts.

Another preferred embodiment of the present invention encompasses compounds of formula (I), in which

X means fluorine,

R ¹ means a heterocycle of the formula attached to a nitrogen atom

where * * denotes the place of attachment to the remainder of the molecule,

R ¹⁰ is fluorine, methyl, hydroxyl, hydroxymethyl, methoxycarbonyl or acetyloxy, p is the number 0, 1 or 2, and in the case when substituents R ¹⁰ occur repeatedly, their meanings can be the same or different, respectively,

R ² means a group of formula ^F CF ₃

CH ₃

- 11 038451 where * denotes the place of attachment of the amide group to the nitrogen atom,

Ar ¹ means a group of formula ***

F where *** denotes the place of attachment to the nitrogen atom, as well as their salts, solvates and solvates of salts.

Also the subject of the present invention are compounds of general formula (I) o o 'χιΥ' ⁸ ' ^Ap1 b), in which X is halogen,

R ¹ means hydrogen, or means -NR4R ⁵ , where R ⁴ means hydrogen, methyl, (C ₂ -C ₄ ) α-alkyl or (C ₃ -C ₆ ) cycloalkyl, and (C ₂ -C ₄ ) alkyl may be substituted by hydroxyl or up to three times fluorine, and

R ⁵ means (C ₁ -C ₆ ) alkyl, (C ₃ -C ₆ ) cycloalkyl, 3-6-membered saturated heterocyclyl or (C ₁ -C ₄ ) alkylsulfonyl, wherein (C ₁ -C ₆ ) alkyl, (C ₃ -C ₆ ) cycloalkyl and 3-6-membered saturated heterocyclyl can be substituted up to three times, the same or differently, with methyl, difluoromethyl, trifluoromethyl, hydroxyl, hydroxycarbonyl, oxo, methoxy, difluoromethoxy, trifluoromethoxy, cyano and further up to four times with fluorine , or

R ⁴ and R ⁵ together with the nitrogen atom to which they are attached form a saturated or partially unsaturated 3-6 membered monocyclic or 6-10 membered bicyclic heterocycle, which may contain one or two additional, identical or different heteroatoms from the series N , O, S, SO and / or SO2 as a ring member, wherein the 3-6 membered monocyclic and 6-10 membered bicyclic heterocycle, respectively, may be substituted with 1-5 substituents independently selected from the group (C1-C4 ) alkyl, difluoromethyl, trifluoromethyl, hydroxyl, hydroxycarbonyl, oxo, (C1-C3) alkoxy, difluoromethoxy, trifluoromethoxy, cyano, (C1-C3) alkoxycarbonyl, aminocarbonyl, mono- (C1-C3) αalkylaminocarbonyl = O) -NHC ( R ^14A , -CH2NHC (= O) R ^14B , -OC (= O) R ¹⁵ , and then up to four times with fluorine, where (C ₁ -C ₄ ) α-alkyl may be substituted once or twice, identically or differently, with hydroxyl , (C ₁ -C ₃ ) alkoxy and up to four times fluorine,

R ^14A and R ^14B are each independently represent a (C1-C3) -alkyl or cyclopropyl, R ¹⁵ represents (C1-C ₄₎ Alkyl,

R ² means a group of the formula

where * denotes the place of attachment of the amide group to the nitrogen atom,

R ^6A means hydrogen, methyl, ethyl, n-propyl, isopropyl, tert-butyl, isobutyl, (2-methyl-prop-1 -yl) or cyclopropyl,

R ^6B means hydrogen, methyl, ethyl, n-propyl, isopropyl, tert-butyl, isobutyl, (2-methyl-prop-1-yl), cyclopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, methoxymethyl or trifluoromethoxymethyl,

R ⁷ means (C ₁ -C ₆ ) alkyl or up to four times substituted by fluorine (C ₃ -C ₅ ) cycloalkyl, and (C ₁ -C ₆ ) alkyl can be substituted by amino, hydroxyl, (C ₁ -C ₆ ) alkoxy and up to five times with fluorine, where (C ₁ -C ₆ ) alkoxy can be substituted up to five times with fluorine,

L ¹ means a bond or a group of the formula -C (R ^8A R ^8B ) - (C (R ^9A R ^9B )) m-, where m is 0 or 1,

R ^8A is hydrogen or methyl,

R ^8B represents hydrogen, methyl, trifluoromethyl, pentafluoroethyl or trifluoromethoxymethyl,

R ^9A and R ^9B independently represent hydrogen or methyl,

Ar ² means phenyl, where phenyl can be substituted from one to three times, identically or differently, with fluorine, chlorine, (C ₁ -C ₃ ) alkyl, difluoromethoxymethyl, trifluoromethoxymethyl and / or trifluoromethyl, or means 5-10 membered monocyclic, bicyclic or tricyclic carbocycle or heterocycle, which may contain one or two additional, identical or different heteroatoms from the series N and / or O as a ring member, and the 5-10 membered monocyclic, bicyclic or tricyclic carbocycle or heterocycle may be substituted by up to three once,

- 12 038451 the same or different, (C ₁ -C ₃ ) α-alkyl, trifluoromethyl, (C ₁ -C ₄ ) alkoxycarbonyl and then up to four times with fluorine,

Ar ¹ means a group of the formula

where *** denotes the place of attachment to the nitrogen atom,

R ^3A means fluorine, chlorine, trifluoromethyl or methyl,

R ^3B means hydrogen or fluorine,

R ^3C means hydrogen, fluorine, chlorine or methyl, or means a pyridine ring bonded to a carbon atom of the ring, and the pyridine ring can be substituted once or twice with fluorine, chlorine, cyano, methyl or trifluoromethyl, as well as their N-oxides, salts , solvates, salts of N-oxides and solvates of N-oxides and salts.

Preferred within the scope of the present invention are compounds in which

X means fluorine,

R ¹ means a heterocycle of formula (I) attached to a nitrogen atom,

where ** denotes the place of attachment to the remainder of the molecule, R ² denotes a group of the formula

where * denotes the place of attachment of the amide group to the nitrogen atom, Ar ¹ denotes a group of the formula

where *** denotes the place of attachment to the nitrogen atom, as well as their salts, solvates and solvates of salts.

Preferred within the scope of the present invention are compounds in which

X means fluorine,

R ¹ means a heterocycle of formula (I) attached to a nitrogen atom,

where ** denotes the place of attachment to the remainder of the molecule, R ² denotes a group of the formula

where * denotes the place of attachment of the amide group to the nitrogen atom, Ar ¹ denotes a group of the formula where *** denotes the place of attachment to the nitrogen atom, as well as their salts, solvates and solvates of salts.

- 13 038451

Another preferred embodiment of the present invention encompasses compounds of formula (I) in which X is fluorine or chlorine.

Another preferred embodiment of the present invention encompasses compounds of formula (I) in which X is fluorine, as well as their N-oxides, salts, solvates, N-oxide salts and N-oxide and salt solvates.

Another preferred embodiment of the present invention encompasses compounds of formula (I) in which X is chlorine, as well as their N-oxides, salts, solvates, N-oxide salts and N-oxide and salt solvates.

Another preferred embodiment of the present invention encompasses compounds of formula (I) in which X is bromine, as well as their N-oxides, salts, solvates, N-oxide salts and N-oxide and salt solvates.

Another preferred embodiment of the present invention encompasses compounds of formula (I), in which R ¹ is NR4R ⁵ , where R ⁴ is methyl or ethyl and R ⁵ is methyl, 2-hydroxyethyl or 2-hydroxypropyl, as well as their N-oxides, salts, solvates, N-oxide salts and N-oxide and salt solvates.

Another preferred embodiment of the present invention encompasses compounds of formula (I), in which

R ¹ means a heterocycle of the formula attached to a nitrogen atom

where ** denotes the place of attachment to the remainder of the molecule,

R ¹⁰ is fluorine, methyl, hydroxyl, hydroxymethyl, methoxycarbonyl or acetyloxy, p is the number 0, 1 or 2, and in the case when substituents R ¹⁰ occur repeatedly, their meanings can be the same or different, respectively,

Y ¹ represents -NH-, -N (CH3) - or -O-, as well as their N-oxides, salts, solvates, salts of N-oxides and solvates of N-oxides and salts.

Another preferred embodiment of the present invention encompasses compounds of formula (I) in which R ¹ is a nitrogen-attached heterocycle of formula

where ** denotes the place of attachment to the remainder of the molecule, as well as their N-oxides, salts, solvates, salts of N-oxides and solvates of N-oxides and salts.

Another preferred embodiment of the present invention encompasses compounds of formula (I) in which R ¹ is a nitrogen-attached heterocycle of formula

where ** denotes the place of attachment to the remainder of the molecule, as well as their N-oxides, salts, solvates, salts of N-oxides and solvates of N-oxides and salts.

Another preferred embodiment of the present invention encompasses compounds of formula (I) in which R ¹ is a nitrogen-attached heterocycle of formula

where ** denotes the place of attachment to the remainder of the molecule, as well as their N-oxides, salts, solvates, salts of N-oxides and solvates of N-oxides and salts.

Another preferred embodiment of the present invention encompasses compounds of formula (I), in which R ¹ is a nitrogen-attached heterocycle of formula

where ** denotes the place of attachment to the remainder of the molecule, as well as their N-oxides, salts, solvates, salts of N-oxides and solvates of N-oxides and salts.

Another preferred embodiment of the present invention encompasses compounds of formula (I) in which R ¹ is trans- (3R, 4R) -3,4-dihydroxypyrrolidin-1-yl of formula

where ** denotes the place of attachment to the remainder of the molecule, as well as their salts, solvates and solvates of salts.

Another preferred embodiment of the present invention encompasses compounds of formula (I) in which R ¹ is cis- (R, S) -3,4-dihydroxypyrrolidin-1-yl of formula

where ** denotes the place of attachment to the remainder of the molecule, as well as their salts, solvates and solvates of salts.

Another preferred embodiment of the present invention encompasses compounds of formula (I) in which R ¹ is a nitrogen-attached heterocycle of formula

where ** denotes the place of attachment to the remainder of the molecule, as well as their N-oxides, salts, solvates, salts of N-oxides and solvates of N-oxides and salts.

Another preferred embodiment of the present invention encompasses compounds of formula (I) in which R ² is a group of formula

where * denotes the place of attachment of the amide group to the nitrogen atom,

R ^6A means hydrogen, methyl or ethyl,

R ^6B means methyl, ethyl, trifluoromethyl, isopropyl or cyclopropyl,

R ⁷ means methyl, ethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, isopropyl, isobutyl, methoxymethyl, trifluoromethoxymethyl or cyclopropyl, as well as their N-oxides, salts, solvates, salts of N-oxides and solvates of N- oxides and salts.

Another preferred embodiment of the present invention encompasses compounds of formula (I) in which R ² is a group of formula

where * denotes the place of attachment of the amide group to the nitrogen atom,

R ^6A means hydrogen, methyl or ethyl,

R ^6B means methyl, ethyl, trifluoromethyl, isopropyl, tert-butyl or cyclopropyl,

R ⁷ means methyl, ethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, isopropyl, isobutyl, methoxymethyl, trifluoromethoxymethyl or cyclopropyl, as well as their N-oxides, salts, solvates, salts of N-oxides and solvates of N- oxides and salts.

Another preferred embodiment of the present invention encompasses compounds of formula (I) in which R ² is a group of formula * —L —Ag ² where * is the point of attachment of the amide moiety to the nitrogen atom,

L ¹ means a bond or a group of the formula -CR ^8A R ^8B -, where R ^8A is hydrogen,

R ^8B is hydrogen, methyl or trifluoromethyl,

Ar ² means a group of the formula

- 15 038451

where # ¹ denotes the place of attachment to the remainder of the molecule, as well as their N-oxides, salts, solvates, salts of N-oxides and solvates of N-oxides and salts.

Another preferred embodiment of the present invention encompasses compounds of formula (I) in which R ² is a group of formula

where * denotes the place of attachment of the amide group to the nitrogen atom,

R ^7A means trifluoromethyl, ethyl or cyclopropyl,

R ^7B means methyl or ethyl,

R ^7C means trifluoromethyl or pentafluoroethyl, as well as their N-oxides, salts, solvates, salts of N-oxides and solvates of N-oxides and salts.

Another preferred embodiment of the present invention encompasses compounds of formula (I) in which R ² is a group of formula

where * denotes the place of attachment of the amide group to the nitrogen atom, as well as their N-oxides, salts, solvates, salts of N-oxides and solvates of N-oxides and salts. Another preferred embodiment of the present invention encompasses compounds of formula (I) in which R ² is a group of formula

where * denotes the place of attachment of the amide group to the nitrogen atom, as well as their N-oxides, salts, solvates, salts of N-oxides and solvates of N-oxides and salts. Another preferred embodiment of the present invention encompasses compounds of formula (I) in which R ² is a group of formula

where * denotes the place of attachment of the amide group to the nitrogen atom, as well as their N-oxides, salts, solvates, salts of N-oxides and solvates of N-oxides and salts.

Another preferred embodiment of the present invention encompasses compounds of formula (I) in which R ² is a group of formula

where * denotes the place of attachment of the amide group to the nitrogen atom,

R ^7A means trifluoromethyl, ethyl or cyclopropyl, as well as their N-oxides, salts, solvates, salts of N-oxides and solvates of N-oxides and salts.

Another preferred embodiment of the present invention encompasses compounds of formula (I) in which R ² is a group of formula

- 16 038451

where * denotes the place of attachment of the amide group to the nitrogen atom,

R ^7B means methyl or ethyl, as well as their N-oxides, salts, solvates, salts of N-oxides and solvates of N-oxides and salts.

Another preferred embodiment of the present invention encompasses compounds of formula (I) in which R ² is a group of formula

H ₃ C SN ₃ , ^ R ^7C where * denotes the place of attachment of the amide group to the nitrogen atom,

R ^7C means trifluoromethyl or pentafluoroethyl, as well as their N-oxides, salts, solvates, salts of N-oxides and solvates of N-oxides and salts.

Another preferred embodiment of the present invention encompasses compounds of formula (I) in which R ² is (2S) -1,1,1-trifluorobutan-2-yl of formula

CF ₃ where * denotes the place of attachment of the amide group to the nitrogen atom, as well as their salts, solvates and solvates of salts.

Another preferred embodiment of the present invention encompasses compounds of formula (I), in which

R ² means (1S) -1-cyclopropyl-2,2,2-trifluoroethyl

where * denotes the place of attachment of the amide group to the nitrogen atom, as well as their salts, solvates and solvates of salts.

Another preferred embodiment of the present invention encompasses compounds of formula (I) in which R ² is a group of formula

where * denotes the place of attachment of the amide group to the nitrogen atom, as well as their salts, solvates and solvates of salts.

Another preferred embodiment of the present invention encompasses compounds of formula (I) in which R ² is a group of formula

where * denotes the place of attachment of the amide group to the nitrogen atom, as well as their salts, solvates and solvates of salts.

Another preferred embodiment of the present invention encompasses compounds of formula (I) in which R ² is a group of formula

where * denotes the place of attachment of the amide group to the nitrogen atom, as well as their salts, solvates and solvates of salts.

Another preferred embodiment of the present invention encompasses compounds of formula (I) in which R ² is a group of formula wherein * is the point of attachment of the amide moiety to the nitrogen atom, as well as their salts, solvates and salt solvates.

- 17 038451

Another preferred embodiment of the present invention encompasses compounds of formula (I) in which R ² is 1,1,1,3,3,3-hexafluoropropan-2-yl, as well as their salts, solvates and salt solvates.

Another preferred embodiment of the present invention encompasses compounds of formula (I) in which R ² is 3,3,4,4,4-pentafluorobutan-2-yl, as well as their salts, solvates and salt solvates.

Another preferred embodiment of the present invention encompasses compounds of formula (I) in which R ² is 1,1,1,2,2-pentafluoropentan-3-yl, as well as their salts, solvates and salt solvates.

Another preferred embodiment of the present invention encompasses compounds of formula (I) in which R ² is 1,1,1-trifluoro-2-methylpropan-2-yl, as well as their salts, solvates and salt solvates.

Another preferred embodiment of the present invention encompasses compounds of formula (I), in which Ar ¹ is a group of formula

where *** denotes the place of attachment to the nitrogen atom, as well as their N-oxides, salts, solvates, salts of N-oxides and solvates of N-oxides and salts.

Another preferred embodiment of the present invention encompasses compounds of formula (I), in which Ar ¹ is a group of formula

where *** denotes the place of attachment to the nitrogen atom, as well as their N-oxides, salts, solvates, salts of N-oxides and solvates of N-oxides and salts.

Another preferred embodiment of the present invention encompasses compounds of formula (I), in which Ar ¹ is a group of formula

where *** denotes the place of attachment to the nitrogen atom, as well as their N-oxides, salts, solvates, salts of N-oxides and solvates of N-oxides and salts.

Another preferred embodiment of the present invention encompasses compounds of formula (I), in which Ar ¹ is a group of formula

where *** denotes the place of attachment to the nitrogen atom, as well as their N-oxides, salts, solvates, salts of N-oxides and solvates of N-oxides and salts.

The definitions of the residues specified in these or preferred combinations of residues are applied independently of the named combinations of residues, also in an arbitrary manner by means of definitions of residues of other combinations.

Combinations of two or more of the aforementioned preferred areas or embodiments are highly preferred.

The abovementioned preferred, particularly preferred and highly preferred definitions of the radicals apply both for the compounds of formula (I) and, accordingly, for all intermediates.

- 18 038451

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

[A] compound of formula (II-A)

Ag ¹ (PA), in which X, R ² and Ar ¹ have the above meanings, Hal is fluorine, chlorine, bromine or iodine, preferably chlorine, is converted with a compound of formula (III)

in which R ¹ has the above meaning, and wherein R ^{1 is} not hydrogen, to a carboxylic acid amide of formula (IA) according to the invention

Ar ¹ (IA), in which X, R ¹ , R ² and Ar ¹ have the above meanings, and where R ¹ does not mean hydrogen; or [B] a compound of formula (IV)

Ar ¹ (IV), in which X, R ¹ and Ar ¹ have the above meanings, is converted with a compound of the formula (V) ^R - ^NH = (V), in which R ² has the above meaning, into a carboxylic acid amide according to the invention of the formula ( I) oh oh

Ar ¹ (I), in which X, R ¹ , R ² and Ar ¹ have the above meanings, and the obtained, if necessary, compounds of formula (I) are separated into their enantiomers and / or diastereoisomers and / or corresponding (i) solvents and / or (ii) with bases or acids are converted into their solvates, salts and / or solvates of salts.

The transformation (III-A) + (III) ^ (I-A) can be accomplished by a nucleophilic substitution reaction or a transition metal-mediated coupling reaction.

The nucleophilic substitution reaction is preferably carried out in the presence of a base. All common inorganic or organic bases are suitable as bases for process step (II-A) + (III) ^ (I-A). These preferably include alkali metal hydroxides such as lithium, sodium or potassium hydroxide, alkali or alkaline earth metal carbonates such as lithium, sodium, potassium or cesium carbonate, alkali metal alcoholates such as lithium, sodium or potassium tert-butylate, alkali metal hydrides such as sodium or potassium hydride, or organic amides such as K, K-diisopropylethylamine (DIPEA), 1,5-diazabicyclo [4.3.0] non-5-ene (DBN) and 1,8-diazabicyclo [5.4.0] undec-7-en (DBU). N, N-diisopropylethylamine (DIPEA) is preferably used. The reaction is generally carried out at temperatures of 0- + 100 ° C, preferably 23-80 ° C.

Inert solvents for process step (II-A) + (III) ^ (IA) are, for example, ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, hydrocarbons such as benzene, toluene, xylene, hexane, cyclohexane or petroleum fractions, halocarbons such as dichloromethane, trichloromethane, carbon tetrachloride, 1,2-dichloroethane, trichlorethylene or chlorobenzene, or other solvents such as acetone, ethyl acetate, acetonitrile, pyridine, dimethylsulfoxide, DM , N, N'-dimethylpropylene urea (DMPU) or N-methylpyrrolidone (NMP). You can also use a mixture of these solvents. Preference is given to using dimethylformamide (DMF) or N-methylpyrrolidone (NMP).

The transition metal-mediated coupling reaction for process step (II-A) + (III) ^ (I-A) in a preferred embodiment of the invention is carried out in the presence of palladium

- 19 038451 catalyst. Suitable palladium catalysts are, for example, palladium (P) acetate, palladium (P) chloride, bis- (triphenylphosphine) palladium (P) chloride, bis- (acetonitrile) palladium (P) chloride, tetrakis (triphenylphosphine) palladium (0), bis- (dibenzylideneacetone) palladium (0), tris- (dibenzylideneacetone) dipalladium (0) or [1,1'-bis- (diphenylphosphino) ferrocene] palladium (P) chloride, if necessary, in combination with a suitable phosphine ligand such as e.g. triphenylphosphine, tri-tert-butylphosphine, 2-dicyclohexylphosphino-2 ', 4', 6'-triisopropylbiphenyl (X-phos), 2-dicyclohexylphosphino-2 ', 6'-dimethoxybiphenyl (S-phos), 1,2, 3,4,5-pentaphenyl-1 '- (di-tert-butylphosphino) ferrocene (Q-phos), 4,5-bis- (diphenylphosphino) -9,9-dimethylxanthene (xantphos), 2,2'-bis - (diphenylphosphino) -1,1'binaphthyl (BINAP), 2-dicyclohexylphosphino-2 '- (N, N-dimethylamino) biphenyl or 2-di-tert-butylphosphino-2' - (N, N-dimethylamino) biphenyl.

The palladium-catalyzed coupling reaction (II-A) + (III) ^ (I-A) is carried out, as a rule, in the presence of a base. Suitable as these are in particular alkali metal carbonates such as sodium, potassium or cesium carbonate, alkali metal phosphates such as sodium or potassium phosphate, alkali metal fluorides such as potassium or cesium fluoride, or alkali metal tert-butylates, as sodium or potassium tert-butylate. The conversion is carried out in an inert solvent such as, for example, toluene, 1,2-dimethoxyethane, tetrahydrofuran, 1,4-dioxane, dimethyl sulfoxide (DMSO), N, N-dimethylformamide (DMF), N, N-dimethylacetamide (DMA) or in their mixtures at temperatures of 80-200 ° C, preferably at 80-150 ° C, with heating in a microwave apparatus being preferred.

Preferably, for this coupling reaction, a catalyst / ligand / base system consisting of palladium (II) acetate, 4,5-bis (diphenylphosphino) -9,9-dimethylxanthene (xantphos) and cesium or potassium carbonate is used and 1 , 4-dioxane.

The coupling reaction (II-A) + (III) ^ (IA) in another preferred embodiment can also be carried out using a copper (I) catalyst such as copper (I) oxide, copper bromide or iodide in the presence of a copper ligand such as trans- N, N'-dimethyl-1,2-cyclohexanediamine, 8-hydroxyquinoline or 1,10-phenanthroline; and an inorganic or organic carbonate base such as potassium, cesium or bis (tetraethylammonium) carbonate. Toluene, xylene, 1,4-dioxane, acetonitrile, dimethyl sulfoxide (DMSO), N, N-dimethylformamide (DMF) or mixtures thereof, optionally with the addition of water, are suitable as an inert solvent for this transformation. A system consisting of copper (I) iodide, trans-N, N'-dimethyl-1,2-cyclohexanediamine and potassium carbonate in dimethylformamide is preferably used. The reaction is carried out generally at temperatures of 50-200 ° C, preferably 60-150 ° C.

The coupling reaction (IV) + (V) ^ (I) [formation of amides] can be carried out either directly with a condensing agent or an activator or with the carboxylic acid chloride, carboxylic ester or carboxylic acid amidazolide obtained in the intermediate step from (IV).

Suitable such condensing agents or activators are, for example, carbodiimides such as, Ν'-diethyl-, Ν, Ν'-dipropyl-, Ν, Ν'-diisopropyl-, N, N'-dicyclohexylcarbodiimide (DCC) or N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride (EDC), phosgene derivatives such as N, N'-carbonyldiimidazole (CDI), isopropyl chloroformate or isobutyl chloroformate, 1,2-oxazolium compounds as 2- ethyl 5-phenyl-1,2-oxazolium-3-sulfate or 2-tert-butyl-5-methylisoxazolium perchlorate, acylamino compounds such as 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline, α-chloroenamines, such as 1-chloro-N, N, 2-trimethylnrop-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 such as n-propane phosphonic acid anhydride (PPA), cyanophosphonic acid diethyl ester, diphenylphosphoryl azide (DPPA), bis- (2-oxo-3-oxazolidinyl) phosphoryl chloride, benzotriazitrismino (dyloxyyl) ) phosphonium hexafluorophosphate or benzotriazol-1-ylox i-tris- (pyrrolidino) phosphonium-hexafluorophosphate (PyBOP), or uronium compounds such as O- (benzotriazol-1-yl) -N, N, N ', N'tetramethyluronium tetrafluoroborate (TBTU), O- (benzotriazole- 1-yl) -N, N, N ', N'-tetramethyluronium hexafluorophosphate (HBTU), O- (1H-6-chlorobenzotriazol-1-yl) -1,1,3,3-tetramethyluronium tetrafluoroborate (TCTU), 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), if necessary in combination with other excipients such as 1-hydroxybenzotriazole (HOBt) or N-hydroxysuccinimide (HOSu), as well as alkali metal carbonate bases such as potassium carbonate or sodium, or tertiary amine bases such as triethylamine, N-methylmorpholine (NMM), N-methylpiperidine (NMP), N, N-diisonropylethylamine (DIPEA), pyridine or 4-N, N-dimethylaminopyridine (DMAP). Preferably, such condensing agents or activators are O- (7-azabenzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium hexafluorophosphate (HATU) in combination with N, N-diisopropylethylamine (DIPEA), and See also n-propane phosphonic acid anhydride (T3P, PPACA) in combination with N, N-diisopropylethylamine (DIPEA).

Compounds of formula (II-A) can be prepared based on a carboxylic acid compound

- 20 038451

he (VI-A), formula (VI-A)

Ar ¹ in which X, Hal and Ar ¹ have the above meanings, is converted with a compound of formula (V) ^r - ^nh 2 in which R ² has the above meaning, into a carboxylic acid amide according to the invention of formula (II-A)

in which X, Hal, R ² and Ar ¹ have the above meanings.

Compounds of formula (I-B) can be prepared analogously to substitution (VI-A) + (V) ^ (II-A), thus converting the carboxylic acid compound of formula (VI-B)

in which X and Ar ¹ have the above meanings, a compound of the formula (V) ^R " ^NH 2 in which R ² has the above meaning, into a carboxylic acid amide according to the invention of formula (IB)

in which X, R ² and Ar ¹ have the above meanings.

The coupling reaction (VI-A) + (V) ^ (II-A) or (VI-B) + (V) ^ (IB) [amide formation] can be carried out either directly with a condensation agent or activator, or with an intermediate step from the carboxylic acid chloride, carboxylic ester or carboxylic acid imidazolide obtained from (VI), analogously to the transformation of (IV) + (V) ^ (I) with the described conditions and reagents. If during the coupling reaction (II-A) HATU is used as an activator, then either a separate, defined product of general formula (II-A) or a mixture with the HATU adduct can be obtained. A HATU adduct is here called a pseudohalide compound, wherein the Hal substituent in general formula (II-A) is substituted by a 3H- [1,2,3] triazolo [4,5-b] pyridin-3-ol group, also called 1-hydroxy- 7-azabenzotriazole. Such a mixture of a halogen compound of general formula (II) and a HATU-adduct can be used analogously to the described transformation also directly as an educt for the sequential reaction (according to (I) or (VIII)).

In a two-stage reaction using carboxylic acid chlorides or carboxylic acid imidazolides derived from (VI), the coupling is carried out with the amine component (V) in the presence of a common base such as sodium or potassium carbonate, triethylamine DIPEA, N-methylmorpholine (NMM), N-mmethylpiperidine (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 methanolate, sodium or potassium tert-butylate, or sodium or potassium hydride.

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

Inert solvents for the mentioned coupling reactions - depending on the method used - are, for example, ethers such as diethyl, diisopropyl, methyl tert-butyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane or bis- (2 -methoxyethyl) ether, hydrocarbons such as benzene, toluene, xylene, pentane, hexane or cyclohexane, halogenated hydrocarbons such as dichloromethane, trichloromethane, carbon tetrachloride, 1,2-dichloroethane, trichlorethylene, or chlorobenzene solvents such as acetone, methyl ethyl ketone, ethyl acetate, acetonitrile, butyronitrile, pyridine, dimethyl sulfoxide (DMSO), N, N-dimethylformamide (DMF), N, N'-dimethylpropylene urea (DMPU) or N-methylpyrrolidinone (NMP). You can also use mixtures of these solvents. N, N-dimethylformamide (DMF) and dichloromethane (DCM) are preferably used in combination with triethylamine. The coupling reaction is generally carried out at temperatures of 0-130 ° C, preferably 20-30 ° C.

Compounds of formula (IV-A), depending on the corresponding substituent standard, can be prepared by:

[C] compound of formula (VII-A) o o

Ar ¹ (VILA), in which X, Hal and Ar ¹ have the above meanings and T is (C ₁ -C ₄ ) α-alkyl or benzyl, is converted in a first step with a compound of formula (III)

in which R ¹ has the above meaning, and wherein R ¹ does not mean hydrogen, to a compound of formula (VIII-A) o o

Ag ¹ (USH-A), in which X, T, R ¹ and Ar ¹ have the above meanings, and wherein R ¹ does not mean hydrogen, and, if necessary, in a second step, the ether residue T is separated into a carboxylic acid according to the invention of the formula ( IV-A)

Ar ¹ (IV-A), in which X, R ¹ and Ar ¹ have the above meanings, and where R ¹ does not mean hydrogen; or [D] a compound of formula (VI-A)

Ar ¹ (VLA), in which X, Hal and Ar ¹ have the above meanings, is converted with a compound of formula (III)

in which R ¹ has the above meaning, and wherein R ¹ does not mean hydrogen, into a carboxylic acid according to the invention of the formula (IV-A)

Ar ¹ (IV-A), in which X, R ¹ and Ar ¹ have the above meanings, and where R ¹ does not mean hydrogen.

The transformation (VII-A) + (III) ^ (VIII-A) [method C] or the transformation (VI-A) + (III) ^ (IV-A) [method D] can respectively be carried out using a nucleophilic substitution reaction or a transition metal-mediated coupling reaction is analogous to the conditions and reagents already described for the transformation (II-A) + (III) ^ (IA).

In a preferred embodiment, the conversion is carried out according to method C in the form of a nucleophilic substitution reaction in the presence of a base, preferably N, N-diisopropylethylamine (DIPEA) is used.

Preferably, dimethylformamide (DMF) or N-methylpyrrolidone (NMP) or acetonitrile is used as solvent.

- 22 038451

In a preferred embodiment, the conversion is carried out according to Method D as a transition metal-mediated coupling reaction in the presence of a suitable palladium catalyst.

It is preferable to use a system consisting of palladium (II) acetate in combination with

4,5-bis- (diphenylphosphino) -9,9-dimethylxanthene (xanphos), cesium or potassium carbonate and 1,4-dioxane as solvent.

Elimination of the ester group T at the technological stage (VIII-A) ^ (IV-A) is carried out by the usual methods, when the ester is treated in an inert solvent with hydrochloric acid or a base, and in the latter variant, the carboxylic acid salt formed first by subsequent treatment with hydrochloric acid converted into free carboxylic acid. In the case of the tert-butyl ester, the cleavage is preferably carried out with an acid. 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.

Suitable solvents for this reaction are water and organic solvents customary for ester cleavage. These include, in particular, alcohols such as methanol, ethanol, n-propanol isopropanol, n-butanol or tert-butanol, ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane or 1,2-dimethoxyethane, or 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 are preferred.

Suitable bases are conventional inorganic bases for the hydrolysis reaction. These preferably include alkali or alkaline earth metal hydroxides such as sodium, lithium, potassium or barium hydroxide, or alkali or alkaline earth metal carbonates such as sodium, potassium or calcium carbonate.

Suitable acids for the cleavage of esters are generally sulfuric acid, hydrogen chloride / hydrochloric acid, hydrogen bromide / hydrobromic acid, phosphoric, acetic, trifluoroacetic acid, toluenesulfonic acid, methanesulfonic acid or trifluoromethanesulfonic acid, or mixtures thereof, optionally with the addition of water. Preference is given to using aqueous hydrochloric acid (18%) in a water / tetrahydrofuran mixture.

The cleavage of the ester is generally carried out at temperatures of -20-100 ° C, preferably 23-120 ° C.

The compounds of the formula (VI-A) as well as the formula (VII-A) can be obtained, depending on the corresponding standard of the substituent, while analogously to the known method (see, for example, EP 0607825 A1, pp. 25-26), the derivative 2,6-dichloronicotinoyl-acrylic acid ester of formula (IX-A)

HaK N Cl Y (IX-A), in which X, Hal and T, which have the above meanings and Y denotes a leaving group such as dimethylamino, methoxy or ethoxy, and also in a first step, preferably in the presence of a suitable base, are converted with the compound based on aminopyridine of formula (X) (X), in which Ar ¹ has the above meanings, and then, in a second step, is converted in the presence of a suitable base into an ester compound of formula (VII-A)

in which X, Hal, Ar ¹ and T have the above meanings, and then, if necessary, under hydrolysis conditions in the next step, the ester compound (VII) is converted into the carboxylic acid compound (VI-A)

in which X, Hal and Ar ¹ have the above meanings, under reaction conditions known in the literature.

Compounds of formula (VI-B) as well as formula (VII-B) can be prepared analogously to the transformation

- 23 038451 (IX-A) + (X) ^ (VII-A) ^ (VI-A), similar to known methods (see, for example, EP 0607825 A1,

S. 25, 26), by the transformation of the 2,6-dichloronicotinoyl-acrylic acid ester derivative of the formula (IX)

in which X and T, which have the above meanings and Y denotes a leaving group such as dimethylamino, methoxy or ethoxy, and in a first step, preferably in the presence of a suitable base, are converted with an aminopyridine-based compound of formula (X) ^ '- ^nh ₂ in which Ar ¹ has the above meanings, and then in a second step is converted in the presence of a suitable base into an ester compound of formula (VII-B)

in which X, Ar ¹ and T have the above meanings, and then, if necessary, under the conditions of hydrolysis in the next step, the ester compound (VII-B) is converted into the carboxylic acid compound (VI-B)

in which X and Ar ¹ have the above meanings, under reaction conditions known in the literature.

Compounds of formula (IX) are known from the literature (see, for example, EP 0607825 A1) or can be prepared analogously to methods known in the literature. Compounds of formulas (III), (V) and (X) can be prepared industrially or as described in the literature, or can be prepared by methods known to a person skilled in the art, analogous to the methods described in the literature. Numerous detailed instructions, as well as bibliographic references for the preparation of the corresponding starting materials are also found in the experimental part in the section on the preparation of starting and intermediate compounds.

The separation of the stereoisomers (enantio- and / or diastereoisomers) of the compounds according to the invention of formula (I) can be carried out using conventional methods known to the person skilled in the art. For this, the chromatographic method of achiral or chiral separation phases is preferably used. The separation of the compounds according to the invention into the corresponding enantiomers and / or diastereoisomers can, if necessary, take place, depending on the purpose, also already at the stage of the individual intermediates (II), (IV) or (VIII), these intermediates being separated form can then be further transformed according to the previously described processing steps. For this separation of stereoisomers from intermediates, the chromatographic method of achiral or chiral separation phases is preferably used simultaneously. Alternatively, separation can also be carried out using a diastereoisomeric salt of a carboxylic acid of formula (IV) with chiral amine bases.

Preparation of compound reaction schemes.

according to the invention can be explained by examples using the following Scheme 1

[a) triethylorthoformate, acetic anhydride; b) DIPEA, DCM, then K ₂ CO ₃ ; c) 18% hydrochloric acid, THF, water].

- 24 038451

Scheme 2

[a) HATU, DIPEA, DMF or T3P, DIPEA, EtOAc; b) Pd (OAc) 2, xantphos, CS2CO3, 1,4-dioxane; c) DIPEA, DMF; d) (COCl) ₂ , cat DMF, THF; e) NaH, DMF or triethylamine, DCM].

Scheme 3

[a) DIPEA, DMF; b) aq. LiOH, THF or 18% hydrochloric acid, THF, water; c) HATU, DIPEA, DMF, room. pace].

Scheme 4

[a) Pd (OAc) ₂ , xantphos, K ₂ CO ₃ , 1,4-dioxane; b) HATU, DIPEA, DMF; c) DIPEA, DMF; d) HATU, DIPEA, DMF].

- 25 038451

Scheme 5

[a) triethylorthoformate, acetic anhydride; b) DIPEA, DCM then K2CO3; c) aq. LiOH, THF or 18% hydrochloric acid, THF, water; d) HATU, DIPEA, DMF or T3P solution, DIPEA, MeCN; e) DIPEA, DMF; f NBS Cat. AIBN, MeCN].

Other compounds of formula (I) according to the invention can also be obtained, if appropriate, by the transformation of functional groups of individual residues and substituents, in particular named among R ¹ and R ² , starting from other compounds obtained by the above methods or in the corresponding steps formulas. The transformations are carried out by conventional methods known to the person skilled in the art and include, for example, reactions such as nucleophilic or electrophilic substitution reaction, transition metal-mediated coupling reaction, reactions for the preparation and addition of metal organols (for example, Grignard reagents or lithium organyls), oxidation reactions or reduction, hydrogenation, halogenation (eg, fluorination, bromination), dehalogenation, amination, alkylation and acylation, the formation of carboxylic acid esters, carboxylic acid amides and sulfonamides, ester cleavage and hydrolysis, and the introduction and removal of temporary protecting groups.

In another aspect, the invention relates to derivatives of general formula (II)

in which X, R ² and Ar ¹ are as defined above for the compounds of formula (I) and Hal is fluorine, chlorine, bromine or iodine, preferably chlorine.

In another aspect, the invention relates to derivatives of general formula (IV)

in which X, R ¹ and Ar ¹ have the meanings given above for the compounds of formula (I). In another aspect, the invention relates to the use of a compound of general formula (II)

in which X, R ² and Ar ¹ have the meanings given above for the compounds of formula (I) and Hal is fluorine, chlorine, bromine or iodine, preferably chlorine, or compounds of general formula (IV)

- 26 038451

in which X, R ¹ and Ar ¹ have the above meanings for compounds of formula (I), to obtain a compound of general formula (I), as described above.

It is not by chance that the compounds according to the invention have a useful pharmacological and pharmacokinetic spectrum of action, therefore they are suitable for use as pharmaceuticals for the treatment and / or prevention of diseases in humans and animals. 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 positively allosteric modulators of the muscarinic M2 receptor and are therefore suitable for the treatment and / or prophylaxis of diseases and pathogenic processes, in particular cardiovascular diseases and / or kidney diseases, in which, during the erroneous regulation of the autonomic nervous system or imbalance the M2 receptor is mistakenly present between the sympathetic and parasympathetic activity of the autonomic nervous system.

The subject of the present invention is positive allosteric modulators of the muscarinic M2 receptor. Allosteric modulators differ significantly from classical, orthosteric ligands. The effect of an allosteric modulator is self-limiting if it stabilizes an agonist compound at high concentrations. In addition, the effect of an allosteric modulator is manifested only in the presence of an endogenous ligand. The allosteric modulator itself has no direct effect on receptor activation. This implies the spatial and temporal specificity of the allosteric influence. Called cooperativity, the interaction of an allosteric and orthosteric ligand with respect to affinity and intrinsic activity is determined by two ligands. In the case of a positive allosteric modulator, the effects of the orthosteric ligand are enhanced (positive cooperativity). Based on their ability to modulate receptor conformations in the presence in the presence of an orthosteric ligand, allosteric ligands can induce fine tuning of pharmacological effects.

In the meaning of this invention, diseases of the cardiovascular system or cardiovascular diseases should be understood, for example, the following diseases: acute and chronic heart failure, arterial hypertension, coronary heart diseases, stable and unstable angina pectoris, myocardial ischemia, myocardial infarction, shock, atherosclerosis, hypertrophy heart, cardiac fibrosis, atrial and ventricular arrhythmia, transistor and ischemic attacks, apoplexy, preeclampsia, inflammatory cardiovascular diseases, peripheral and cardiac vascular diseases, peripheral circulation disorders, pulmonary arterial hypertension, spasms of coronary and peripheral arteries, thrombosis edema formation, such as pulmonary edema, cerebral edema, renal edema or edema caused by heart failure, as well as restenosis, as after thrombolytic therapy, percutaneous transluminal angioplasty (PTA), percutaneous transluminal coronary angioplasty (PTCA), heart transplantation and bypass surgery, as well as micro- and macrovascular disorders (vasculitis), repercussion disorders, arterial and venous thrombosis, microalbuminuria, cardiac weakness, endothelial dysfunction, peripheral and peripheral vascular diseases, peripheral and peripheral vascular disorders , edema caused by heart failure, increased levels of fibrinogen and low density lipoprotein (LDL), and increased concentrations of plasminogen activator inhibitor 1 (PAI-1).

In the meaning of this invention, the concept of heart failure also includes special or similar forms of diseases such as acute decompensated heart failure, right ventricular failure, left ventricular failure, heart failure, ischemic cardiomyopathy, dilated cardiomyopathy, congenital heart disease, valvular heart disease, heart failure with valvular heart disease, mitral stenosis, mitral valve insufficiency, aortic valve stenosis, aortic valve insufficiency, tricuspid valve stenosis, tricuspid valve insufficiency, pulmonary valve stenosis, pulmonary artery valve insufficiency, combined valvular heart disease, myocarditis, chronic myocarditis, acute myocarditis , viral myocarditis, heart failure in diabetes, alcoholic cardiomyopathy, chronic heart disease, heart failure with intact ejection fraction (HFpEF), diastolic kaya heart failure, as well as heart failure with a reduced ejection fraction (HfrEF), systolic heart failure.

Within the meaning of this invention, the term includes atrial arrhythmia and ventricular arrhythmia, as well as specific or related forms of diseases such as atrial fibrillation, paroxysmal atrial fibrillation, intermittent atrial fibrillation, constant atrial fibrillation,

- 27 038451 atrial flutter, sinus arrhythmia, sinus tachycardia, passive heterotopia, active heterotopia, interstitial extrasystole, extrasystoles, impulse conduction disturbance, sinus node syndrome, carotid sinus hypersensitivity, tachycardia, atrioventricular tachycardia syndrome, atrioventricular tachycardia syndrome Wolff-Parkinson-White), nodoventricular tachycardia, latent additional conduction pathway, continuous atrioventricular reciprocal tachycardia, focal atrial tachycardia, atrioventricular ectopic tachycardia, atrial ventricular tachycardia, ventricular tachycardia, ventricular tachycardia, ventricular tachycardia

Within the meaning of this invention, the term coronary heart disease also includes specific or related forms of diseases such as ischemic heart disease, stable angina pectoris, acute coronary syndrome, unstable angina pectoris, NSTEMI (low ST myocardial infarction), STEMI (ST elevation infarction), ischemic myocardial damage, cardiac arrhythmias and myocardial infarction.

Furthermore, the compounds according to the invention are useful for the prophylaxis and / or treatment of polycystic kidney disease (PBD) and Parkhon's syndrome (PND).

The compounds according to the invention are also useful for the treatment and / or prophylaxis of renal diseases, in particular acute and chronic renal failure.

In the meaning of this invention, the term acute renal failure includes acute forms of kidney disease, renal failure with or without the need for dialysis, as well as diseases underlying kidney disease or related diseases such as renal hypoperfusion, intradialytic hypotension, hypovolemia (for example, dehydration, blood loss), shock, acute glomerulonephritis, hemolytic uremic syndrome (HUS), vascular catastrophe (arterial or venous thrombosis or embolism), cholesterol embolism, Bens-Jones protein in plasmacytoma, acute supravesical or subvesical obstruction of the kidney outflow such as rejection of a transplanted kidney, kidney damage caused by immune complexes, tubular dilation, hyperphosphatemia and / or acute kidney disease, which may be characterized by the need for dialysis; as well as acute interstitial kidney disease due to kidney resection, dehydration caused by diuresis, uncontrolled high blood pressure with malignant hypertension, blockages and urinary tract infections and amyloidosis, as well as systemic glomerular diseases such as rheumatic immunological systemic diseases such as systemic lupus erythematosus , renal artery thrombosis, renal vein thrombosis, analgesic nephropathy and renal tubular acidosis, and acute interstitial kidney disease caused by X-ray contrast media and drugs.

In the meaning of this invention, the term acute renal failure includes chronic forms of kidney disease, renal failure with or without the need for dialysis, as well as diseases underlying kidney disease, or related diseases such as renal hypoperfusion, intradialytic hypotension, obstructive uropathy, glomerulopathy, glomerular and tubular proteinuria, renal edema, hematuria, primary, secondary, and chronic glomerulonephritis, membranous and membranoproliferative glomerulonephritis, Alport syndrome, glomerulosclerosis, tubulointerstitial diseases, nephropathic nephritis such as primary or renal diseases such as primary or renal diseases as rejection of a transplanted kidney, kidney damage caused by immune complexes, diabetic and nondiabetic nephropathy, pyelonephritis, kidney cyst, nephrosclerosis, hypertensive nephrosclerosis and nephrotic syndrome, which e diagnostically can be characterized, for example, by abnormally low excretion of creatine and / or water, abnormally high blood concentrations of urea, nitrogen, potassium and / or creatinine, altered activity of renal enzymes, such as glutamine synthetase, altered molarity or urine volume, increased microalbuminuria , macroalbuminuria, glomerular damage and damage to arterioles, tubular dilation, hyperphosphatemia and / or the need for dialysis, as well as renal cell cancer, after kidney resection, dehydration caused by diuresis, uncontrolled increase in blood pressure with malignant hypertension and urinary tract infections amyloidosis, as well as systemic glomerular diseases such as rheumatic immunological systemic diseases such as systemic lupus erythematosus, renal artery stenosis, renal artery thrombosis, renal vein thrombosis, analgesic nephropathy and renal tubular acidosis. Also chronic interstitial kidney disease caused by X-ray contrast agents as well as drugs, metabolic syndrome and dyslipidemia. The present invention also includes the use of compounds according to the invention for the treatment and / or prevention of the consequences of renal failure, such as pulmonary edema, heart failure, uremia, anemia, electrolyte disturbances (eg hyperkalemia, hyponatremia), impaired bone metabolism and impaired carbohydrate metabolism. ...

Furthermore, the compounds according to the invention are also suitable for the treatment and / or prevention of pulmonary arterial hypertension (PAH) and other types of pulmonary hypertension (PH), chronic obstructive pulmonary diseases (COPD), acute obstructive airway syndrome (OOSDP), acute pulmonary damage (ALP), alpha-1-antitrypsin deficiency (DAAT), pulmonary fibrosis, pulmonary emphysema (eg, smoking-induced pulmonary emphysema), cystic fibrosis (CF), acute coronary syndrome (ACS), inflammation of the heart muscle (myocarditis), and other autoimmune heart diseases (pericarditis, endocarditis, valvulitis, aortitis, cardiomyopathy), cardiogenic shock, aneurysm, sepsis (SIRS), multiple organ failure (MODS, MOF), inflammatory kidney disease, chronic intestinal inflammation (CVD, Crohn's disease, UC) , pancreatitis, peritonitis, rheumatoid diseases, inflammatory skin diseases, and inflammatory 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 an 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), obliterating bronchiolitis, bronchiectasis, pneumonia, idiopathic interstitial pneumonia, farmer's lungs and related diseases, coughs and colds (chronic inflammatory cough, iatrogenic cough), nasal mucosa inflammation and medication seasonal, allergic rhinitis, such as hay fever) and polyps.

The compounds described in the present invention are also substances for the treatment of diseases of the central nervous system, which are characterized by a violation of the NO / cGMP system. In particular, they are useful for improving sensation, ability to concentrate, learning or improving memory after cognitive disorders, which, in particular, occur during situations / diseases / syndromes, such as, for example, mild cognitive impairment, learning and memory problems found in senile age, amnesia in elderly people, vascular dementia, traumatic brain injury, apoplexy stroke, dementia that occurs after stroke (post-stroke dementia), post-traumatic complications after traumatic brain injury, general impairment of concentration, impaired concentration in children with learning disabilities and memory, Alzheimer's disease, Lewy body dementia, dementia with atrophy of the frontal lobes, including Pick syndrome, Parkinson's disease, progressive nuclear palsy, dementia with corticobasal degeneration, amyotrophic lateral sclerosis (ALS), Huntington's disease, demyelination, multiple sclerosis, thalamic degenerationdementia with Creutzfeldt-Jakob disease, HIV dementia, schizophrenia with dementia, or Korsakoff psychosis. They are also useful for the treatment and / or prevention of diseases of the central nervous system, such as phobias, anxiety and depressions, bipolar disorder, sexual dysfunctions and sleep disorders due to the central nervous system, as well as for the regulation of pathological eating and drug eating disorders.

Furthermore, the compounds according to the invention are also suitable for the treatment and / or prevention of urological diseases such as urinary incontinence, in particular stress incontinence, urge incontinence, reflex and overflow incontinence, overactive bladder, neurogenic detrusor overactivity, idiopathic detrusor hyperactivity, benign prostatic hyperplasia (BPH syndrome), lower urinary tract symptoms (LUTS = lower urinary tract symptoMC).

Furthermore, the compounds according to the invention are suitable for the treatment and / or prevention of gastroenterological diseases such as esophageal diseases, vomiting, achalasia, gastroesophageal reflux disease, gastric diseases such as gastritis, intestinal diseases such as diarrhea, constipation, malassimilation syndrome, postcholecystectomy syndrome, Crohn's disease, ulcerative colitis, microscopic colitis, and irritable bowel syndrome.

Furthermore, the compounds according to the invention are suitable for the treatment and / or prophylaxis of painful conditions such as, for example, menstrual irregularities, dysmenorrhea, endometriosis, preterm labor, toxicosis.

Due to their biochemical and pharmacological profile, the compounds according to the invention are particularly suitable for the treatment and / or prevention of heart failure, coronary heart disease, atrial and ventricular arrhythmias, renal failure and nephropathy.

In addition, the compounds according to the invention can be used for the treatment and / or prevention of primary and secondary Raynaud's phenomenon, microcirculatory disorders, lameness, peripheral and autonomic neuropathy, diabetic neuropathy, diabetic microangiopathy, diabetic retinopathy, trophic ulcers on the extremities, gangrene, CREST syndrome, erythematosis, onychomycosis, rheumatic diseases, and to accelerate wound healing.

Further, the compounds according to the invention are suitable for the treatment and / or prevention of ophthalmic diseases such as glaucoma, age-related macular degeneration (AMD), dry (non-exudative) AMD, wet (exudative, neovascular) AMD, choroidal neovascularization (CNV), diabetic retinopathy , atrophic changes in the retinal pigment epithelium (RPE), hypertrophied changes in the retinal pigment epithelium, macular edema, diabetes

- 29 038451 tic edema of the macular zone of the retina, obstruction of the retinal veins, choroidal obstruction of the retinal veins, edema of the macular zone of the retina; edema of the macular area of the retina caused by obstruction of the retinal veins; angiogenesis on the anterior surface of the eye, such as corneal angiogenesis, for example, after keratitis, corneal transplant or keratoplasty; corneal angiogenesis caused by hypoxia (with constant contact lens wear), pterygium, retinal edema and internal retinal edema. Furthermore, the compounds according to the invention are suitable for the treatment and / or prevention of increased and high intraocular pressure due to traumatic hyphema, periorbital edema, postoperative viscoelastic retention or intraocular inflammation.

In addition, the compounds according to the invention are used for the treatment and / or prevention of hepatitis, neoplasms, osteoporosis, glaucoma and gastric paresis.

Furthermore, the compounds according to the invention are also suitable for the regulation of cerebral blood supply and thus represent an effective treatment for migraine. They are also suitable for the prevention and prevention of the consequences of cerebral apoplexy, such as apoplexy, cerebral ischemia and traumatic brain injury. Also, the compounds according to the invention can be used to suppress painful conditions, neuralgia and tinnitus.

The previously named well-described human diseases with comparable etiology can also occur in other mammals and can also be treated with the compounds of this invention.

In the present invention, such a concept as treatment or treatment includes restraining, slowing down, delaying, alleviating, weakening, reducing, reducing, suppressing, suppressing or curing a disease, ailment, disease, damage or disorder related to health, development, course or the progression of such a condition and / or symptoms of such a condition. At the same time, the concept of therapy is synonymous with the concept of treatment.

The terms prevention or prophylaxis in the framework of this invention can be used synonymously and mean the prevention or reduction of the risk of acquiring, getting, experiencing or having a disease, illness, disease, damage or disorders related to health, the development, course or progression of such a condition and / or symptoms. such a state.

Treatment or prevention of illness, illness, disease, injury or health related disorder may be complete or partial.

Thus, another object of the present invention is the use of the compounds according to the invention for the treatment and / or prophylaxis of diseases, in particular of the aforementioned diseases.

Another object of the present invention is the use of the compounds according to the invention for the manufacture of medicaments for the treatment and / or prophylaxis of diseases, in particular of the aforementioned diseases.

Thus, another object of the present invention is a medicament containing at least one compound according to the invention for the treatment and / or prophylaxis of diseases, in particular of the aforementioned diseases.

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

A further object of the present invention is a method for the treatment and / or prevention of diseases, in particular the previously mentioned diseases, by using an active amount of at least one compound according to the invention.

Another object of the present invention is the compounds according to the invention for use in a method for the treatment and / or prophylaxis of diseases, in particular the previously mentioned diseases.

The compounds according to the invention can be used alone or, if necessary, in combination with one or more additional pharmacologically active substances, as long as these combinations do not lead to undesirable and unacceptable side effects. Therefore, another object of the present invention is medicinal substances that contain at least one compound according to the invention and one or more other biologically active substances, in particular for the treatment and / or prevention of the previously mentioned diseases. As these suitable combinations of active substances, for example and preferably, there are to be mentioned:

biologically active substances that lower pressure, for example and preferably from the group of calcium antagonists, angiotensin AII antagonists, ACE inhibitors, NEP inhibitors, vasopeptidase inhibitors, endothelin antagonists, renin inhibitors, alpha-receptor blockers, beta-receptor blockers, receptor antagonists prokinase, as well as diuretics;

antiarrhythmic biologically active substances, such as and preferably sodium channel blockers beta-receptor blockers, potassium channel blockers, potassium antagonists, If-channel blockers, digitalis, parasympathetic agents (vagolytics), sympathomimetic agents and other antiarrhythmics such as adenosine, adenosine agonists receptors as well as vernacalant;

- 30 038451 positive inotropic active compounds such as cardiac glycoside (digoxin), β-adrenergic and dopamine agonists such as isoproterenol, epinephrine, norepinephrine, dopamine and dobutamine;

vasopressin receptor antagonists such as, and preferably, conivaptan, tolvaptan, lixivaptan, mosavaptan, satavaptan, SR-121463, RWJ 676070 or BAY 86-8050, as well as compounds described in WO 2010/105770, WO2011 / 104322 and WO 2016/071212 ;

natriuretic peptides such as atrial natriuretic peptide (ANP), type B natriuretic peptide (BNP, nesiritide), type C natriuretic peptide (CNP), or urodilatin;

cardiac myosin activators such as omecamtiv mecarbil (CK-1827452);

calcium sensitizers, such as levosimendan, compounds that affect the metabolism of cardiac energy, such as and preferably etomoxir, dichloroacetate, ranolazine or trimetazidine, full or partial agonists of the A1 adenosine receptor, such as GS-9667 (formerly known as CVT-3619 ), capadenozone, neladenozone and BAY 1067197;

compounds that affect the heart rate, such as ivabradine;

compounds that interfere with the degradation of cyclic guanosine monophosphate (cGMP) and / or cyclic adenosine monophosphate (cAMP), for example phosphodiesterase (PDE) inhibitors 1, 2, 3, 4 and / or 5, in particular PDE 5 inhibitors like sildenafil and tadadenafil , udenafil, desantafil, avanafil, myrodenafil, lodenafil, or PF-00489791;

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

bronchodilator agents, for example and preferably from the group of beta-adrenal receptor antagonists, in particular albuterol, isoproterenol, metaproterenol, terbutaline, formoterol or salmeterol, or from the group of anticholinergic agents, in particular ipratropium bromide;

anti-inflammatory drugs, for example and preferably from the group of glucocorticoids, such as, in particular, prednisone, prednisolone, methylprednisolone, triamcinolone, dexamethasone, beclomethasone, betamethasone, flunisolid, budesonide or fluticasone, as well as non-steroidal anti-inflammatory drugs, in particular NSAIDs, such as , acetylsalicylic acid (aspirin), ibuprofen and naproxen, 5-aminoacetylsalicylic acid derivatives, leukotriene receptor antagonists, TNF-alpha inhibitors and chemokine receptor antagonists like CCR1, 2 and / or 5 inhibitors;

biologically active substances that affect 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-methylglutaryl coenzyme A reductase or squalene synthase, acyl-CoA inhibitors -cholesterol acyltransferase, cholesterol ester transfer inhibitors, inhibitors of microsomal triglyceride transfer protein, antagonists of alpha, gamma and / or δ receptors activated by peroxisomal proliferators, cholesterol absorption blockers, lipase inhibitors, polymeric acid adsorbers lipoprotein (s);

compounds that inhibit 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;

compounds that inhibit the breakdown and rearrangement of the extracellular matrix, for example and preferably inhibitors of the matrix metalloprotease (MMP), in particular inhibitors of chymase, stromelysin, collagenase, gelatinase and aggrecanase (especially MMP-1, MMP-3, MMP-8, MMP-9, MMP-10, MMP-11 and MMP-13) as well as metalloelastases (MMP-12) and neutrophil elastases (HNE) such as sivelastat or DX-890;

compounds that block the binding of serotonin to its receptors, for example and preferably 5-HT _2b receptor antagonists;

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

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

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

compounds that increase the synthesis of cGMP, such as sGC modulators, such as, and preferably, riociguat, cynaciguat, vericiguat or BAY 1101042 prostacyclin analogs, such as and preferably iloprost, beraprost, treprostinil or epoprostenol;

soluble epoxide hydrolase (sEH) inhibiting compounds 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;

- 31 038451 active substances that alter glucose metabolism such as insulins, biguanides, thiazolidinediones, sulfonylureas, acarbose, DPP4 inhibitors, GLP-1 analog or SGLT-1 inhibitor.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a kinase inhibitor, such as, and preferably, bortezomib, canertinib, erlotinib, gefitinib, imatinib, lapatinib, letaurtinib, lonafarnib, nintedanib, dasatinib, nilotinib, telotinibitinib, imatinib , brivanib, pazopanib, pegaptinib, pelitinib, semaxanib, sorafenib, regorafenib, sunitinib, tandutinib, tipifarnib, vatalanib, fasudil, lonidamine, leflunomide, BMC-3354825 or Y-27632.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a serotonin receptor antagonist, such as, and preferably, PRX-08066.

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

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with an antithrombotic agent, such as, for example and preferably with aspirin, clopidogrel, ticlopidine or dipyridamole.

In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a thrombin inhibitor, such as, and preferably, dabigatran, ximelagatran, melagatran, bivalirudin or clexane.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a glycoprotein (GP) IIb-IIIa antagonist, such as, for example and preferably with tirofiban or abciximab.

In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a factor Xa inhibitor, such as, and preferably, rivaroxaban, edoxaban (DU-176b), apixaban, otamixaban, fidexaban, rasaxaban, fondaparinux, idraparinux, PMD-3112, YN 150, KFA-1982, EMD-503982, MCN-17, mLN-1021, DX 9065a, DPC 906, JTV 803, SSR-126512 or SSR-128428.

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

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

Pressure lowering agents are preferably understood to mean compounds from the group of calcium antagonists, angiotensin AII antagonists, ACE blockers, endothelin antagonists, renin inhibitors, alpha-receptor blockers, beta-receptor blockers, mineralocorticoid receptor antagonists, rockinase inhibitors, and diuretics.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a calcium antagonist, such as, for example and preferably with nifedipine, amlodipine, verapamil or diltiazem.

In a preferred embodiment of the invention, the compounds of the invention are administered in combination with an alpha-1 receptor blocker, such as, and preferably, prazosin.

In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a beta-1 receptor blocker, such as, 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.

In a preferred embodiment of the invention, the compounds of the invention are administered in combination with angiotensin AII antagonists, such as, for example and preferably, lozsartan, candesartan, valsartan, telmisartan or embursatan, irbesartan, olmesartan, eprosartan or azilsartan, or with dual angiotensin AII antagonists / NEP as for example and preferably with entresto (LCZ696, valsartan / sacubitrile).

In a preferred embodiment of the invention, the compounds of the invention are administered in combination with an angiotensin converting enzyme inhibitor such as, for example and preferably with enalapril, captoropril, lisinopril, ramipril, delapril, fosinopril, quinopril, perindopril or trandopril.

In a preferred embodiment of the invention, the compounds of the invention are administered in combination with an endothelin antagonist, such as, and preferably, bosentan, darusentan, ambrisentan, avossentan, macitentan, atrazentan or sitaxsentan.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a TGF beta antagonist, such as, for example and preferably with pirfenidone or fresolimumab.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a TNF alpha antagonist, such as, for example and preferably with adalimumamob.

- 32 038451

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

SPP-800.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with HIF-PH inhibitors, such as, for example and preferably with molidustat or roxadustat.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with mineralocorticoid receptor antagonists, such as, and preferably, spironolactone and eplerenone, fineronone.

In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a rockinase inhibitor, such as and preferably with fasudil, Y-27632, SLx-2119, BF-66851, BF-66852, BF-66853, KI-23095, SB- 772077, GSK-269962A or BA-1049.

In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a diuretic such as furosemide, torasemide, bumetanide and pyrethanide, with a potassium-sparing diuretic such as amiloride and triamterene, with an aldosterone antagonist such as spironolactone, potassium canrenoate and eplerenone; and a thiazide diuretic such as hydrochlorothiazide, chlorthalidone, xypamide and indapamide.

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

In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a cholesteryl ester transfer inhibitor, such as, and preferably, torcetrapib (CP-529 414), anacetrapib, JJT-705 or the CETP vaccine (Avant).

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a thyroid receptor antagonist, such as and preferably with D-thyroxine, 3,5,3'-triiodothyronine (T3), CGS 23425 or axithyrome (CGS 26214).

In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor from the statin class, such as, for example, and preferably with lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rosuvastatin or pitavastatin.

In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a squalene synthase inhibitor, such as, for example and preferably BMC-188494 or TAK-475.

In a preferred embodiment of the invention, the compounds of the invention are administered in combination with an acyl-CoA cholesterol acyltransferase inhibitor, such as, for example and preferably with avasimibe, melinamide, pactimib, eflucimib or SMP-797.

In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a microsomal triglyceride transfer protein inhibitor such as, for example and preferably implitapid, BMC-201038, R-103757 or JTT-130.

In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a PPAR-gamma agonist, such as, for example and preferably pioglitazone or rosiglitazone.

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

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

In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a lipase inhibitor, such as, and preferably, orlistat.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a polymeric bile acid adsorber, such as, for example and preferably with cholestyramine, colestirol, coleswam, cholestagel or colestimide.

In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a bile acid reabsorption blocker, such as and preferably with ASBT inhibitors (= IBAT), such as AZD-7806, S-8921, AK-105, BARI-1741 , SC-435 or SC-635.

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

- 33 038451

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with sGC modulators (soluble guanylate cyclase modulators), such as, for example and preferably with riociguat, cynaciguat, vericiguat or BAY 1101042.

In a preferred embodiment of the invention, the compounds of the invention are administered in combination with one of the active substances affecting glucose metabolism, such as, for example and preferably with insulin, sulfonylurea, acarbose, DPP4 inhibitors, GLP-1 analogue or SGLT-1 inhibitor.

Particularly preferred are combinations of the compounds according to the invention with one or more additional biologically active substances selected from the group consisting of blood pressure lowering active substances, antiarrhythmic biologically active substances, vasopressin receptor antagonists, PDE5 inhibitors, platelet aggregation blockers, sGC activators and sGC stimulants.

Another object of the present invention is medicinal substances that 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 compounds according to the invention can act systemically and / or locally. For this purpose, they can be used in any suitable way, such as, for example, oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, dermal, transdermal, instillation of drugs in the eyes, ear canal, or as an implant or stent.

For these uses, the compounds according to the invention can be produced in a suitable administration form.

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

Parenteral administration can occur regardless of the stage of absorption (eg, intravenous, intra-arterial, intracardiac, intravertebral or intra-lumbar) or including the stage of absorption (eg, by inhalation, intramuscularly, by subcutaneous injection, intradermal injection, percutaneous or intraperitoneal injection). For parenteral administration, forms of administration and other preparations for injections and infusions in the form of solutions, suspensions, emulsions, lyophilisates or sterile powders are suitable.

Suitable for other modes of use are, for example, dosage forms for inhalation (and other powder inhalers, nebulizers, aerosols with dispensers), drops, solutions or sprays for nasal administration, tablets, films / wafers or capsules taken by the lingual, sublingual or buccal route. , suppositories, ear or eye preparations, vaginal capsules, aqueous suspensions (conventional lotions, suspensions or lotions with a low fat content), fat-soluble suspensions, ointments, creams, transdermal therapeutic systems (such as patches), milk, pastes, foams, powders, implants, or stents.

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

The compounds according to the invention can be converted into the indicated administration forms. This can be done in a known manner by mixing with inert, non-toxic, pharmaceutically acceptable excipients. These excipients include other fillers (eg microcrystalline cellulose, lactose, mannitol), solvents (eg liquid polyethylene glycols), emulsifiers and dispersants or wetting agents (eg sodium dodecyl sulfate, polyoxysorbitanoleate), binders (eg polyvinyl pyrrolidone) synthetic and natural polymers (eg albumin), stabilizers (eg antioxidants such as ascorbic acid), colorants (eg inorganic pigments such as iron oxide) and taste and / or odor enhancers.

Preferably, for parenteral administration, an amount of about 0.001-1 mg / kg is used, particularly preferably 0.01-0.5 mg / kg body weight 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 body weight.

Despite this, sometimes it is necessary to deviate from the indicated dosage, namely, depending on the body weight, the method of application, the individual attitude to the biologically active substance, the method of preparation and the time or periods of time in which the application is carried out. Thus, in some cases it may be sufficient to apply less than the specified minimum amount, in

- 34 038451 while in other cases it is necessary to exceed the specified upper limit. If a larger amount is used, it may be advisable to divide it into more single doses per day.

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

A. Examples

Abbreviations. and abbreviations .________________________________________________

AAV General technological instructions abs. absolutely AIBN azobis (isobutyronitrile) aq. aqueous, aqueous solution br: lat. (with NMR signal) Approx. Example Bu butyl with concentration sa. about, about cat. catalytically CDI (CDI) carbonyldiimidazole CI chemical ionization (at MS) d doublet (at NMR) d day (days) DCM dichloromethane dd doublet doublet (at NMR) de diastereoisomeric excess DEA diethylamine dest. distilled DIPEA Ν, Ν-diisopropylethylamine DMAP 4-K ^ -dimethylaminopyridine DMF Ν, Ν-dimethylformamide dmso dimethyl sulfoxide dt triplet doublet (at NMR) d. Th. theor. exit (during chemical exit) her enantiomeric excess EI electron impact ionization (at MS)

- 35 038451

ent enantiomeric, enantiomer Aq. equivalent (s) ESI electrospray ionization (with MS) Et ethyl GC gas chromatography GC / MC Gas chromatography coupled to mass spectrometry h watch) HATU O- (7-azabenzotriazol-1-yl) -X, X, No., No. tetramethyluronium hexafluorophosphate HPLC HPLC (high pressure liquid chromatography, high performance liquid chromatography) konz. concentrate (in solution) LC liquid chromatography LC / MC liquid chromatography coupled to mass spectrometry Lit. literary source m multiplet (at NMR) M molar (in solution) Me methyl min minute (minutes) MC mass spectrometry NBS 1-bromopyrrolidine-2,5-dione NMR nuclear magnetic resonance spectroscopy q (or quart) quartet (at NMR) qd doublet quartet (at NMR) count quantitative yield (during chemical yield) quint. quintet (at NMR) gas racemate RP reverse phase (reverse phase, HPLC) KT room temperature KT retention time (HPLC, LC / MS) sec: singlet (at NMR) sept septetg (at NMR) SFH supercritical liquid chromatography t: triplet (at NMR) tBu tert-butyl td triplet doublet (NMR) TFA trifluoroacetic acid THF tetrahydrofuran Uv ultraviolet spectrometry cp. compared v / v volume to volume ratio (solution) xanthophos 9,9-dimethyl-4,5-bis- (diphenylphosphino) -xanthene ZUS. together

Methods of high-performance liquid chromatography and liquid chromatography coupled with mass spectrometry:

- 36 038451

Method 1.

Instrument: Waters Acquity SQD UPLC System; columns: Waters Acquity UPLC HSS T3 1.8 μm 50x1 mm; eluent A: 1 l of water + 0.25 ml of 99% formic acid, eluent B: 1 l of acetonitrile + 0.25 ml of 99% formic acid; gradient: 0.0 min 90% A m 1.2 min 5% A m 2.0 min 5% A; oven: 50 ° C; flow: 0.40 ml / min; UV indication: 208-400 nm.

Method 2.

MS Instrument: Waters (Micromass) QM; HPLC instrument: Agilent 1100 series; speakers: Agient ZORBAX Extend-C18 3.0x50 mm 3.5-Micron; solvent A: 1 l of water + 0.01 ml of ammonium carbonate, eluent B: 1 l of acetonitrile; gradient: 0.0 min 98% A m 0.2 min 98% A m 3.0 min 5% A m 4.5 min 5% A; oven: 40 ° C; flow: 1.75 ml / min; UV indication: 210 nm.

Method 3.

Mass spectrometry instrument type: Thermo Scientific FT-MC; UHPLC + instrument type: Thermo Scientific UltiMate 3000; Waters columns, HSST3, 2.1x75 mm, C18 1.8 μm; solvent A: 1 l of water + 0.01% formic acid, eluent B: 1 l of acetonitrile + 0.01% of formic acid; gradient: 0.0 min 10% B m 2.5 min 10% B m 1.7 min 95% B m 23.5 min 95% B; oven: 50 ° C; flow: 0.90 ml / min; UV indication: 210 nm / Optimum Integration Path 210-300 nm.

Method 4.

Instrument: Waters Acquity SQD UPLC System; columns: Waters Acquity UPLC HSS T3 1.8 μm 50x1 mm; eluent A: 1 l of water + 0.25 ml of 99% formic acid, eluent B: 1 l of acetonitrile + 0.25 ml of 99% formic acid; gradient: 0.0 min 95% A m 6.0 min 5% A m 7.5 min 5% A; oven: 50 ° C; flow: 0.35 ml / min; UV indication: 210-400 nm.

Method 5.

Instrument: Agilent MC Quad 6150; HPLC: Agilent 1290; columns: Waters Acquity UPLC HSS T3 2.1.8 μm 50x1 mm; eluent A: 1 l of water + 0.25 ml of 99% formic acid, eluent B: 1 l of acetonitrile + 0.25 ml of 99% formic acid; gradient: 0.0 min 90% A m 0.3 min 90% A m 1.7 min 5% A m 3.0 min 5% A; oven: 50 ° C; flow: 1.20 ml / min; UV indication: 205-.05 nm.

Method 6.

Instrument: Thermo DFS, Trace GC Ultra; Columns: Restek RTX-35, 15 mx 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 and 300 ° C (leave at 3.33).

Other data.

The percentages in the following examples and tests are, unless otherwise indicated, mass percent; parts are mass parts. Solvent ratio, dilution ratio and data on liquid concentration in solutions refer to volume, respectively.

In the purification of the compounds according to the invention by preparative HPLC by the methods described above, in which the eluents contain additives such as trifluoroacetic acid, formic acid or ammonia, the compounds according to the invention can be formed 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. This salt can be converted by various methods known to those skilled in the art to the corresponding free base or acid.

The purity data generally refers to the corresponding peak integration in the LC / MS chromatogram and can additionally be ascertained using the ^{l ·} H-NMR spectrum. If no purity is indicated, it is generally 100% pure by automatic peak integration in the LC / MS chromatogram, or the purity is not determined.

Output data in% theory. output is generally corrected for purity if specified as <100% purity. When loading substances containing a solvent or contaminated substances, the yield can formally be> 100%; in these cases, the yield is not corrected for solvent or purity.

The following sample descriptions of the ^{l ·} H-NMR signal combination are partially selected directly from the ACD SpecManagers data (ACD / Labs Release 12.00, Product version 12.5) and are taken into account as appropriate. In addition to this L-NMR data, under certain circumstances, there are additional extended signals caused by the molecular dynamics present (in particular in the range of 2.50-4.20 ppm), which are not indicated separately. Part of the SpecManager data is manually negotiated. Manually agreed or provided descriptions are usually oriented towards the external properties of these signals and, if necessary, do not fully comply with a rigorous, physically correct interpretation. Typically, data refers to a chemical shift towards the center of said signal. With a wide multiplet, interval data are presented. Signals covered with solvent or water are either compared empirically, or do not indicate. Very extended signals, for example, caused by rapid rotation of parts of molecules or due to substituted protons, are also available empirically (often indicated as a wide multiplet or wide singulet) or not indicated.

37 038451 ¹ H-NMR data of selected examples were recorded as ¹ H-NMR peak list. For each signal peak, the δ-value is first reported in ppm and then the signal intensity is indicated in parentheses. Data pair δ-value - the signal strength of the various signal peaks separated from each other by commas. Therefore, the list of peaks of examples has the form: δ1 (intensity!), Δ ₂ (intensity ₂ ), .., δ ₁ (intensity ^, .., δ _η (intensity ^.

The intensity of the 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 ratio of the signal intensity. Wide signals can represent multiple peaks or the middle of the signal and its relative intensity compared to the strongest signal in the spectrum. The 'H-NMR peak lists are similar to the classic ¹ H-NMR printed lists and usually contain all peaks that mention classical NMR interpretations. In addition, they can, like the classic ¹ H-NMR printed lists, show signals from solvents, stereoisomers of the desired compounds, which are also the subject of the invention, and / or peaks of impurities. The stereoisomer peaks of the target compounds and / or the impurity peaks generally have a lower intensity than the peaks of the target compounds (eg,> 90% pure). Such stereoisomers and / or impurities may be representative of the respective preparation methods. Thus, their peaks can assist in recognizing the reproduction of our by-product fingerprint method. An examiner who evaluates the peaks of the required compounds using known methods (MestreC, ACD modeling, or using empirical, analyzed expected values), as needed, can isolate the peaks of the required compounds, and, if necessary, apply an additional intensity filter. Such isolation would be similar to the aforementioned peak mapping in the classical interpretation of 1H-NMR. A detailed description of the presentation of NMR data in the form of peak lists can be found in the publication Citation of NMR Peakllst 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 program 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, the MinimumHeight parameter should be set to <1%.

Melting points and melting range, unless otherwise indicated, are not corrected.

For all reactants and reagents, the preparation of which is not further described in detail, 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 are starting materials that are not generally available, there is a reference to the published literature, which describes their preparation.

General technological instructions.

AAV1.

A solution of the corresponding carboxylic acid (1-2 equiv.) In DMF (0.08-0.12 M) was mixed with Ν, Ν-diisopropylethylamine (1.4-1.5 equiv. Or 2.4-3.0 equiv. If an amine was used as the hydrochloride) and HATU (1.0 -1.65 equiv.) And the mixture was stirred for 30 min at room temperature. Then the corresponding amine (1.04-1.5 equiv.) Was added and the mixture was re-stirred for 0.25-2 h at room temperature. The reaction was then terminated by adding water and 1M aqueous hydrochloric acid. The precipitate was filtered off, taken up in DCM, dried over magnesium sulfate, filtered off, and the solvent was removed under reduced pressure. Alternatively, it was extracted after acidification with ethyl acetate and the combined organic phases were dried over magnesium or sodium sulfate, filtered and the solvent was removed under reduced pressure. The starting material was then purified either by normal phase chromatography (silica gel, eluent: cyclohexane ethyl ester of acetic acid or dichloromethane-methanol) or by preparative RP-HPLC (reverse phase HPLC) (water-acetonitrile gradient). Alternatively, the reaction mixture was diluted with a small amount of acetonitrile, water and formic acid and the resulting crude solution was purified by RP-HPLC (water-acetonitrile gradient). Other alternative processing options, if any, are described in the respective experiments.

AAV2.

Heated potassium or cesium carbonate (1.5-2.5 equiv.) In a reaction vessel under vacuum. Cooled to room temperature and filled with argon. Palladium acetate (0.1-0.36 eq.), 9,9-dimethyl-4,5bis- (diphenylphosphino) xanthene (xantphos, 0.18-0.36 eq.) And dioxane (0.04-0.12 M) were added and the suspension was degassed for 10 min at room temperature in a stream of argon. Then the corresponding amide (1.0-1.0 eq.) And the corresponding 7-chloro-4-oxo-1,4-dihydro-1,8-naphthyridine (1.0 eq.) Were added. Stirred for 1 h (or until complete conversion after analytical HPLC or thin layer chromatography) with appropriate solvent mixtures) at 80-110 ° C. Then it was cooled to room temperature and all volatiles were removed under reduced pressure, or, alternatively, the reaction mixture was poured onto water, the pH was adjusted with 1 M aqueous hydrochloric acid pH 1, ex- traged with ethyl acetate, the combined organic phases were washed with saturated, aqueous sodium chloride solution, dried over magnesium sulfate, filtered and the solvent was removed under reduced pressure. The starting material was then purified either by normal phase chromatography (eluent: cyclohexane-ethyl acetate or dichloromethane-methanol) or by preparative RP-HPLC (water-acetonitrile gradient). Alternatively, the reaction mixture was diluted with a small amount of acetonitrile, water and formic acid or TFA and the resulting crude solution was purified by RP-HPLC (water-acetonitrile gradient). Other alternative processing options, if any, are described in the respective experiments.

AAV3.

A solution of the corresponding 7-chloro-4-oxo-1,4-dihydro-1,8-naphthyridine in DMF (0.10-0.22 M) was mixed with the corresponding amine (1.2 eq.) And DIPEA (1.5-3.5 eq.). The reaction solution was stirred overnight at room temperature. The starting material was then either purified after aqueous work-up and extraction with an appropriate organic solvent by normal phase chromatography (eluent: cyclohexane-ethyl acetate or dichloromethane-methanol) or by preparative RP-HPLC (water-acetonitrile gradient). Alternatively, the reaction mixture was diluted with a small amount of acetonitrile, water and formic acid and the resulting crude solution was purified by RP-HPLC (water-acetonitrile gradient). Other alternative processing options, if any, are described in the respective experiments.

Initial and intermediate compounds

Example 1A.

7-Chloro-1 - (2,6-difluorophenyl) -6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-ethyl ester of carboxylic acid

A solution of 6.00 g (17.8 mmol) 2 - [(2,6-dichloro-5-fluoropyridin-3-yl) carbonyl] -3-ethyl ester of ethoxyacrylic acid (preparation described in US Pat. No. 4,840,954 A, Example G, step 1, c 7) and 3.23 g (24.9 mmol) of 2,6-difluoroaniline in 30 ml of dichloromethane were mixed with 21.8 ml (125 mmol) of DIPEA and stirred for 4 h at room temperature. Then 2.47 g (17.8 mmol) of potassium carbonate was added and the mixture was heated overnight in a reverse flow. The mixture was diluted with 200 ml of dichloromethane and washed twice with 150 ml of 1M aqueous hydrochloric acid. The organic phase was decanted, dried over sodium sulfate, filtered and the solvent was removed under reduced pressure. Diluted with 80 ml of tert-butyl methyl ether, the precipitate was evacuated and washed with 10 ml of tert-butyl methyl ether. This gave 3.22 g (45% theory, 95.7% purity) of the title compound.

LCMS (Method 1): Rt = 0.96 min; MS (ESIpos): m / z = 383 [M + H] +.

'H-NMR (400 MHz, DMSO-de) δ [ppm]: 8.95 (s, 1H), 8.57 (d, 1H), 7.80-7.71 (m, 1H), 7.50-7.43 (m, 2H), 4.25 (q, 2H), 1.26 (t, 3H).

Example 2A.

7-Chloro-1 - (2,6-difluorophenyl) -6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid

3.22 g (8.41 mmol) of 7-chloro-1- (2,6-difluorophenyl) -6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-ethyl ester of carboxylic acid was placed in 25.2 ml of water, was mixed with 25.2 ml of 36% aqueous hydrochloric acid and 25.2 ml of THF and stirred for 4 h at 110 ° C. The reaction mixture was cooled to room temperature, the precipitate was evacuated, washed twice with 30 ml of water and dried in a high vacuum. This gave 4.1 g (col., 96.8% pure) of the title compound.

LCMS (Method 1): Rt = 0.96 min; MS (ESIpos): m / z = 355 [M + H] +.

'H-NMR (400 MHz, DMSO-de) δ [ppm]: 13.70 (s, 1H), 9.25 (s, 1H), 8.76 (d, 1H), 7.80-7.72 (m, 1H), 7.517.43 (m, 2H).

Example 3A.

7-Chloro-1 - (2,6-difluorophenyl) -6-fluoro-4-oxo-N - [(2S) -1,1,1-trifluorobutan-2-yl] -1,4-dihydro-1, 8naphthyridine-3-carboxylic acid amide

- 39 038451

According to AAV1, 1.00 g (2.82 mmol) of 7-chloro-1- (2,6-difluorophenyl) -6-fluoro-4-oxo-1,4dihydro-1,8-naphthyridine-3-carboxylic acid were combined with 553 mg (3.38 mmol) (2S) -1,1,1-trifluorobutane-2-amine hydrochloride in the presence of 1.29 g (3.38 mmol) HATU and 1.96 ml (11.3 mmol) DIPEA in 20 ml DMF. Stir for 1 min and add the reaction solution to a mixture of water, 1M aqueous hydrochloric acid and ethyl acetate. The phases were separated and the aqueous phase was extracted four times with 50 ml of ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and the solvent was removed under reduced pressure. The starting material was dissolved in a small amount of ethyl acetate and purified using normal phase chromatography (cyclohexane ethyl acetate, 5: 1). The fractions were combined, concentrated in vacuo, and the residue was lyophilized overnight from acetonitrile. This gave 331 mg (25% theory, 100% purity) of the title compound.

LCMS (Method 3): Rt = 2.32 min; MS (ESIpos): m / z = 464 [M + H] +.

'H-NMR (400 MHz, DMSO-d6) δ [ppm]: 9.84 (d, 1H), 9.12 (s, 1H), 8.72 (d, 1H), 7.80-7.72 (m, 1H), 7.517.44 (m, 2H), 4.85-4.71 (m, 1H), 1.96-1.83 (m, 1H), 1.75-1.61 (m, 1H), 0.98 (t, 3H).

Example 4A.

7-Chloro-1 - (2,4,6-trifluorophenyl) -6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-ethyl ester of carboxylic acid

A solution of 12.0 g (35.7 mmol) 2 - [(2,6-dichloro-5-fluoropyridin-3-yl) carbonyl] -3-ethyl ester of ethoxyacrylic acid (US4840954 A, Example G, step 1, p. 7) and 7.35 g (49.9 mmol) of 2,4,6-trifluoroaniline in 60 ml of dichloromethane was mixed with 43.5 ml (250 mmol) of DIPEA and stirred for 4 h at room temperature. Then 4.93 g (35.7 mmol) of potassium carbonate was added and the mixture was heated overnight by reflux. The mixture was then diluted with 200 ml of dichloromethane and washed three times with 150 ml of 1M aqueous hydrochloric acid. The organic phase was dried over sodium sulfate, filtered and the solvent was removed under reduced pressure. It was diluted with 100 ml of tert-butyl methyl ether, the precipitate was evacuated and washed three times with 20 ml of tert-butyl methyl ether and dried in a high vacuum. This gave 8.80 mg (58% theory, 94.6% purity) of the title compound.

LCMS (Method 1): _Rt = 1.01 min; MS (ESIpos): m / z = 401 [M + H] +.

'H-NMR (400 MHz, DMSO-d6) δ [ppm]: 8.97 (s, 1H), 8.56 (d, 1H), 7.67-7.56 (m, 2H), 4.26 (q, 2H), 1.28 (t , 3H).

Example 5A.

-Chloro-6-fluoro-4-oxo-1 - (2,4,6-trifluorophenyl) -1,4-dihydro-1,8-naphthyridine-3-carboxylic acid

8.80 g (21.9 mmol) of 7-chloro-1- (2,4,6-trifluorophenyl) -6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-ethyl ester of carboxylic acid was placed in 66.2 ml water, mixed with 66.2 ml of 36% aqueous hydrochloric acid and 66.2 ml of THF and stirred for 4 h at 110 ° C. The reaction mixture was cooled to room temperature, the precipitate was evacuated, washed four times with 40 ml of water and dried in a high vacuum. This gave 7.37 g (89% theory, 99% purity) of the title compound.

LCMS (Method 3): _Rt = 1.84 min; MS (ESIpos): m / z = 373 [M + H] +.

'H-NMR (400 MHz, DMSO-d6) δ [ppm]: 13.67 (s, 1H), 9.28 (s, 1H), 8.76 (d, 1H), 7.68-7.59 (m, 2H).

Example 6A.

7 - [(3R, 4R) -3,4-Dihydroxypyrrolidin-1-yl] -6-fluoro-4-oxo-1- (2,4,6-trifluorophenyl) -1,4-dihydro- 40 038451

1,8-naphthyridine-3-carboxylic acid

To a solution of 3.60 g (9.66 mmol) of 7-chloro-1- (2,4,6-trifluorophenyl) -6-fluoro-4-oxo-1,4-dihydro-1,8 naphthyridine-3-carboxylic acid and 1.48 g ( 10.6 mmol) (3R, 4R) -pyrrolidine-3,4-diol hydrochloride in 50 ml of DMF at room temperature was added 5.89 ml (33.8 mmol) of DIPEA. Stirred for 1 hour at room temperature. Then the reaction mixture was mixed with 150 ml of water and 100 ml of aqueous 1 M hydrochloric acid and the formed precipitate was pumped off. The residue was washed with water and dried under high vacuum. This gave 3.96 mg (93% theory, 94.6% purity) of the title compound.

LCMS (Method 3): _Rt = 1.23 min; MS (ESIpos): m / z = 440 [M + H] +.

¹ H-NMR (500 MHz, DMSO-d ,.) δ [ppm]: 15.01 (s, 1H), 9.05 (s, 1H), 8.07 (d, 1H), 7.64-7.54 (m, 2H), 5.305 .14 (m, 2H), 4.09-3.64 (m, 4H), 3.28-3.21 (m, 0.6H, partially with water resonance), 3.15-3.01 (m, 1H).

Example 7A.

6-Fluoro-7 - [(4S) -4-hydroxy-2-oxopyrrolidin-1-yl] -4-oxo-1 - (2,4,6-trifluorophenyl) -1,4-dihydro-1,8naphthyridine- 3-carboxylic acid

According to AAV2, 100 mg (268 μmol) of 7-chloro-1- (2,4,6-trifluorophenyl) -6-fluoro-4-oxo-1,4-dihydro-1,8 naphthyridine-3-carboxylic acid was converted with 32.6 mg (322 μmol) (4S) -4-hydroxypyrrolidin-2-one in the presence of 92.7 mg (671 μmol) potassium carbonate, 6.0 mg (27 μmol) palladium acetate and 33 mg (54 μmol) xanphos in 2.4 ml dioxane at 90 ° C for 1 h. The reaction mixture was diluted with 1 ml of aqueous 1M hydrochloric acid and 1 ml of DMSO and immediately purified by preparative HPLC (acetonitrile-water with formic acid, C18 RP-HPLC). This gave 61.7 mg (42% theory, 80% purity) of the title compound.

LCMS (Method 3): _Rt = 1.19 min; MS (ESIpos): m / z = 438 [M + H] +.

Example 8A.

7 - [(3S, 4S) -3,4-Dihydroxypyrrolidin-1-yl] -6-fluoro-4-oxo-1- (2,4,6-trifluorophenyl) -1,4-dihydro-1,8naphthyridine- 3-carboxylic acid

To a solution of 240 mg (644 μmol) 7-chloro-1- (2,4,6-trifluorophenyl) -6-fluoro-4-oxo-1,4-dihydro-1,8 naphthyridine-3-carboxylic acid and 73.0 mg ( 10.6 mmol) (3R, 4R) -pyrrolidine-3,4-diol in 3.3 ml of DMF was added 280 ml (33.8 mmol) of DIPEA at room temperature. Stirred for 1 hour at room temperature. The reaction mixture was diluted with 0.4 ml of aqueous 1 M hydrochloric acid and 1 ml of acetonitrile and immediately purified by preparative HPLC (acetonitrile-water with formic acid, C18 RP-HPLC). This gave 232 mg (74% theory, 94.4% purity) of the title compound.

LC-MS (Method 1): R _t = 0.69 min; MS (ESIpos): m / z = 440 [M + H] +.

¹ H-NMR (500 MHz, DMSO-d ,,) δ [ppm]: 15.01 (s, 1H), 9.05 (s, 1H), 8.07 (d, 1H), 7.64-7.55 (m, 2H), 5.335 .10 (m, 2H), 4.10-3.63 (m, 4H), 3.29-3.20 (m, 0.8H, partially with water resonance), 3.15-3.00 (m, 1H).

Example 9A.

7 - [(3R, 4S) -3,4-Dihydroxypyrrolidin-1-yl] -6-fluoro-4-oxo-1- (2,4,6-trifluorophenyl) -1,4-dihydro1,8-naphthyridine- 3-carboxylic acid

- 41 038451

To a solution of 250 mg (671 μmol) 7-chloro-1- (2,4,6-trifluorophenyl) -6-fluoro-4-oxo-1,4-dihydro-1,8 naphthyridine-3-carboxylic acid and 103 mg ( 738 μmol) of cis-pyrrolidine-3,4-diol hydrochloride in 3.3 ml of DMF at room temperature was added 409 μl (2.35 mmol) of DIPEA. Stirred for 1 hour at room temperature. The reaction mixture was acidified with 7 ml of aqueous 1 M hydrochloric acid, mixed with 15 ml of water, and the precipitate was evacuated. The residue was washed with water and lyophilized. This gave 256 mg (86% theory, 99% purity) of the title compound.

LC-MS (Method 1): R _t = 0.71 min; MS (ESIpos): m / z = 440 [M + H] +.

'H-NMR (500 MHz, DMSO-de) δ [ppm]: 15.0 (s, 1H), 9.05 (s, 1H), 8.05 (d, 1H), 7.63-7.54 (m, 2H), 5.154.89 (m, 2H), 4.13-3.86 (m, 3H), 3.61 (br. s, 1H), 3.21 (br. s, 1H), 3.04 (br. s, 1H).

Example 10A.

6-Fluoro-7 - [(3 S) -3-hydroxypyrrolidin-1-yl] -4-oxo-1 - (2,4,6-trifluorophenyl) -1,4-dihydro-1,8 naphthyridine-3-carboxylic acid

7-Chloro-6-fluoro-4-oxo-1 - (2,4,6-trifluorophenyl) -1,4-dihydro-1,8-naphthyridine-3-carboxylic acid (800 mg, 2.15 mmol) was placed in 8 ml of DMF, mixed with (3S) -pyrrolidin-3-ol (206 mg, 2.36 mmol) and Ν, Ν-diisopropylethylamine (1.3 ml, 7.5 mmol), and the mixture was stirred for 2 h at room temperature. The reaction mixture was poured onto water, mixed with 1M hydrochloric acid and ethyl acetate. The organic phase was separated and the aqueous phase was extracted three times with ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution, dried over sodium sulfate and concentrated. The product was stirred with acetonitrile, filtered off, washed again with chilled acetonitrile and dried. This gave 770 mg (85% theory, 100% purity) of the title compound.

LCMS (Method 1): Rt = 0.82 min; MS (ESIpos): m / z = 424 [M + H] +.

¹ H-NMR (400 MHz, DMSO-de) δ [ppm]: -0.008 (2.22), 0.008 (2.03), 1.909 (0.87), 2.074 (16.00), 3.222 (0.71), 3.875 (0.53), 4.309 ( 0.50), 5.024 (1.35), 7.565 (2.70), 7.586 (4.97), 7.608 (2.81), 8.037 (5.77), 8.068 (5.70), 9.043 (10.89), 15.025 (9.55).

Example 11A.

N - [(1S) -1-Cyclopropyl-2,2,2-trifluoroethyl] -6-fluoro-4-oxo-7- (3H- [1,2,3] triazolo [4,5-b] pyridine- 3yloxy) -1 - (2,4,6-trifluorophenyl) -1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to AAV1, 500 mg (1.34 mmol) of 7-chloro-1- (2,6-difluorophenyl) -6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid was converted with 283 mg (1.61 mmol) (1S) -1-cyclopropyl-2,2,2trifluoroethanamine hydrochloride in the presence of 612 mg (1.61 mmol) HATU and 935 μL (5.37 mmol) DIPEA in 10 ml DMF. Stirred for 1 hour at room temperature and added the reaction solution to a mixture of water and ethyl acetate. The phases were separated and the aqueous phase was extracted four times with 50 ml of ethyl acetate. The organic phases were combined with 50 ml of pH 7 buffer solution and washed twice with 50 ml of saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and thickened. The substance was dissolved in ethyl acetate and filtered through silica gel and purified using normal phase chromatography (cyclohexane-ethyl acetate gradient). The fractions were combined, concentrated in vacuo, and the residue was lyophilized overnight from acetonitrile. This gave 534 mg (66% theory, 99% purity) of the title compound.

LCMS (Method 3): _Rt = 2.21 min; MS (ESIpos): m / z = 594 [M + H] +.

- 42 038451 'H-NMR (400 MHz, DMSO-de) δ [ppm]: 10.01 (d, 1H), 8.96 (s, 1H), 8.88 (d, 1H), 8.74 (dd, 1H), 8.63 ( dd,

1H), 7.65 (dd, 1H), 7.05-6.97 (m, 2H), 4.42-4.37 (m, 1H), 1.28-1.17 (m, 1H), 0.71-0.51 (m, 3H), 0.36-0.28 ( m,

1H).

Example 12A.

6-Fluoro-4-oxo-7- (3 H- [1,2,3] triazolo [4,5-b] pyridin-3 -yloxy) -N - [(2S) -1,1,1-trifluorobutane -2-yl] -1 (2,4,6-trifluorophenyl) -1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to AAV1, 500 mg (1.34 mmol) of 7-chloro-1- (2,6-difluorophenyl) -6-fluoro-4-oxo-1,4dihydro-1,8-naphthyridine-3-carboxylic acid was converted with 263 mg (1.61 mmol) (S) -1,1,1-trifluorobutan-2-amine hydrochloride in the presence of 612 mg (1.61 mmol) HATU and 935 μL (5.37 mmol) DIPEA in 9.5 ml DMF. Stirred for 1 hour at room temperature and added the reaction solution to a mixture of water and ethyl acetate. The phases were separated and the aqueous phase was extracted four times with 50 ml of ethyl acetate. The organic phases with 50 ml of pH 7 buffer and washed twice with 50 ml of saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and thickened. The substance was dissolved in ethyl acetate and filtered through silica gel and purified using normal phase chromatography (cyclohexane-ethyl acetate gradient). The fractions were combined, concentrated in vacuo, and the residue was lyophilized overnight from acetonitrile. 522 mg (66% of theory, 99% purity) of the title compound was obtained.

LCMS (Method 3): Rt = 2.19 min; MS (ESIpos): m / z = 582 [M + H] +.

'H-NMR (400 MHz, DMSO-de) δ [ppm]: 9.85 (d, 1H), 8.97 (s, 1H), 8.87 (d, 1H), 8.74 (dd, 1H), 8.63 (dd, 1H ), 7.65 (dd, 1H), 7.06-6.96 (m, 2H), 4.81-4.66 (m, 1H), 1.94-1.81 (m, 1H), 1.73-1.59 (m, 1H), 0.96 (t, 3H ).

Example 13A.

tert-Butyl-4- [6 - {[(1S) -1-cyclopropyl-2,2,2-trifluoroethyl] carbamoyl} -3-fluoro-5-oxo-8- (2,4,6 trifluorophenyl) -5 , 8-dihydro-1,8-naphthyridin-2-yl] piperazine-1-carboxylate

7-Chloro-N - [(1S) -1-cyclopropyl-2,2,2-trifluoroethyl] -6-fluoro-4-oxo-1- (2,4,6-trifluorophenyl) -1,4 dihydro-1, 8-naphthyridine-3-carboxamide (60.0 mg, 122 μmol) was placed in 1.2 ml of acetonitrile, mixed with tert-butyl piperazine-1-carboxylate (45.3 mg, 243 μmol) and, Ν-diisopropylethylamine (74 μL, 430 μmol ) and stirred for 2 h at room temperature. The reaction solution was concentrated in vacuo and used in the next step without purification. 113 mg of the title compound was obtained (quant. Yield, about 69% purity).

LCMS (Method 3): Rt = 2.61 min; MS (ESIpos): m / z = 644 [M + H] ⁺ .

Example 14A.

tert-Butyl- (2S) -4- [6 - {[(1S) -1-cyclopropyl-2,2,2-trifluoroethyl] carbamoyl} -3-fluoro-5-oxo-8- (2,4,6trifluorophenyl ) -5,8-dihydro-1,8-naphthyridin-2-yl] -2-methylpiperazine-1-carboxylate

7-Chloro-N - [(1S) -1-cyclopropyl-2,2,2-trifluoroethyl] -6-fluoro-4-oxo-1- (2,4,6-trifluorophenyl) -1,4 dihydro-1, 8-naphthyridine-3-carboxamide (60.0 mg, 122 μmol) was placed in 1.2 ml of DMF, mixed with tert-butyl- (2S) -2-methylpiperazine-1-carboxylate (34.1 mg, 170 μmol) and Ν, Ν-diisopropylethylamine (74 μl, 430 μmol) and stirred for 1 h at room temperature. The reaction solution was taken up in ethyl acetate and shaken three times with half-saturated ammonium chloride solution. The combined aqueous phases were extracted once with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. Received 82 mg of the target compound (91% theory. V., Purity 90%).

LC-MS (Method 3): R _t = 2.64 min; MS (ESIpos): m / z = 658 [M + H] ⁺ .

Example 15A.

7-Chloro-1- (3,5-difluoropyridin-2-yl) -6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid ethyl ester

A solution of 6.00 g (17.8 mmol) 2 - [(2,6-dichloro-5-fluoropyridin-3-yl) carbonyl] -3-ethyl ester of ethoxyacrylic acid (US 4840954, 1989, Example G, step 1, p. 7 ) and 3.25 g (25.0 mmol) of 2-amino-3,5-difluoropyridine in 30 ml of dichloromethane were mixed with 21.8 ml (125 mmol) of DIPEA and stirred for 4 h at room temperature. Then, 2.47 g (17.8 mmol, 1 eq.) Of potassium carbonate was added and the mixture was heated overnight by reflux. Then another equivalent of potassium carbonate was added and heated further overnight by reverse flow. Then another equivalent of potassium carbonate was added and heated further for 3 days in reverse flow. The mixture was diluted with 200 ml of dichloromethane and washed twice with 200 ml of 1M aqueous hydrochloric acid. The organic phase was dried over sodium sulfate, filtered and the solvent was removed under reduced pressure. It was diluted with 80 ml of tert-butyl methyl ether, the precipitate was evacuated, washed with 10 ml of tert-butyl methyl ether and dried in a high vacuum. This gave 3.73 g (54% theory, 99% purity) of the title compound.

LCMS (Method 1): Rt = 0.93 min; MS (ESIpos): m / z = 384 [M + H] ⁺ .

1H-NMR (400 MHz, DMSO-de,) δ [ppm]: 8.92 (s, 1H), 8.66 (d, 1H), 8.56 (d, 1H), 8.44-8.37 (m, 1H), 4.26 (q , 2H), 1.28 (t, 3H).

Example 16A.

7-Chloro-1- (3,5-difluoropyridin-2-yl) -6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid

3.60 g (9.38 mmol) of 7-chloro-1- (3,5-difluoropyridin-2-yl) -6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine 3-ethyl ester of carboxylic acid was placed in 28.3 ml of water, mixed with 28.3 ml of 36% aqueous hydrochloric acid and 28.3 ml of THF, and stirred again for 4 h at 110 ° C. Then, in turn, was added twice 28.3 ml of 36% aqueous hydrochloric acid and stirred for 2 days at 110 ° C. The reaction mixture was cooled to room temperature, the precipitate was evacuated, washed again with water, and dried in a high vacuum. This gave 3.25 g (96% theory, 99% purity) of the title compound.

LCMS (Method 1): Rt = 0.90 min; MS (ESIpos): m / z = 356 [M + H] +.

¹ H-NMR (400 MHz, DMSO-de) δ [ppm]: 13.71 (s, 1H), 9.18 (s, 1H), 8.76 (d, 1H), 8.68 (dd, 1H), 8.46-8.39 (m , 1H).

Example 17A.

1- (3,5-Difluoropyridin-2-yl) -7 - [(3R, 4R) -3,4-dihydroxypyrrolidin-1-yl] -6-fluoro-4-oxo-1,4-dihydro-1,8- naphthyridine-3-carboxylic acid

To a solution of 1.50 g (4.22 mmol) of 7-chloro-1- (3,5-difluoropyridin-2-yl) -6-fluoro-4-oxo-1,4-dihydro-1,8 naphthyridine-3-carboxylic acid and 648 mg (4.64 mmol) of (3R, 4R) -pyrrolidine-3,4-diol hydrochloride in 21 ml of DMF was added 2.57 ml (14.8 mmol) of DIPEA at room temperature. Stirred for

- 44 038451 h at room temperature. Acidified with 1M hydrochloric acid and then diluted with 100 ml of water and 50 ml of ethyl acetate. The phases were separated and the aqueous phase was extracted twice with 50 ml of ethyl acetate. The combined organic phases were washed twice with 50 ml of pH7 buffer solution and once with 50 ml of saturated sodium chloride solution, dried over sodium sulfate, filtered and thickened. The residue was stirred with 20 ml of tert-butyl methyl ether, decanted and the residue dried in a high vacuum. This gave 1.41 g (78% theory, 99% purity) of the title compound.

LCMS (Method 3): Rt = 1.07 min; MS (ESIpos): m / z = 423 [M + H] +.

¹ H-NMR (500 MHz, DMSO-d ₆ ) δ [ppm]: 15.02 (s, 1H), 8.96 (s, 1H), 8.66-8.61 (m, 1H), 8.41-8.34 (m, 1H), 8.07 (d, 1H), 5.34-5.06 (m, 2H), 4.14-3.59 (m, 4H), 3.44-3.20 (m, 1H, partially or with water resonance), 3.193.01 (m, 1H).

Example 18A.

1- (3,5-Difluoropyridin-2-yl) -6-fluoro-7 - [(3S) -3-hydroxypyrrolidin-1-yl] -4-oxo-1,4-dihydro-1,8naphthyridin-3- carboxylic acid.

According to AAV3 300 mg (843 μmol) 7-chloro-1- (3,5-difluoropyridin-2-yl) -6-fluoro-4-oxo-1,4dihydro-1,8-naphthyridine-3-carboxylic acid in 3.1 ml of DMF was mixed with 81 mg (928 μmol) of (S) -3-pyrrolidinol and 0.514 ml (2.95 mmol) of DIPEA and stirred for 1 h at room temperature. Then again 20 mg (232 μmol) of (S) -3-pyrrolidinol was added and the mixture was stirred for 1 hour at room temperature. The reaction mixture was diluted with water and immediately purified by preparative HPLC (acetonitrile-water with formic acid, C18 RP-HPLC). This gave 244 mg (72% theory, 100% purity) of the title compound.

LCMS (Method 3): Rt = 1.36 min; MS (ESIpos): m / z = 407 [M + H] +.

Example 19A.

- (3,5-Difluoropyridin-2-yl) -6-fluoro-7- (3-hydroxyazetidin-1-yl) -4-oxo-1,4-dihydro-1,8naphthyridine-3-carboxylic acid

To a solution of 500 mg (1.41 mmol) of 7-chloro-1- (3,5-difluoropyridin-2-yl) -6-fluoro-4-oxo-1,4-dihydro1,8-naphthyridine-3-carboxylic acid and 169 mg (1.55 mmol) of 3-hydroxyazetidine hydrochloride in 7 ml of DMF at room temperature was added 857 μl (4.92 mmol) of DIPEA. Stirred for 2.5 h at room temperature. Acidified with 1 M hydrochloric acid, diluted with 30 ml of water and 30 ml of ethyl acetate. The precipitate was pumped out (the first fraction of the product). The phases were separated and the aqueous phase was extracted twice with 15 ml of ethyl acetate. The combined organic phases were washed twice with 15 ml of pH 7 buffer solution and once with 15 ml of saturated sodium chloride solution, dried over sodium sulfate, filtered and thickened. The residue was stirred with 210 ml of tert-butyl methyl ether, decanted and the residue dried in high vacuum (second product fraction). Combined, 476 mg (86% theory, 99% purity) of the title compound was obtained.

LCMS (Method 3): Rt = 1.35 min; MS (ESIpos): m / z = 393 [M + H] +.

¹ H-NMR (500 MHz, DMSO-d ₆ ) δ [ppm]: 14.98 (s, 1H), 8.95 (s, 1H), 8.62 (d, 1H), 8.39-8.31 (m, 1H), 8.05 ( d, 1H), 5.80 (d, 1H), 4.81-3.50 (m, 5H).

Example 20A.

- (3,5-Difluoropyridin-2-yl) -6-fluoro-7- (3-hydroxy-3-methylazetidin-1-yl) -4-oxo-1,4-dihydro-1,8 naphthyridine-3-carboxylic acid.

To a solution of 500 mg (1.41 mmol) 7-chloro-1- (3,5-difluoropyridin-2-yl) -6-fluoro-4-oxo-1,4-dihydro1,8-naphthyridine-3-carboxylic acid and 191 mg (1.55 mmol) of 3-methylazetidin-3-ol-hydrochloride in 7 ml of DMF was added 857 μl (4.92 mmol) of DIPEA at room temperature. Stirred for 2 hours at room temperature. The mixture was acidified with aqueous 1 M hydrochloric acid, diluted with 40 ml of water, and the precipitate was evacuated. The residue was washed three times with 5 ml of water each and dried under high vacuum. This gave 534 mg (93% theory, 99% purity) of the title compound.

LCMS (Method 3): Rt = 1.43 min; MS (ESIpos): m / z = 407 [M + H] +.

1H-NMR (500 MHz, DMSO-d ₆ ) δ [ppm]: 14.98 (s, 1H), 8.95 (s, 1H), 8.62 (d, 1H), 8.39-8.32 (m, 1H), 8.06 (d , 1H), 5.72 (s, 1H), 4.48-3.49 (m, 4H), 1.38 (s, 3H).

Example 21A.

Ethyl (22) -2 - [(2,6-dichloro-5-fluoropyridin-3-yl) carbonyl] -3-ethoxyacrylate.

Ethyl 3- (2,6-dichloro-5-fluoropyridin-3-yl) -3-oxopropanoate (19.5 g, 69.6 mmol) and orthoformic acid triethyl ester (23.1 ml, 140 mmol) were placed in acetic anhydride (46 ml , 490 mmol) and the mixture was stirred at 140 ° C overnight. The reaction mixture was then thickened under vacuum and converted without further processing for subsequent steps. We proceeded from the quantitative yield.

LCMS (Method 1): Rt = 1.00 min; MS (ESIpos): m / z = 336 [M + H] +.

Example 22A.

Ethyl 7-chloro-1- (2-chloro-4,6-difluorophenyl) -6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylate

- 45 038451 (mixture of atropisomers).

In an argon atmosphere, ethyl- (22) -2 - [(2,6-dichloro-5-fluoropyridin-3-yl) carbonyl] -3-ethoxyacrylate (24.0 g, 71.4 mmol) and 2-chloro-4,6-difluoroaniline (16.3 g, 100 mmol) was taken up in 120 ml of dichloromethane and mixed at room temperature with N, N-diisopropylethylamine (87 ml, 500 mmol). The reaction solution was stirred for 4 hours at room temperature. Then potassium carbonate (9.87 g, 71.4 mmol) was added and stirred overnight by reflux. The reaction mixture was cooled, diluted with 300 ml of dichloromethane and washed three times with 180 ml of 1 M hydrochloric acid. The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo. The suspension thus obtained was stirred in 150 ml of tert-butyl methyl ether. The solution was concentrated in vacuo. The resulting starting material was purified by chromatography on silica gel (eluent: cyclohexane / ethyl acetate 10/1 to 5/1 to 2/1). Received 13.75 g of the target compound (46% theory. V., Purity 99%).

LCMS (Method 3): Rt = 1.98 min; MS (ESIpos): m / z = 417 [M + H] +.

Example 23A.

7-Chloro-1- (2-chloro-4,6-difluorophenyl) -6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid (mixture of atropisomers).

Ethyl 7-chloro-1- (2-chloro-4,6-difluorophenyl) -6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylate (6.00 g, 99% purity , 14.2 mmol) was suspended in 43 ml of THF. Water (43 ml) and concentrated hydrochloric acid (43 ml) were added and the mixture was left stirring for 4 hours at a bath temperature of 110 ° C. The organic solvent was then concentrated in vacuo. The suspension was mixed with 20 ml of water and the formed precipitate was filtered off. Received 5.12 mg of the target compound (92% theory. V. 99% purity).

LCMS (Method 3): Rt = 1.93 min; MS (ESIpos): m / z = 389 [M + H] ⁺ .

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: -0.008 (3.01), 0.008 (2.85), 2.327 (0.79), 2.671 (0.75), 7.752 (1.44), 7.758 (2.19), 7.774 (2.10), 7.782 (6.12), 7.794 (2.31), 7.805 (5.86), 7.816 (1.78), 8.760 (8.43), 8.778 (8.40), 9.250 (16.00), 13.654 (2.73).

Example 24A.

7-Chloro-1- (2-chloro-4,6-difluorophenyl) -N - [(1S) -1-cyclopropyl-2,2,2-trifluoroethyl] -6-fluoro-4-oxo-1,4dihydro- 1,8-naphthyridine-3-carboxamide (mixture of atropisomers).

7-Chloro-1- (2-chloro-4,6-difluorophenyl) -6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid (mixture of atropisomers, 1.50 g, 3.85 mmol) was placed in 34 ml of DMF. HATU (1.47 g, 3.85 mmol) and N, N-diisopropylethylamine (1.6 ml, 9.3 mmol) were added and stirred for 30 min at room temperature. Then (1S) -1-cyclopropyl-2,2,2-trifluoroethanamine hydrochloride (745 mg, 4.24 mmol) was added and left stirring for 2 min at room temperature. The reaction took place without control of the reaction. The mixture was added to 340 ml of water. The precipitated solid was filtered off and dried under high vacuum. Received 2.13 mg of the target compound (62% theory. V., Purity 57%).

LCMS (Method 3): Rt = 2.46 min; MS (ESIpos): m / z = 510 [M + H] ⁺ .

Example 25A.

1- (2-Chloro-4,6-difluorophenyl) -7 - [(3R, 4R) -3,4-dihydroxypyrrolidin-1-yl] -6-fluoro-4-oxo-1,4-dihydro-1,8- naphthyridine-3-carboxylic acid (mixture of atropisomers).

To a solution of 500 mg (1.29 mmol) 7-chloro-1- (2-chloro-4,6-difluorophenyl) -6-fluoro-4-oxo-1,4-dihydro-1,8 naphthyridine-3-carboxylic acid (mixture of atropisomers) and 648 mg (4.64 mmol) of (3R, 4R) -pyrrolidine3,4-diol hydrochloride in 21 ml of DMF at room temperature was added 2.57 ml (14.8 mmol) of DIPEA. Stirred for 12 hours at room temperature. The mixture was stirred in 100 ml of water and the precipitate was evacuated. The residue was washed with water and dried under high vacuum. This gave 463 mg (78% theory, 99% purity) of the title compound.

LCMS (Method 3): Rt = 1.30 min; MS (ESIpos): m / z = 456 [M + H] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 15.04 (s, 1H), 9.01 (s, 1H), 8.07 (d, 1H), 7.80-7.69 (m, 1H),), 5.22 (br. s, 2H), 4.09-3.64 (m, 4H), 3.28-3.17 (m, 1H), 3.11-2.94 (m, 1H).

Example 26A.

1- (2,6-Difluorophenyl) -7 - [(3R, 4R) -3,4-dihydroxypyrrolidin-1-yl] -6-fluoro-4-oxo-1,4-dihydro-1,8naphthyridine-3- carboxylic acid.

To a solution of 1.00 g (2.82 mmol) of 7-chloro-1- (2,6-difluorophenyl) -6-fluoro-4-oxo-1,4-dihydro-1,8 naphthyridine-3-carboxylic acid and 433 mg (3.10 mmol ) (3R, 4R) -pyrrolidine-3,4-diol hydrochloride in 15.4 ml of DMF at room temperature was added 1.72 ml (9.87 mmol) of DIPEA. Stirred for 2 hours at room temperature. Then the mixture was acidified with 1 M hydrochloric acid, diluted with 200 ml of water and 100 ml of ethyl acetate. The phases were separated and the aqueous phase was extracted twice with 50 ml of ethyl acetate. The combined organic phases were washed twice with 25 ml of pH 7 buffer solution and once with 50 ml of saturated sodium chloride solution, dried over magnesium sulfate, filtered and thickened. This gave 1.03 g (87% theory, 100% purity) of the title compound.

- 46 038451

LCMS (Method 3): Rt = 1.19 min; MS (ESIpos): m / z = 422 [M + H] +.

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 15.04 (s, 1H), 9.01 (s, 1H), 8.08 (d, 1H), 7.78-7.68 (m, 1H),), 7.47 -7.39 (m, 2H), 5.28-5.14 (m, 2H), 4.09-3.62 (m, 4H), 3.26-3.15 (m, 1H), 3.08-2.96 (m, 1H).

Example 27A.

Ethyl- (22) -3-ethoxy-2 - [(2,5,6-trichloropyridin-3-yl) carbonyl] acrylate

Took ethyl 3-oxo-3- (2,5,6-trichloropyridin-3-yl) propanoate (1.6 g, 5.40 mmol) and (diethoxymethoxy) ethane (1.80 ml, 1.3 mmol) and added acetic anhydride (3.31 ml , 35.1 mmol). Stirred overnight at 140 ° C. The mixture was evaporated and converted further without further purification (receiving 100% conversion).

Example 28A.

Ethyl 6,7-dichloro-4-oxo-1- (2,4,6-trifluorophenyl) -1,4-dihydro-1,8-naphthyridine-3-carboxylate.

Ethyl (22) -3-ethoxy-2 - [(2,5,6-trichloropyridin-3-yl) carbonyl] acrylate (intake: 1.90 g, 5.39 mmol) from the preliminary step and 2.4, 6-trifluoroaniline (1.11 g, 7.54 mmol) in 50 ml of dichloromethane. N, N-diisopropylethylamine (6.6 ml, 38 mmol) was added and stirred for 4 h at room temperature. Potassium carbonate (745 mg, 5.39 mmol) was then added and stirred back flow overnight. The reaction mixture was diluted with 120 ml of dichlomethane and washed twice with 40 ml of 1M hydrochloric acid, dried and thickened. The residue was purified through silica gel (solvent: cyclohexane / ethyl acetate = 4: 1). The fractions containing the substance thickened. This gave 0.298 g (13% theory, 100% purity) of the title compound.

LCMS (Method 1): Rt = 1.08 min; MS (ESIpos): m / z = 417 [M + H] ⁺ .

Example 29A.

6,7-Dichloro-4-oxo-1- (2,4,6-trifluorophenyl) -1,4-dihydro-1,8-naphthyridine-3-carboxylic acid.

292 mg of ethyl 6,7-dichloro-4-oxo-1- (2,4,6-trifluorophenyl) -1,4-dihydro-1,8-naphthyridine-3-carboxylate (700 μmol) was put in THF (4.0 ml, 49 mmol), ethanol (2.0 ml, 34 mmol) and water (1.0 ml) and acidified at room temperature with concentrated hydrochloric acid (about 2 ml) and then stirred for 4 days at 110 ° C. The residue was filtered off, washed with water and dried overnight under high vacuum. This gave 253 mg (90% theory, 97% purity) of the title compound.

LCMS (Method 3): Rt = 1.99 min; MS (ESIpos): m / z = 389 [M + H] ⁺ .

Example 30A.

6-Chloro-7 - [(3R, 4R) -3,4-dihydroxypyrrolidin-1-yl] -4-oxo-1- (2,4,6-mrifluorophenyl) -1,4-dihydro1,8-naphthyridine- 3-carboxylic acid.

253 mg of 6,7-dichloro-4-oxo-1- (2,4,6-trifluorophenyl) -1,4-dihydro-1,8-naphthyridine-3-carboxylic acid (97% purity, 631 μmol) was dissolved in DMF (6.0 ml, 78 mmol). (3R, 4R) -pyrrolidine-3,4 diol hydrochloride (99.8 mg, 97% purity, 694 μmol) and N, N-diisopropylethylamine (384 μL, 2.2 mmol) were added and stirred for 1 h at room temperature. Diluted with 20 ml of water, 5 ml of 1M hydrochloric acid and 20 ml of ethyl acetate. The organic phases were separated and the aqueous phase was extracted three times with 20 ml of ethyl acetate. The combined organic phases were washed twice with 20 ml of buffer solution (pH 7) and 20 ml of saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and thickened. This gave 172 mg (57% theory, 95% purity) of the title compound.

LCMS (Method 3): Rt = 1.33 min; MS (ESIpos): m / z = 456 [M + H] ⁺ .

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.150 (0.50), 0.008 (4.41), 0.146 (0.53), 1.157 (0.75), 1.175 (1.58), 1.193 (1.14), 1.211 ( 0.80), 1.229 (0.63), 1.263 (0.54), 1.988 (2.86), 2.327 (0.86), 2.366 (0.56), 2.670 (1.04), 2.710 (0.65), 2.731 (7.25), 2.891 (9.16), 3.940 ( 5.63), 4.003 (0.85), 4.021 (1.18), 4.038 (1.09), 4.056 (0.63), 4.176 (0.54), 4.194 (0.51), 5.210 (10.86), 5.216 (10.51), 5.754 (0.55), 7.582 ( 5.35), 7.604 (9.75), 7.626 (5.44), 7.952 (1.08), 8.314 (15.84), 9.065 (16.00), 14.776 (6.50).

Example 31A.

7-Chloro-6-fluoro-4-oxo-1- (2,4,6-trifluorophenyl) -1,4-dihydro-1,8-naphthyridine-3-carbonyl chloride.

To a solution of 300 mg (805 μmol) 7-chloro-6-fluoro-4-oxo-1- (2,4,6-trifluorophenyl) -1,4-dihydro-1,8 naphthyridine-3-carboxylic acid in 6 ml of THF 180 μL (2.40 mmol) of thionyl chloride was added and re-stirred for 3 h with reverse flow and then all volatiles were removed under reduced pressure. The original product was used at the next stage without processing (take into account the quantitative conversion).

Example 32A.

7-Chloro-N- (2,6-dichlorophenyl) -6-fluoro-4-oxo-1- (2,4,6-trifluorophenyl) -1,4-dihydro-1,8-naphthyridine-3carboxamide.

To a solution of 314 mg (803 μmol) 7-chloro-6-fluoro-4-oxo-1- (2,4,6-trifluorophenyl) -1,4-dihydro-1,8 naphthyridine-3-carbonyl chloride in 20 ml of dichloromethane at At room temperature, 340 μL (2.40 mmol) of triethylamine and 156 mg (963 μmol) of 2,6-dichloroaniline were added. Stirred for 30 min at room temperature and overnight at 50 ° C. The reaction mixture was thickened and taken up in dichloromethane, washed twice with 1 M aqueous hydrochloric acid, dried over magnesium sulfate, filtered, and the solvent was removed under reduced pressure. The starting material was purified by preparative HPLC (column: acetonitrile / water / 0.1% formic acid). Got

255 mg (61% theory, 100% purity) of the title compound.

LCMS (Method 1): Rt = 1.28 min; MS (ESIpos): m / z = 516 [M + H] +.

¹ H-NMR (400 MHz, DMSO-de) δ [ppm]: -0.149 (0.50), -0.008 (5.02), 0.008 (4.03), 0.146 (0.49), 1.245 (0.63), 1.260 (0.75), 1.275 (0.44), 2.073 (11.19), 2.328 (0.67), 2.367 (0.63), 2.524 (2.42), 2.670 (0.76), 2.710 (0.70), 2.891 (0.41), 7.381 (3.22), 7.402 (6.06), 7.422 (4.60), 7.596 (16.00), 7.608 (4.71), 7.616 (13.09), 7.629 (7.60), 7.652 (4.03), 8.767 (6.42), 8.786 (6.40), 9.250 (10.90), 11.287 (9.23).

Example 33A.

Ethyl 2 - [(2,5-dichloropyridin-3-yl) carbonyl] -3- (dimethylamino) acrylate.

2.0 g (10.42 mmol) of 2,5-dichloronicotinic acid in 27 ml of dichloromethane at room temperature was mixed with 1.34 ml (15.39 mmol) of oxalyl chloride and 4 drops of DMF and stirred for 1.5 h at room temperature. Then the clear solution was evaporated, mixed with toluene and again evaporated (twice). The resulting intermediate product was dissolved in 67 ml of toluene, mixed with 2.17 ml of 15.60 mmol) of triethylamine and 1.94 g (13.54 mmol) of ethyl (2E) -3- (dimethylamino) acrylate. The mixture was stirred for 2.5 h at 90 ° C, cooled, filtered, and evaporated to dryness. The starting material was purified by silica gel chromatography (eluent: cyclohexane / ethyl acetate = 1: 1). This gave 4.10 g (qty., 95% pure) of the title compound.

LCMS (Method 1): Rt = 0.76 min; MS (ESIpos): m / z = 317 [M + H] ⁺ .

Example 34A.

Ethyl 6-chloro-1 - (2,4-difluorophenyl) -4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylate.

To a solution of 2.00 g (6.31 mmol) ethyl 2 - [(2,5-dichloropyridin-3-yl) carbonyl] -3 (dimethylamino) acrylate in 15 ml of ethanol was added 770 μL (7.60 mmol) of 2,4-difluoroaniline in 3.8 ml of THF and the reaction mixture was stirred overnight at room temperature. Then the solvent was removed under reduced pressure, the residue was taken up in 20 ml of DMF and mixed with 1.31 g (9.48 mmol) of potassium carbonate. Then the suspension was stirred for 1 h at 100 ° C, then cooled to room temperature and water was added to 50 ml. The residue was filtered off and washed three times with water. This gave 1.06 g (46% theory, 91% purity) of the title compound, which was used in the following steps without further purification.

LCMS (Method 1): Rt = 0.99 min; MS (ESIpos): m / z = 365 [M + H] ⁺ .

1H NMR (400 MHz, DMSO-d6): δ ppm = 8.80 (d, 1H), 8.78 (s, 1H), 8.59 (d, 1H), 7.80-7.88 (m, 1H), 7.577.65 (m, 1H), 7.31-7.39 (m, 1H), 4.24 (q, 2H), 1.28 (t, 3H).

Example 35A.

6-chloro-1- (2,4-difluorophenyl) -4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid

To a suspension of 1.10 g (3.02 mmol) of ethyl 6-chloro-1- (2,4-difluorophenyl) -4-oxo-1,4-dihydro-1,8 naphthyridine-3-carboxylate in 10 ml of THF and 3.6 ml of water was added 127 mg (3.02 mmol) of lithium hydrochloride monohydrate and the reaction mixture was stirred for 1 h at room temperature. Then it was diluted with 20 ml of THF and 20 ml of water and the pH value was adjusted with 1 M aqueous hydrochloric acid. Ethyl acetate was added and the aqueous phase was extracted three times with ethyl acetate. The organic phase was dried over sodium sulfate, filtered and the solvent was removed in vacuo. This gave 0.90 g (86% theory, 97% purity) of the title compound.

LCMS (Method 1): Rt = 0.96 min; MS (ESIpos): m / z = 337 [M + H] ⁺ .

¹ H-NMR (400 MHz, DMSO-d6): δ ppm = 13.98 (br s, 1H), 9.10 (s, 1H), 8.95 (d, 1H), 8.80 (d, 1H), 7.807.89 (m , 1H), 7.58-7.67 (m, 1H), 7.26-7.47 (m, 1H).

Example 36A.

6-Chloro-1- (2,4-difluorophenyl) -4-oxo-1,4-dihydro-1,8-naphthyridine-3-carbonyl chloride.

58 μL (670 μmol ) oxalic acid dichloride and DMF (catalytic amount). The reaction mixture was stirred for 1 hour at room temperature and refluxed for another hour. Then all volatiles were removed under reduced pressure. The original product was used at the next stage without processing (take into account the quantitative conversion).

Example 37A.

7-Chloro-N - [(1S) -1-cyclopropyl-2,2,2-trifluoroethyl] -6-fluoro-4-oxo-1- (2,4,6-trifluorophenyl) -1,4 dihydro-1, 8-naphthyridine-3-carboxamide.

7-Chloro-6-fluoro-4-oxo-1- (2,4,6-trifluorophenyl) -1,4-dihydro-1,8-naphthyridine-3-carboxylic acid (100 mg, 268 μmol) was placed in 2.5 ml of acetonitrile, (1S) -1-cyclopropyl-2,2,2trifluoroethanamine hydrochloride (51.8 mg, 295 μmol) and Ν, Ν-diisopropylethylamine (190 μl, 1.1 mmol) were added. Then it was mixed with a T3P solution (propane phosphonic acid cycloanhydride, 50% in ethyl acetate, 190 μl, 320 μmol). The reaction solution was stirred overnight at room temperature. Then the reaction mixture was mixed with water and the precipitated solid was filtered off and

- 48 038451 dried under high vacuum. Received 145 mg of the target compound (col. Yield).

LCMS (Method 3): Rt = 2.42 min; MS (ESIpos): m / z = 494 [M + H] +.

Ή-NMR (400 MHz, DMSO-de) δ [ppm]: -0.150 (0.74), 0.146 (0.69), 0.335 (4.38), 0.348 (3.99), 0.359 (2.50), 0.567 (5.66), 0.579 (6.91) ), 0.590 (7.00), 0.624 (1.67), 0.651 (2.50), 0.670 (4.11), 0.687 (2.47), 1.224 (2.32), 1.237 (3.75), 1.245 (3.07), 1.257 (3.55), 1.268 (2.06 ), 2.328 (1.49), 2.366 (1.19), 2.669 (1.43), 2.710 (1.01), 4.370 (2.03), 4.391 (3.66), 4.411 (3.61), 4.433 (1.94), 5.754 (2.89), 7.602 (6.41 ), 7.624 (12.45), 7.647 (6.50), 8.709 (9.33), 8.728 (9.33), 9.157 (16.00), 9.972 (6.97), 9.996 (6.88).

Example 38A.

N-Benzyl-1,1,1,2,2-pentafluorobutane-3-amine (racemate).

To a solution of 2.00 g (12.2 mmol) of 3,3,4,4,4-pentafluorobutan-2-one in 10 ml of dichloromethane at 0 ° C were added 5.40 ml (18.3 mmol) of titanium tetraisopropoxide and 2.66 ml (24.4 mmol) of benzylamine. Stirred for 90 min at room temperature before being cooled back to 0 ° C. Then 2.14 g (34.1 mmol) of sodium cyanoborohydride, 36 ml of methanol and a 3 A molar sieve were added. Warmed to room temperature and stirred for 2 days. The reaction mixture was suitably mixed with a little water and ethyl acetate and filtered. The filtrate was washed twice with saturated aqueous sodium hydrogen carbonate solution and once with saturated aqueous sodium chloride solution. The organic phase was dried over sodium sulfate, filtered and the solvent was removed under reduced pressure. The residue was purified twice by normal phase chromatography (ethyl acetate / cyclohexane 1/20) to give 1.65 g (48% theory, 91% purity) of the title compound.

LCMS (Method 6): Rt = 2.17 min; MS (ESIpos): m / z = 254 [M + H] ⁺ .

¹ H-NMR (500 MHz, DMSO-d ₆ ) δ [ppm]: 7.28-7.36 (m, 4H), 7.20-7.27 (m, 1H), 3.83 (dd, 1H), 3.72 (dd, 1H), 3.22-3.30 (m, 1H), 2.43-2.48 (m, 1H), 1.20 (d, 3H).

Example 39A.

1,1,1,2,2-Pentafluorobutane-3-amine hydrochloride (racemate).

To a solution of 1.50 g (5.92 mmol) of N-benzyl-1,1,1,2,2-pentafluoropentan-3-amine in 27.4 ml of methanol was added 150 mg of palladium on carbon (10%) and hydrogenated for 6 h at normal pressure. and room temperature. Then the reaction mixture was filtered through a millipore filter and the solvent was removed under reduced pressure. Then the receiver with the solvent obtained after distillation was placed in a flask and mixed with 4N. aqueous hydrochloric acid dioxane and thickened again. The residue was washed with diethyl ether, the precipitate was evacuated and dried in a high vacuum. This gave 456 mg (39% theory, 100% purity) of the title compound.

¹ H-NMR (500 MHz, DMSO-d6) δ [ppm]: 9.21 (br. S, 3H), 4.40-4.29 (m, 1H), 1.41 (d, 3H).

Example 40A.

N-Benzyl-1,1,1,2,2-pentafluoropentane-3-amine (racemate).

To a solution of 2.00 g (11.4 mmol) of 1,1,1,2,2-pentafluoropentan-3-one in 10 ml of dichloromethane at 0 ° C, 5.03 ml (17.0 mmol) of titanium tetraisopropoxide and 2.48 ml (22.7 mmol) of benzylamine were added. Stirred for 90 min at room temperature before being cooled back to 0 ° C. Then, 2.00 g (31.8 mmol) of sodium cyanoborohydride, 36 ml of methanol and a 3 A molar sieve were added. Warmed to room temperature and stirred for 2 days. The reaction mixture was then appropriately mixed with a little water and ethyl acetate and filtered. The filtrate was washed twice with saturated aqueous sodium hydrogen carbonate solution and once with saturated aqueous sodium chloride solution. The organic phase was dried over sodium sulfate, filtered and the solvent was removed under reduced pressure. The residue was purified by normal phase chromatography (ethyl acetate / cyclohexane 1/20) to give 989 mg (25% theory, 76% purity) of the title compound.

LCMS (Method 1): Rt = 1.27 min; MS (ESIpos): m / z = 268 [M + H] ⁺ .

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 7.21-7.36 (m, 5H), 3.73-3.85 (m, 2H), 3.05-3.20 (m, 1H), 1.631.75 (m , 1H), 1.49-1.61 (m, 1H), 1.15-1.20 (m, 1H), 0.96 (t, 3H).

Example 41A.

1,1,1,2,2-Pentafluoropentane-3-amine hydrochloride (racemate)

To a solution of 980 mg (2.75 mmol, 75% purity) of the compound from Example 40A in 11.3 ml of methanol was added 75 mg of palladium on carbon (10%) and hydrogenated for 6 h at normal pressure and room temperature. Then the reaction mixture was filtered through a millipore filter and the solvent was removed under reduced pressure. Then the receiver with the solvent obtained after the distillation was placed in a flask and mixed with 4 M aqueous hydrochloric acid dioxane and thickened again. The residue was washed with diethyl ether, the precipitate was evacuated and dried in a high vacuum. This gave 379 mg (65% theory, 100% purity) of the title compound.

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: 8.97 (br. S, 3H), 4.16-4.28 (m, 1H), 1.67-1.94 (m, 2H), 1.05 (t, 3H) ...

Example 41B.

- 49 038451

7-Chloro-4-oxo-1- (2,4,6-trifluorophenyl) -1,4-dihydro-1,8-naphthyrvdine-3-ethyl ester of carboxylic acid.

A solution of 12.1 g (38.0 mmol) 2 - [(2,6-dichloropyridin-3-yl) carbonyl] -3-ethyl ester of ethoxyacrylic acid (CAS 157373-27-8) and 7.83 g (53.2 mmol) 2.4, 6-trifluoroaniline in 60.5 ml of DCM was mixed with 46.4 ml (266 mmol) of DIPEA and stirred for 4 h at room temperature. Then 5.26 g (38.0 mmol) of potassium carbonate was added and the mixture was heated overnight in a reverse flow. Diluted with 200 ml of dichloromethane and washed twice with 150 ml of 1M aqueous hydrochloric acid. The organic phase was dried over sodium sulfate, filtered and the solvent was removed under reduced pressure. The resulting suspension was diluted with 80 ml of tert-butyl methyl ether, the precipitate was evacuated, washed with 10 ml of tert-butyl methyl ether and dried in a high vacuum. This gave 8.60 g (58% theory, 99% purity) of the title compound.

LCMS (Method 1): Rt = 0.97 min; 383 [M + H] +.

Example 41C.

7-Chloro-4-oxo-1- (2,4,6-trifluorophenyl) -1,4-dihydro-1,8-naphthyridine-3-carboxylic acid.

8.60 g (22.5 mmol) of 7-chloro-4-oxo-1- (2,4,6-trifluorophenyl) -1,4-dihydro-1,8-naphthyridine-3-ethyl ester of carboxylic acid (Example 100A) was placed in 67.7 ml of water, mixed with 67.7 ml of 36% aqueous hydrochloric acid and 67.7 ml of THF, and stirred for 4.5 h at 110 ° C. The reaction mixture was cooled to room temperature. The residue was evacuated, washed again with water and dried under high vacuum. This gave 7.87 g (98% theory, 99% purity) of the title compound.

LCMS (Method 1): Rt = 0.95 min; MS (ESIpos): m / z = 355 [M + H] ⁺ .

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 13.83 (s, 1H), 9.27 (s, 1H), 8.78 (d, 1H), 7.82 (d, 1H), 7.67-7.59 ( m, 2H).

Example 42A.

6-Fluoro-7- (morpholin-4-yl) -4-oxo-1- (2,4,6-trifluorophenyl) -1,4-dihydro-1,8-naphthyridine-3carboxylic acid.

To a solution of 600 mg (1.61 mmol) 7-chloro-6-fluoro-4-oxo-1- (2,4,6-trifluorophenyl) -1,4-dihydro-1,8 naphthyridine-3-carboxylic acid and 200 μl ( 2.30 mmol) of morpholine in 8.0 ml of DMF at room temperature was added 840 μl (4.80 mmol) of DIPEA. Stirred overnight at room temperature. The reaction mixture was diluted with acetonitrile, a little and formic acid, and the starting material was purified by preparative HPLC (column: acetonitrile / water / 0.1% formic acid). This gave 658 mg (97% theory, 100% purity) of the title compound.

LCMS (Method 3): Rt = 1.76 min; MS (ESIpos): m / z = 424 [M + H] ⁺ .

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: -0.149 (0.48), 0.146 (0.51), 2.328 (0.72), 2.367 (0.64), 2.671 (0.77), 2.711 (0.64), 3.558 (12.72), 3.570 (14.98), 3.602 (16.00), 3.615 (13.62), 5.754 (1.56), 7.568 (4.70), 7.591 (8.79), 7.613 (4.66), 8.159 (7.09), 8.192 (7.01), 9.099 (13.11), 14.766 (1.97).

Example 43A.

7-Chloro-6-fluoro-N- (1,1,1,3,3,3-hexafluoropropan-2-yl) -4-oxo-1- (2,4,6-trifluorophenyl) -1,4- dihydro1,8-naphthyridine-3-carboxamide.

To a solution of 600 mg (1.61 mmol) 7-chloro-6-fluoro-4-oxo-1- (2,4,6-trifluorophenyl) -1,4-dihydro-1,8 naphthyridine-3-carboxylic acid, 296 mg (1.77 mmol) 1,1,1,3,3,3-hexafluoropropan-2-amine and 840 μL (4.80 mmol) of DIPEA in 14 mL of ethyl acetate was added dropwise 3.8 mL (6.40 mmol) 2,4,6 -tripropyl-1,3,5,2,4,6-trioxatriphosphorinan-2,4,6-trioxide (T3P, 50% in DMF). Stirred overnight at 80 ° C. The reaction mixture was poured onto water and ethyl acetate and the phases were separated. The organic phase was washed with water, dried over sodium sulfate, filtered and the solvent was removed under reduced pressure. The residue was dissolved in a small amount of acetonitrile, filtered through a millipore filter and purified in three steps by preparative HPLC (column: acetonitrile / water / 0.1% formic acid).

This gave 414 mg (49% theory, 100% purity) of the title compound.

LCMS (Method 3): Rt = 2.47 min; MS (ESIpos): m / z = 522 [M + H] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: -0.149 (0.77), -0.008 (7.00), 0.146 (0.77), 2.073 (0.49), 2.328 (0.60), 2.367 (0.60), 2.671 (0.69), 2.711 (0.60), 6.375 (0.60), 6.394 (1.45), 6.412 (2.11), 6.418 (2.09), 6.437 (2.25), 6.454 (1.48), 6.472 (0.55), 7.616 (5.90), 7.638 (11.25), 7.660 (5.93), 8.756 (9.74), 8.774 (9.85), 9.288 (16.00), 10.694 (6.45), 10.720 (6.28).

Example 44A.

7-Chloro-1- (3,5-difluoropyridin-2-yl) -6-fluoro-N- (1,1,1,3,3,3-hexafluoropropan-2-yl) -4-oxo-1, 4dihydro-1,8-naphthyridine-3-carboxamide.

To a solution of 250 mg (703 μmol) 7-chloro-1- (3,5-difluoropyridin-2-yl) -6-fluoro-4-oxo-1,4-dihydro1,8-naphthyridine-3-carboxylic acid, 129 mg (773 μmol) 1,1,1,3,3,3-hexafluoropropan-2-amine and 370 μL (2.10 mmol) of DIPEA in 10 ml of ethyl acetate was added dropwise 1.7 ml (2.80 mmol) 2.4 , 6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinan-2,4,6-trioxide (T3P, 50% in ethyl

- 50 038451 acetic acid ester). Stirred overnight at 80 ° C. The reaction mixture was mixed with 50 ml of water. The residue was evacuated, washed again with water and dried under high vacuum. This gave 259 mg (69% theory, 94% purity) of the title compound.

LCMS (Method 3): Rt = 2.34 min; MS (ESIpos): m / z = 505 [M + H] +.

Ή-NMR (400 MHz, DMSO-de) δ [ppm]: -0.149 (1.14), 0.146 (1.21), 0.931 (1.84), 0.949 (3.59), 0.967 (1.98), 1.175 (0.70), 1.243 (2.59 ), 1.260 (2.64), 1.273 (1.61), 1.298 (0.51), 1.487 (1.14), 1.496 (1.19), 1.668 (0.58), 1.988 (0.51), 2.328 (1.28), 2.366 (0.93), 2.670 (1.21 ), 2.710 (0.89), 6.406 (1.45), 6.424 (2.05), 6.448 (2.17), 6.467 (1.38), 8.399 (2.33), 8.405 (2.89), 8.426 (4.48), 8.443 (2.54), 8.449 (2.66 ), 8.615 (0.49), 8.682 (10.68), 8.688 (9.63), 8.753 (9.52), 8.772 (9.52), 8.922 (0.42), 9.184 (1.75), 9.217 (16.00), 9.284 (0.44), 10.705 (5.78 ), 10.731 (5.69).

Example 45A.

7-Chloro-4-oxo-N- [1,1,1,2,2-pentafluoropentan-3-yl] -1- (2,4,6-trifluorophenyl) -1,4-dihydro-1,8naphthyridine- 3-carboxamide (racemate).

To a solution of 250 mg (705 μmol) 7-chloro-4-oxo-1- (2,4,6-trifluorophenyl) -1,4-dihydro-1,8 naphthyridine-3-carboxylic acid, 166 mg (775 μmol) 1,1,1,2,2-pentafluoropentan-3-amine hydrochloride (racemate) and 490 μl (2.80 mmol) of DIPEA in 7.0 ml of ethyl acetate was added dropwise 1.6 ml (2.80 mmol) 2,4,6-1ripropyl -1,3,5,2,4,6-trioxa1riphosphorinan-2,4,6-trioxide (T3P, 50% in ethyl acetate). Stirred overnight at 80 ° C. The reaction mixture was mixed with 50 ml of water. The aqueous phase was extracted twice with ethyl acetate. All organic phases were dried over sodium sulfate, filtered off and the solvent was removed under reduced pressure. This gave 360 mg (89% theory, 90% purity) of the title compound.

LCMS (Method 3): Rt = 2.45 min; MS (ESIpos): m / z = 514 [M + H] ⁺ .

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: -0.149 (0.93), -0.008 (7.96), 0.008 (8.00), 0.146 (0.79), 0.834 (0.71), 0.852 (1.07), 0.950 (1.23), 0.968 (0.79), 1.180 (0.89), 1.234 (2.12), 1.266 (0.69), 1.285 (0.99), 1.302 (0.54), 1.410 (15.56), 1.427 (15.60), 1.497 (0.62), 2.328 (1.15), 2.367 (0.93), 2.671 (1.07), 2.711 (0.83), 4.998 (0.77), 5.020 (1.35), 5.044 (1.59), 5.062 (1.61), 5.086 (1.31), 5.107 (0.69), 7.596 (6.17), 7.618 (11.61), 7.640 (6.35), 7.648 (2.20), 7.754 (0.50), 7.773 (12.55), 7.794 (13.00), 7.811 (1.47), 7.832 (1.53), 8.741 (12.74), 8.762 (12.37), 8.772 (1.71), 8.793 (1.37), 9.057 (0.40), 9.143 (16.00), 9.273 (1.69), 9.986 (6.15), 10.010 (5.94).

Example 46A.

7 - [(3R, 4R) -3,4-Dihydroxypyrrolidin-1-yl] -4-oxo-N- [1,1,1,2,2-pentafluoropentan-3-yl] -1- (2,4 , 6trifluorophenyl) -1,4-dihydro-1,8-naphthyridine-3-carboxamide (mixture of diastereoisomers).

According to AAV3, 360 mg (700 μmol) of 7-chloro-4-oxo-N- [1,1,1,2,2-pentafluoropentan-3-yl] 1- (2,4,6-trifluorophenyl) -1 was converted, 4-dihydro-1,8-naphthyridine-3-carboxamide with 81.9 mg (586 μmol) (3R, 4R) pyrrolidine-3,4-diol hydrochloride and 430 μL (2.50 mmol) DIPEA in 4 ml DMF. The reaction mixture was mixed with 1N. hydrochloric acid and extracted with ethyl acetate. The organic phase was dried over sodium sulfate, filtered and the solvent was removed under reduced pressure. The starting material was purified by preparative HPLC (column: acetonitrile / water / 0.1% formic acid). This gave 242 mg (60% theory, 100% purity) of the title compound.

LCMS (Method 3): Rt = 1.86 min; MS (ESIpos): m / z = 581 [M + H] ⁺ .

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 0.008 (2.01), 0.946 (7.17), 0.965 (16.00), 0.983 (7.77), 1.618 (0.90), 1.636 (1.25), 1.644 ( 1.05), 1.652 (1.50), 1.662 (1.35), 1.671 (1.20), 1.679 (1.40), 1.697 (1.00), 1.920 (1.30), 2.073 (0.80), 2.329 (0.80), 2.368 (0.70), 2.524 ( 2.46), 2.671 (0.85), 2.711 (0.75), 3.055 (2.76), 3.087 (3.71), 3.239 (2.36), 3.262 (1.76), 3.353 (3.76), 3.606 (2.06), 3.627 (1.71), 3.929 ( 3.46), 4.050 (3.46), 4.826 (0.80), 4.850 (1.15), 4.876 (1.10), 4.902 (0.85), 5.144 (4.97), 5.152 (4.97), 5.235 (5.02), 5.244 (4.87), 6.770 ( 7.32), 6.792 (7.52), 7.544 (2.71), 7.566 (4.82), 7.584 (2.76), 8.268 (8.58), 8.290 (8.13), 8.815 (14.50), 10.470 (4.97), 10.495 (4.76).

Example 47A.

7-Chloro-4-oxo-N- [3,3,4,4,4-pentafluorobutan-2-yl] -1- (2,4,6-trifluorophenyl) -1,4-dihydro-1,8 naphthyridine- 3-carboxamide (racemate).

To a solution of 250 mg (705 μmol) 7-chloro-4-oxo-1- (2,4,6-trifluorophenyl) -1,4-dihydro-1,8 naphthyridine-3-carboxylic acid, 155 mg (775 μmol) 3,3,4,4,4-pentafluorobutan-2-amine hydrochloride (racemate) and 490 μl (2.80 mmol) of DIPEA in 7.0 ml of ethyl acetate was added dropwise 1.6 ml (2.80 mmol) 2,4,6-tripropyl -1,3,5,2,4,6-trioxatriphosphorinan-2,4,6-trioxide (T3P, 50% in ethyl acetate). Stirred for 30 min at 80 ° C. The solvent was removed under reduced pressure and the starting material was purified by preparative HPLC (column: acetonitrile / water / 0.1% formic acid). This gave 325 mg (83% theory, 90% purity) of the title compound.

LCMS (Method 3): Rt = 2.37 min; MS (ESIpos): m / z = 500 [M + H] ⁺ .

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: -0.149 (1.17), -0.008 (16.00), 0.008 (8.86), 0.146 (1.23), 0.849 (0.84), 0.942 (1.10), 0.959 (0.65), 1.233 (1.59), 1.283 (0.62), 1.409 (11.07), 1.426 (10.77), 1.487 (0.55), 2.327

- 51 038451 (1.53), 2.366 (1.43), 2.524 (9.70), 2.670 (1.62), 2.710 (1.46), 5.020 (0.94), 5.042 (1.20), 5.060 (1.20), 5.086 (1.01), 7.595 (4.38 ), 7.617 (8.11), 7.639 (4.35), 7.772 (8.18), 7.793 (8.31), 7.811 (0.97), 7.832 (1.04), 8.741 (8.18), 8.761 (7.89), 8.772 (1.07), 8.793 (0.88 ), 9.142 (10.90), 9.272 (1.14), 9.985 (4.28), 10.009 (4.19).

Example 48A.

7 - [(3R, 4R) -3,4-Dihydroxypyrrolidin-1-yl] -4-oxo-N- [3,3,4,4,4-pentafluorobutan-2-yl] -1- (2,4 , 6trifluorophenyl) -1,4-dihydro-1,8-naphthyridine-3-carboxamide (mixture of diastereoisomers).

According to AAV3, 325 mg (650 μmol) of 7-chloro-4-oxo-N- [3,3,4,4,4-pentafluorobutan-2-yl] 1- (2,4,6-trifluorophenyl) -1 was converted, 4-dihydro-1,8-naphthyridine-3-carboxamide (racemate) with 76.1 mg (545 μmol) (3R, 4R) -pyrrolidine-3,4-diol hydrochloride and 400 μL (2.30 mmol) DIPEA in 3.7 ml DMF. The reaction mixture was mixed with 1N hydrochloric acid and extracted with ethyl acetate. The organic phase was dried over sodium sulfate, filtered and the solvent was removed under reduced pressure. The starting material was purified by preparative HPLC (column: acetonitrile / water / 0.1% formic acid). This gave 239 mg (65% theory, 100% purity) of the title compound.

LCMS (Method 3): Rt = 1.76 min; MS (ESIpos): m / z = 567 [M + H] +.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 1.388 (15.08), 1.401 (16.00), 2.672 (0.88), 3.053 (3.67), 3.086 (4.68), 3.601 (3.82), 3.929 ( 6.14), 4.052 (6.04), 5.005 (2.33), 5.146 (6.42), 5.237 (6.35), 6.768 (5.34), 6.790 (5.44), 7.564 (8.09), 8.261 (5.29), 8.283 (5.16), 8.808 ( 8.64), 10.549 (4.91), 10.573 (4.81).

Example 49A.

7-Chloro-4-oxo-N- (1,1,1-trifluoro-2-methylpropan-2-yl) -1- (2,4,6-trifluorophenyl) -1,4-dihydro-1,8naphthyridine- 3-carboxamide.

To a solution of 250 mg (705 μmol) 7-chloro-4-oxo-1- (2,4,6-trifluorophenyl) -1,4-dihydro-1,8 naphthyridine-3-carboxylic acid, 127 mg (775 μmol) 1,1,1-trifluoro-2-methylpropan-2-amine hydrochloride and 490 μl (2.80 mmol) of DIPEA in 7.0 ml of ethyl acetate was added dropwise 1.6 ml (2.80 mmol) 2,4,6-tripropyl-1, 3,5,2,4,6-trioxatriphosphorinan-2,4,6-trioxide (T3P, 50% in ethyl acetate). Stirred for 30 min at 80 ° C. The solvent was removed under reduced pressure and the reaction mixture was mixed with 50 ml of water. The formed precipitate was filtered off, washed again with water and dried. This gave 297 mg (88% theory, 97% purity) of the title compound.

LCMS (Method 3): Rt = 2.34 min; MS (ESIpos): m / z = 464 [M + H] ⁺ .

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: -0.062 (0.91), -0.008 (0.99), 0.008 (1.16), 1.653 (16.00), 7.597 (1.19), 7.618 (2.22), 7.641 (1.22), 7.767 (2.50), 7.788 (2.63), 8.746 (2.59), 8.767 (2.51), 9.080 (3.17), 10.101 (2.55).

Example 50A.

7 - [(3R, 4R) -3,4-Dihydroxypyrrolidin-1-yl] -4-oxo-N- (1,1,1-trifluoro-2-methylpropan-2-yl) -1- (2,4 , 6trifluorophenyl) -1,4-dihydro-1,8-naphthyridine-3-carboxamide.

According to AAV3, 297 mg (666 μmol) of 7-chloro-4-oxo-N- (1,1,1-trifluoro-2-methylpropan-2yl) -1- (2,4,6-trifluorophenyl) -1,4 α-dihydro-1,8-naphthyridine-3-carboxamide with 102 mg (733 μmol) (3R, 4R) -pyrrolidine-3,4-diol hydrochloride and 410 μL (2.30 mmol) DIPEA in 6.0 ml DMF. The reaction mixture was mixed with 20 ml of water and aqueous 1N. hydrochloric acid. The formed precipitate was filtered off, washed again with water and dried. This gave 272 mg (77% theory, 100% purity) of the title compound.

LCMS (Method 3): Rt = 1.73 min; MS (ESIpos): m / z = 531 [M + H] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: -0.008 (1.79), 0.008 (1.49), 1.634 (16.00), 2.073 (5.68), 3.052 (0.77), 3.083 (1.03), 3.226 ( 0.66), 3.235 (0.76), 3.257 (0.63), 3.268 (0.68), 3.348 (1.35), 3.593 (0.56), 3.603 (0.65), 3.621 (0.52), 3.630 (0.49), 3.923 (0.97), 4.046 ( 0.97), 6.759 (1.98), 6.782 (2.03), 7.545 (0.73), 7.567 (1.31), 7.585 (0.74), 8.266 (2.23), 8.289 (2.10), 8.739 (3.50), 10.653 (2.89).

Example 51A.

7-Chloro-N - [(1S) -1-cyclopropyl-2,2,2-trifluoroethyl] -4-oxo-1- (2,4,6-mrifluorophenyl) -1,4-dihydro-1,8naphthyridine- 3-carboxamide.

To a solution of 4.00 g (11.3 mmol) 7-chloro-4-oxo-1- (2,4,6-trifluorophenyl) -1,4-dihydro-1,8 naphthyridine-3-carboxylic acid, 2.18 g (12.4 mmol) (1S) -1-cyclopropyl-2,2,2-trifluoroethanamine hydrochloride and 7.9 ml (45.0 mmol) of DIPEA in 110 ml of ethyl acetate was added dropwise 26 ml (45.0 mmol) 2,4,6-tripropyl-1, 3,5,2,4,6-trioxatriphosphorinan-2,4,6-trioxide (T3P, 50% in ethyl acetate). Stirred for 30 min at 80 ° C. The solvent was removed under reduced pressure and the reaction mixture was mixed with 150 ml of water. The residue was filtered off, washed again with water and dried. This gave 5.30 g (95% theory, 96% purity) of the title compound.

LCMS (Method 3): Rt = 2.33 min; MS (ESIpos): m / z = 476 [M + H] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: -0.149 (0.55), -0.062 (4.39), 0.008 (4.02), 0.146 (0.52), 0.322 (1.81), 0.335 (3.73), 0.348 (3.42), 0.361 (1.95), 0.370 (1.38), 0.566 (5.17), 0.580 (6.61), 0.589 (5.43), 0.609

- 52 038451 (2.33), 0.623 (1.38), 0.645 (1.67), 0.652 (2.21), 0.666 (3.50), 0.679 (1.90), 0.688 (2.13), 0.694 (2.24), 0.716 (0.40), 0.850 (0.43 ), 0.934 (1.01), 1.157 (1.38), 1.175 (2.70), 1.193 (1.52), 1.202 (0.83), 1.215 (1.55), 1.223 (2.13), 1.235 (3.76), 1.244 (3.07), 1.256 (3.56 ), 1.265 (2.10), 1.275 (1.49), 1.282 (1.41), 1.300 (0.57), 1.486 (0.80), 1.989 (4.83), 2.329 (1.01), 2.367 (0.89), 2.524 (4.77), 2.671 (1.03 ), 2.711 (0.83), 4.003 (0.43), 4.021 (1.18), 4.039 (1.15), 4.056 (0.40), 4.243 (0.49), 4.261 (0.40), 4.341 (0.60), 4.361 (1.87), 4.382 (3.22 ), 4.403 (3.04), 4.424 (1.61), 4.444 (0.43), 7.594 (6.32), 7.617 (11.78), 7.639 (6.18), 7.699 (0.43), 7.776 (11.69), 7.797 (12.21), 8.748 (12.18 ), 8.769 (11.75), 8.940 (0.46), 9.126 (16.00), 10.025 (6.55), 10.049 (6.26).

Example 52A

N - [(1S) -1-Cyclopropyl-2,2,2-trifluoroethyl] -7 - [(3R, 4R) -3,4-dihydroxypyrrolidin-1-yl] -4-oxo-1 (2,4, 6-trifluorophenyl) -1,4-dihydro-1,8-naphthyridine-3-carboxamide.

According to AAV3, 5.30 g (11.1 mmol) of 7-chloro-N - [(1S) -1-cyclopropyl-2,2,2-trifluoroethyl] 4-oxo-1- (2,4,6-trifluorophenyl) -1, 4-dihydro-1,8-naphthyridine-3-carboxamide with 1.87 g (13.4 mmol) (3R, 4R) -pyrrolidine-3,4-diol hydrochloride and 6.8 ml (39.0 mmol) DIPEA in 50 ml DMF. The reaction mixture was mixed with 400 ml of water and aqueous 1N hydrochloric acid. The residue was filtered off, washed again with water and dried. This gave 5.47 g (91% theory, 100% purity) of the title compound.

LCMS (Method 3): Rt = 1.71 min; MS (ESIpos): m / z = 543 [M + H] +.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: -0.149 (0.74), -0.061 (4.97), -0.008 (6.91), 0.008 (5.18), 0.146 (0.66), 0.324 (1.75) , 0.334 (2.68), 0.346 (2.68), 0.358 (2.07), 0.370 (1.01), 0.510 (1.88), 0.522 (2.81), 0.535 (2.49), 0.547 (2.58), 0.556 (2.24), 0.567 (2.75) , 0.578 (2.32), 0.588 (2.16), 0.598 (1.73), 0.612 (1.10), 0.626 (1.37), 0.636 (1.52), 0.647 (2.47), 0.657 (2.16), 0.662 (2.11), 0.670 (2.03) , 0.682 (1.01), 0.691 (0.72), 0.944 (1.48), 1.165 (0.82), 1.177 (1.44), 1.186 (1.99), 1.198 (3.15), 1.206 (2.49), 1.218 (3.32), 1.231 (2.32) , 1.238 (1.99), 1.263 (1.33), 1.398 (0.59), 2.328 (0.85), 2.367 (0.78), 2.524 (2.62), 2.670 (0.80), 2.711 (0.68), 2.731 (3.21), 2.891 (3.89) , 3.056 (3.25), 3.088 (4.25), 3.230 (2.62), 3.239 (2.98), 3.261 (2.35), 3.272 (2.32), 3.353 (4.10), 3.600 (2.37), 3.609 (2.71), 3.627 (2.20) , 3.637 (1.99), 3.927 (3.89), 4.050 (3.89), 4.356 (1.39), 4.377 (2.41), 4.398 (2.39), 4.418 (1.25), 5.145 (3.74), 5.233 (3.53), 6.772 (8.20) , 6.794 (8.43), 7.543 (3.17), 7.566 (5.60), 7.583 (3.19), 7.953 (0.51), 8.271 (9.72), 8.293 (9.13), 8.798 (16.00), 10.558 (5.71), 10.582 (5.45).

Example 53A.

1,1,1,2,2-Pentafluoro-N - [(1S) -1-phenylethal] pentane-3-imine.

1,1,1,2,2-Pentafluoropentan-3-one (50.0 g, 284 mmol) was taken up in 2 L of diethyl ether and cooled to 0 ° C. Then (1S) -1-phenylethanamine (34.4 g, 284 mmol) and triethylamine (79 ml, 570 mmol) were quickly added and then titanium (IV) chloride (1 M in toluene, 140 ml, 140 mmol). The ice bath was then removed and the mixture was warmed to room temperature. The reaction mixture was then heated for 1 hour under reflux and then stirred at room temperature overnight. The reaction mixture was mixed with kieselguhr, stirred for 1 hour, then filtered through kieselguhr and washed well with diethyl ether. The filtrate was evaporated at a water bath temperature of 20 ° C. The starting product was used without further purification in the next step. 79 g (col. Yield) of the title compound were obtained.

Example 54A.

1,1,1,2,2-Pentafluoro-N - [(1S) -1-phenylethyl] pentane-3-amine hydrochloride (pure enantiomers).

1,1,1,2,2-Pentafluoro-N - [(1S) -1-phenylethyl] pentan-3-imine (79 g, 283 mmol) was placed in 640 ml of dichloromethane, then 130 ml of DMF and molar sieve 3 A and stirred for 1 hour at room temperature. The reaction mixture was cooled to -50 ° C and trichlorosilane (86 ml, 850 mmol) was slowly added dropwise. After 30 minutes and at an internal temperature of -70 to -50 ° C, quenching was carried out first with saturated sodium bicarbonate solution and then with solid sodium bicarbonate until pH 7 was reached. Dichloromethane was added and the phases were separated. The organic phase was dried over sodium sulfate and then 200 ml of hydrogen chloride in diethyl ether (2M solution) was added and the starting material was evaporated in vacuo. This gave 48.6 g (54% of theory) of the title compound.

¹ H-NMR (400 MHz, DMSO-de) δ [ppm]: 7.82 (br. S, 1H), 7.26 -7.60 (m, 5H), 4.13 (br. S, 1H), 3.20 (br. S, 1H), 1.40-1.77 (m, 5H), 0.80 (t, 3H).

Example 55A.

1,1,1,2,2-Pentafluoropentane-3-amine hydrochloride (pure enantiomers).

48.6 g (153 mmol) 1,1,1,2,2-pentafluoro-N - [(1S) -1-phenylethyl] pentane-3-amine hydrochloride (pure enantiomers, from Example 54A) was dissolved in 250 ml of ethanol and mixed with 4.86 g of palladium (11) hydrochloride (20% on carbon) and then hydrogenated overnight at room temperature and normal pressure. The precipitate was filtered off, washed well and the filtrate was carefully evaporated. This gave 31.7 g (97% of theory) of the title compound.

¹ H-NMR (400 MHz, DMSO-de) δ [ppm]: 9.16 (br. S, 3H), 4.12-4.28 (m, 1H), 3.47 (br. S, 1H), 1.69-1.96 (m, 2H), 1.06 (t, 3H).

Example 56A

- 53 038451

3,3,4,4,4-Pentafluoro-N - [(1S) -1-phenylethyl] butan-2-imine.

3,3,4,4,4-Pentafluorobutan-2-one (200 g, 1.23 mol) was taken up in 6.4 L of diethyl ether and cooled to -40 ° C. Then (1S) -1-phenylethanamine (160 ml, 1.2 mol) and triethylamine (340 ml, 2.5 mol) were quickly added and then titanium (IV) chloride (1 M in toluene, 620 ml, 620 mmol). The ice bath was then removed and the mixture was warmed to room temperature. The reaction mixture was then heated for 1 hour under reflux and then stirred at room temperature overnight. The reaction mixture was mixed with celite, stirred for 1 hour, then filtered through celite and washed well with diethyl ether. The filtrate was evaporated at a water bath temperature of 25 ° C. The residue was mixed with cyclohexane and again filtered through celite and washed with cyclohexane. The filtrate was evaporated at a water bath temperature of 25 ° C. The starting product was used without further purification in the next step. This gave 289 g (88% of theory) of the title compound.

Example 57A.

3,3,4,4,4-Pentafluoro-N - [(1S) -1-phenylethyl] butan-2-amine hydrochloride (pure enantiomers).

3,3,4,4,4-Pentafluoro-N - [(1S) -1-phenylethyl] butan-2-imine (239 g, 901 mmol) was placed in 1.9 L of dichloromethane, then 420 ml of DMF and a molar sieve 3A were added and stirred for 1 hour at room temperature. Then the reaction mixture was cooled to -50 ° C and trichlorosilane (270 ml, 2.7 mol) was slowly added dropwise. After 30 minutes and at an internal temperature of -70 ° C to -50 ° C, the quenching process was carried out carefully with semi-concentrated sodium bicarbonate solution until a pH of 7 was reached. Dichloromethane was added and the phases were separated. The organic phase was dried over sodium sulfate and then 2.2 L of hydrogen chloride in diethyl ether (2 M solution) was added and the starting material was evaporated in vacuo. This gave 192 g (70% of theory) of the title compound.

LCMS (Method 1): Rt = 1.22 min; MS (ESIpos): m / z = 268 [M-HCl + H] ⁺ .

Example 58A.

3,3,4,4,4-Pentafluorobutane-2-amine hydrochloride (pure enantiomers).

192 g (632 mmol) 3,3,4,4,4-pentafluoro-N - [(1S) -1-phenylethyl] butane-2-amine hydrochloride (pure enantiomers, from Example 57A) was dissolved in 1.2 L ethanol and mixed with 19.2 g of palladium (11) hydrochloride (20% on carbon) and then hydrogenated overnight at room temperature and normal pressure. The precipitate was filtered off, washed well and the filtrate was carefully evaporated. This gave 117 g (93% theory) of the title compound.

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: 9.29 (br. S, 3H), 4.22-4.44 (m, 1H), 1.42 (d, H).

Example 59A.

7-Chloro-6-fluoro-4-oxo-N- [1,1,1,2,2-pentafluoropentan-3-yl] -1- (2,4,6-trifluorophenyl) -1,4-dihydro- 1,8 naphthyridine-3-carboxamide (racemate).

7-Chloro-6-fluoro-4-oxo-1- (2,4,6-trifluorophenyl) -1,4-dihydro-1,8-naphthyridine-3-carboxylic acid (200 mg, 537 μmol) was placed in 1.3 ml of acetonitrile, 1,1,1,2,2-pentafluoropentane-3amine hydrochloride (racemate, 138 mg, 644 μmol) and Ν, Ν-diisopropylethylamine (370 μL, 2.1 mmol) were added and then mixed with 380 μL (50% purity, 640 μmol) T3P solution (propane phosphonic acid cycloanhydride, 50% in ethyl acetate). The reaction mixture was stirred overnight and then added to water. The mixture was purified from acetonitrile and extracted three times with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. Received 282 mg of the target compound (97% theory. V., Purity 98%).

LCMS (Method 3): Rt = 2.53 min; MS (ESIpos): m / z = 532 [M + H] +.

Example 60A.

7-Chloro-6-fluoro-4-oxo-N- [1,1,1,2,2-pentafluoropentan-3-yl] -1- (2,4,6-trifluorophenyl) -1,4-dihydro- 1,8 naphthyridine-3-carboxamide (pure enantiomers).

7-Chloro-6-fluoro-4-oxo-1 - (2,4,6-trifluorophenyl) -1,4-dihydro-1,8-naphthyridine-3-carboxylic acid (5.00 g, 13.4 mmol) was placed in 33 ml of acetonitrile. Added 3.44 g, (16.1 mmol) 1,1,1,2,2 pentafluoropentane-3-amine hydrochloride (pure enantiomers from Example 55A) and, Ν-diisopropylethylamine (9.3 ml, 54 mmol). Then it was mixed with a T3P solution (propane phosphonic acid cycloanhydride, 50% in ethyl acetate, 9.5 ml, 50% purity, 16 mmol) and the mixture was stirred overnight at room temperature. The reaction solution was mixed with water. A viscous suspension formed. It was acidified with dilute hydrochloric acid and stirred for 1 hour at room temperature. The solid was filtered off, then washed again with water and dried under high vacuum. 6.69 g of compound was obtained (84% theoretical, 90% purity).

LCMS (Method 5): Rt = 1.67 min; MS (ESIpos): m / z = 532 [M + H] +.

Example 61A.

tert-Butyl-4- [3-fluoro-5-oxo-6 - {[1,1,1,2,2-pentafluoropentan-3-yl] carbamoyl} -8- (2,4,6trifluorophenyl) -5, 8-dihydro-1,8-naphthyridin-2-yl] -2- (hydroxymethyl) piperazine-1-carboxylate (mixture of diastereoisomers).

7-Chloro-6-fluoro-4-oxo-N- [1,1,1,2,2-pentafluoropentan-3-yl] -1- (2,4,6-trifluorophenyl) -1,4-dihydro- 1,8 naphthyridine-3-carboxamide (pure enantiomers from Example 60A, 200 mg, 90% pure, 338 μmol)

- 54 038451 was placed in 1.7 ml of DMF, mixed with Ν, Ν-diisopropylethylamine (590 µl, 3.4 mmol) and tert-butyl (2 (hydroxymethyl) piperazine-1-carboxylate (80.5 mg, 372 µmol) at room temperature. the solution was stirred for 1 hour at room temperature The reaction solution was mixed with water and extracted three times with ethyl acetate The combined organic phases were washed twice with water, dried over sodium sulfate, filtered and evaporated.The starting product was purified by chromatography on silica gel (eluent: cyclohexane / ethyl acetate = 2/1) 204 mg of the title compound (85% theory, 100% purity) was obtained as a mixture of a diastereoisomeric mixture of two diastereoisomers.

LCMS (Method 5): Rt = 1.62 min; MS (ESIpos): m / z = 712 [M + H] +.

Example 62A.

7-Chloro-6-fluoro-4-oxo-N- [3,3,4,4,4-pentafluorobutan-2-yl] -1- (2,4,6-trifluorophenyl) -1,4-dihydro- 1,8 naphthyridine-3-carboxamide (racemate).

7-Chloro-6-fluoro-4-oxo-1 - (2,4,6-trifluorophenyl) -1,4-dihydro-1,8-naphthyridine-3-carboxylic acid (200 mg, 537 mmol) was placed in 1.3 ml of acetonitrile. Added 1,1,1,2,2-pentafluorobutane-3-amine hydrochloride (racemate, 129 mg, 644 μmol) and N, N-diisopropylethylamine (370 μL, 2.1 mmol) and then mixed with 380 μL (50% purity, 640 μmol) T3P-solution (propane phosphonic acid cycloanhydride, 50% in ethyl acetate). The reaction solution was stirred overnight. The reaction solution was poured onto water and precipitated. The solid was filtered off and dried overnight under high vacuum. Received 250 mg of the compound (76% theory. V., Purity 84%).

LCMS (Method 3): Rt = 2.45 min; MS (ESIpos): m / z = 518 [M + H] ⁺ .

Example 63A.

7-Chloro-6-fluoro-4-oxo-N- (3,3,4,4,4-pentafluoro-2-methylbutan-2-yl) -1- (2,4,6-trifluorophenyl) -1, 4dihydro -1,8-naphthyridine-3-carboxamide.

7-Chloro-6-fluoro-4-oxo-1 - (2,4,6-trifluorophenyl) -1,4-dihydro-1,8-naphthyridine-3-carboxylic acid (1.50 g, 4.03 mmol) was placed in 38 ml of acetonitrile. 3,3,4,4,4-pentafluoro-2-methylbutane-2amine hydrochloride (1.12 g, 5.23 mmol) and N, N-diisonropylethylamine (3.5 μl, 2.1 mmol) were added and then mixed with 3.6 ml (50% purity, 6.0 μmol) T3P-solution (propane phosphonic acid cycloanhydride, 50% in ethyl acetate). The reaction solution was stirred overnight at room temperature. Then, the reaction solution was mixed with water. Under vacuum conditions, the solution was almost completely freed from acetonitrile, after a certain period of time the solid precipitated on evaporation. The precipitated solid was washed with water. The solid was dried under high vacuum. Received 1.96 g of the target compound (91% theory. V. 99% purity).

LCMS (Method 3): Rt = 2.50 min; MS (ESIpos): m / z = 532 [M + H] ⁺ .

Example 64A.

Ethyl (22) -2 - [(2,6-dichloro-5-fluoropyridin-3-yl) carbonyl] -3-ethoxyacrylate.

Ethyl 3- (2,6-dichloro-5-fluoropyridin-3-yl) -3-oxopropanoate (500 mg, 1.79 mmol) and (diethoxymethoxy) ethane (590 μL, 3.6 mmol) were placed in acetic anhydride (1.2 ml , 12 mmol) and stirred at 140 ° C overnight. The reaction mixture was evaporated and converted without further purification in the following steps.

LCMS (Method 1): Rt = 1.01 min; MS (ESIpos): m / z = 336 [M + H] ⁺ .

Example 65A.

Ethyl 7-chloro-6-fluoro-1- (4-fluoro-2,6-dimethylphenyl) -4-oxo-1,4-dihydro-1,8-naphthyridine-3carboxylate.

Ethyl- (22) -2 - [(2,6-dichloro-5-fluoropyridin-3-yl) carbonyl] -3-ethoxyacrylate (9.36 g, 27.8 mmol) and 4-fluoro-2,6-dimethylaniline (4.65 g , 33.4 mmol) was added to 47 ml of dichloromethane and mixed at room temperature with N, N-diisonronylethylamine (34 ml, 194.9 mmol) (exothermic reaction). The reaction solution was stirred for 4 hours at room temperature. Potassium carbonate (3.85 g, 27.84 mmol) was then added and stirred overnight by reflux. The reaction mixture was then cooled, diluted with dichloromethane and washed with 1M hydrochloric acid until color change. The organic phase was dried over sodium sulfate, filtered, evaporated and dried under high vacuum. The starting material was purified by chromatography on silica gel (eluent: cyclohexane / ethyl acetate: 5/1 to cyclohexane / ethyl acetate: 3/1) 6.47 g of the title compound (58% theory, 99% purity) were obtained.

LCMS (Method 3): Rt = 2.00 min; MS (ESIpos): m / z = 393 [M + H] ⁺ .

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: -0.008 (0.95), 0.008 (0.78), 1.254 (2.75), 1.271 (5.79), 1.289 (2.77), 1.975 (16.00), 2.523 (0.61), 4.205 (0.87), 4.222 (2.65), 4.240 (2.61), 4.258 (0.82), 5.754 (3.81), 7.188 (2.22), 7.211 (2.23), 8.543 (1.72), 8.561 (5.10).

Example 66A.

7-Chloro-6-fluoro-1 - (4-fluoro-2,6-dimethylphenyl) -4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid.

Ethyl 7-chloro-6-fluoro-1- (4-fluoro-2,6-dimethylphenyl) -4-oxo-1,4-dihydro-1,8-naphthyridine-3 carboxylate (6.47 g, 99% purity, 16.3 mmol) was suspended in 49 ml of THF. Added 49 ml

- 55 038451 water and 49 ml of concentrated hydrochloric acid and the mixture was left stirring for 4 hours at a bath temperature of 110 ° C. THF was thickened in a vacuum. The aqueous phase was mixed with 100 ml of water with cooling in an ice bath. A solid precipitated out. It was filtered off and washed three times with water.

Received 5.35 g of the target compound (89% theory. V., Purity 99%).

LCMS (Method 1): Rt = 1.03 min; MS (ESIpos): m / z = 365 [M + H] +.

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.957 (16.00), 1.975 (0.43), 7.195 (2.23), 7.218 (2.20), 8.775 (1.30), 8.794 (1.29), 8.871 (2.87) ...

Example 67A.

7-Chloro-N - [(1S) -1-cyclopropyl-2,2,2-trifluoroethyl] -6-fluoro-1- (4-fluoro-2,6-dimethylphenyl) -4-oxo-1,4dihydro- 1,8-naphthyridine-3-carboxamide.

-Chloro-6-fluoro-1 - (4-fluoro-2,6-dimethylphenyl) -4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid (1.00 g, 2.74 mmol) was placed in 25.5 ml of acetonitrile, added (1S) -1-cyclopropyl-2,2,2trifluoroethanamine hydrochloride (530 mg, 3.02 mmol) and N, N-diisopropylethylamine (1.9 ml, 11 mmol), then mixed with 1.9 ml (3.29 mmol) T3P- solution (propane phosphonic acid cycloanhydride, 50% in ethyl acetate). The reaction solution was stirred overnight at room temperature. (1S) -1-cyclopropyl-2,2,2-mfluoroethanamine hydrochloride (144 mg, 823 μmol), 0.32 ml (1.1 mmol) of a T3P solution (propane phosphonic acid cycloanhydride, 50% in ethyl acetate) and N , N-diisopropylethylamine (0.48 ml, 2.74 mmol). The reaction solution was stirred over the weekend at room temperature. The mixture was then purified from acetonitrile and extracted twice with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and dried under high vacuum. The residue was purified by column chromatography (silica gel; solvent: dichloromethane / cyclohexane = 7.5 / 1). Received 1.05 g (99% purity, 78% theory. V.) Of the target compound.

LCMS (Method 1): Rt = 1.28 min; MS (ESIpos): m / z = 486 [M + H] ⁺ .

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 0.008 (1.25), 0.339 (0.87), 0.353 (0.89), 0.364 (0.51), 0.554 (0.81), 0.567 (1.37), 0.582 ( 1.20), 0.601 (0.63), 0.610 (0.52), 0.651 (0.46), 0.666 (0.81), 0.671 (0.70), 0.684 (0.55), 1.219 (0.47), 1.231 (0.87), 1.240 (0.65), 1.251 ( 0.75), 1.264 (0.44), 1.957 (16.00), 4.361 (0.43), 4.382 (0.73), 4.402 (0.73), 4.422 (0.40), 5.754 (3.95), 7.193 (3.42), 7.216 (3.43), 8.709 ( 7.53), 8.726 (2.88), 10.138 (1.51), 10.162 (1.49).

Example 68A.

7-Chloro-6-fluoro-4-oxo-N- (3,3,4,4,4-pentafluorobutan-2-yl) -1- (2,4,6-trifluorophenyl) -1,4-dihydro- 1,8 naphthyridine-3-carboxamide (pure enantiomers).

7-Chloro-6-fluoro-4-oxo-1- (2,4,6-trifluorophenyl) -1,4-dihydro-1,8-naphthyridine-3-carboxylic acid (500 mg, 1.34 mmol) was placed in 5 ml of acetonitrile. 3,3,4,4,4-pentafluorobutane-2-amine hydrochloride (pure enantiomers) (321 mg, 1.61 mmol) and N, N-diisopropylethylamine (930 μL, 5.4 mmol) were added. Then T3P solution (solution of propane phosphonic acid anhydride 50% in ethyl acetate) (950 μL, 50% purity, 1.6 mmol) was added and stirred overnight at room temperature. The reaction solution was poured onto water. The acetonitrile was evaporated and the residue was extracted three times with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated. This gave 785 mg (99% theory, 88% purity) of the title compound.

LCMS (Method 5): Rt = 1.60 min; MS (ESIpos): m / z = 518 [M + H] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: -0.149 (1.04), -0.008 (8.48), 0.008 (8.27), 0.146 (1.00), 0.891 (0.71), 0.910 (0.58), 1.157 (2.01), 1.175 (4.01), 1.193 (2.59), 1.244 (2.51), 1.259 (2.92), 1.356 (0.67), 1.411 (14.66), 1.429 (14.62), 1.455 (0.92), 1.473 (0.84), 1.511 (2.26), 1.528 (2.21), 1.864 (0.50), 1.988 (6.56), 2.328 (1.46), 2.367 (1.80), 2.671 (1.50), 2.711 (1.75), 4.003 (0.58), 4.021 (1.50), 4.039 (1.55), 4.057 (0.54), 5.000 (0.71), 5.022 (1.34), 5.045 (1.59), 5.065 (1.55), 5.088 (1.25), 5.109 (0.67), 7.270 (0.58), 7.337 (0.71), 7.347 (0.71), 7.367 (1.21), 7.385 (1.13), 7.401 (1.50), 7.418 (0.84), 7.467 (0.75), 7.490 (0.58), 7.604 (6.02), 7.626 (11.07), 7.648 (5.81), 8.412 (0.50), 8.574 (0.46), 8.687 (0.92), 8.702 (10.11), 8.721 (9.78), 8.750 (0.50), 9.055 (1.21), 9.173 (16.00), 9.877 (0.46), 9.896 (0.50), 9.938 (5.89), 9.961 (5.68).

Example 69A.

1-tert-Butyl-2-ethyl- (2R, 3S) -3-hydroxypyrrolidine-1,2-dicarboxylate.

Ethyl (3S) -3-hydroxy-D-prolineate (1.13 g, 7.08 mmol) was taken up in 50 ml of dichloromethane. Triethylamine (3.0 ml, 21 mmol) and di-tert-butyl dicarbonate (1.8 ml, 7.8 mmol) were added and the mixture was stirred overnight at room temperature. The reaction mixture was mixed with saturated, aqueous sodium hydrogen carbonate solution. The organic phase was dried over sodium sulfate, filtered and concentrated. The residue was taken up in ethyl acetate and washed twice with 1M hydrochloric acid. The organic phase was dried over sodium sulfate, filtered and concentrated. This gave 1.3 g (57% theory, 80% purity) of the title compound.

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 1.152 (0.77), 1.170 (1.65), 1.178 (1.69), 1.188 (0.96), 1.195 (3.23), 1.213 (1.56), 1.321 (16.00 ), 1.383 (8.03), 1.988 (0.75), 3.266 (0.62), 3.294 (0.42), 3.404 (0.44), 3.409 (0.43), 3.423 (0.42), 4.019 (0.41), 4.037 (0.44), 4.046 (0.70 ), 4.064 (0.85), 4.082 (0.46), 4.111 (0.57), 4.129

- 56 038451 (0.54), 4.150 (1.28), 4.156 (0.42), 4.167 (1.45), 4.433 (0.46), 4.449 (0.53), 5.398 (1.16), 5.410 (1.11).

Example 70A.

tert-Butyl (2S, 3 S) -3-hydroxy-2- (hydroxymethyl) pyrrolidine-1-carboxylate.

1-tert-Butyl-2-ethyl- (2R, 3S) -3-hydroxypyrrolidine-1,2-dicarboxylate (1.30 g, 5.01 mmol) was placed in 20 ml of THF under argon and cooled to 0 ° C. Lithium borohydride (10 ml, 2.0 M, 20 mmol) was added at 0 ° C and the mixture was stirred overnight at room temperature. The reaction mixture was cooled to 0 ° C and carefully mixed with saturated aqueous ammonium chloride solution. Added dichloromethane and dispensed through an Extrelud cartridge. The organic phase was evaporated and the residue was dried under high vacuum. This gave 506 mg (37% theory, 80% purity) of the title compound.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 1.391 (16.00), 1.409 (2.86), 1.860 (0.40), 3.601 (0.62), 3.608 (0.58), 3.615 (0.78), 3.629 ( 0.46), 3.633 (0.42).

Example 71A.

(2S, 3 S) -2- (Hydroxymethyl) pyrrolidine-3-olhydrochloride.

1-tert-Butyl-2-ethyl- (2R, 3S) -3-hydroxypyrrolidine-1,2-dicarboxylate (506 mg, 1.95 mmol) was placed in 20 ml of 4N aqueous hydrochloric acid in dioxane and stirred overnight at room temperature ... The reaction mixture was evaporated and the residue was dried under high vacuum. This gave 380 mg (127% theory, 80% purity) of the title compound.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: -0.149 (1.17), -0.008 (10.39), 0.008 (8.46), 0.146 (1.12), 0.912 (0.42), 1.130 (0.62), 1.180 (0.99), 1.235 (1.17), 1.259 (1.59), 1.276 (1.51), 1.292 (1.07), 1.308 (0.84), 1.356 (3.67), 1.596 (1.31), 1.847 (3.37), 1.857 (3.45), 1.862 (3.72), 1.872 (5.90), 1.876 (5.04), 1.881 (5.11), 1.884 (4.79), 1.891 (4.81), 1.895 (5.01), 1.900 (4.59), 1.954 (1.36), 1.974 (3.15), 1.985 (4.12), 1.998 (5.48), 2.008 (7.59), 2.032 (4.96), 2.042 (3.97), 2.055 (1.89), 2.067 (1.84), 2.073 (2.08), 2.090 (0.97), 2.104 (1.54), 2.115 (2.06), 2.139 (1.81), 2.148 (1.44), 2.182 (0.84), 2.328 (1.96), 2.367 (1.04), 2.524 (1.24), 2.666 (1.02), 2.670 (1.44), 2.675 (0.99), 2.711 (0.45), 3.150 (3.84), 3.161 (5.23), 3.174 (6.15), 3.187 (6.55), 3.201 (5.83), 3.212 (6.23), 3.236 (5.95), 3.241 (5.93), 3.260 (3.82), 3.306 (6.40), 3.322 (7.64), 3.343 (6.05), 3.364 (2.90), 3.450 (8.83), 3.462 (8.88), 3.474 (8.33), 3.490 (7.32), 3.502 (6.38), 3.609 (10.64), 3.631 (10.54), 3.638 (14.78), 3.660 (13. 59), 3.680 (3.32), 3.699 (3.27), 3.708 (2.68), 3.712 (3.00), 3.733 (11.88), 3.746 (12.38), 3.762 (9.30), 3.774 (9.13), 4.073 (4.22), 4.106 ( 5.66), 4.266 (4.34), 4.274 (4.49), 4.300 (16.00), 4.669 (2.95), 4.678 (4.94), 5.329 (0.72), 7.112 (1.49), 7.240 (1.56), 7.368 (1.41), 8.748 ( 2.90), 9.193 (1.39), 9.383 (1.81), 10.016 (0.45).

Example 72A.

Ethyl 3 - (2,6-dichloropyridin-3-yl) -3-oxopropanoate.

1500 ml of THF was placed in an argon atmosphere and 2,6-dichloronicotinic acid (200 g, 1.04 mol) was added. 4-Dimethylaminopyridine (63.6 g, 521 mmol) and 1,1'-carbonyldimidazole (253 g, 1.56 mol) were added in portions (evolution of gas). The mixture was stirred for 24 hours at room temperature. A precipitate formed (suspension 1). In another flask was placed potassium-3-ethoxy-3-oxopropanoate (266 g, 1.56 mol) in 1000 ml of THF and mixed with magnesium chloride (179 g, 1.87 mol). The suspension was re-stirred for 24 h at 50 ° C (suspension 2). Then suspension 2 was added to suspension 1 and stirred for 24 hours at room temperature. The mixture was then stirred in 5 L of ice and about 20 L of water and the pH was adjusted with about 500 ml of hydrochloric acid / water (1: 1) to 4. Then it was extracted twice with ethyl acetate. The organic phases were washed with 10% NaCl solution. The phases were separated, dried with magnesium sulfate, evaporated and dried under high vacuum. 255 g of the target compound was obtained (93.5% of theory).

LCMS (Method 1): Rt = 0.89 min; MS (ESIpos): m / z = 261 [M + H] +.

Example 73A.

Ethyl (22) -2 - [(2,6-dichloropyridin-3-yl) carbonyl] -3-ethoxyacrylate.

Took ethyl 3- (2,6-dichloropyridin-3-yl) -3-oxopropanoate (4 g, 15 mmol) and (diethoxymethoxy) ethane (5 ml, 30 mmol) and mixed with acetic anhydride (11.7 ml, 99 mmol). The reaction mixture was stirred for 24 h at 140 ° C and after cooling, the mixture was evaporated. Received 5.3 g of the target compound (109% theory. V.).

Example 74A.

N-Benzyl-1,1-dicyclopropylmethanimine.

Dicyclopropylmethanone (13 ml, 110 mmol) was taken up in 430 ml diethyl ether and cooled to -40 ° C. Then 1-phenylmethanamine (12 ml, 110 mmol) and triethylamine (32 ml, 230 mmol) were quickly added and then titanium (IV) chloride (57 ml, 57 mmol, 1 M in toluene) was slowly added dropwise at an internal temperature of 0 ° C. ). The ice bath was then removed and the mixture was allowed to warm to room temperature. The mixture was then stirred for 1 hour under reflux. The mixture was stirred for 3 hours at room temperature. Then celite was added and stirred for 1 hour. Then it was filtered through celite and washed several times with diethyl ether. The filtrate was carefully evaporated at a bath temperature of 30 ° C. Received 18.86 g of the target compound (73% theory. V., Purity 88%).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 0.542 (1.44), 0.550 (3.04), 0.558 (4.43), 0.562 (2.41), 0.565 (2.73), 0.571 (3.30), 0.578 ( 5.02), 0.585 (2.16), 0.664 (2.05), 0.671 (4.51), 0.678 (3.98), 0.683 (5.39), 0.690

- 57 038451 (3.22), 0.700 (1.42), 0.830 (0.46), 0.839 (1.51), 0.843 (9.08), 0.877 (5.06), 0.881 (2.92), 0.887 (7.68), 0.894 (1.93), 0.966 (4.42) ), 0.971 (4.39), 0.979 (4.47), 0.984 (1.44), 1.218 (2.55), 1.230 (1.31), 1.238 (1.20), 1.250 (0.98), 1.963 (3.02), 1.971 (0.92), 1.975 (1.51 ), 1.984 (1.09), 2.128 (0.77), 2.134 (2.24), 2.142 (0.78), 2.147 (2.02), 0.851 (8.62), 0.855 (8.05), 0.863 (8.85), 0.868 (1.79), 0.901 (0.41 ), 0.907 (0.50), 0.922 (0.49), 0.956 (4.15), 0.996 (1.28), 1.186 (0.70), 1.198 (1.38), 1.206 (0.55), 1.929 (0.78), 1.942 (1.59), 1.949 (1.59 ), 1.954 (1.44), 1.997 (0.66), 2.104 (0.65), 2.115 (1.21), 2.122 (1.20), 2.153 (1.01), 2.166 (0.60), 2.299 (7.88), 3.217 (0.51), 3.313 (4.75 ), 4.582 (16.00), 7.142 (0.84), 7.162 (1.77), 7.174 (1.38), 7.180 (2.56), 7.191 (2.64), 7.202 (1.07), 7.208 (1.78), 7.212 (1.21), 7.230 (1.81 ), 7.235 (0.73), 7.249 (2.09), 7.255 (1.43), 7.260 (2.42), 7.268 (1.78), 7.276 (10.04), 7.282 (12.94), 7.289 (1.48), 7.299 (6.19), 7.303 (2.61 ), 7.315 (0.93), 7.318 (1. 58).

Example 75A.

N-Benzyl-1,1-dicyclopropyl-2,2,2-trifluoroethanamine hydrochloride.

N-Benzyl-1,1-dicyclopropylmethanimine (35.4 g, 89% purity, 158 mmol) was placed in a mixture of 320 ml of acetonitrile and 70 ml of DMF and cooled to 0 ° C. Potassium hydrodifluoride (39.5 g, 506 mmol) was added to 0 ° C and mixed with TFA (22 ml, 280 mmol) at 0 ° C. Then trimethyl (trifluoromethyl) silane (82 ml, 550 mmol) was added dropwise. The reaction mixture was stirred for 4 hours at room temperature. The reaction mixture was cooled to 0 ° C, mixed with potassium hydrodifluoride (9.26 g, 119 mmol) and trimethyl (trifluoromethyl) silane (18 ml, 120 mmol). The reaction solution continued to stir overnight at room temperature. The mixture was mixed with potassium bifluoride (9.26 g, 119 mmol), trifluoroacetic acid (4.9 ml, 63 mmol) and trimethyl (trifluoromethyl) silane (12 ml, 79 mmol) and stirred for 3.5 h at room temperature. Then, trimethyl (trifluoromethyl) silane (23 ml, 160 mmol) was added and the mixture was stirred for 2.5 h at 60 ° C. The mixture was mixed with saturated, aqueous sodium carbonate solution and extracted twice with ethyl acetate. The combined organic phases were washed once with saturated aqueous sodium chloride solution, dried over sodium sulfate and filtered. The filtrate was then mixed with 4 M HCl in dioxane (400 ml, 1.6 mol) and rotated at a water bath temperature of 30 ° C. The residue was purified using flash chromatography (cyclohexane / dichloromethane 20/1 after cyclohexane / dichloromethane 10/1). Received 10.64 g of the target compound (22% theory. V., Purity 99%).

LCMS (Method 1): Rt = 1.31 min; MS (ESIpos): m / z = 270 [M-HCl + H] ⁺ .

¹ H-NMR (400 MHz, DMSO-de) delta [ppm]: -0.008 (1.25), 0.008 (1.56), 0.591 (10.11), 0.750 (13.34), 0.876 (1.90), 0.952 (1.06), 1.091 ( 6.01), 1.236 (1.18), 1.906 (0.42), 2.329 (0.82), 2.367 (0.46), 2.571 (0.49), 2.589 (0.63), 2.671 (0.80), 2.711 (0.55), 3.615 (0.68), 4.212 ( 4.68), 5.107 (0.66), 7.358 (13.21), 7.375 (16.00), 7.502 (7.66).

Example 76A

1,1-Dicyclopropyl-2,2,2-trifluoroethanamine hydrochloride.

N-Benzyl-1,1-dicyclopropyl-2,2,2-trifluoroethanamine hydrochloride (10.6 g, 34.8 mmol) in an argon atmosphere was placed in 200 ml of ethanol, mixed with 1 M hydrochloric acid in ethanol (170 ml) and palladium on active coal (3.70 g, 10% purity). Hydrogenated for 60 min at normal pressure and room temperature. The mixture was filtered through celite, the filtrate was mixed with 4M hydrochloric acid in dioxane (87 ml, 350 mmol) and evaporated at a water bath temperature of 30 ° C. The residue was mixed with diethyl ether, stirred for 10 minutes and the resulting solid was filtered off. Received 6.39 g of the target compound (84% theory. V.) And converted in the next steps without additional purification.

LCMS (Method 1): Rt = 0.49 min; MS (ESIpos): m / z = 180 [M-HCl + H] +.

¹ H-NMR (400 MHz, DMSO-a ₆ ) δ [ppm]: 0.489 (2.34), 0.502 (4.38), 0.512 (7.72), 0.524 (12.33), 0.535 (11.32), 0.546 (9.58), 0.557 ( 10.43), 0.569 (9.17), 0.581 (11.40), 0.591 (13.47), 0.603 (8.94), 0.614 (4.93), 0.626 (3.21), 0.778 (2.86), 0.791 (6.70), 0.803 (9.45), 0.815 ( 13.47), 0.827 (13.55), 0.838 (11.65), 0.850 (13.01), 0.862 (13.43), 0.874 (9.35), 0.886 (6.06), 0.899 (2.37), 1.056 (4.75), 1.070 (9.13), 1.078 ( 10.15), 1.091 (16.00), 1.099 (6.84), 1.105 (8.35), 1.113 (7.66), 1.126 (3.14), 8.942 (2.96).

Example 77A.

N-Benzyl-1,1-dicyclopropyl-2,2,3,3,3-pentafluoropropane-1-amine hydrochloride.

N-Benzyl-1,1-dicyclopropylmethanimine (4.00 g, 20.1 mmol) in an argon atmosphere was placed in a mixture of 40 ml of acetonitrile and 8.9 ml of DMF and cooled to 0 ° C. Potassium hydrodifluoride (5.02 g, 64.2 mmol) was added at 0 ° C and mixed with TFA (2.8 mL, 36 mmol) at 0 ° C. Then trimethyl (pentafluoroethyl) silane (12 ml, 70 mmol) was added dropwise. The reaction mixture was stirred for 3 days at room temperature. The mixture was stirred for 7.5 h at 60 ° C. The mixture was mixed with 20 ml of acetonitrile and 4.5 ml of DMF and cooled to 0 ° C. At 0 ° C, potassium hydrodifluoride (1.88 g, 24.1 mmol), trifluoroacetic acid (770 μL, 10 mmol) and trimethyl (trifluoromethyl) silane (5.3 mL, 30 mmol) were added and stirred overnight at room temperature. The mixture was mixed with saturated, aqueous sodium carbonate solution and extracted twice with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate and filtered. The filtrate was then mixed with 4M HCl in dioxane (50 ml, 200 mmol) and evaporated. The residue was purified by chromatography on silica gel (solvent: cyclohexane / dichloromethane: 20/1). Fractions of pro 58 038451 duct were combined, the filtrate was mixed with 4 M hydrochloric acid in dioxane (50 ml, 200 mmol) and evaporated at a water bath temperature of 30 ° C. Received 2.14 g of the target compound (30% theory., Purity

99%).

LCMS (Method 1): Rt = 1.39 min; MS (ESIpos): m / z = 320 [M-HCl + H] ⁺ .

Ή-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 0.008 (1.21), 0.331 (1.50), 0.354 (4.75), 0.365 (5.92), 0.376 (5.94), 0.385 (4.06), 0.397 (2.65) ), 0.450 (2.43), 0.461 (3.95), 0.470 (6.34), 0.482 (6.37), 0.491 (5.64), 0.502 (3.07), 0.515 (2.14), 0.648 (6.10), 0.659 (6.45), 0.668 (6.49 ), 0.680 (7.00), 0.690 (6.84), 0.703 (4.80), 0.909 (2.14), 0.930 (4.98), 0.944 (7.05), 0.957 (4.27), 0.978 (1.50), 2.329 (0.40), 3.568 (11.42 ), 4.046 (14.52), 7.064 (0.43), 7.098 (0.47), 7.128 (0.48), 7.194 (2.29), 7.212 (5.53), 7.229 (4.28), 7.279 (6.89), 7.298 (16.00), 7.316 (12.69 ), 7.331 (13.22), 7.349 (5.73).

Example 78A.

1,1-Dicyclopropyl-2,2,3,3,3-pentafluoropropan-1-amine hydrochloride.

N-Benzyl-1,1-dicyclopropyl-2,2,3,3,3-pentafluoropropane-1-amine hydrochloride (3.22 g, 9.06 mmol) was mixed in an argon atmosphere with 90 ml of ethanol, 45 ml of 1 M hydrochloric acid in ethanol and (964 mg, 10% purity) palladium on active carbon. Hydrogenated for 45 min at normal pressure and room temperature. The mixture was filtered through celite, washed well with ethanol, mixed with 23 ml of 4M hydrochloric acid in dioxane and evaporated at a water bath temperature of 30 ° C. The residue was mixed with diethyl ether, stirred for 10 minutes and the resulting solid was filtered off. The product was then converted without purification. 1.64 g of the target compound was obtained (68% of theory).

Ή-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: -0.150 (1.30), -0.008 (13.14), 0.008 (11.58), 0.146 (1.12), 0.540 (12.55), 0.550 (12.29), 0.572 (11.02), 0.605 (12.52), 0.791 (12.35), 0.875 (10.67), 1.060 (4.89), 1.080 (11.64), 1.094 (16.00), 1.128 (3.30), 2.328 (2.12), 2.366 (0.80), 2.670 (2.12), 2.710 (0.65), 8.767 (1.97).

Example 79A

N - [(E) -Cyclopropylmethylene] -2-methylpropane-2-sulfinamide (enantiomer 1).

(S) -2-Methylpropane-2-sulfinamide (8.65 g, 71.3 mmol) in an argon atmosphere was placed in 430 ml of dichloromethane and mixed with cyclopropanecarbaldehyde (11 ml, 140 mmol) and anhydrous copper sulfate (II) (34.2 g, 214 mmol ) at room temperature. The mixture was stirred overnight at room temperature. The reaction mixture was filtered through celite, washed with diethyl ether, the filtrate was evaporated and concentrated in high vacuum. Received 15.3 g of the target compound (99% theory. V., Purity about 80%).

LCMS (Method 1): Rt = 0.73 min; MS (ESIpos): m / z = 174 [M + H] ⁺ .

Ή-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.952 (0.47), 0.958 (0.76), 0.964 (0.55), 0.967 (0.45), 0.970 (0.53), 1.041 (0.67), 1.055 (1.45) , 1.061 (0.80), 1.068 (0.56), 1.070 (0.52), 1.082 (1.02), 1.092 (16.00), 5.751 (1.54), 7.389 (0.82), 7.409 (0.82).

Example 80A.

N- [1-Cyclopropyl-2,2,3,3,3-pentafluoropropyl] -2-methylpropane-2-sulfinamide (diastereoisomer 1).

N - [(E) -Cyclopropylmethylene] -2-methylpropane-2-sulfinamide (enantiomer 1) (5.00 g, 28.9 mmol) was placed together with tetramethylammonium fluoride (6.45 g, 69.3 mmol) into a container under argon atmosphere. After 14 h, the reaction vessel was removed from the container and the mixture was mixed with 110 ml of THF and at -55 ° C was slowly mixed with a solution of trimethyl (pentafluoroethyl) silane (13 ml, 72 mmol) dissolved in 170 ml of THF. After the final addition, the mixture was stirred for 30 minutes and then carefully mixed with 50 ml of saturated aqueous ammonium chloride solution and 165 ml of water at -30 ° C. The aqueous phase was extracted twice with tert-butyl methyl ether. The combined organic phases were washed respectively once with water and saturated aqueous sodium chloride solution. The organic phase was dried over sodium sulfate, filtered and concentrated. The starting material was purified using silica gel (solvent: cyclohexane 100% to cyclohexane / ethyl acetate 2/1). Received 4.9 g of the target compound (58% theory. V., De> 95%).

LCMS (Method 1): Rt = 0.92 min; MS (ESIpos): m / z = 294 [M + H] ⁺ .

Example 81A.

1-Cyclopropyl-2,2,3,3,3-pentafluoropropane-1-amine hydrochloride (enantiomer 1).

N- [1-Cyclopropyl-2,2,3,3,3-pentafluoropropyl] -2-methylpropane-2-sulfinamide (diastereoisomer 1) (4.10 g, 14.0 mmol) was taken up in 130 ml of diethyl ether and 25 ml of methanol. Then, it was added dropwise at room temperature with 2 N hydrochloric acid in diethyl ether (130 ml, 250 mmol) and stirred for 2.5 h at room temperature. Then the reaction mixture was evaporated at a water bath temperature of 30 ° C. The residue was mixed with 10 ml of acetonitrile, filtered off and washed with a couple of drops of acetonitrile. Received 2.1 g of the target compound (65% theory. V., Purity 98%).

LCMS (Method 1): Rt = 0.31 min; MS (ESIpos): m / z = 190 [M-HCl + H] +.

Ή-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.543 (2.57), 0.556 (4.32), 0.569 (5.47), 0.584 (3.62), 0.604 (0.54), 0.669 (0.44), 0.685 (1.59) , 0.699 (3.25), 0.718 (8.78), 0.733 (16.00), 0.748 (15.55), 0.759 (5.58), 0.767 (3.55), 1.019 (0.99), 1.038 (2.50), 1.045 (5.40), 1.050 (3.89) , 1.064 (3.94), 1.077 (3.57), 1.103 (14.10), 1.270 (0.53), 2.330 (0.40), 2.363 (0.83), 3.167 (10.46), 3.671 (6.50), 3.685 (5.12), 3.697 (4.27) , 3.712 (3.56), 3.723

- 59 038451 (7.42), 3.739 (2.98), 3.751 (2.86), 3.765 (2.47), 4.059 (0.82), 9.207 (10.25).

Example 82A.

N - [(E) -Cyclopropylmethylene] -2-methylpropane-2-sulfinamide (enantiomer 2).

(R) -2-Methylpropαn-2-sulfinamide (13.0 g, 107 mmol) in an argon atmosphere was placed in 640 ml of dichloromethane and mixed with cyclopropanecarbaldehyde (15.0 g, 214 mmol) and anhydrous copper sulfate (II) (51.2 g, 321 mmol ) at room temperature. The mixture was stirred overnight at room temperature. The reaction mixture was filtered through celite, washed with diethyl ether, the filtrate was evaporated and concentrated in high vacuum. Received 18.9 g of the target compound (100% theory. V., Purity about 98%).

LCMS (Method 1): Rt = 0.72 min; MS (ESIpos): m / z = 174 [M + H] +.

¹ H-NMR (400 MHz, DMSO-de) δ [ppm]: 0.952 (0.48), 0.958 (0.77), 0.964 (0.57), 0.967 (0.47), 0.969 (0.54), 1.055 (0.76), 1.061 (0.80 ), 1.068 (0.57), 1.070 (0.53), 1.081 (1.07), 1.092 (16.00), 7.389 (0.83), 7.409 (0.82).

Example 83A.

N- [1-Cyclopropyl-2,2,3,3,3-pentafluoropropyl] -2-methylpropane-2-sulfinamide (diastereoisomer 2).

N - [(E) -Cyclopropylmethylene] -2-methylpropane-2-sulfinamide (enantiomer 2) (5.10 g, 98% purity, 28.8 mmol) was placed together with tetramethylammonium fluoride (6.45 g, 69.2 mmol) into a container under argon. After 14 h, the reaction vessel was removed from the container and the mixture was mixed with 110 ml of THF and at -55 ° C was slowly mixed with a solution of trimethyl (pentafluoroethyl) silane (13 ml, 72 mmol) dissolved in 170 ml of THF. After the final addition, the mixture was stirred for 30 minutes and then carefully mixed with 50 ml of saturated aqueous ammonium chloride solution and 165 ml of water at -30 ° C. The aqueous phase was extracted twice with tert-butyl methyl ether. The combined organic phases were washed respectively once with water and saturated aqueous sodium chloride solution. The organic phase was dried over sodium sulfate, filtered and concentrated. The starting material was purified using silica gel (solvent: cyclohexane 100% to cyclohexane / ethyl acetate 2/1). Received 5.8 g of the target compound (69% theory. Vy., De> 95%).

LCMS (Method 1): Rt = 0.92 min; MS (ESIpos): m / z = 294 [M + H] ⁺ .

Example 84A.

1-Cyclopropyl-2,2,3,3,3-pentafluoropropane-1-amine hydrochloride (enantiomer 2).

N- [1-Cyclopropyl-2,2,3,3,3-pentafluoropropyl] -2-methylpropane-2-sulfinamide (diastereoisomer 2) (5.00 g, 17.0 mmol) was taken up in 150 ml of diethyl ether and 31 ml of methanol. Then dropwise at room temperature was mixed with 2n. hydrochloric acid in diethyl ether (150 ml, 2.0 M, 300 mmol) and stirred for 2.5 h at room temperature. Then, the reaction solution was evaporated at a water bath temperature of 30 ° C. The residue was stirred with 10 ml of acetonitrile, filtered off and washed with a couple of drops of acetonitrile. Received 2.5 g of the target compound (64% theory. V., Purity 98%).

LCMS (Method 1): Rt = 0.33 min; MS (ESIpos): m / z = 190 [M-HCl + H] +.

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: -0.008 (1.70), 0.008 (1.55), 0.549 (4.38), 0.565 (4.26), 0.574 (3.54), 0.586 (2.02), 0.688 ( 2.56), 0.706 (9.75), 0.723 (16.00), 0.743 (10.93), 0.765 (2.53), 0.783 (0.70), 1.014 (0.92), 1.029 (1.97), 1.046 (3.89), 1.058 (3.39), 1.072 ( 2.94), 1.086 (1.64), 1.103 (0.66), 2.329 (0.53), 2.671 (0.54), 3.669 (2.36), 3.683 (2.43), 3.695 (2.47), 3.710 (2.40), 3.722 (2.51), 3.737 ( 2.41), 3.748 (2.39), 3.763 (2.17), 9.063 (5.76).

Example 85A.

N - [(ΓE) -2,2-Dimethylpropylidene] -2-methylpropane-2-sulfinamide (enantiomer 1).

(S) -2-Methylpropane-2-sulfinamide (15.0 g, 124 mmol) in an argon atmosphere was placed in 650 ml of dichloromethane and mixed with pivaldehyde (27 ml, 250 mmol) and anhydrous copper sulfate (II) (59.3 g, 371 mmol ) at room temperature. The mixture was stirred for 4 days at room temperature. The reaction mixture was filtered through celite, washed with diethyl ether, the filtrate was evaporated and concentrated in high vacuum. 22.7 g of the target compound was obtained (97% of theory).

LCMS (Method 1): Rt = 0.93 min; MS (ESIpos): m / z = 190 [M + H] ⁺ .

¹ H-NMR (400 MHz, DMSO-de) δ [ppm]: 1.013 (0.56), 1.079 (2.03), 1.102 (15.53), 1.113 (1.97), 1.120 (16.00), 1.271 (1.00), 7.814 (1.55 ).

Example 86A.

2-Methyl-N- [1,1,1,2,2-pentafluoro-4,4-dimethylpentan-3-yl] propane-2-sulfinamide (diastereoisomer 1).

N - [(1E) -2,2-Dimethylpropylidene] -2-methylpropane-2-sulfinamide (enantiomer 1) (3.50 g,

18.5 mmol) were placed together with tetramethylammonium fluoride (4.13 g, 44.4 mmol) into a container under argon atmosphere. After 14 h, the reaction vessel was removed from the container and the mixture was mixed with 56 ml of THF and, at -78 ° C, slowly mixed with a solution of trimethyl (pentafluoroethyl) silane (8.1 ml, 46 mmol) dissolved in 82 ml of THF. The reaction mixture was stirred for 3.5 h at -78 ° C. The reaction solution was mixed with a saturated ammonium chloride aqueous solution and water at about -50 ° C. The aqueous phase was extracted twice with ethyl acetate. The combined organic phases were washed respectively once with water and saturated aqueous sodium chloride solution. The organic phase was dried over sodium sulfate, filtered and thickened. The residue is purified using silica gel (solvent: cyclohexane, then cyclohexane / ethyl acetate: 5/1). Received 4.25 g of the target compound (73% theory. V., Purity 98%, de> 95%).

LCMS (Method 4): Rt = 3.30 min; MS (ESIpos): m / z = 310 [M + H] +.

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: -0.008 (1.33), 0.008 (0.58), 1.054 (0.45), 1.058 (0.43), 1.104 (7.77), 1.106 (7.67), 1.178 ( 16.00), 1.201 (1.02), 2.519 (0.54), 2.524 (0.57), 5.114 (0.43), 5.137 (0.41).

Example 87A.

1,1,1,2,2-Pentafluoro-4,4-dimethylpentan-3-amine hydrochloride (enantiomer 1).

2-Methyl-N- [1,1,1,2,2-pentafluoro-4,4-dimethylpentan-3-yl] propane-2-sulfinamide (diastereoisomer 1) (4.14 g, 98% purity, 13.1 mmol) was placed in 240 ml of diethyl ether and 48 ml of methanol. Then mixed with 2n. hydrochloric acid in diethyl ether (240 ml, 480 mmol) and stirred for 2.5 h at room temperature. Then, the reaction solution was evaporated at a water bath temperature of 35 ° C. The residue was mixed with about 5 ml of diethyl ether, filtered off and the residue was dried. It was mixed with 20 ml of 20% potassium hydroxide solution and extracted three times with dichloromethane. The combined organic phases were mixed with 2N. hydrochloric acid in diethyl ether and evaporated at a water bath temperature of 35 ° C and dried under high vacuum. 2.94 g of the target compound was obtained (89% of theory), which was used in the following steps without additional purification.

LCMS (Method 1): Rt = 0.81 min; MS (ESIpos): m / z = 206 [M-HCl + H] +.

Example 88A.

N - [(1E) -2,2-Dimethylpropylidene] -2-methylpropane-2-sulfinamide (enantiomer 2).

(R) -2-Methylpropane-2-sulfinamide (15.0 g, 124 mmol) in an argon atmosphere was placed in 650 ml of dichloromethane and mixed with pivaldehyde (27 ml, 250 mmol) and anhydrous copper sulfate (II) (59.3 g, 371 mmol ) at room temperature. The mixture was stirred for 4 days at room temperature. Copper sulfate (24.7 g, 155 mmol) was added again and stirred overnight at room temperature. The reaction mixture was filtered through celite, washed with diethyl ether, the filtrate was evaporated and concentrated in high vacuum. Received 20.15 g of the target compound (86% theory. V.).

LCMS (Method 1): Rt = 0.94 min; MS (ESIpos): m / z = 190 [M + H] +.

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.078 (14.51), 1.102 (16.00), 1.113 (1.88), 1.120 (15.93), 1.270 (1.08), 5.290 (0.56), 7.814 (1.44 ).

Example 89A.

2-Methyl-N- [1,1,1,2,2-pentafluoro-4,4-dimethylnenman-3-yl] propane-2-sulfinamide (diastereoisomer 2).

In an argon atmosphere (the flask and tetramethylammonium fluoride were placed in a box for drying overnight) N - [(1E) -2,2-dimethylpropylidene] -2-methylpropane-2-sulfinamide (enantiomer 2) (4.38 g, 80% purity, 18.5 mmol ) was placed together with tetramethylammonium fluoride (4.13 g, 44.4 mmol) into a container under argon. After 14 h, the reaction vessel was removed from the container and the mixture was mixed with 56 ml of THF and, at -78 ° C, slowly mixed with a solution of trimethyl (pentafluoroethyl) silane (8.1 ml, 46 mmol) dissolved in 82 ml of THF. The reaction mixture was stirred for 3 h at -70 ° C and then left to thaw slowly overnight at room temperature with stirring. The reaction solution was carefully mixed with a saturated aqueous solution of ammonium chloride and water. The aqueous phase was extracted twice with ethyl acetate. The combined organic phases were washed respectively once with water and saturated aqueous sodium chloride solution. The organic phase was dried over sodium sulfate, filtered and concentrated. The residue was purified using silica gel (solvent: 100% cyclohexane, then cyclohexane / ethyl acetate: 2/1). 3.81 g of the target compound was obtained (65% of theory, purity 98%, de> 90%).

LCMS (Method 4): Rt = 3.30 min; MS (ESIpos): m / z = 310 [M + H] +.

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 1.054 (0.40), 1.059 (0.42), 1.104 (7.59), 1.106 (7.75), 1.178 (16.00), 1.201 (1.05), 5.113 (0.42 ).

Example 90A.

1,1,1,2,2-Pentafluoro-4,4-dimethylpentan-3-amine hydrochloride (enantiomer 2).

2-Methyl-N- [1,1,1,2,2-pentafluoro-4,4-dimethylpentan-3-yl] propane-2-sulfinamide (diastereoisomer 2) (3.73 g, 12.0 mmol) was placed in 220 ml of diethyl ether and 44 ml of methanol. Then mixed with 2n. hydrochloric acid in diethyl ether (220 ml, 440 mmol) and stirred for 2.5 h at room temperature. Then, the reaction solution was evaporated at a water bath temperature of 35 ° C. The residue was stirred with diethyl ether and dried under high vacuum. Received 2.48 g of the target compound (81% theory. V., Purity 95%).

LCMS (Method 1): Rt = 0.80 min; MS (ESIpos): m / z = 206 [M-HCl + H] +.

Example 91A.

7-Chloro-N- [1-cyclopropyl-2,2,3,3,3-pentafluoropropyl] -6-fluoro-4-oxo-1- (2,4,6-trifluorophenyl) -1,4 dihydro-1, 8-naphthyridine-3-carboxamide (enantiomer 1).

7-Chloro-6-fluoro-4-oxo-1 - (2,4,6-trifluorophenyl) -1,4-dihydro-1,8-naphthyridine-3-carboxylic acid (300 mg, 805 mmol) was placed in 7.5 ml of acetonitrile. Added 1-cyclopropyl-2,2,3,3,3- 61 038451 pentafluoropropane-1-amine hydrochloride (enantiomer 1) (204 mg, 98% purity, 886 μmol) and Ν, Ν-diisopropylethylamine (560 μL, 3.2 mmol ). The mixture was then mixed with a T3P solution (propane phosphonic acid cycloanhydride, 50% in ethyl acetate, 570 μl, 970 μmol). The reaction solution was stirred overnight at room temperature. The mixture was mixed with water and the precipitated solid was filtered off, washed with water and dried under high vacuum. 439 mg of the target compound was obtained (99% theory, 99% purity).

LCMS (Method 3): Rt = 2.53 min; MS (ESIpos): m / z = 544 [M + H] +.

Ή-NMR (400 MHz, DMSO-de) δ [ppm]: -0.149 (1.22), -0.008 (9.36), 0.008 (8.14), 0.146 (0.95), 0.328 (1.83), 0.338 (2.78), 0.350 ( 2.78), 0.363 (2.07), 0.373 (1.05), 0.542 (2.14), 0.554 (3.12), 0.566 (2.71), 0.580 (2.58), 0.589 (2.34), 0.600 (2.68), 0.612 (2.54), 0.622 ( 2.10), 0.668 (1.29), 0.688 (2.51), 0.699 (2.31), 0.712 (2.14), 0.734 (0.81), 1.243 (0.85), 1.264 (1.76), 1.276 (2.64), 1.285 (2.07), 1.297 ( 2.58), 2.073 (0.58), 2.328 (1.53), 2.367 (1.05), 2.670 (1.56), 2.711 (0.88), 4.442 (0.68), 4.466 (1.63), 4.488 (2.00), 4.507 (2.03), 4.530 ( 1.63), 4.554 (0.64), 7.602 (5.39), 7.624 (10.27), 7.646 (5.42), 8.719 (9.63), 8.738 (9.63), 9.167 (16.00), 10.048 (5.32), 10.072 (5.32).

Example 92A.

7-Chloro-N- [1-cyclopropyl-2,2,3,3,3-pentafluoropropyl] -6-fluoro-4-oxo-1- (2,4,6-trifluorophenyl) -1,4 dihydro-1, 8-naphthyridine-3-carboxamide (enantiomer 2).

7-Chloro-6-fluoro-4-oxo-1- (2,4,6-trifluorophenyl) -1,4-dihydro-1,8-naphthyridine-3-carboxylic acid (300 mg, 805 mmol) was placed in 7.5 ml of acetonitrile. Added 1-cyclopropyl-2,2,3,3,3pentafluoropropan-1-amine hydrochloride (enantiomer 2) (204 mg, 98% purity, 886 μmol) and, Ν-diisopropylethylamine (560 μL, 3.2 mmol). The mixture was then mixed with a T3P solution (propane phosphonic acid cycloanhydride, 50% in ethyl acetate, 570 μL, 970 μmol). The reaction solution was stirred overnight at room temperature. The mixture was mixed with water and the precipitated solid was filtered off, washed with water and dried under high vacuum. 422 mg of the target compound was obtained (96% theoretical, 100% purity).

LCMS (Method 3): Rt = 2.52 min; MS (ESIpos): m / z = 544 [M + H] ⁺ .

Ή-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: -0.149 (0.93), -0.008 (7.99), 0.008 (6.97), 0.146 (0.89), 0.316 (0.84), 0.328 (2.12), 0.338 (3.25), 0.351 (3.23), 0.363 (2.48), 0.374 (1.19), 0.530 (0.88), 0.542 (2.44), 0.553 (3.54), 0.566 (3.10), 0.579 (2.86), 0.589 (2.57), 0.600 (3.16), 0.611 (2.79), 0.622 (2.43), 0.633 (2.04), 0.646 (1.15), 0.667 (1.46), 0.678 (1.71), 0.688 (2.81), 0.700 (2.63), 0.713 (2.41), 0.721 (1.24), 0.734 (0.78), 1.243 (0.60), 1.256 (1.20), 1.264 (1.77), 1.276 (2.90), 1.285 (2.34), 1.296 (2.85), 1.308 (1.57), 1.317 (1.00), 1.329 (0.42), 2.074 (2.03), 2.328 (0.75), 2.367 (0.58), 2.671 (0.77), 2.711 (0.55), 4.442 (0.77), 4.466 (1.97), 4.488 (2.26), 4.508 (2.30), 4.530 (1.93), 4.554 (0.71), 7.601 (5.75), 7.623 (11.11), 7.646 (5.82), 8.719 (9.38), 8.738 (9.40), 9.167 (16.00), 10.048 (6.22), 10.072 (6.09).

Example 93A.

7-Chloro-N- (1,1-dicyclopropyl-2,2,2-trifluoroethyl) -6-fluoro-4-oxo-1- (2,4,6-trifluorophenyl) -1,4 dihydro-1,8- naphthyridine-3-carboxamide.

7-Chloro-6-fluoro-4-oxo-1- (2,4,6-trifluorophenyl) -1,4-dihydro-1,8-naphthyridine-3-carboxylic acid (100 mg, 268 μmol), 1, 1-dicyclopropyl-2,2,2-trifluoroethanamine hydrochloride (63.7 mg, 295 µmol) and, Ν-diisopropylethylamine (160 µl, 940 µmol) were placed in 2.4 ml of ethyl acetate. A T3P solution (propane phosphonic acid cycloanhydride, 50% in ethyl acetate; 630 μL, 1.1 mmol) was added and the mixture was stirred for 2 h at 80 ° C. The mixture was mixed with water and extracted twice with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and evaporated. The residue was purified by preparative HPLC (RP18 columns, eluent: acetonitrile / water gradient with the addition of 0.1% trifluoroacetic acid). The combined product fractions were evaporated. The residue was dissolved in dichloromethane and washed twice with saturated aqueous sodium hydrogen carbonate solution. The combined aqueous phases were reextracted twice with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated. Received 101 mg of the target compound (70% theory. V. 99% purity).

LCMS (Method 1): Rt = 1.33 min; MS (ESIpos): m / z = 534 [M + H] ⁺ .

Ή-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: -0.149 (1.44), -0.008 (11.48), 0.008 (10.40), 0.146 (1.35), 0.486 (1.29), 0.499 (2.28), 0.509 (4.55), 0.521 (5.24), 0.532 (5.99), 0.544 (3.36), 0.554 (2.88), 0.578 (1.80), 0.589 (3.87), 0.603 (4.52), 0.610 (5.81), 0.625 (7.01), 0.636 (5.63), 0.646 (6.26), 0.658 (7.40), 0.671 (6.17), 0.683 (5.48), 0.697 (5.66), 0.707 (5.99), 0.720 (4.25), 0.730 (2.79), 0.744 (1.02), 1.234 (1.17), 1.527 (1.98), 1.541 (4.13), 1.548 (4.34), 1.563 (7.58), 1.577 (4.04), 1.584 (3.72), 1.597 (1.59), 2.323 (1.65), 2.328 (2.22), 2.366 (1.05), 2.523 (5.48), 2.665 (1.77), 2.670 (2.40), 2.710 (1.17), 5.754 (0.48), 7.599 (5.66), 7.621 (10.64), 7.643 (5.84), 8.754 (10.37), 8.773 (10.40), 9.117 (16.00), 9.409 (12.46).

Example 94A.

7-Chloro-1N- (1,1-dicyclopropyl-2,2,3,3,3-pentafluoropropyl) -6-fluoro-4-oxo-1- (2,4,6-trifluorophenyl) 1,4-dihydro -1,8-naphthyridine-3-carboxamide.

7-Chloro-6-fluoro-4-oxo-1- (2,4,6-trifluorophenyl) -1,4-dihydro-1,8-naphthyridine-3-carboxylic acid

- 62 038451 (140 mg, 376 μmol), 1,1-dicyclopropyl-2,2,3,3,3-pentafluoropropane-1-amine hydrochloride (110 mg, 413 μmol) and N, N-diisopropylethylamine (230 μl, 1.3 μmol) was taken up in ethyl acetate. A T3P solution (propane phosphonic acid cycloanhydride, 50% in ethyl acetate; 890 μL, 1.5 mmol) was added and the mixture was stirred for 2 h at 80 ° C. The mixture was mixed with water and extracted twice with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and evaporated. The residue was purified by preparative HPLC (RP18 columns, eluent: acetonitrile / water gradient with the addition of 0.1% trifluoroacetic acid). The combined product fractions were evaporated. The residue was dissolved in dichloromethane and washed twice with saturated aqueous sodium hydrogen carbonate solution. The combined aqueous phases were reextracted twice with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated. 88 mg of the target compound was obtained (40% theoretical, 99% purity).

LCMS (Method 1): Rt = 1.44 min; MS (ESIpos): m / z = 584 [M + H] +.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: -0.149 (0.61), -0.008 (4.76), 0.008 (4.40), 0.146 (0.56), 0.489 (1.21), 0.501 (2.46), 0.511 (3.85), 0.524 (5.52), 0.537 (5.23), 0.546 (3.52), 0.559 (2.46), 0.597 (1.64), 0.609 (3.74), 0.624 (4.52), 0.631 (6.04), 0.645 (6.88), 0.657 (5.30), 0.668 (6.10), 0.681 (6.68), 0.695 (5.21), 0.708 (1.89), 0.737 (2.53), 0.751 (5.27), 0.763 (5.87), 0.774 (4.85), 0.786 (3.29), 0.800 (1.19), 1.233 (0.96), 1.589 (1.67), 1.604 (3.78), 1.611 (4.10), 1.625 (6.63), 1.639 (3.88), 1.660 (1.40), 2.328 (0.83), 2.367 (0.48), 2.671 (0.90), 2.710 (0.50), 5.755 (0.47), 7.597 (5.68), 7.619 (10.97), 7.641 (5.82), 8.759 (9.67), 8.778 (9.61), 9.126 (16.00), 9.386 (11.83).

Example 95A.

7-Chloro-6-fluoro-4-oxo-N- [1,1,1,2,2-pentafluoro-4,4-dimethylpentan-3-yl] -1- (2,4,6-trifluorophenyl) - 1,4dihydro-1,8-naphthyridine-3-carboxamide (enantiomer 1).

7-Chloro-6-fluoro-4-oxo-1- (2,4,6-trifluorophenyl) -1,4-dihydro-1,8-naphthyridine-3-carboxylic acid (300 mg, 805 mmol) was placed in 7.5 ml of acetonitrile. Added 1,1,1,2,2-pentafluoro-4,4-dimethylpentan3-amine hydrochloride (enantiomer 1) (214 mg, 100% purity, 886 μmol) and N, N-diisopropylethylamine (560 μL, 3.2 mmol). Added T3P solution (propane phosphonic acid cycloanhydride, 50% in ethyl acetate; 570 μL, 970 μmol). The reaction solution was stirred overnight at room temperature. Once again, 1,1,1,2,2-pentafluoro-4,4-dimethylpentan-3-amine hydrochloride (enantiomer 1) (97 mg, 403 μmol) z was added to the reaction solution and stirred for two days at room temperature. 1,1,1,2,2-pentafluoro-4,4-dimethylpentan-3-amine hydrochloride (enantiomer 1) (97 mg, 403 μmol), N, N-diisopropylethylamine (280 μl, 1.6 mmol) were added and T3P solution (propane phosphonic acid cycloanhydride 50% in ethyl acetate; 285 μl, 480 μmol) to the reaction solution and stirred for 2 days at room temperature. The reaction solution was diluted with dichloromethane and washed twice with water. The combined aqueous phases were back-extracted with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated. The residue was purified using silica gel (solvent: cyclohexane / ethyl acetate - gradient: ethyl acetate 4% - 32%). Received 318 mg of the target compound (71% theory. V., 100% purity).

LCMS (Method 5): Rt = 1.72 min; MS (ESIpos): m / z = 560 [M + H] ⁺ .

Example 96A.

7-Chloro-6-fluoro-4-oxo-N- [1,1,1,2,2-pentafluoro-4,4-dimethylpentan-3-yl] -1- (2,4,6-trifluorophenyl) - 1,4dihydro-1,8-naphthyridine-3-carboxamide (enantiomer 2).

7-Chloro-6-fluoro-4-oxo-1 - (2,4,6-trifluorophenyl) -1,4-dihydro-1,8-naphthyridine-3-carboxylic acid (300 mg, 805 mmol) was placed in 7.5 ml of acetonitrile. Added 1,1,1,2,2-pentafluoro-4,4-dimethylpentan3-amine hydrochloride (enantiomer 2) (214 mg, 100% purity, 886 μmol) and N, N-diisopropylethylamine (560 μL, 3.2 mmol). Added T3P solution (propane phosphonic acid cycloanhydride, 50% in ethyl acetate; 570 μL, 970 μmol). The reaction solution was stirred overnight at room temperature. Once again, 1,1,1,2,2-pentafluoro-4,4-dimethylpentan-3-amine hydrochloride (enantiomer 2) (97 mg, 403 µmol) was added to the reaction solution and stirred for two days at room temperature. 1,1,1,2,2-pentafluoro-4,4-dimethylpentan-3-amine hydrochloride (enantiomer 2) (97 mg, 403 μmol), N, N-diisopropylethylamine (280 μl, 1.6 mmol) were added and T3P solution (propane phosphonic acid cycloanhydride 50% in ethyl acetate; 285 μl, 480 μmol) to the reaction solution and stirred for 2 days at room temperature. The reaction solution was diluted with dichloromethane and washed twice with water. The combined aqueous phases were back-extracted with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated. The residue was purified using silica gel (solvent: cyclohexane / ethyl acetate - gradient: ethyl acetate 4% - 32%). Received 373 mg of the target compound (82% theory. V., 99% purity).

LCMS (Method 5): Rt = 1.73 min; MS (ESIpos): m / z = 560 [M + H] ⁺ .

Example 97A.

7-Chloro-4-oxo-N- [3,3,4,4,4-pentafluorobutan-2-yl] -1- (2,4,6-trifluorophenyl) -1,4-dihydro-1,8naphthyridine- 3-carboxamide (pure enantiomers).

To a solution of 2.50 g (7.05 mmol) 7-chloro-4-oxo-1- (2,4,6-trifluorophenyl) -1,4-dihydro-1,8

- 63 038451 naphthyridine-3-carboxylic acid, 1.55 g (7.75 mmol) 3,3,4,4,4-pentafluorobutane-2-amine hydrochloride (pure enantiomers) and 3.7 ml (21.1 mmol) DIPEA in 70 ml ethyl ether acetic acid was added dropwise 16.5 ml (28.2 mmol) 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinan-2,4,6-trioxide (T3P, 50% in ethyl acetate ). Stirred overnight at 80 ° C. The reaction mixture was evaporated and poured onto water. The precipitate was filtered off, dissolved in DCM, dried over sodium sulfate, filtered off, and the solvent was removed under reduced pressure. The starting product was used without further purification in the next step. This gave 3.35 g (95% theory, 100% purity) of the title compound.

LCMS (Method 3): Rt = 2.34 min; MS (ESIpos): m / z = 500 [M + H] +.

¹ H-NMR (400 MHz, DMSO-de) δ [ppm]: -0.149 (0.92), 0.146 (0.85), 0.928 (1.24), 0.943 (1.22), 1.175 (0.71), 1.244 (1.98), 1.259 ( 2.16), 1.274 (1.27), 1.409 (15.77), 1.426 (16.00), 1.488 (0.94), 1.988 (1.17), 2.328 (1.68), 2.367 (1.01), 2.670 (1.82), 2.711 (1.04), 4.998 ( 0.81), 5.020 (1.36), 5.043 (1.68), 5.062 (1.73), 5.086 (1.43), 5.107 (0.78), 7.595 (5.78), 7.618 (11.30), 7.640 (5.82), 7.773 (10.54), 7.794 ( 11.10), 8.741 (11.23), 8.761 (10.77), 9.142 (15.95), 9.986 (6.05), 10.010 (5.92).

Example 98A.

7 - [(3S) -3-Hydroxypyrrolidin-1-yl] -4-oxo-N- [3,3,4,4,4-pentafluorobutan-2-yl] -1- (2,4,6trifluorophenyl) - 1,4-dihydro-1,8-naphthyridine-3-carboxamide (pure enantiomers).

According to AAV3, 5.00 g (10.0 mmol) of 7-chloro-4-oxo-N- [3,3,4,4,4-pentafluorobutan-2-yl] -1 (2,4,6-trifluorophenyl) -1 was converted, 4-dihydro-1,8-naphthyridine-3-carboxamide (pure enantiomers) with 1.36 g (11.0 mmol) of (3S) -pyrrolidin-3-ol-hydrochloride and 7.0 ml (40.0 mmol) of Ν, Ν-diisopropylethylamine in 37 ml dimethylformamide. The reaction mixture was poured onto water and extracted three times with ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution, dried over sodium sulfate and evaporated. The starting product was purified using normal phase chromatography (cyclohexane-ethyl acetate gradient). This gave 4.99 g (88% theory, 97% purity) of the title compound.

LCMS (Method 1): Rt = 1.04 min; MS (ESIpos): m / z = 551 [M + H] ⁺ .

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: -0.149 (0.51), 0.147 (0.51), 1.157 (0.52), 1.175 (1.05), 1.193 (0.49), 1.385 (14.87), 1.402 (14.89), 1.788 (0.91), 1.921 (1.77), 1.989 (2.75), 2.329 (0.83), 2.367 (0.42), 2.671 (0.79), 2.711 (0.44), 3.051 (1.08), 3.083 (1.84), 3.163 (2.28), 3.185 (2.68), 3.518 (2.49), 3.534 (2.97), 4.021 (0.47), 4.039 (0.47), 4.270 (1.69), 4.387 (1.43), 4.961 (2.74), 4.984 (1.50), 5.007 (1.64), 5.052 (3.17), 6.744 (1.70), 6.773 (2.76), 6.798 (2.07), 7.530 (3.28), 7.553 (6.61), 7.575 (3.83), 8.265 (3.13), 8.286 (2.86), 8.805 (16.00), 10.551 (6.33), 10.575 (6.15).

Examples of execution

Example 1.

1- (2,6-Difluorophenyl) -7 - [(3R, 4R) -3,4-dihydroxypyrrolidin-1-yl] -6-fluoro-4-oxo-N- (4,4,4-trifluoro2-methylbutane -2-yl) -1,4-dihydro-1,8-naphthyridine-3-carboxylic acid amide.

According to AAV1, 99.9 mg (237 μmol) of 1- (2,6-difluorophenyl) -7 - [(3R, 4R) -3,4-dihydroxypyrrolidin-1-yl] -6-fluoro-4-oxo-1,4-dihydro -1,8-naphthyridine-3-carboxylic acid with 40.1 mg (284 μmol) 4,4,4-trifluoro-2-methylbutan-2-amine in the presence of 108 mg (284 μmol) HATU and 103 μL (593 μmol) DIPEA in 2.4 ml of DMF. The reaction mixture was immediately purified using preparative HPLC [at UV max: 265 nm, columns: Chromatorex C18, 10 μm, 125x30 mm, solvent: acetonitrile / 0.05% formic acid - gradient (0-3 min 10% acetonitrile, up to 35 min 90 % acetonitrile and the next 3 min 90% acetonitrile)]. The product fractions were combined, freed from solvent and lyophilized. 107 mg (82% theory, 99% purity) of the title compound was obtained.

LCMS (Method 3): Rt = 1.76 min; MS (ESIpos): m / z = 545 [M + H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 10.10 (s, 1H), 8.67 (s, 1H), 8.00 (d, 1H), 7.77-7.66 (m, 1H), 7.477.36 ( m, 2H), 5.18 (br. s, 2H), 4.09-3.51 (br. m, 4H), 3.27-2.86 (m, 4H).

Example 2.

N - [(1S) -1-Cyclopropyl-2,2,2-trifluoroethyl] -1- (2,6-difluorophenyl) -7 - [(3R, 4R) -3,4 dihydroxypyrrolidin-1-yl] -6- fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid amide.

According to AAV1, 99.9 mg (237 μmol) of 1- (2,6-difluorophenyl) -7 - [(3R, 4R) -3,4-dihydroxypyrrolidin-1-yl] -6-fluoro-4-oxo-1,4-dihydro -1,8-naphthyridine-3-carboxylic acid with 49.9 mg (284 μmol) (1S) -1-cyclopropyl-2,2,2-trifluoroethanamine hydrochloride in the presence of 108 mg (284 μmol) HATU and 103 μL (593 μmol) DIPEA in 2.4 ml DMF. Then the reaction mixture was immediately purified using preparative HPLC [at UV max: 265 nm, columns: Chromatorex C18, 10 μm, 125x30 mm, solvent: acetonitrile / 0.05% formic acid - gradient (0-3 min 10% acetonitrile, up to 35 min 90% acetonitrile and the next 3 minutes 90% acetonitrile)]. The product fractions were combined, freed from solvent and lyophilized. This gave 100 mg (77% theory, 99% purity) of the title compound.

LCMS (Method 3): Rt = 1.77 min; MS (ESIpos): m / z = 543 [M + H] ⁺ .

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: 10.49 (d, 1H), 8.78 (s, 1H), 8.02 (d, 1H), 7.76-7.67 (m, 1H),

- 64 038451

7.46-7.38 (m, 2H), 5.19 (br. S, 2H), 4.45-4.32 (m, 1H), 4.11-3.53 (br. M, 4H), 3.27-2.89 (m, 2H), 1.27-1.16 (m,

1H), 0.70-0.49 (m, 3H), 0.38-0.28 (m, 1H).

Example 3.

1- (2,6-Difluorophenyl) -7 - [(3R, 4R) -3,4-dihydroxypyrrolidin-1-yl] -6-fluoro-4-oxo-N - [(2S) -1,1,1trifluorobutane -2-yl] -1,4-dihydro-1,8-naphthyridine-3-carboxylic acid amide.

According to AAV1, 100 mg (237 μmol) of 1- (2,6-difluorophenyl) -7 - [(3R, 4R) -3,4-dihydroxypyrrolidin-1-yl] -6-fluoro-4-oxo-1,4-dihydro -1,8-naphthyridine-3-carboxylic acid with 46.6 mg (285 μmol) (2S) -1,1,1-mfluorobutan-2-amine hydrochloride in the presence of 108 mg (285 μmol) HATU and 103 μL (593 μmol) DIPEA in 2.4 ml DMF. Then the reaction mixture was diluted with 2 ml of aqueous hydrochloric acid and purified using preparative HPLC [at UV max: 265 nm, columns: Chromatorex C18, 10 μm, 125x30 mm, solvent: acetonitrile / 0.05% formic acid - gradient (0-3 min 10 % acetonitrile, up to 35 min 90% acetonitrile and the next 3 min 90% acetonitrile)]. The product fractions were combined, freed from solvent and lyophilized. This gave 32.7 mg (26% theory, 100% purity) of the title compound.

LCMS (Method 1): Rt = 0.92 min; MS (ESIpos): m / z = 531 [M + H] ⁺ .

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: 10.36 (d, 1H), 8.79 (s, 1H), 8.02 (d, 1H), 7.77-7.67 (m, 1H), 7.47-7.38 (m, 2H), 5.19 (br. s, 2H), 4.81-4.67 (m, 1H), 4.10-3.56 (br. m, 4H), 3.27-2.90 (m, 2H), 1.94-1.82 (m, 1H), 1.71-1.58 (m, 1H), 0.97 (t, 1H).

Example 4.

1- (2,6-Difluorophenyl) -6-fluoro-7 - [(2-hydroxyethyl) (methyl) amino] -4-oxo-N - [(2S) -1,1,1-trifluorobutan2-yl] - 1,4-dihydro-1,8-naphthyridine-3-carboxylic acid amide.

According to AAV3, 50.0 mg (108 μmol) of 7-chloro-1- (2,6-difluorophenyl) -6-fluoro-4-oxo-N [(2S) -1,1,1-trifluorobutan-2-yl] - 1,4-dihydro-1,8-naphthyridine-3-carboxylic acid amide with 8.91 mg (119 μmol) 2- (methylamino) ethanol in the presence of 66 μL (0.38 mmol) DIPEA in 0.5 mL DMF. Then it was diluted with acetonitrile, water and 0.2 ml of aqueous hydrochloric acid and the resulting solution was purified by preparative HPLC (acetonitrile-water with formic acid, C18 RP-HPLC). The product fractions were combined, concentrated in vacuo and lyophilized from acetonitrile / water overnight. This gave 37.9 mg (70% theory, 100% purity) of the title compound.

LCMS (Method 3): _Rt = 1.97 min; MS (ESIpos): m / z = 503 [M + H] +.

'H-NMR (400 MHz, DMSO-d6) δ [ppm]: 10.33 (d, 1H), 8.81 (s, 1H), 8.01 (d, 1H), 7.75-7.65 (m, 1H), 7.45-7.37 (m, 2H), 4.80-4.67 (m, 2H), 3.51-3.35 (m, 4H), 3.05 (s, 3H), 1.94-1.82 (m, 1H), 1.71-1.58 (m, 1H), 0.97 (t, 3H).

Example 5.

N- (Bicyclo [1.1.1] pent-1-yl) -1- (2,6-difluorophenyl) -7 - [(3R, 4R) -3,4-dihydroxypyrrolidin-1-yl] -6fluoro-4- oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid amide.

According to AAV1, 100 mg (237 μmol) of 1- (2,6-difluorophenyl) -7 - [(3R, 4R) -3,4-dihydroxypyrrolidin-1-yl] -6-fluoro-4-oxo-1,4-dihydro -1,8-naphthyridine-3-carboxylic acid with 34.1 mg (285 μmol) bicyclo [1.1.1] pentan-1-amine hydrochloride in the presence of 108 mg (285 μmol) HATU and 103 μL (593 μmol) DIPEA in 2.4 ml DMF. The reaction mixture was then diluted with 2 ml aqueous hydrochloric acid and purified twice by preparative HPLC [at UV max .: 265 nm, columns: Chromatorex C18, 10 μm, 125x30 mm, solvent: acetonitrile / 0.05% formic acid - gradient (0-3 min 10% acetonitrile, up to 35 min 90% acetonitrile and the next 3 min 90% acetonitrile)]. The product fractions were combined, freed from solvent and lyophilized. This gave 3 mg (2% theory, 100% purity) of the title compound.

LCMS (Method 3): Rt = 1.65 min; MS (ESIpos): m / z = 487 [M + H] +.

Example 6.

7 - [(3R, 4R) -3,4-Dihydroxypyrrolidin-1-yl] -6-fluoro-4-oxo-N - [(2S) -1,1,1-trifluorobutan-2-yl] -1 ( 2,4,6-trifluorophenyl) -1,4-dihydro-1,8-naphthyridine-3-carboxylic acid amide.

According to AAV3, 417 mg (717 μmol) of 6-fluoro-4-oxo-7- (1- [1,2,3] triazole [4,5-b] pyridin1-yloxy) -N - [(2S) -1 , 1,1-trifluorobutan-2-yl] -1- (2,4,6-trifluorophenyl) -1,4-dihydro-1,8-naphthyridine-3amide carboxylic acid with 120 mg (861 μmol) (3R, 4R ) -pyrrolidine-3,4-diol hydrochloride in the presence of 437 μl (2.51 mmol) of DIPEA in 7.25 ml of DMF. Then the reaction solution was poured onto 80 ml of water, acidified with 2 ml of aqueous 1 M hydrochloric acid, the precipitate was evacuated and washed with water. The precipitate was taken up in 6 ml of acetonitrile and purified by preparative HPLC (acetonitrile-water with formic acid, C18 RP-HPLC). The product fractions were combined, concentrated in vacuo and the residue was lyophilized overnight from acetonitrile / water. This gave 296 mg (74% theory, 99% purity) of the title compound.

LCMS (Method 3): Rt = 1.78 min; MS (ESIpos): m / z = 549 [M + H] +.

'H-NMR (400 MHz, DMSO-d6) δ [ppm]: 10.34 (d, 1H), 8.84 (s, 1H), 8.02 (d, 1H), 7.62-7.53 (m, 2H), 5.20 (br . s, 2H), 4.82-4.67 (m, 1H), 4.13-3.54 (br. m, 4H), 3.28-2.95 (m, 2H), 1.94-1.81 (m, 1H), 1.72-1.57 (m, 1H), 0.97 (t, 1H).

- 65 038451

Example 7.

N - [(1S) -1-Cyclopropyl-2,2,2-trifluoroethyl] -7 - [(3R, 4R) -3,4-dihydroxypyrrolidin-1-yl] -6-fluoro-4oxo-1 - (2 , 4,6-trifluorophenyl) -1,4-dihydro-1,8-naphthyridine-3-carboxylic acid amide.

According to AAV1, 1.00 g (2.28 mmol) 7 - [(3R, 4R) -3,4-dihydroxypyrrolidin-1-yl] -6fluoro-4-oxo-1- (2,4,6-trifluorophenyl) -1.4 -dihydro-1,8-naphthyridine-3-carboxylic acid with 480 mg (2.73 mmol) (1S) -1-cyclopropyl-2,2,2-trifluoroethanamine hydrochloride in the presence of 1.04 g (2.73 mmol) HATU and 991 μL (5.69 mmol) DIPEA in 23 ml of DMF, then acidified with aqueous 1 M hydrochloric acid, diluted with 200 ml of water and 100 ml of ethyl acetate. The phases were separated and the aqueous phase was extracted twice with 60 ml of ethyl acetate. The combined organic phases were washed with 50 ml of pH 7 buffer solution and 50 ml of saturated sodium chloride solution, dried over magnesium sulfate, filtered and thickened. The residue was purified by normal phase chromatography (cyclohexane-ethyl acetate), fractions were combined, concentrated in vacuo and lyophilized overnight from acetonitrile / water. This gave 1.05 g (83% theory, 100% purity) of the title compound.

LCMS (Method 3): Rt = 1.81 min; MS (ESIpos): m / z = 561 [M + H] +.

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: 10.48 (d, 1H), 8.83 (s, 1H), 8.02 (d, 1H), 7.62-7.52 (m, 2H), 5.20 (br . s, 2H), 4.45-4.31 (m, 1H), 4.11-3.55 (br. m, 4H), 3.29-2.95 (m, 2H), 1.26-1.14 (m, 1H), 0.70-0.48 (m, 3H), 0.38-0.28 (m, 1H).

Example 8.

7 - [(3R, 4R) -3,4-Dihydroxypyrrolidin-1-yl] -6-fluoro-4-oxo-N- [3,3,4,4,4-pentafluorobutan-2-yl] -1 ( 2,4,6-trifluorophenyl) -1,4-dihydro-1,8-naphthyridine-3-carboxylic acid amide (mixture of diastereoisomers).

According to AAV1, 2.77 g (6.31 mmol) 7 - [(3R, 4R) -3,4-dihydroxypyrrolidin-1-yl] -6fluoro-4-oxo-1- (2,4,6-trifluorophenyl) -1.4 -dihydro-1,8-naphthyridine-3-carboxylic acid with 1.51 g (7.57 mmol) of 3,3,4,4,4-pentafluorobutan-2-amine hydrochloride (racemate) in the presence of 2.88 g (7.57 mmol) HATU and 3.84 ml (22.1 mmol) DIPEA in 30 ml DMF. Then, the reaction solution was added dropwise to a mixture of 3 ml of aqueous 1M hydrochloric acid and 300 ml of ice water. The formed precipitate was filtered off, dried and purified using normal phase chromatography (cyclohexane-ethyl acetate). This gave 2.40 g (65% theory, 100% purity) of the title compound.

LCMS (Method 3): Rt = 1.84 min; MS (ESIpos): m / z = 585 [M + H] +.

2.40 g of the title compound (mixture of diastereoisomers) was separated by chiral SFC into diastereoisomers (preparative SFC: Daicel Chiralpak AD columns, 5 μm, 250x30 mm; solvent: 85% carbon dioxide, 15% isopropanol; temperature: 38 ° C; flow : 130 ml / min; pressure: 140 bar; UV indication: 210 nm).

Received (as elution from the column) 1.15 g of diastereoisomer 1 from Example 9 (99% de) Rt = 3.23 min, 1.09 g of diastereoisomer 2 from Example 10 (94% de) Rt = 4.79 min [analytical SFC: columns Daicel Chiralpak AD- 3.3μm, 100x4.6mm; solvent: 90% carbon dioxide, 10% isopropanol; temperature: 60 ° C; flow: 3.0 ml / min; pressure: 130 bar; UV indication: 220 nm].

Diastereoisomer 1 was purified using normal phase chromatography (cyclohexane ethyl ester of acetic acid). Received 903 mg (24% theory. Y., 99% purity) of the compound from Example 9.

Diastereoisomer 2 was purified using normal phase chromatography (cyclohexane ethyl ester of acetic acid). 912 mg (25% theory, 99% purity) of the compound from Example 10 was obtained.

Example 9.

7 - [(3R, 4R) -3,4-Dihydroxypyrrolidin-1-yl] -6-fluoro-4-oxo-N- [3,3,4,4,4-pentafluorobutan-2-yl] -1 ( 2,4,6-trifluorophenyl) -1,4-dihydro-1,8-naphthyridine-3-carboxylic acid amide (diastereoisomer 1).

LCMS (Method 3): Rt = 1.84 min; MS (ESIpos): m / z = 585 [M + H] +.

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: 10.46 (d, 1H), 8.84 (s, 1H), 8.01 (d, 1H), 7.62-7.53 (m, 2H), 5.20 (br . s, 2H), 5.10-4.93 (m, 1H), 4.11-3.55 (br. m, 4H), 3.29-2.95 (m, 2H), 1.39 (d, 3H).

Example 10.

7 - [(3R, 4R) -3,4-Dihydroxypyrrolidin-1-yl] -6-fluoro-4-oxo-N- [3,3,4,4,4-pentafluorobutan-2-yl] -1 ( 2,4,6-trifluorophenyl) -1,4-dihydro-1,8-naphthyridine-3-carboxylic acid amide (diastereoisomer 2).

LCMS (Method 3): Rt = 1.84 min; MS (ESIpos): m / z = 585 [M + H] +.

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 10.47 (d, 1H), 8.84 (s, 1H), 8.01 (d, 1H), 7.62-7.54 (m, 2H), 5.20 (br. s, 2H), 5.10-4.93 (m, 1H), 4.11-3.57 (br. m, 4H), 3.29-2.96 (m, 2H), 1.39 (d, 3H).

The following execution examples were obtained similarly to Example 8 according to AAV1:

- 66 038451

Example Name according to IUPAC nomenclature Build LCMS (Method): retention time; detectable mass -NMR amine used (yield, purity) AND 7 - [(ZK, 4K) -3,4-dihydroxypyrrolidin-1-yl] -6-fluoro-4-oxo-M - [(28) -1,1,1 trifluoro-4-methylpentan-2-yl] - 1 - (2,4,6-trifluorophenyl) -1,4-dihydro-1,8naftir Idin-3-carboxamide LC-MS (method 1): R _t = 1.07 min; MS (ESIpos): m / z = 577 [M + H] ⁺ -NMR (400 MHz, DMSO-bb) δ [ppm]: 0.008 (1.63), 0.882 (15.82), 0.898 (15.97), 0.940 (15.69 ), 0.956 (16.00), 1.527 (0.65), 1.562 (2.61), 1.590 (2.10), 1.640 (2.07), 1.650 (3.07), 1.676 (3.98), 1.703 (1.66), 2.328 (0.72), 2.366 (0.49 ), 2.524 (2.17), 2.670 (0.75), 2.710 (0.47), 3.070 (0.79), 3.696 (0.83), 3.904 (1.68), 4.017 (1.18), 4.815 (1.32), 4.838 (1.35), 4.857 (0.78 ), 5.201 (2.98), 7.554 (2.23), 7.558 (2.44), 7.575 (4.26), 7.580 (4.31), 7.597 (2.46), 7.993 (6.91), 8.025 (6.83), 8.847 (12.23), 10.316 (4.89 ), 10.340 (4.71). (2S) -1,1,1-trifluoro-4-methylpentane-2-amine hydrochloride (75% theoretical, 99% pure) 12 X- (bicyclo [1.1.1] pent-1-yl) -7 - [(ZK, 4K) -3,4-dihydroxypyrrolidin-1-yl] -6fluoro-4-oxo-1 - (2,4,6 -trifluorophenyl) -1,4-dihydro-1,8-naphthyr idin-3 carboxamide LCMS (Method 1): R _t = 0.91 min; MS (ESIpos): m / z = 505 [M + H] ⁺ -NMR (400 MHz, DMSO-bb) δ [ppm]: 2.074 (0.98), 2.094 (16.00), 2.477 (2.52), 2.519 (0.42 ), 5.188 (0.90), 7.557 (0.60), 7.579 (1.03), 7.599 (0.60), 7.949 (1.39), 7.981 (1.36), 8.696 (2.25), 10.195 (1.71). bicyclo [1.1.1] pentane-1-amine hydrochloride (69% theoretical, 100% pure) 13 7 - [(3E, 4E) -3,4-dihydroxypyrrolidin-1-yl] -6-fluoro-4-oxo-M- (4,4,4-trifluoro-2methylbutan-2-yl) -1 - (2 , 4,6-trifluorophenyl) -1,4-dihydro-1,8-naphthyr idin-3 carboxamide LCMS (Method 3): R _t = 1.8 min; MS (ESIpos): m / z = 563 [M + H] ⁺ -NMR (400 MHz, DMSO-db) δ [ppm]: 1.480 (16.00), 2.902 (0.72), 2.932 (2.07), 2.963 (2.01 ), 2.992 (0.69), 3.908 (0.59), 5.192 (1.67), 7.552 (1.20), 7.573 (2.17), 7.595 (1.21), 7.980 (2.69), 8.012 (2.63), 8.724 (4.96), 10.086 (3.27 ). 4,4,4-trifluoro-2-methylbutane-2-amine hydrochloride (92% theoretical, 100% pure) fourteen 7 - [(3E, 4E) -3,4-dihydroxypyrrolidin-1-yl] -6-fluoro-4-oxo-M - [(2E) -1,1,1 trifluoro-4-methylpentan-2-yl] - 1 - (2,4,6-trifluorophenyl) -1,4-dihydro-1,8naphthyr idin-3-carboxamide

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LCMS (Method 1): _Rt = 1.07 min; MS (ESIpos): m / z = 577 [M + H] ⁺ -NMR (400 MHz, DMSO-c16) δ [ppm]: -0.008 (2.52), 0.008 (2.37), 0.882 (15.72), 0.898 ( 15.79), 0.940 (15.66), 0.956 (16.00), 1.528 (0.63), 1.534 (0.59), 1.555 (1.28), 1.563 (2.58), 1.571 (1.29), 1.591 (2.06), 1.640 (1.99), 1.650 ( 2.98), 1.676 (3.84), 1.704 (1.62), 1.713 (1.08), 2.329 (0.42), 2.524 (1.33), 2.671 (0.45), 3.070 (0.76), 3.694 (0.77), 3.912 (1.65), 4.018 ( 1.13), 4.816 (1.26), 4.839 (1.29), 4.858 (0.73), 5.201 (4.77), 7.556 (3.83), 7.578 (6.91), 7.599 (3.80), 7.994 (7.11), 8.026 (6.94), 8.848 ( 12.19), 10.318 (4.80), 10.342 (4.57). (2R) -1,1,1-trifluoro-4-methylpentane-2-amine hydrochloride (73% theory, 97% purity) 15 7 - [(3R, 4R) -3,4-dihydroxypyrrolidin-1-yl] -b-fluoro-N- [(2R) -3 -methylbutane-2yl] -4-oxo-1 - (2,4,6 -triftorfenil) -1,4-dihydro-1,8-naftir Idin-3-carboxamide LCMS (method 3): R _t = 1.67 min; MS (ESIpos): m / z = 509 [M + H] ⁺ -NMR (400 MHz, DMSO-c16) δ [ppm]: -0.008 (2.45), 0.008 (1.92), 0.900 (14.25), 0.918 ( 16.00), 0.924 (14.85), 0.941 (14.39), 1.098 (14.84), 1.115 (14.90), 1.731 (0.46), 1.747 (1.23), 1.764 (1.75), 1.778 (1.69), 1.795 (1.13), 1.811 ( 0.41), 2.328 (0.43), 2.519 (1.74), 2.524 (1.27), 2.671 (0.43), 3.070 (0.46), 3.269 (0.67), 3.276 (0.53), 3.680 (0.48), 3.887 (2.02), 3.903 ( 2.66), 3.908 (2.44), 3.921 (2.64), 3.938 (2.04), 3.954 (1.12), 5.191 (3.01), 7.550 (2.38), 7.571 (4.17), 7.592 (2.37), 7.992 (5.69), 8.024 ( 5.64), 8.711 (9.43), 9.868 (3.38), 9.890 (3.30). (2R) -3-methylbutan-2-amine (75% theoretical, 99% pure) 16 7 - [(3R, 4R) -3,4-dihydroxypyrrolidin-1-yl] -b-fluoro-N- [(2 S) -3-methylbutane-2yl] -4-oxo-1 - (2,4, 6-trifluorophenyl) -1,4-dihydro-1,8-naftir Idin-3-carboxamide LCMS (method 3): R _t = 1.67 min; MS (ESIpos): m / z = 509 [M + H] ⁺ -NMR (400 MHz, DMSO-c16) δ [ppm]: 0.008 (1.40), 0.901 (14.31), 0.918 (16.00), 0.925 (14.98 ), 0.942 (14.43), 1.099 (14.84), 1.116 (14.86), 1.731 (0.49), 1.748 (1.30), 1.765 (1.85), 1.778 (1.73), 1.795 (1.14), 3.063 (0.51), 3.680 (0.53 ), 3.888 (2.11), 3.904 (2.84), 3.922 (2.79), 3.939 (2.15), 5.194 (4.39), 7.550 (2.81), 7.572 (4.99), 7.593 (2.71), 7.994 (6.12), 8.026 (6.00 ), 8.713 (11.30), 9.870 (3.57), 9.892 (3.45). (2S) -3-methylbutan-2-amine (77% theoretical, 100% pure)

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17 7 - [(3E, 4E) -3,4-dihydroxypyrrolidin-1-yl] -6-fluoro-X - [(28) -1-methoxy-3methylbutan-2-yl] -4-oxo-1 - (2 , 4,6-trifluorophenyl) -1,4-dihydro-1,8-naphthyridine 3-carboxamide LCMS (Method 3): R _t = 1.58 min; MS (ESIpos): m / z = 539 [M + H] ⁺ -NMR (400 MHz, DMSO-ab) δ [ppm]: -0.008 (1.71), 0.008 (1.47), 0.912 (10.53), 0.929 ( 10.84), 1.903 (0.49), 1.920 (0.75), 1.936 (0.74), 1.953 (0.46), 3.269 (16.00), 3.352 (0.72), 3.365 (0.83), 3.377 (1.17), 3.390 (1.12), 3.439 ( 1.10), 3.453 (1.22), 3.464 (0.76), 3.477 (0.70), 3.919 (0.46), 3.965 (0.52), 3.980 (0.91), 3.994 (0.99), 4.002 (1.00), 4.017 (0.87), 5.192 ( 1.07), 7.553 (0.86), 7.573 (1.56), 7.594 (0.86), 8.000 (2.37), 8.031 (2.31), 8.723 (4.24), 9.926 (1.34), 9.949 (1.29). (2 S) -1-methoxy-3-methylbutane-2-amine hydrochloride (87% theoretical, 99% pure) eighteen 7 - [(ZK, 4K) -3,4-dihydroxypyrrolidin-1-yl] -6-fluoro-4-oxo-1- (2,4,6trifluorophenyl) -X - [(28) -1,1,1 -trifluoropropan-2-yl] -1,4-dihydro-1,8naphthyr idin-3 -carboxamide LCMS (Method 1): R _t = 0.89 min; MS (ESIpos): m / z = 535 [M + H] ⁺ -NMR (400 MHz, DMSO-ab) δ [ppm]: -0.008 (3.40), 1.366 (15.93), 1.383 (16.00), 2.328 ( 0.75), 2.367 (0.46), 2.670 (0.72), 2.710 (0.46), 3.065 (0.82), 3.692 (0.82), 3.906 (1.71), 4.011 (1.21), 4.842 (0.45), 4.861 (1.18), 4.882 ( 1.82), 4.902 (1.87), 4.920 (1.20), 5.199 (4.80), 7.555 (2.86), 7.577 (5.42), 7.598 (2.83), 7.990 (8.04), 8.022 (7.89), 8.837 (14.74), 10.383 ( 5.19), 10.406 (4.90). (2 S) -1,1,1 -trifluor propan-2-amine (77% theoretical, 99% purity) 19 N- [(1R) -1 -cyclopropylethyl] -7 - [(3R, 4R) -3,4-dihydroxypyrrolidin-1 -yl] -6fluoro-4-oxo-1 - (2,4,6-trifluorophenyl) - 1,4-dihydro-1,8-naftir Idin 3-carboxamide LCMS (method 3): R _t = 1.63 min; MS (ESIpos): m / z = 507 [M + H] ⁺ -NMR (400 MHz, DMSO-C16) δ [ppm]: -0.150 (0.68), -0.008 (6.67), 0.008 (5.02), 0.146 (0.68), 0.218 (1.10), 0.229 (1.68), 0.241 (2.46), 0.249 (2.36), 0.261 (1.43), 0.266 (1.39), 0.278 (2.30), 0.287 (2.75), 0.299 (1.94), 0.310 (1.26), 0.322 (0.55), 0.394 (0.65), 0.402 (0.65), 0.414 (1.85), 0.425 (2.27), 0.435 (2.59), 0.447 (3.11), 0.461 (2.75), 0.469 (2.01), 0.482 (1.59), 0.491 (0.62), 0.940 (0.45), 0.952 (0.87), 0.960 (1.30), 0.972 (2.27), 0.980 (1.46), 0.992 (2.14), 1.004 (1.10), 1.012 (0.74), 1.215 (15.87), 1.231 (16.00),

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2.327 (1.13), 2.366 (1.00), 2.523 (3.85), 2.670 (1.23), 2.710 (1.10), 3.064 (0.55), 3.482 (0.42), 3.498 (1.39), 3.518 (2.56), 3.535 (2.49), 3.553 (1.33), 3.571 (0.49), 3.679 (0.62), 3.917 (1.39), 5.189 (4.15), 7.546 (3.17), 7.568 (5.73), 7.589 (3.21), 7.975 (6.25), 8.007 (6.19), 8.708 (10.85), 9.864 (4.05), 9.884 (3.92). (1R) -1 -cyclopropylethanamine (76% theoretical, 100% pure) twenty N - [(l S) -l-cyclopropylethyl] -7 - [(ZK, 4K) -3,4-dihydroxypyrrolidin-1-yl] -6fluoro-4-oxo-1 - (2,4,6-trifluorophenyl) -1,4-dihydro-1,8-naphthyr idin-3 carboxamide LCMS (Method 3): R _t = 1.62 min; MS (ESIpos): m / z = 507 [M + H] ⁺ -NMR (400 MHz, DMSODb) δ [ppm]: -0.149 (0.42), -0.008 (4.00), 0.008 (2.96), 0.146 (0.42 ), 0.207 (0.46), 0.218 (1.12), 0.229 (1.67), 0.241 (2.46), 0.249 (2.39), 0.261 (1.42), 0.266 (1.39), 0.278 (2.32), 0.287 (2.75), 0.299 (1.93 ), 0.310 (1.19), 0.321 (0.56), 0.394 (0.60), 0.402 (0.67), 0.414 (1.84), 0.425 (2.23), 0.435 (2.56), 0.448 (3.05), 0.456 (1.96), 0.461 (2.72 ), 0.470 (1.98), 0.482 (1.60), 0.491 (0.60), 0.502 (0.44), 0.940 (0.44), 0.952 (0.88), 0.960 (1.26), 0.972 (2.25), 0.980 (1.44), 0.984 (1.40 ), 0.992 (2.16), 1.005 (1.09), 1.012 (0.74), 1.215 (15.91), 1.232 (16.00), 2.328 (0.61), 2.367 (0.60), 2.524 (2.23), 2.670 (0.65), 2.710 (0.58 ), 3.073 (0.54), 3.484 (0.40), 3.501 (1.35), 3.520 (2.49), 3.537 (2.46), 3.556 (1.30), 3.573 (0.44), 3.673 (0.56), 3.909 (1.32), 5.190 (4.47 ), 7.547 (2.51), 7.568 (4.49), 7.589 (2.51), 7.976 (6.25), 8.008 (6.18), 8.709 (10.70), 9.864 (4.05), 9.884 (3.89). (1S) -1 -cyclopropylethanamine (77% theoretical, 100% pure) 21 X- (dicyclopropylmethyl) -7 - [(ZI, 4I) -3,4-dihydroxypyrrolidin-1-yl] -6-fluoro4-oxo-1 - (2,4,6-trifluorophenyl) -1,4-dihydro- naftir Idin 1,8-3-carboxamide LC-MS (method 1): R _t = 0.94 min; MS (ESIpos): m / z = 533 [M + H] ⁺ -NMR (400 MHz, DMSODb) δ [ppm]: -0.149 (1.11), -0.008 (9.56), 0.008 (7.59), 0.146 (1.11 ), 0.299 (15.57), 0.311 (15.27), 0.322 (4.14), 0.370 (2.56), 0.393 (6.91), 0.415 (5.85), 0.452 (4.99), 0.472 (6.31), 0.498 (1.92), 1.016 (2.82 ), 1.029 (5.25), 1.036 (3.41), 1.049 (4.99), 1.061 (2.60), 2.328 (2.22), 2.367 (1.11), 2.670 (2.13), 2.710 (1.07), 3.221 (2.22), 3.239 (4.44 ), 3.261 (4.74), 3.280 (2.86), 3.903 (1.79), 5.189 (5.16), 7.545 (3.50), 7.568 (6.27), 7.588 (3.58), 7.988 (9.09), 8.020 (8.75), 8.709 (16.00 ), 9.892 (5.03), 9.914 (4.82).

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1,1-dicyclopropylmethanamine (61% theoretical, 99% pure) 22 M- (1,1-difluoro-2-methylpropan-2-yl) -7 - [(3K, 4K) -3,4-dihydroxypyrrolidin-1yl] -6-fluoro-4-oxo-1 - (2,4 , 6-trifluorophenyl) -1,4-dihydro-1,8-naphthyr idin-3 carboxamide LCMS (Method 1): Rt = 0.93 min; MS (ESIpos): m / z = 531 [M + H] ⁺ -NMR (400 MHz, DMSO-bb) δ [ppm]: -0.008 (1.57), 0.008 (1.50), 1.434 (16.00), 2.073 ( 0.74), 2.328 (0.48), 2.670 (0.52), 3.910 (0.55), 5.192 (1.49), 6.277 (0.88), 6.420 (1.62), 6.562 (0.73), 7.554 (1.10), 7.577 (1.94), 7.597 ( 1.10), 7.987 (2.44), 8.019 (2.41), 8.750 (4.28), 10.232 (3.14). 1,1-difluoro-2-methylpropane-2-amine hydrochloride (57% theoretical, 100% pure) 23 7 - [(3R, 4R) -3,4-dihydroxypyrrolidin-1-yl] -6-fluoro-4-oxo-M- (1,1,1-trifluoro-2 methylpropan-2-yl) -1 - ( 2,4,6-trifluorophenyl) -1,4-dihydro-1,8-naphthyr idin-3 carboxamide LCMS (Method 3): Rt = 1.77 min; MS (ESIpos): m / z = 549 [M + H] ⁺ -NMR (400 MHz, DMSO-bb) δ [ppm]: -0.008 (0.89), 0.008 (0.56), 1.633 (16.00), 2.520 ( 0.82), 2.524 (0.74), 3.908 (0.50), 5.194 (1.18), 7.557 (0.97), 7.579 (1.58), 7.600 (0.89), 8.008 (2.21), 8.040 (2.14), 8.775 (3.54), 10.561 ( 2.95). 1,1,1-trifluoro-2-methylpropane-2-amine hydrochloride (63% theoretical, 100% purity) 24 7 - [(3R, 4R) -3,4-dihydroxypyrrolidin-1-yl] - M- (2,4-dimethylpentan-3-yl) -6fluoro-4-oxo-1 - (2,4,6-trifluorophenyl ) -1,4-dihydro-1,8-naphthyr idin-3 carboxamide LCMS (Method 3): Rt = 1.87 min; MS (ESIpos): m / z = 537 [M + H] ⁺ -NMR (400 MHz, DMSO-bb) δ [ppm]: -0.008 (0.92), 0.008 (0.71), 0.865 (13.39), 0.877 ( 15.46), 0.881 (16.00), 0.893 (13.11), 1.810 (0.43), 1.827 (1.26), 1.844 (2.06), 1.860 (2.00), 1.877 (1.16), 2.524 (0.55), 3.640 (0.71), 3.656 ( 1.27), 3.666 (0.90), 3.672 (0.89), 3.681 (1.31), 3.697 (0.75), 3.911 (0.57), 5.198 (1.63), 7.550 (1.24), 7.572 (2.16), 7.592 (1.23), 8.013 ( 3.06), 8.045 (2.98), 8.727 (5.38), 9.761 (1.66), 9.786 (1.59). 2,4-dimethylpentane-3-amine (57% theoretical, 100% purity)

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25 X- (2-cyclopropylpropan-2-yl) -7 - [(ZK, 4K) -3,4-dihydroxypyrrolidin-1-yl] -6fluoro-4-oxo-1 - (2,4,6-trifluorophenyl) - 1,4-dihydro-1,8-naftir Idin 3-carboxamide LCMS (method 3): R _t = 1.79 min; MS (ESIpos): m / z = 521 [M + H] ⁺ -NMR (400 MHz, DMSO-c16) δ [ppm]: 0.397 (5.62), 0.414 (4.00), 1.290 (0.69), 1.311 (16.00 ), 1.325 (0.79), 5.187 (1.10), 7.550 (0.76), 7.572 (1.33), 7.593 (0.73), 7.993 (1.77), 8.024 (1.73), 8.680 (3.16), 9.863 (2.07). 2-cyclopropylpropan-2-amine (95% theoretical, 100% pure) 26 7 - [(3E, 4E) -3,4-dihydroxypyrrolidin-1-yl] -6-fluoro-4-oxo-M - [(2) -1 (trifluoromethoxy) butan-2-yl] -1- (2 , 4,6-trifluorophenyl) -1,4-dihydro-1,8 naphthyr idin-3-carboxamide (mixture of diastereoisomers) LCMS (Method 3): R _t = 1.78 min; MS (ESIpos): m / z = 579 [M + H] ⁺ -NMR (400 MHz, DMSO-c16) δ [ppm]: -0.008 (2.02), 0.008 (1.73), 0.922 (6.79), 0.941 ( 16.00), 0.959 (7.44), 1.550 (0.56), 1.568 (0.97), 1.585 (1.26), 1.603 (1.40), 1.622 (0.89), 1.633 (0.55), 1.651 (1.04), 1.663 (1.19), 1.669 ( 1.15), 1.682 (1.27), 1.698 (0.74), 1.716 (0.46), 2.074 (1.63), 2.328 (0.45), 2.524 (1.32), 2.671 (0.43), 3.069 (0.51), 3.685 (0.52), 3.911 ( 1.21), 4.148 (2.09), 4.162 (2.31), 4.176 (3.98), 4.183 (4.11), 4.194 (4.10), 4.211 (2.53), 5.193 (3.51), 7.552 (2.57), 7.574 (4.50), 7.595 ( 2.53), 7.995 (6.24), 8.026 (6.06), 8.762 (10.71), 9.985 (2.62), 10.005 (2.44). 1 - (trifluoromethoxy) butane-2-amine hydrochloride (racemate) (54% theoretical, 100% pure) 27 7 - [(3E, 4E) -3,4-dihydroxypyrrolidin-1-yl] -6-fluoro-4-oxo-M - [(3) -1,1,1,2,2pentafluoropentan-3-yl] - 1 - (2,4,6-trifluorophenyl) -1,4-dihydro-1,8-naphthyr idin-3 carboxamide (mixture of diastereoisomers) LCMS (Method 3): _Rt = 1.93 min; MS (ESIpos): m / z = 599 [M + H] ⁺ -NMR (400 MHz, DMSO-c16) δ [ppm]: 0.944 (7.18), 0.962 (16.00), 0.981 (7.74), 1.619 (0.90 ), 1.638 (1.31), 1.654 (1.50), 1.663 (1.39), 1.673 (1.34), 1.681 (1.41), 1.699 (1.00), 1.922 (1.31), 2.329 (0.58), 2.672 (0.66), 3.079 (0.81 ), 3.693 (0.86), 3.905 (1.75), 4.012 (1.22), 4.852 (1.12), 4.879 (1.06), 5.208 (3.80), 7.557 (3.27), 7.579 (5.89), 7.599 (3.25), 8.005 (7.21 ), 8.037 (7.04), 8.850 (14.56), 10.377 (4.69), 10.402 (4.39). 1,1,1,2,2-pentafluoropentane-3-amine hydrochloride (racemate) (85% theoretical, 99% pure)

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28 7- [(3R, 4R) -3,4-dihydroxypyrrolidin-1-yl] -6-φτορ-Ν- (2-methyl pentan-3-yl) -4oxo-1 - (2,4,6-trifluorophenyl) -1,4-dihydro-1,8-naphthyridine-3-carboxamide (mixture of diastereoisomers) LCMS (Method 3): _Rt = 1.80 min; MS (ESIpos): m / z = 523 [M + H] ⁺ -NMR (400 MHz, DMSO-bb) δ [ppm]: 0.008 (1.53), 0.851 (4.76), 0.869 (11.65), 0.878 (11.15 ), 0.888 (7.46), 0.896 (16.00), 0.915 (10.32), 1.380 (0.55), 1.397 (0.79), 1.414 (1.00), 1.436 (1.06), 1.454 (0.71), 1.538 (0.78), 1.550 (0.92 ), 1.568 (1.02), 1.584 (0.72), 1.602 (0.49), 1.794 (0.89), 1.810 (1.24), 1.824 (1.23), 1.840 (0.80), 2.328 (0.45), 3.680 (0.42), 3.764 (0.53 ), 3.777 (0.93), 3.788 (1.29), 3.799 (1.63), 3.811 (1.29), 3.822 (0.87), 3.834 (0.59), 3.907 (0.94), 5.199 (2.67), 7.551 (2.01), 7.573 (3.53 ), 7.594 (1.96), 7.999 (4.29), 8.031 (4.21), 8.716 (8.19), 9.768 (2.51), 9.792 (2.39). 2-methylpentane-3-amine hydrochloride (racemate) (31% theoretical, 100% pure)

Example 29.

- [(3R, 4R) -3,4-Dihydroxypyrrolidin-1-yl] -6-fluoro-X- (2-methylpentan-3-yl) -4-oxo-1 - (2,4,6trifluorophenyl) -1 , 4-dihydro-1,8-naphthyridine-3-carboxamide (diastereoisomer 1).

mg 7 - [(3R, 4R) -3,4-dihydroxypyrrolidin-1-yl] -6-fluoro-X- (2-methylpentan-3-yl) -4-oxo-1 - (2,4,6trifluorophenyl) -1,4-dihydro-1,8-naphthyridine-3-carboxamide (mixture of diastereoisomers) was separated into diastereoisomers by preparative HPLC (preparative HPLC: Daicel® Chiralpak OX-H column, 5 μm, 250x20 mm; solvent: 80% n- heptane / 20% isopropanol; flow 15 ml / min; temperature: 35 ° C, indication: 265 nm).

Diastereoisomer 1: 13 mg (> 99% de).

Rt = 6.27 min [analytical HPLC: Daicel® Chiralpak OX-H column, 1 ml / min; 5 microns, 250x4.6 mm; solvent: 75% isohexane / 25% isopropanol + 0.2% DEA; detection: 265 nm].

LCMS (Method 3): Rt = 1.80 min; MS (ESIpos): m / z = 523 [M + H] ⁺ .

Example 30.

- [(3R, 4R) -3,4-Dihydroxypyrrolidin-1-yl] -6-fluoro-X- (2-methylpentan-3-yl) -4-oxo-1 - (2,4,6trifluorophenyl) -1 , 4-dihydro-1,8-naphthyridine-3-carboxamide (diastereoisomer 2).

mg 7 - [(3R, 4R) -3,4-dihydroxypyrrolidin-1-yl] -6-fluoro-X- (2-methylpentan-3-yl) -4-oxo-1 - (2,4,6trifluorophenyl) -1,4-dihydro-1,8-naphthyridine-3-carboxamide (mixture of diastereoisomers) was separated into diastereoisomers by preparative HPLC (preparative HPLC: Daicel® Chiralpak OX-H column, 5 μm, 250x20 mm; solvent: 80% n- heptane / 20% isopropanol; flow 15 ml / min; temperature: 35 ° C, indication: 265 nm).

Diastereoisomer 2: 13 mg (> 99% de).

Rt = 7.35 min [analytical HPLC: Daicel® Chiralpak OX-H column, 1 ml / min; 5 microns, 250x4.6 mm; solvent: 75% isohexane / 25% isopropanol + 0.2% DEA; detection: 265 nm].

LCMS (Method 3): Rt = 1.80 min; MS (ESIpos): m / z = 523 [M + H] ⁺ .

Example 31.

- [(3R, 4R) -3,4-Dihydroxypyrrolidin-1-yl] -6-fluoro-4-oxo-X - [(2) -1 - (trifluoromethoxy) butan-2-yl] 1 - (2, 4,6-trifluorophenyl) -1,4-dihydro-1,8-naphthyridine-3-carboxamide (diastereoisomer 1).

218 mg 7 - [(3R, 4R) -3,4-dihydroxypyrrolidin-1-yl] -6-fluoro-4-oxo-N - [(2) -1- (trifluoromethoxy) butan2-yl] -1- ( 2,4,6-trifluorophenyl) -1,4-dihydro-1,8-naphthyridine-3-carboxamide (mixture of diastereoisomers) was separated into diastereoisomers by preparative HPLC (preparative HPLC: Daicel® Chiralpak ID column, 5 μm, 250x20 mm; solvent: 85% n-heptane / 15% isopropanol; flow 15 ml / min; temperature: 30 ° C, indication: 220 nm).

Diastereoisomer 1: 63.7 mg (99% de).

Rt = 5.50 min [analytical HPLC: Daicel® Chiralpak ID column, 1 ml / min; 5 microns, 250x4.6 mm; solvent: 80% isohexane / 20% propanool; detection: 220 nm].

LCMS (Method 3): Rt = 1.78 min; MS (ESIpos): m / z = 579 [M + H] ⁺ .

Example 32.

- [(3R, 4R) -3,4-Dihydroxypyrrolidin-1-yl] -6-fluoro-4-oxo-X - [(2) -1 - (trifluoromethoxy) butan-2-yl] 1- (2, 4,6-trifluorophenyl) -1,4-dihydro-1,8-naphthyridine-3-carboxamide (diastereoisomer 2).

218 mg 7 - [(3R, 4R) -3,4-dihydroxypyrrolidin-1-yl] -6-fluoro-4-oxo-N - [(2) -1- (trifluoromethoxy) butan2-yl] -1- ( 2,4,6-trifluorophenyl) -1,4-dihydro-1,8-naphthyridine-3-carboxamide (mixture of diastereoisomers) was separated into diastereoisomers by preparative HPLC (preparative HPLC: column

- 73 038451

Daicel® Chiralpak ID, 5 μm, 250x20 mm; solvent: 85% n-heptane / 15% isopropanol; flow ml / min; temperature: 30 ° C, indication: 220 nm).

Diastereoisomer 2: 64.2 mg (97.6% de).

Rt = 6.23 min [analytical HPLC: Daicel® Chiralpak ID column, 1 ml / min; 5 microns, 250x4.6 mm; solvent: 80% isohexane / 20% propanool; detection: 220 nm].

LCMS (Method 3): Rt = 1.78 min; MS (ESIpos): m / z = 579 [M + H] +.

Example 33.

7 - [(3R, 4R) -3,4-Dihydroxypyrrolidin-1-yl] -6-fluoro-4-oxo-N - [(3) -1,1,1,2,2-pentafluoropentan-3-yl ] 1- (2,4,6-trifluorophenyl) -1,4-dihydro-1,8-naphthyridine-3-carboxamide (diastereoisomer 1).

292 mg 7 - [(3R, 4R) -3,4-dihydroxypyrrolidin-1-yl] -6-fluoro-4-oxo-N - [(3) -1,1,1,2,2-pentafluoropentane-3 -yl] -1- (2,4,6-trifluorophenyl) -1,4-dihydro-1,8-naphthyridine-3-carboxamide (mixture of diastereoisomers) was separated into diastereoisomers by preparative HPLC (preparative HPLC: Daicel® Chiralpak IA column , 5 μm, 250x20 mm; solvent: 85% n-heptane / 15% isopropanol; flow 15 ml / min; temperature: 30 ° C, indication: 220 nm).

Diastereoisomer 1: 111.6 mg (> 99% de).

Rt = 6.10 min [analytical HPLC: Daicel® Chiralpak IA column, 1 ml / min; 5 microns, 250x4.6 mm; solvent: 80% isohexane / 20% isopropanol; detection: 265 nm].

LCMS (Method 3): Rt = 1.93 min; MS (ESIpos): m / z = 599 [M + H] ⁺ .

Example 34.

7 - [(3R, 4R) -3,4-Dihydroxypyrrolidin-1-yl] -6-fluoro-4-oxo-N - [(3) -1,1,1,2,2-pentafluoropentan-3-yl ] 1- (2,4,6-trifluorophenyl) -1,4-dihydro-1,8-naphthyridine-3-carboxamide (diastereoisomer 2).

292 mg 7 - [(3R, 4R) -3,4-dihydroxypyrrolidin-1-yl] -6-fluoro-4-oxo-N - [(3) -1,1,1,2,2-pentafluoropentane-3 -yl] -1- (2,4,6-trifluorophenyl) -1,4-dihydro-1,8-naphthyridine-3-carboxamide (mixture of diastereoisomers) was separated into diastereoisomers by preparative HPLC (preparative HPLC: Daicel® Chiralpak IA column , 5 μm, 250x20 mm; solvent: 85% n-heptane / 15% isopropanol; flow 15 ml / min; temperature: 30 ° C, indication: 220 nm).

Diastereoisomer 2: 110.1 mg (99.5% de).

Rt = 6.76 min [analytical HPLC: Daicel® Chiralpak IA column, 1 ml / min; 5 microns, 250x4.6 mm; solvent: 80% isohexane / 20% isopropanol; detection: 265 nm].

LCMS (Method 3): Rt = 1.93 min; MS (ESIpos): m / z = 599 [M + H] ⁺ .

Example 35.

(3R, 4R) -1- [3-Fluoro-5-oxo-6 - {[(2S) -1,1,1-trifluorobutan-2-yl] carbamoyl} -8- (2,4,6-mfluorophenyl ) 5,8-dihydro-1,8-naphthyridin-2-yl] -4-hydroxypyrrolidin-3-yl-acetate.

(7 - [(3R, 4R) -3,4-Dihydroxypyrrolidin-1-yl] -6-fluoro-4-oxo-N - [(2S) -1,1,1-trifluorobutan-2-yl] -1 (2,4,6-trifluorophenyl) -1,4-dihydro-1,8-naphthyridine-3-carboxylic acid amide (60.0 mg, 109 μmol) was dissolved in dichloromethane (1.0 ml) and mixed with dimethylaminopyridine (1.34 mg, 10.9 Acetyl chloride (5.4 μL, 77 μmol) was added dropwise at 0 ° C and stirred for 3 h at room temperature.The reaction mixture was thickened and the residue was taken up in acetonitrile and purified by preparative HPLC (acetonitrile-water with formic acid, C18 RP-HPLC) Product fractions were combined, concentrated and lyophilized overnight from acetonitrile / water to give 25.9 mg (39% theory, 99% purity) of the title compound.

LCMS (Method 3): Rt = 2.07 min; MS (ESIpos): m / z = 591 [M + H] ⁺ .

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: -0.149 (0.90), -0.008 (7.72), 0.008 (6.90), 0.146 (0.88), 0.952 (2.34), 0.971 (5.26), 0.989 (2.57), 1.625 (0.47), 1.642 (0.53), 1.651 (0.53), 1.661 (0.51), 1.668 (0.53), 1.685 (0.41), 1.852 (0.41), 1.871 (0.49), 1.881 (0.58), 1.897 (0.45), 1.990 (16.00), 2.328 (0.68), 2.523 (1.81), 2.670 (0.68), 2.710 (0.41), 4.139 (0.45), 4.738 (0.51), 4.951 (0.41), 5.607 (0.94), 7.555 (1.38), 7.577 (2.51), 7.599 (1.40), 8.036 (2.20), 8.067 (2.20), 8.858 (5.18), 10.300 (1.75), 10.324 (1.68).

- 74 038451

The following reactions were obtained similarly to Example 1 according to AAV1:

Example Name according to IUPAC nomenclature Build LCMS (Method): retention time; detectable mass Y-NMR used amine (yield, purity) 36 7 - [(3K, 4K) -3,4-dihydroxypyrrolidin-1-yl] -6-fluoro-4-oxo-M - [(2K) 1,1,1-trifluorobutan-2-yl] -1 - ( 2,4,6-trifluorophenyl) -1,4-dihydro-1,8naftir Idin-3-carboxamide LCMS (method 3): R _t = 1.78 min; MS (ESIpos): m / z = 549 [M + H] ⁺ -NMR (400 MHz, DMSO-db) δ [ppm]: -0.149 (0.60), -0.008 (5.32), 0.008 (4.91), 0.147 (0.57), 0.950 (7.28), 0.969 (16.00), 0.987 (7.85), 1.604 (1.06), 1.622 (1.40), 1.629 (1.28), 1.639 (1.74), 1.647 (1.55), 1.657 (1.47), 1.664 (1.70), 1.682 (1.28), 1.851 (1.32), 1.860 (1.51), 1.868 (1.47), 1.879 (1.74), 1.885 (1.51), 1.895 (1.32), 1.904 (1.13), 1.914 (0.98), 2.328 (1.36), 2.366 (0.94), 2.524 (4.68), 2.670 (1.43), 2.710 (0.98), 3.067 (0.79), 3.691 (0.87), 3.906 (1.81), 4.012 (1.25), 4.735 (1.43), 4.754 (1.36), 5.200 (4.83), 7.558 (3.89), 7.580 (6.87), 7.601 (3.89), 7.999 (7.58), 8.030 (7.51), 8.840 (13.17), 10.329 (5.21), 10.353 (5.02). (2R) -1,1,1-trifluorobutane-2-amine hydrochloride (69% theoretical, 99% pure) 37 6-chlorop-N - [(lS) -l-cyclopropyl-2,2,2-triφtopethyl] -7 - [(3R, 4R) -3,4-dihydroxypyrrolidin-1-yl] -4-oxo-1 - (2 , 4,6-trifluorophenyl) -1,4digidro- naftir Idin 1,8-3-carboxamide LCMS (method 3): R _t = 1.89 min; MS (ESIpos): m / z = 577.11 [M + H] ⁺ -NMR (400 MHz, DMSO-db) δ [ppm]: -0.008 (1.73), 0.008 (1.41), 0.320 (1.55), 0.330 ( 2.59), 0.342 (2.48), 0.353 (1.79), 0.365 (1.00), 0.522 (1.67), 0.534 (2.52), 0.547 (2.55), 0.553 (2.84), 0.571 (2.95), 0.580 (2.20), 0.591

- 75 038451

(1.98), 0.601 (1.63), 0.615 (0.97), 0.630 (1.27), 0.639 (1.31), 0.650 (2.61), 0.660 (2.01), 0.667 (1.80), 0.685 (0.98), 0.693 (0.58), 1.170 (0.48), 1.182 (1.01), 1.190 (1.45), 1.203 (2.41), 1.212 (1.79), 1.223 (2.40), 1.235 (1.31), 1.244 (0.87), 2.329 (0.60), 2.367 (0.41), 2.524 (2.02), 2.671 (0.70), 2.711 (0.47), 3.683 (0.57), 3.930 (5.71), 4.342 (1.32), 4.363 (2.25), 4.384 (2.19), 4.405 (1.19), 5.188 (9.80), 5.196 (9.81), 7.564 (3.82), 7.585 (6.78), 7.607 (3.80), 8.284 (16.00), 8.856 (13.94), 10.356 (5.25), 10.379 (5.07). (1S) -1 -cyclopropyl-2,2,2-trifluoroethanamine hydrochloride (81% theoretical, 99% pure) 38 6-chloro-7 - [(3E, 4E) -3,4-dihydroxypyrrolidin-1-yl] -4-oxo-M - [(28) 1,1,1-trifluorobutan-2-yl] -1 - ( 2,4,6-trifluorophenyl) -1,4-dihydro-1,8naftir Idin-3-carboxamide LCMS (method 3): R _t = 1.86 min; MS (ESIpos): m / z = 565 [M + H] ⁺ -NMR (400 MHz, DMSO-bb) δ [ppm]: -0.008 (1.70), 0.008 (1.59), 0.951 (7.25), 0.970 ( 16.00), 0.988 (7.86), 1.609 (1.08), 1.626 (1.45), 1.633 (1.27), 1.644 (1.73), 1.652 (1.56), 1.662 (1.48), 1.669 (1.66), 1.687 (1.24), 1.832 ( 0.43), 1.850 (1.31), 1.860 (1.52), 1.869 (1.52), 1.879 (1.75), 1.885 (1.54), 1.895 (1.33), 1.904 (1.13), 1.913 (0.96), 2.328 (0.61), 2.367 ( 0.50), 2.524 (1.95), 2.671 (0.63), 2.711 (0.53), 3.671 (0.56), 3.930 (5.75), 4.735 (1.45), 4.750 (1.34), 5.185 (13.17), 5.192 (13.00), 7.566 ( 4.26), 7.588 (7.94), 7.610 (4.20), 8.279 (13.40), 8.865 (12.98), 10.212 (5.29), 10.236 (4.98). (2S) -1,1,1-trifluorobutane-2-amine hydrochloride (72% theoretical, 99% pure) 39 1 - (3,5-difluoropyridin-2-yl) -7 - [(3K, 4K) -3,4-dihydroxypyrrolidin-1 yl] -6-fluoro-4-oxo-M - [(2) -3, 3,4,4,4-pentafluorobutan-2-yl] -1,4-dihydro1,8-naphthyridine-3-carboxamide (mixture of diastereoisomers) LCMS (Method 3): _Rt = 1.71 min; MS (ESIpos): m / z = 568 [M + H] ⁺ -NMR (400 MHz, DMSO-bb) δ [ppm]: -0.149 (0.43), -0.008 (4.17), 0.008 (3.72), 0.146 (0.45), 1.389 (16.00), 1.405 (15.88), 2.328 (0.93), 2.367 (0.71), 2.524 (2.99), 2.670 (0.91), 2.711 (0.68), 3.067 (0.88), 3.691 (1.06), 3.918 (3.12), 4.976 (1.14), 4.997 (1.93), 5.018 (2.30), 5.041 (2.36), 5.063 (2.17), 5.084 (1.55), 5.102 (1.09), 5.200 (5.07), 7.997 (7.54), 8.028 (7.69), 8.329

- 76 038451

(2.76), 8.351 (5.01), 8.373 (2.71), 8.616 (11.67), 8.622 (10.91), 8.837 (7.39), 8.844 (8.07), 10.451 (7.34), 10.475 (7.07). 3,3,4,4,4-pentafluorobutane-2-amine hydrochloride (racemate) (78% theoretical, 99% pure) 40 1 - (2-chloro-4,6-difluorophenyl) -7 - [(3K, 4K) -3,4-dihydroxypyrrolidin-1 yl] -6-fluoro-4-oxo-M - [(28) -1, -triftorbutan 1,1-2-yl] -1,4-dihydro-1,8naftiridin-3-carboxamide (mixture of atropisomers) LCMS (method 3): R _t = 1.83 min; MS (ESIpos): m / z = 565 [M + H] ⁺ -NMR (400 MHz, DMSO-c16) δ [ppm]: 0.008 (1.02), 0.949 (4.31), 0.958 (5.08), 0.967 (9.96 ), 0.977 (9.85), 0.985 (5.50), 0.995 (4.62), 1.603 (0.66), 1.614 (0.80), 1.621 (1.07), 1.638 (1.64), 1.648 (1.55), 1.657 (1.71), 1.664 (1.33 ), 1.674 (1.24), 1.681 (0.93), 1.692 (0.76), 1.852 (1.27), 1.862 (1.49), 1.870 (1.55), 1.880 (1.71), 1.898 (1.31), 1.905 (1.13), 1.915 (0.91 ), 2.328 (0.73), 2.366 (0.58), 2.524 (2.35), 2.670 (0.78), 2.710 (0.62), 3.018 (0.87), 3.220 (0.93), 3.693 (0.95), 3.891 (1.82), 4.013 (1.37 ), 4.734 (1.57), 4.750 (1.47), 5.202 (4.19), 7.686 (0.84), 7.693 (1.27), 7.709 (1.69), 7.717 (2.44), 7.728 (3.11), 7.732 (3.15), 7.740 (3.53 ), 7.751 (3.53), 7.763 (2.35), 8.004 (7.55), 8.035 (7.54), 8.794 (16.00), 10.347 (3.64), 10.351 (3.73), 10.371 (3.57), 10.375 (3.55). (2S) -1,1,1-trifluorobutane-2-amine hydrochloride (83% theoretical, 100% pure) 41 1 - (2-chloro-4,6-difluorophenyl) -7 - [(3E, 4E) -3,4-dihydroxypyrrolidin-1 yl] -6-fluoro-4-oxo-M- (1,1,1 - trifluoro-2-methylpropan-2-yl) -1,4-digidro1,8-naphthyridine-3-carboxamide (mixture of atropisomers) LCMS (method 3): R _t = 1.85 min; MS (ESIpos): m / z = 565 [M + H] ⁺ -NMR (400 MHz, DMSO-C16) δ [ppm]: -0.008 (1.27), 0.008 (0.95), 1.634 (16.00), 2.524 ( 0.91), 3.894 (0.45), 5.193 (1.23), 7.709 (0.41), 7.717 (0.65), 7.726 (0.67), 7.732 (0.70), 7.739 (0.91), 7.749 (0.72), 7.764 (0.59), 8.012 ( 1.99), 8.044 (1.97), 8.723 (3.93), 10.582 (2.93). 1,1,1-trifluoro-2-methylpropan-2-amine (96% theoretical, 99% purity) 42 1- (2-chloro-4,6-difluorophenyl) -X - [(18) -1-cyclopropyl-2,2,2- trifluoroethyl] -7 - [(3E, 4E) -3,4-dihydroxypyrrolidin-1-yl] -6-fluoro-4-

- 77 038451

oxo-1,4-dihydro-1,8-naphthyr idin-3-carboxamide (mixture of atropisomers) LCMS (Method 3) R _t = 1.86 min; MS (ESIpos): m / z = 577 [M + H] ⁺ -NMR (400 MHz, DMSO-bb) δ [ppm]: -0.149 (0.75), -0.008 (7.24), 0.008 (5.85), 0.146 (0.80), 0.317 (1.19), 0.328 (2.21), 0.340 (2.61), 0.351 (2.36), 0.363 (1.54), 0.374 (0.62), 0.526 (2.24), 0.543 (2.26), 0.555 (2.21), 0.565 (2.36), 0.575 (2.54), 0.586 (2.24), 0.596 (1.92), 0.610 (1.29), 0.624 (1.02), 0.634 (1.34), 0.644 (1.92), 0.655 (2.24), 0.668 (1.99), 0.677 (1.49), 1.167 (0.47), 1.179 (1.00), 1.187 (1.42), 1.199 (2.44), 1.209 (1.87), 1.220 (2.44), 1.232 (1.34), 1.241 (0.85), 1.253 (0.42), 2.327 (1.12), 2.366 (0.77), 2.523 (3.66), 2.665 (0.95), 2.670 (1.24), 2.710 (0.82), 3.015 (0.85), 3.221 (0.90), 3.687 (0.95), 3.894 (1.79), 4.013 (1.37), 4.340 (0.80), 4.359 (1.64), 4.378 (2.12), 4.399 (1.64), 4.418 (0.75), 5.199 (4.33), 7.684 (0.85), 7.691 (1.39), 7.701 (1.37), 7.707 (1.59), 7.715 (2.76), 7.724 (2.84), 7.730 (2.86), 7.737 (3.66), 7.747 (3.09), 7.761 (2.36), 8.008 (7.12), 8.039 (7.07), 8.785 (16.00), 10.486 (4.95), 10.510 (4.70). (1S) -1-cyclopropyl-2,2,2-trifluoroethanamine hydrochlor op id (81% theoretical, 99% pure) 43 1- (2-chloro-4,6-difluorophenyl) -X - [(18) -1-cyclopropylethyl] -7 - [(3E, 4E) 3,4-dihydroxypyrrolidin-1-yl] -6-fluoro-4 -oxo-1,4-dihydro-1,8naphthyridine-3-carboxamide (mixture of atropisomers) LCMS (Method 3): R _t = 1.67 min; MS (ESIpos): m / z = 523 [M + H] ⁺ -NMR (400 MHz, DMSO-bb) δ [ppm]: -0.008 (6.44), 0.008 (2.37), 0.217 (1.40), 0.228 ( 2.02), 0.240 (2.94), 0.251 (2.63), 0.264 (1.75), 0.277 (2.10), 0.285 (2.72), 0.292 (2.28), 0.305 (1.58), 0.401 (0.92), 0.412 (1.75), 0.422 ( 2.76), 0.433 (3.20), 0.443 (3.59), 0.453 (3.51), 0.459 (2.85), 0.467 (3.11), 0.479 (1.88), 0.487 (1.23), 0.959 (1.27), 0.964 (1.45), 0.971 ( 2.02), 0.977 (2.10), 0.984 (1.93), 0.991 (1.93), 0.996 (1.71), 1.004 (1.14), 1.213 (12.01), 1.220 (11.79), 1.230 (11.88), 1.236 (10.48), 2.328 ( 1.01), 2.366 (0.75), 2.519 (5.57), 2.670 (1.01), 2.710 (0.70), 3.008 (0.70), 3.488 (1.14), 3.507 (2.24), 3.524 (2.98), 3.540 (2.10), 3.560 ( 1.05), 3.669 (0.75), 3.894 (1.75), 5.186 (5.92), 7.676 (1.01), 7.682 (1.40), 7.693 (1.71), 7.698 (1.84), 7.706 (2.54), 7.717 (3.07), 7.722 ( 3.07), 7.729 (3.42), 7.739

- 78 038451

(2.98), 7.751 (2.15), 7.980 (7.80), 8.011 (7.63), 8.653 (16.00), 9.881 (3.29), 9.887 (3.20), 9.902 (3.16), 9.906 (2.94). (S) -1 -cyclopropylethanamine (84% theoretical, 99% pure) 44 l- (2-chlorop-4,6-diftopphenyl) -N - [(lR) -l-cyclopropylethyl] -7 - [(3R, 4R) 3,4-dihydroxypyrrolidin-1-yl] -6-fluoro-4 -oxo-1,4-dihydro-1,8naphthyridine-3-carboxamide (mixture of atropisomers) LCMS (Method 3): R _t = 1.67 min; MS (ESIpos): m / z = 523 [M + H] ⁺ -NMR (400 MHz, DMSO-c1b) δ [ppm]: -0.008 (1.78), 0.008 (1.48), 0.218 (1.23), 0.229 ( 2.01), 0.240 (2.94), 0.252 (2.71), 0.265 (1.58), 0.279 (2.08), 0.286 (2.81), 0.294 (2.36), 0.307 (1.73), 0.328 (0.45), 0.392 (0.43), 0.402 ( 0.78), 0.413 (1.63), 0.423 (2.69), 0.434 (3.19), 0.445 (3.77), 0.454 (3.59), 0.459 (2.86), 0.467 (3.19), 0.480 (2.03), 0.487 (1.31), 0.501 ( 0.65), 0.959 (1.18), 0.964 (1.36), 0.972 (1.93), 0.977 (2.11), 0.984 (1.88), 0.992 (2.01), 0.997 (1.81), 1.004 (1.23), 1.010 (1.05), 1.213 ( 11.53), 1.220 (12.21), 1.229 (12.16), 1.236 (11.68), 2.328 (0.53), 2.367 (0.48), 2.524 (1.93), 2.671 (0.60), 2.711 (0.50), 3.006 (0.70), 3.227 ( 0.78), 3.486 (1.16), 3.505 (2.36), 3.522 (3.27), 3.539 (2.36), 3.558 (1.18), 3.575 (0.40), 3.677 (0.78), 3.898 (1.76), 5.188 (5.70), 7.676 ( 0.85), 7.684 (1.66), 7.692 (1.36), 7.700 (1.63), 7.707 (3.09), 7.715 (2.56), 7.730 (3.99), 7.738 (2.84), 7.749 (2.66), 7.754 (2.44), 7.979 ( 8.26), 8.011 (8.16), 8.653 (16.00), 9.88 6 (3.74), 9.904 (3.77). (R) -1 -cyclopropylethanamine (91% theoretical, 99% pure)

Example 45.

1- (3,5-Difluoropyridin-2-yl) -7 - [(3R, 4R) -3,4-dihydroxypyrrolidin-1-yl] -6-fluoro-4-oxo-N - [(2) 3, 3,4,4,4-pentafluorobutan-2-yl] -1,4-dihydro-1,8-naphthyridine-3-carboxamide (diastereoisomer 1).

486 mg 1- (3,5-difluoropyrigin-2-yl) -7 - [(3R, 4R) -3,4-dihydroxypyrroligin-1-yl] -6-fluoro-4-oxo-N [(2) - 3,3,4,4,4-pentafluorobutan-2-yl] -1,4-dihydro-1,8-naphthyridine-3-carboxamide (mixture of diastereoisomers) was separated by chiral HPLC into diastereoisomers (preparative HPLC: Daicel® column Chiralpak IE, 5 μm, 250x20 mm; solvent: 70% n-heptane / 30% isopropanol + 0.2% diethylamine; flow 15 ml / min; temperature: 25 ° C, indication: 270 nm).

Diastereoisomer 1: 172.5 mg (> 99% de).

Rt = 4.82 min [analytical HPLC: Daicel® Chiralpak IE column, 1 ml / min; 3 μm, 50x4.6 mm; solvent: 80% isohexane / 20% isopropanol + 0.2% diethylamine; detection: 220 nm].

Example 46.

1- (3,5-Difluoropyrigin-2-yl) -7 - [(3R, 4R) -3,4-dihydroxypyrroligin-1-yl] -6-fluoro-4-oxo-N - [(2) 3, 3,4,4,4-pentafluorobutan-2-yl] -1,4-dihydro-1,8-naphthyridine-3-carboxamide (diastereoisomer 2).

486 mg 1- (3,5-difluoropyrigin-2-yl) -7 - [(3R, 4R) -3,4-dihydroxypyrroligin-1-yl] -6-fluoro-4-oxo-N [(2) - 3,3,4,4,4-pentafluorobutan-2-yl] -1,4-dihydro-1,8-naphthyridine-3-carboxamide (mixture of diastereoisomers) was separated by chiral HPLC into diastereoisomers (preparative HPLC: Daicel® column Chiralpak IE, 5 μm, 250x20 mm; solvent: 70% n-heptane / 30% isopropanol + diethylamine; flow 15 ml / min; temperature: 25 ° C, indication: 270 nm).

Diastereoisomer 2: 160.3 mg (> 99% de).

Rt = 7.11 min [analytical HPLC: Daicel® Chiralpak IE column, 1 ml / min; 3 μm, 50x4.6 mm; solvent: 80% isohexane / 20% isopropanol + 0.2% diethylamine; detection: 220 nm].

Example 47.

1- (2-Chloro-4,6-difluorophenyl) -7 - [(3R, 4R) -3,4-dihydroxypyrroligin-1-yl] -6-fluoro-4-oxo-N - [(2S) 1, 1,1-trifluorobutan-2-yl] -1,4-dihydro-1,8-naphthyridine-3-carboxamide (atropoisomer 1).

103 mg 1- (2-chloro-4,6-difluorophenyl) -7 - [(3R, 4R) -3,4-dihydroxypyrrolidin-1-yl] -6-fluoro-4-oxo-N [(2S) - 1,1,1-trifluorobutan-2-yl] -1,4-dihydro-1,8-naphthyridine-3-carboxamide (mixture of atropisomers) was separated by chiral HPLC into atropisomers (preparative HPLC: Daicel® Chiralpak IG, 5 μm, 250x20 mm; solvent: 75% n-heptane / 25% isopropanol + 0.2% diethylamine; according to 79 038451 current 15 ml / min; temperature: 30 ° C, indication: 265 nm).

Atropoisomer 1: 38 mg (> 99% de).

Rt = 4.71 min [analytical HPLC: Daicel® Chiralpak IG column, 1 ml / min; 5 microns, 250x4.6 mm;

solvent: 70% isohexane / 30% isopropanol + 0.2% diethylamine; detection: 265 nm].

Example 48.

1- (2-Chloro-4,6-difluorophenyl) -7 - [(3R, 4R) -3,4-dihydroxypyrrolidin-1-yl] -6-fluoro-4-oxo-N - [(2S) 1, 1,1-trifluorobutan-2-yl] -1,4-dihydro-1,8-naphthyridine-3-carboxamide (atropoisomer 2).

103 mg 1- (2-chloro-4,6-difluorophenyl) -7 - [(3R, 4R) -3,4-dihydroxypyrrolidin-1-yl] -6-fluoro-4-oxo-N [(2S) - 1,1,1-trifluorobutan-2-yl] -1,4-dihydro-1,8-naphthyridine-3-carboxamide (mixture of atropisomers) was separated by chiral HPLC into atropisomers (preparative HPLC: Daicel® Chiralpak IG, 5 μm, 250x20 mm; solvent: 75% n-heptane / 25% isopropanol + 0.2% diethylamine; flow 15 ml / min; temperature: 30 ° C, indication: 265 nm).

Atropoisomer 2: 40 mg (> 99% de).

Rt = 5.95 min [analytical HPLC: Daicel® Chiralpak IG column, 1 ml / min; 5 microns, 250x4.6 mm; solvent: 70% isohexane / 30% isopropanol + 0.2% diethylamine; detection: 265 nm].

Example 49.

1- (2-Chloro-4,6-difluorophenyl) -7 - [(3R, 4R) -3,4-dihydroxypyrrolidin-1-yl] -6-fluoro-4-oxo-N- (1,1,1 trifluoro -2-methylpropan-2-yl) -1,4-dihydro-1,8-naphthyridine-3-carboxamide (atropisomer 1).

119 mg 1- (2-chloro-4,6-difluorophenyl) -7 - [(3R, 4R) -3,4-dihydroxypyrrolidin-1-yl] -6-fluoro-4-oxo-N (1,1, 1-trifluoro-2-methylpropan-2-yl) -1,4-dihydro-1,8-naphthyridine-3-carboxamide (mixture of atropisomers) was separated by chiral HPLC into atropisomers (preparative HPLC: YMC column Chiralart Amylose SA, 5 μm, 250x30 mm; solvent: 80% n-heptane / 20% isopropanol + 0.2% diethylamine; flow rate 30 ml / min; temperature: 30 ° C, indication: 265 nm).

Atropoisomer 1: 26 mg (> 99% de).

R _t = 4.86 min [analytical HPLC: YMC Chiralart Amylose SA column, 1 ml / min; 5 microns, 250x4.6 mm; solvent: 70% n-heptane / 30% isopropanol, 0.2% diethylamine; detection: 265 nm].

Example 50.

1- (2-Chloro-4,6-difluorophenyl) -7 - [(3R, 4R) -3,4-dihydroxypyrrolidin-1-yl] -6-fluoro-4-oxo-N- (1,1,1 trifluoro -2-methylpropan-2-yl) -1,4-dihydro-1,8-naphthyridine-3-carboxamide (atropisomer 2).

119 mg 1- (2-chloro-4,6-difluorophenyl) -7 - [(3R, 4R) -3,4-dihydroxypyrrolidin-1-yl] -6-fluoro-4-oxo-N (1,1, 1-trifluoro-2-methylpropan-2-yl) -1,4-dihydro-1,8-naphthyridine-3-carboxamide (mixture of atropisomers) was separated by chiral HPLC into atropisomers (preparative HPLC: YMC column Chiralart Amylose SA, 5 μm, 250x30 mm; solvent: 80% n-heptane / 20% isopropanol + 0.2% diethylamine; flow rate 30 ml / min; temperature: 30 ° C, indication: 265 nm).

Atropoisomer 2: 25 mg (99% de).

Rt = 5.42 min [analytical HPLC: YMC Chiralart Amylose SA column, 1 ml / min; 5 microns, 250x4.6 mm; solvent: 70% n-heptane / 30% isopropanol, 0.2% diethylamine; detection: 265 nm].

Example 51.

1- (2-Chloro-4,6-difluorophenyl) -N - [(1S) -1-cyclopropyl-2,2,2-trifluoroethyl] -7 - [(3R, 4R) -3,4 dihydroxypyrrolidin-1-yl ] -6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide (atropisomer 1).

103 mg 1- (2-chloro-4,6-difluorophenyl) -N - [(1S) -1-cyclonronyl-2,2,2-trifluoroethyl] -7 - [(3R, 4R) -3,4 dihydroxypyrrolidine-1 -yl] -6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide (mixture of atropisomers) was separated by chiral HPLC into atropisomers (preparative HPLC: Daicel® Chiralpak AD-H column, 5 μm, 250x20 mm; solvent: 80% n-heptane / 20% ethanol; flow 25 ml / min; temperature: 40 ° C, indication: 210 nm).

Atropoisomer 1: 30 mg (99% de).

R _t = 6.04 min [analytical HPLC: Daicel® Chiralpak AI column, 1 ml / min; 5 microns, 250x4.6 mm; solvent: 80% isohexane / 20% ethanol; indication: 235 nm].

Example 52.

1- (2-Chloro-4,6-difluorophenyl) -N - [(1S) -1-cyclopropyl-2,2,2-trifluoroethyl] -7 - [(3R, 4R) -3,4-dihydroxypyrrolidine-1 -yl] -6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide (atropisomer 2).

103 mg 1- (2-chloro-4,6-difluorophenyl) -N - [(1S) -1-cyclopropyl-2,2,2-trifluoroethyl] -7 - [(3R, 4R) -3,4 dihydroxypyrrolidine-1 -yl] -6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide (mixture of atropisomers) was separated by chiral HPLC into atropisomers (preparative HPLC: Daicel® Chiralpak AD-H column, 5 μm, 250x20 mm; solvent: 80% n-heptane / 20% ethanol; flow 25 ml / min; temperature: 40 ° C, indication: 210 nm).

Atropoisomer 2: 30 mg (89% de).

R _t = 7.33 min [analytical HPLC: Daicel® Chiralpak AI column, 1 ml / min; 5 microns, 250x4.6 mm; solvent: 80% isohexane / 20% ethanol; indication: 235 nm].

Example 53.

N - [(1S) -1-Cyclonropyl-2,2,2-trifluoroethyl] -6-fluoro-7- (3-hydroxy-3-methylazetidin-1-yl) -4-oxo-1- 80 038451 (2 , 4,6-trifluorophenyl) -1,4-dihydro-1,8-naphthyrvdine-3-carboxyamide.

mg N - [(1S) -1-cyclopropyl-2,2,2-trifluoroethyl] -6-fluoro-4-oxo-7- (3H- [1,2,3] triazolo [4,5b] pyridine-3 -yloxy) -1- (2,4,6-trifluorophenyl) -1,4-dihydro-1,8-naphthyridine-3-carboxamide (84.3 μmol) was dissolved in DMF (980 μL). 3-Methylazetidine-3-ol-hydrochloride (20.8 mg, 169 μmol) and Ν, Ν-diisopropylethylamine (51 μL, 290 μmol) were added and stirred for 2 h at room temperature. Then the reaction mixture was mixed with 0.3 ml of 1N. hydrochloric acid and 1 ml acetonitrile and purified by preparative HPLC (acetonitrile-water with formic acid, C18 RP-HPLC). The product fractions were pooled, thickened and lyophilized overnight from acetonitrile / water. This gave 36.2 mg (78% theory, 99% purity) of the title compound.

LCMS (Method 1): Rt = 1.13 min; MS (ESIpos): m / z = 545 [M + H] +.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: -0.008 (2.92), 0.008 (2.80), 0.314 (0.84), 0.325 (1.33), 0.337 (1.27), 0.349 (1.02), 0.360 (0.50), 0.512 (0.90), 0.522 (1.35), 0.535 (1.27), 0.545 (1.38), 0.564 (1.40), 0.574 (1.14), 0.585 (1.02), 0.594 (0.87), 0.608 (0.52), 0.625 (0.77), 0.634 (0.73), 0.645 (1.26), 0.656 (1.01), 0.667 (0.95), 1.177 (0.55), 1.185 (0.79), 1.198 (1.31), 1.206 (0.92), 1.218 (1.38), 1.230 (0.71), 1.382 (16.00), 2.328 (0.67), 2.367 (0.45), 2.670 (0.60), 2.711 (0.41), 3.896 (0.45), 4.350 (0.73), 4.372 (1.28), 4.394 (1.17), 4.413 (0.68), 5.673 (9.48), 7.535 (2.55), 7.557 (4.79), 7.579 (2.54), 8.000 (4.69), 8.028 (4.62), 8.835 (8.40), 10.440 (2.87), 10.464 (2.65).

Example 54.

N - [(1S) -1-Cyclonropyl-2,2,2-trifluoroethyl] -6-fluoro-7- (3-hydroxyazetugin-1-yl) -4-oxo-1- (2,4,6trifluorophenyl) - 1,4-dihydro-1,8-naphthyridine-3-carboxamide.

mg N - [(1S) -1-cyclonropyl-2,2,2-trifluoroethyl] -6-fluoro-4-oxo-7- (3H- [1,2,3] triazolo [4,5b] pyridine-3 -yloxy) -1- (2,4,6-trifluorophenyl) -1,4-dihydro-1,8-naphthyridine-3-carboxamide (84.3 μmol) was dissolved in DMF (980 μL). Azetidin-3-ol-hydrochloride (18.5 mg, 169 μmol) and N, N-diisopropylethylamine (51 μL, 290 μmol) were added and stirred for 2 h at room temperature. Then the reaction mixture was mixed with 0.3 ml of 1N. hydrochloric acid and 1 ml acetonitrile and purified by preparative HPLC (acetonitrile-water with formic acid, C18 RP-HPLC). The product fractions were pooled, thickened and lyophilized overnight from acetonitrile / water. This gave 32.2 mg (71% theory, 99% purity) of the title compound.

LCMS (Method 1): Rt = 1.08 min; MS (ESIpos): m / z = 531 [M + H] ⁺ .

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: -0.149 (0.55), -0.008 (6.99), 0.008 (4.19), 0.146 (0.49), 0.314 (2.27), 0.324 (3.51), 0.337 (3.32), 0.348 (2.57), 0.360 (1.23), 0.511 (2.49), 0.522 (3.55), 0.534 (3.29), 0.545 (3.63), 0.563 (3.70), 0.573 (2.93), 0.584 (2.64), 0.594 (2.21), 0.608 (1.40), 0.624 (1.96), 0.634 (1.95), 0.644 (3.27), 0.655 (2.74), 0.660 (2.57), 0.667 (2.47), 0.676 (1.25), 0.689 (0.81), 1.164 (0.76), 1.176 (1.47), 1.185 (2.06), 1.197 (3.32), 1.205 (2.49), 1.217 (3.15), 1.229 (1.72), 1.238 (1.19), 1.250 (0.49), 2.328 (0.85), 2.366 (0.70), 2.524 (4.17), 2.670 (0.85), 2.710 (0.57), 3.821 (1.08), 4.330 (1.23), 4.350 (2.42), 4.371 (3.53), 4.392 (3.34), 4.412 (1.87), 4.501 (0.94), 4.517 (2.23), 4.528 (3.61), 4.544 (3.31), 4.555 (1.74), 4.571 (0.57), 5.741 (9.80), 5.757 (9.35), 7.532 (5.86), 7.555 (10.75), 7.577 (5.65), 7.992 (9.11), 8.020 (8.88), 8.832 (16.00), 10.439 (6.76), 10.462 (6.37).

Example 55.

N - [(1S) -1-Cyclonropyl-2,2,2-trifluoroethyl] -6-fluoro-7 - [(2-hydroxyethyl) (methyl) amino] -4-oxo-1 (2,4,6- trifluorophenyl) -1,4-dihydro-1,8-naphthyridine-3-carboxamide.

mg N - [(1S) -1-cyclopropyl-2,2,2-trifluoroethyl] -6-fluoro-4-oxo-7- (3H- [1,2,3] triazolo [4,5b] pyridine-3 -yloxy) -1- (2,4,6-trifluorophenyl) -1,4-dihydro-1,8-naphthyridine-3-carboxamide (135 μmol) was dissolved in DMF (980 μL). 2- (methylamino) ethanol (20.3 mg, 270 μmol) and N, N-diisopropylethylamine (82 μl, 470 μmol) were added and stirred for 2 h at room temperature. The reaction mixture was mixed with 0.2 ml of 1N. hydrochloric acid and 2 ml acetonitrile and purified by preparative HPLC (acetonitrile-water with formic acid, C18 RP-HPLC). The product fractions were pooled, thickened and lyophilized overnight from acetonitrile / water. This gave 45.1 mg (62% theory, 99% purity) of the title compound.

LCMS (Method 1): Rt = 1.09 min; MS (ESIpos): m / z = 533 [M + H] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: -0.149 (0.80), -0.008 (7.20), 0.146 (0.77), 0.319 (1.97), 0.329 (3.20), 0.341 (3.09), 0.353 (2.45), 0.365 (1.17), 0.513 (2.13), 0.525 (3.31), 0.538 (2.91), 0.548 (3.25), 0.567 (3.33), 0.577 (2.75), 0.588 (2.40), 0.598 (2.05), 0.612 (1.25), 0.626 (1.68), 0.636 (1.63), 0.647 (2.93), 0.657 (2.53), 0.663 (2.40), 0.670 (2.37), 0.679 (1.15), 0.691 (0.80), 1.166 (0.59), 1.178 (1.23), 1.187 (1.81), 1.199 (3.04), 1.208 (2.21), 1.219 (2.99), 1.231 (1.63), 1.240 (1.12), 1.252 (0.48), 2.327 (1.49), 2.366 (1.23), 2.523 (5.39), 2.669 (1.60), 2.710 (1.20), 3.076 (9.76), 3.442 (6.83), 3.470 (5.87), 4.331 (0.40), 4.351 (1.63), 4.373 (2.85), 4.393 (2.80), 4.414 (1.49), 4.713 (2.96), 4.725 (6.51), 4.738 (3.01), 7.539 (5.52), 7.561 (10.56), 7.583 (5.60), 7.994 (9.63), 8.028 (9.44), 8.849 (16.00), 10.436 (6.37), 10.459 (6.16).

Example 56.

N- (Dicyclonropylmethyl) -1 - (3,5-difluoropyridin-2-yl) -6-fluoro-7- (3-hydroxy-3-methylazetidin-1 yl) -4-oxo-1,4-dihydro-1 , 8-naphthyridine-3-carboxamide.

- 81 038451 mg 1- (3,5-difluoropyridin-2-yl) -6-fluoro-7- (3-hydroxy-3-methylazetidin-1-yl) -4-oxo-1,4-dihydro1,8- naphthyridine-3-carboxylic acid (123 μmol) was dissolved in DMF (980 μl). HATU (56.2 mg, 148 μmol), N, N-diisopropylethylamine (54 μL, 308 μmol) and 1,1-dicyclopropylmethanamine (15.1 mg, 135 μmol) were added and stirred for 2 h at room temperature. The reaction mixture was mixed with 0.1 ml of 1 M hydrochloric acid and 1 ml of acetonitrile and purified by preparative HPLC (acetonitrile-water with formic acid, C18 RP-HPLC). The product fractions were pooled, thickened and lyophilized overnight from acetonitrile / water. This gave 48.7 mg (78% theory, 99% purity) of the title compound.

LCMS (Method 1): Rt = 1.04 min; MS (ESIpos): m / z = 500 [M + H] +.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: -0.008 (3.14), 0.008 (2.56), 0.300 (6.52), 0.387 (1.96), 0.397 (2.30), 0.416 (1.48), 0.455 (1.94), 0.475 (2.68), 1.031 (2.06), 1.044 (2.01), 1.382 (16.00), 2.323 (0.44), 2.328 (0.58), 2.524 (1.88), 2.670 (0.60), 3.235 (1.02), 3.254 (2.27), 3.276 (2.41), 3.928 (0.72), 5.676 (6.09), 7.985 (4.45), 8.014 (4.40), 8.292 (1.04), 8.298 (1.18), 8.316 (1.67), 8.319 (1.81), 8.337 (1.07), 8.343 (1.16), 8.591 (5.22), 8.597 (4.96), 8.753 (9.26), 9.856 (2.93), 9.878 (2.87).

Example 57.

6-Fluoro-7 - [(2S) -2- (hydroxymethyl) piperidin-1-yl] -4-oxo-N - [(2S) -1,1,1-trifluorobutan-2-yl] -1 (2 , 4,6-trifluorophenyl) -1,4-dihydro-1,8-naphthyridine-3-carboxamide.

mg 6-fluoro-4-oxo-7- (3H- [1,2,3] triαzolo [4,5-b] pyridin-3-yloxy) -N - [(2S) -1,1,1-trifluorobutane -2yl] -1- (2,4,6-trifluorophenyl) -1,4-dihydro-1,8-naphthyridine-3-carboxamide (86.0 µmol) was dissolved in DMF (980 µl). (2S) -piperidin-2-ylmethanol (19.8 mg, 172 μmol) and N, N-diisopropylethylαmine (52 μL, 300 μmol) were added and stirred for 2 h at room temperature. The reaction mixture was then mixed with 0.3 ml of 1 M hydrochloric acid and 1 ml of acetonitrile and purified by preparative HPLC (acetonitrile-water with formic acid, C18 RP-HPLC). The product fractions were pooled, thickened and lyophilized overnight from acetonitrile / water. This gave 37.3 mg (77% theory, 99% purity) of the title compound.

LCMS (Method 3): Rt = 2.25 min; MS (ESIpos): m / z = 561 [M + H] +.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: -0.149 (0.55), -0.008 (4.87), 0.008 (4.03), 0.146 (0.52), 0.948 (7.19), 0.967 (16.00), 0.985 (7.82), 1.344 (1.09), 1.376 (1.34), 1.471 (1.90), 1.530 (3.44), 1.549 (5.64), 1.577 (2.47), 1.606 (1.34), 1.624 (1.56), 1.631 (1.36), 1.641 (1.47), 1.703 (0.91), 1.723 (1.95), 1.740 (1.83), 1.832 (1.74), 1.886 (1.54), 1.896 (1.34), 1.905 (1.15), 1.914 (0.66), 2.925 (1.07), 2.955 (1.99), 2.988 (1.07), 3.479 (1.90), 3.559 (1.20), 3.574 (2.02), 3.588 (1.77), 3.616 (3.01), 4.676 (6.53), 4.689 (2.97), 4.737 (1.41), 4.758 (1.83), 1.649 (1.65), 1.659 (1.59), 1.666 (1.77), 1.684 (0.43), 1.851 (1.31), 1.861 (1.54), 1.869 (1.56), 1.879 (0.98), 2.367 (0.70), 2.519 (3.11), 2.524 (2.47), 2.711 (1.00), 3.495 (1.47), 3.506 (2.47), 3.520 (2.63), 3.536 (0.68), 3.855 (1.79), 3.888 (1.68), 4.288 (2.04), 4.662 (1.32), 7.531 (1.43), 7.535 (1.41), 7.550 (3.99), 7.555 (4.15), 7.573 (4.28), 7.578 (3.88), 7.597 (1.36), 8.001 (8.41), 8.036 (8.14), 8.869 (13.96), 10.274 (5.15), 10.298 (4.94).

Example 58.

N- (1S) -1-Cyclopropyl-2,2,2-trifluoroethyl] -6-fluoro-7 - [(2S) -2- (hydroxymethyl) piperidin-1-yl] -4oxo-1- (2,4 , 6-trifluorophenyl) -1,4-dihydro-1,8-naphthyridine-3-carboxamide.

mg N - [(1S) -1-cyclopropyl-2,2,2-trifluoroethyl] -6-fluoro-4-oxo-7- (1H- [1,2,3] triazolo [4,5b] pyridine-1 -yloxy) -1- (2,4,6-trifluorophenyl) -1,4-dihydro-1,8-naphthyridine-3-carboxylic acid amide and 50 mg N - [(1S) -1-cyclopropyl-2,2 , 2-trifluoroethyl] -6-fluoro-4-oxo-7- (3H- [1,2,3] triazolo [4,5-b] pyridine-3yloxy) -1- (2,4,6-trifluorophenyl) -1,4-dihydro-1,8-naphthyridine-3-carboxamide (84.3 μmol) was dissolved in DMF (980 μL). (2S) -piperidin-2-ylmethanol (19.4 mg, 169 μmol) and N, N-diisopropylethylαmine (51 μL, 290 μmol) were added and stirred for 2 h at room temperature. The reaction mixture was mixed with 0.3 ml of 1N. hydrochloric acid and 1 ml acetonitrile and purified by preparative HPLC (acetonitrile-water with formic acid, C18 RP-HPLC). The product fractions were pooled, thickened and lyophilized overnight from acetonitrile / water. This gave 36.5 mg (75% theory, 99% purity) of the title compound.

LCMS (Method 1): Rt = 1.21 min; MS (ESIpos): m / z = 573 [M + H] +.

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: -0.149 (0.72), -0.008 (6.54), 0.008 (5.08), 0.147 (0.62), 0.318 (1.64), 0.330 (2.51), 0.342 (2.47), 0.353 (1.96), 0.516 (1.76), 0.528 (2.59), 0.539 (2.36), 0.550 (2.63), 0.568 (2.76), 0.579 (2.15), 0.589 (2.00), 0.599 (1.66), 0.613 (1.02), 0.628 (1.49), 0.637 (1.40), 0.648 (2.51), 0.659 (2.08), 0.664 (1.98), 0.670 (1.96), 1.189 (1.51), 1.201 (2.61), 1.209 (1.87), 1.221 (2.57), 1.233 (1.44), 1.377 (1.34), 1.472 (2.00), 1.532 (3.55), 1.551 (5.84), 1.577 (2.55), 1.723 (1.98), 1.740 (1.87), 2.328 (1.13), 2.367 (0.70), 2.524 (3.19), 2.670 (1.08), 2.711 (0.70), 2.924 (1.10), 2.954 (2.10), 2.987 (1.15), 3.479 (1.00), 3.495 (1.47), 3.506 (2.59), 3.520 (2.74), 3.536 (1.95), 3.574 (2.08), 3.587 (1.85), 3.859 (1.95), 3.892 (1.79), 4.286 (2.17), 4.352 (1.30), 4.373 (2.30), 4.394 (2.32), 4.414 (1.25), 4.662 (2.95), 4.675 (6.42), 4.688 (2.87), 7.533 (1.59), 7.547 (3.89), 7.553 (4.38), 7.569 (4.48), 7.576 (3.85), 7.590 (1.53), 8.006 (8.95), 8.041 (8.61), 8.860 (16.00), 1 0.414 (5.44), 10.437 (5.10).

- 82 038451

Example 59.

N - [(1S) -1-Cyclopropyl-2,2,2-trifluoroethyl] -6-fluoro-7 - [(4S) -4-hydroxy-2-oxopyrrolidin-1-yl] -4oxo-1- (2 , 4,6-trifluorophenyl) -1,4-dihydro-1,8-naphthyridine-3-carboxamide.

According to AAV1, 61.7 mg (80% purity, 113 μmol) was converted 6-fluoro-7 - [(4S) -4-hydroxy-2oxopyrrolidin-1-yl] -4-oxo-1- (2,4,6-trifluorophenyl) -1,4-dihydro-1,8-naphthyridine-3-carboxylic acid with 29.7 mg of (1S) -1-cyclopropyl-2,2,2-trifluoroethanamine hydrochloride (169 μmol) in the presence of 64.4 mg (169 μmol) HATU and 98 μl (560 μmol) DIPEA in 3.0 ml DMF. The reaction mixture was diluted with 0.5 ml aqueous hydrochloric acid and purified using preparative HPLC [at UV max: 265 nm, columns: Chromatorex C18, 10 μm, 125x30 mm, solvent: acetonitrile / 0.05% formic acid gradient (0-3 min 10% acetonitrile , up to 35 min 90% acetonitrile and the next 3 min 90% acetonitrile)]. The product fractions were combined, freed from solvent and lyophilized. This gave 27.2 mg (43% theory, 100% purity) of the title compound.

LCMS (Method 3): Rt = 1.80 min; MS (ESIpos): m / z = 559 [M + H] +.

Example 60.

N-tert-Butyl-7- (dimethylamino) -6-fluoro-4-oxo-1- (2,4,6-trifluorophenyl) -1,4-dihydro-1,8 naphthyridine-3-carboxamide.

7-Chloro-6-fluoro-4-oxo-1 - (2,4,6-trifluorophenyl) -1,4-dihydro-1,8-naphthyridine-3-carboxylic acid (120 mg, 322 μmol) was placed in 2.4 ml of DMF, mixed with HATU (147 mg, 386 μmol) and N, N-diisopropylethylαmine (200 μL, 1.1 mmol) and stirred for 30 min at room temperature. Added 2-methylpropan-2-amine (41 μl, 390 μmol) and stirred for 5 min at room temperature. After 5 minutes, the reaction mixture was reacted with water. The resulting suspension was left overnight. The next morning, a solid formed that can be pumped out. This residue was purified by column chromatography (silica gel; solvent: dichloromethane / methanol gradient: 100/0 to 100/1). This gave 23 mg (16% of theory) of the target compound.

LCMS (Method 3): _Rt = 2.32 min; MS (ESIpos): m / z = 437 [M + H] ⁺ .

Example 61.

7- (Dimethylamino) -6-fluoro-N- (2-methylbutan-2-yl) -4-oxo-1- (2,4,6-trifluorophenyl) -1,4-dihydro-1,8naphthyridine-3 - carboxamide.

7-Chloro-6-fluoro-4-oxo-1 - (2,4,6-trifluorophenyl) -1,4-dihydro-1,8-naphthyridine-3-carboxylic acid (120 mg, 322 μmol) was placed in 2.4 ml of DMF, mixed with HATU (147 mg, 386 μmol) and N, N-diisopropylethylamine (200 μL, 1.1 mmol) and stirred for 30 min at room temperature. Added 2-methylbutan-2-amine (45 μl, 390 μmol) and stirred for 5 min at room temperature. After 5 minutes, the reaction mixture was reacted with water. The resulting suspension was left overnight. The next morning, a solid formed that can be pumped out. This residue was purified by column chromatography (silica gel; solvent: dichloromethane / methanol gradient: 100/0 to 100/1). 19 mg (13% of theory) of the target compound were obtained.

LCMS (Method 3): Rt = 2.42 min; MS (ESIpos): m / z = 451 [M + H] ⁺ .

Example 62.

7- (Dimethylamino) -6-fluoro-4-oxo-N- (1,1,1-trifluoro-2-methylnropan-2-yl) -1- (2,4,6-trifluorophenyl) 1,4-dihydro -1,8-naphthyridine-3-carboxamide.

7-Chloro-6-fluoro-4-oxo-1 - (2,4,6-trifluorophenyl) -1,4-dihydro-1,8-naphthyridine-3-carboxylic acid (120 mg, 322 μmol) was placed in 2.4 ml of DMF, mixed with HATU (147 mg, 386 μmol) and N, N-diisonropylethylamine (200 μL, 1.1 mmol) and stirred for 30 min at room temperature. 1,1,1-trifluoro-2-methylpropan-2-amine (49.1 mg, 386 μmol) was added and stirred for 5 min at room temperature. After 5 minutes, the reaction mixture was reacted with water. The resulting suspension was left overnight. The next morning, a solid formed that can be pumped out. This residue was purified by column chromatography (silica gel; solvent: dichloromethane / methanol gradient: 100/0 to 100/1). Received 30 mg (19% theory. V.) Of the target compound.

LCMS (Method 3): Rt = 2.42 min; MS (ESIpos): m / z = 491 [M + H] ⁺ .

Example 63.

7- (Dimethylamino) -6-fluoro-4-oxo-N- (4,4,4-trifluoro-2-methylbutan-2-yl) -1- (2,4,6-trifluorophenyl) -1,4 dihydro - 1,8-naphthyridine-3-carboxamide.

7-Chloro-6-fluoro-4-oxo-1 - (2,4,6-trifluorophenyl) -1,4-dihydro-1,8-naphthyridine-3-carboxylic acid (120 mg, 322 μmol) was placed in 2.4 ml of DMF, mixed with HATU (147 mg, 386 μmol) and N, N-diisonropylethylamine (200 μL, 1.1 mmol) and stirred for 30 min at room temperature. 4,4,4-trifluoro-2-methylbutane-2-amine hydrochloride (68.6 mg, 386 μmol) was added and stirred for 5 min at room temperature. After 5 minutes, the reaction mixture was reacted with water. The resulting suspension was left overnight. The next morning, a solid formed that can be pumped out. This residue was purified by column chromatography (silica gel; solvent: dichloromethane / methanol gradient: 100/0 to 100/1). Received 24 mg (15% theory. Y.) Of the target compound.

LCMS (Method 3): Rt = 2.42 min; MS (ESIpos): m / z = 505 [M + H] ⁺ .

- 83 038451

Example 64.

N - [(1S) -1-Cyclopropyl-2,2,2-trifluoroethyl] -6-fluoro-7 - {[(2S) -2-hydroxypropyl] (methyl) amino} -4oxo-1- (2,4 , 6-trifluorophenyl) -1,4-dihydro-1,8-naphthyridine-3-carboxamide.

7-Chloro-N - [(1S) -1-cyclopropyl-2,2,2-trifluoroethyl] -6-fluoro-4-oxo-1- (2,4,6-trifluorophenyl) -1,4 dihydro-1, 8-naphthyridine-3-carboxamide (60.0 mg, 122 μmol) was placed in 1.2 ml of DMF, mixed with (2S) -1- (methylamino) propan-2-ol (21.7 mg, 243 μmol) and N, N-diisopropylethylamine (74 μl, 430 μmol) and stirred for 2 h at room temperature. The reaction mixture was mixed with acetonitrile / water and purified by preparative HPLC (RP18 columns, eluent: acetonitrile / water gradient with the addition of 0.1% trifluoroacetic acid). The product fractions were combined and concentrated in vacuo. The residue was taken up in dichloromethane and washed twice with saturated aqueous sodium hydrogen carbonate solution. The combined aqueous phases were back-extracted once with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. Received 47 mg of the target compound (70% theory. V.).

LCMS (Method 3): Rt = 2.15 min; MS (ESIpos): m / z = 547 [M + H] +.

¹ H-NMR (400 MHz, DMSO-de) δ [ppm]: -0.149 (0.68), -0.059 (5.17), -0.008 (4.04), 0.008 (3.41), 0.146 (0.41), 0.318 (1.61), 0.328 (2.49), 0.340 (2.44), 0.352 (1.95), 0.364 (0.96), 0.512 (1.71), 0.523 (2.54), 0.535 (2.29), 0.547 (2.57), 0.555 (1.96), 0.566 (2.64), 0.576 (2.19), 0.586 (1.99), 0.597 (1.62), 0.611 (1.01), 0.625 (1.41), 0.636 (1.41), 0.646 (2.39), 0.656 (2.07), 0.662 (2.01), 0.670 (2.00), 0.678 (1.03), 0.690 (0.76), 0.834 (7.90), 0.849 (7.89), 1.166 (0.69), 1.178 (1.23), 1.186 (1.66), 1.198 (2.72), 1.207 (1.98), 1.219 (2.71), 1.231 (1.99), 1.251 (0.59), 2.074 (0.65), 2.329 (0.46), 2.671 (0.42), 3.160 (4.79), 3.460 (2.29), 3.490 (1.88), 3.705 (1.53), 4.354 (1.31), 4.375 (2.27), 4.396 (2.20), 4.417 (1.17), 4.738 (5.75), 4.750 (5.64), 5.755 (2.37), 7.561 (3.16), 7.582 (5.63), 7.603 (3.10), 7.989 (8.41), 8.023 (8.17), 8.841 (16.00), 10.441 (5.22), 10.464 (5.04).

Example 65.

N - [(1S) -1-Cyclopropyl-2,2,2-trifluoroethyl] -7- [ethyl (2-hydroxypropyl) amino] -6-fluoro-4-oxo-1 (2,4,6-trifluorophenyl) -1,4-dihydro-1,8-naphthyridine-3-carboxamide (mixture of diastereoisomers).

7-Chloro-N - [(1S) -1-cyclopropyl-2,2,2-trifluoroethyl] -6-fluoro-4-oxo-1- (2,4,6-trifluorophenyl) -1,4 dihydro-1, 8-naphthyridine-3-carboxamide (80.0 mg, 162 μmol) was placed in 1.6 ml of acetonitrile, mixed with 1- (ethylamino) propan-2-ol (33.4 mg, 324 μmol; racemate) and Ν, Ν-diisopropylethylamine (99 μl , 570 μmol) and stirred for 2 h at room temperature. Then, the reaction solution was concentrated in vacuo. The residue was taken up in ethyl acetate and mixed with water. The aqueous phase was acidified with 1 M hydrochloric acid and extracted twice. The organic phase was shaken once with saturated aqueous sodium hydrogen carbonate solution, washed once with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated in vacuo. 76 mg of the target compound was obtained (82% of theory).

LCMS (Method 3): Rt = 2.23 min; MS (ESIpos): m / z = 561 [M + H] ⁺ .

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: -0.149 (0.87), -0.008 (7.43), 0.008 (7.19), 0.146 (0.84), 0.329 (2.28), 0.342 (2.25), 0.514 (1.80), 0.525 (2.61), 0.549 (2.52), 0.568 (2.61), 0.577 (2.19), 0.588 (2.07), 0.626 (1.32), 0.647 (2.43), 0.851 (6.17), 1.013 (5.51), 1.157 (1.05), 1.175 (2.52), 1.185 (1.74), 1.197 (2.94), 1.206 (2.22), 1.217 (2.82), 1.238 (1.89), 1.988 (3.09), 2.328 (1.86), 2.367 (0.93), 2.670 (1.86), 2.711 (1.05), 3.061 (0.93), 3.418 (2.19), 3.455 (2.55), 3.575 (1.14), 3.710 (1.59), 4.021 (0.84), 4.039 (0.81), 4.350 (1.20), 4.370 (2.22), 4.391 (2.22), 4.412 (1.17), 4.736 (4.04), 4.748 (3.96), 7.566 (3.06), 7.588 (5.51), 7.607 (3.12), 7.996 (8.21), 8.031 (8.03), 8.843 (16.00), 10.439 (5.21), 10.463 (5.00).

Example 66.

N - [(1S) -1-Cyclopropyl-2,2,2-trifluoroethyl] -7- [ethyl (2-hydroxypropyl) amino] -6-fluoro-4-oxo-1 (2,4,6-trifluorophenyl) -1,4-dihydro-1,8-naphthyridine-3-carboxamide (diastereoisomer 1).

mg N - [(1S) -1-cyclopropyl-2,2,2-trifluoroethyl] -7- [ethyl (2-hydroxypropyl) amino] -6-fluoro-4-oxo1- (2,4,6-trifluorophenyl) -1,4-dihydro-1,8-naphthyridine-3-carboxamide (mixture of diastereoisomers) was separated into diastereoisomers by preparative HPLC (preparative HPLC: Daicel® Chiralpak AD-H column, 5 μm, 250x20 mm; eluent: 80% n- heptane / 20% isopropanol; flow 15 ml / min; temperature: 25 ° C, indication: 210 nm).

Diastereoisomer 1: 30 mg (> 99% de).

Rt = 1.37 min [analytical HPLC: Daicel® Chiralpak AD column, 1 ml / min; 3 μm, 50x4.6 mm; solvent: 80% isohexane / 20% isopropanol; detection: 220 nm].

LCMS (Method 3): Rt = 2.25 min; MS (ESIpos): m / z = 561 [M + H] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: -0.008 (1.84), 0.008 (1.52), 0.321 (1.83), 0.331 (2.88), 0.343 (2.85), 0.355 (2.22), 0.367 ( 1.10), 0.503 (0.76), 0.515 (1.97), 0.526 (2.98), 0.539 (2.67), 0.550 (2.97), 0.557 (2.12), 0.568 (3.14), 0.578 (2.48), 0.589 (2.26), 0.599 ( 1.84), 0.613 (1.18), 0.627 (1.69), 0.637 (1.61), 0.648 (2.73), 0.659 (2.37), 0.664 (2.19), 0.670 (2.15), 0.680 (1.11), 0.684 (1.10), 0.692 ( 0.80), 0.852 (6.50), 0.863 (6.50), 1.012 (5.79), 1.165 (0.66), 1.177 (1.26), 1.185 (1.75), 1.198 (2.95), 1.206 (2.09), 1.218 (2.89), 1.230 ( 1.55), 1.238 (1.05), 1.250 (0.45), 2.328 (0.82), 2.333 (0.60), 2.367 (0.56), 2.519 (3.02), 2.524 (2.34), 2.666 (0.58), 2.670 (0.80), 2.675 ( 0.58), 2.710 (0.51), 3.075 (0.94), 3.419 (2.44), 3.454 (2.73), 3.578 (1.05), 3.708

- 84 038451 (1.64), 4.347 (1.48), 4.368 (2.54), 4.389 (2.50), 4.410 (1.34), 4.735 (4.60), 4.747 (4.46), 7.566 (3.23), 7.587 (5.73), 7.606 (3.23) ), 7.996 (9.12), 8.031 (8.91), 8.843 (16.00), 10.440 (6.11), 10.463 (5.86).

Example 67.

N - [(1S) -1-Cyclopropyl-2,2,2-trifluoroethyl] -7- [ethyl (2-hydroxypropyl) amino] -6-fluoro-4-oxo-1 (2,4,6-trifluorophenyl) -1,4-dihydro-1,8-naphthyridine-3-carboxamide (diastereoisomer 2).

mg N - [(1S) -1-cyclopropyl-2,2,2-trifluoroethyl] -7- [ethyl (2-hydroxypropyl) amino] -6-fluoro-4-oxo1- (2,4,6-trifluorophenyl) -1,4-dihydro-1,8-naphthyridine-3-carboxamide (mixture of diastereoisomers) was separated into diastereoisomers by preparative HPLC (preparative HPLC: Daicel® Chiralpak AD-H column, 5 μm, 250x20 mm; eluent: 80% n- heptane / 20% isopropanol; flow 15 ml / min; temperature: 25 ° C, indication: 210 nm).

Diastereoisomer 2: 30 mg (> 99% de).

Rt = 2.31 min [analytical HPLC: Daicel® Chiralpak AD column, 1 ml / min; 3 μm, 50x4.6 mm; solvent: 80% isohexane / 20% isopropanol; detection: 220 nm].

LCMS (Method 3): Rt = 2.25 min; MS (ESIpos): m / z = 561 [M + H] +.

Ή-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 0.318 (1.80), 0.328 (2.83), 0.340 (2.58), 0.514 (1.98), 0.525 (3.01), 0.537 (2.55), 0.548 (2.78 ), 0.567 (2.79), 0.576 (2.35), 0.588 (2.12), 0.626 (1.52), 0.647 (2.48), 0.657 (2.17), 0.851 (6.26), 1.013 (5.57), 1.177 (1.33), 1.185 (1.71 ), 1.198 (2.72), 1.218 (2.67), 1.230 (1.43), 2.328 (1.15), 2.671 (1.04), 3.063 (1.04), 3.420 (2.39), 3.453 (2.67), 3.585 (1.11), 3.711 (1.63 ), 4.350 (1.49), 4.371 (2.39), 4.393 (2.19), 4.413 (1.31), 4.737 (4.38), 4.749 (4.05), 7.567 (3.32), 7.588 (5.50), 7.607 (2.95), 7.997 (7.99 ), 8.032 (7.81), 8.844 (16.00), 10.440 (5.11), 10.463 (5.00).

Example 68.

1- (2-Chloro-4,6-difluorophenyl) -N - [(1S) -1-cyclo-propyl-2,2,2-trifluoroethyl] -6-fluoro-7- (2-oxa-6azaspiro [3.3] hept -6-yl) -4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide trifluoroacetate (mixture of atropisomers).

7-Chloro-1- (2-chloro-4,6-difluorophenyl) -N - [(1S) -1-cyclopropyl-2,2,2-trifluoroethyl] -6-fluoro-4-oxo-1,4dihydro- 1,8-naphthyridine-3-carboxamide (mixture of atropisomers, purity 57%, 90.0 mg, 176 μmol) was placed in 1.7 ml of DMF, mixed with ethanedic acid-2-oxa-6-azaspiro [3.3] heptane (1: 1) ( 46.7 mg, 247 μmol) and N, N-diisonropylethylamine (150 μL, 880 μmol) and stirred overnight at room temperature. The reaction mixture was mixed with acetonitrile / water and purified by preparative HPLC (RP18 columns, eluent: acetonitrile / water gradient with the addition of 0.1% trifluoroacetic acid). (Faction 1). The product fractions were combined and concentrated in vacuo. The residue was taken up in dichloromethane and washed twice with saturated aqueous sodium hydrogen carbonate solution. The combined aqueous phases were back-extracted once with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. Received 74 mg of the target compound (60% theory. V., Purity 98%).

LCMS (Method 3): Rt = 2.28 min; MS (ESIpos): m / z = 573 [M-TFA + H] +.

Ή-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 0.006 (0.44), 0.313 (0.41), 0.322 (0.73), 0.331 (0.87), 0.341 (0.77), 0.350 (0.49), 0.524 (0.72 ), 0.536 (0.69), 0.544 (0.68), 0.552 (0.50), 0.561 (0.59), 0.571 (0.77), 0.580 (0.71), 0.587 (0.60), 0.597 (0.45), 0.635 (0.46), 0.644 (0.64 ), 0.652 (0.79), 0.663 (0.77), 0.672 (0.54), 1.188 (0.50), 1.197 (0.83), 1.205 (0.69), 1.213 (0.78), 1.222 (0.48), 2.073 (6.12), 2.519 (0.49 ), 4.339 (0.49), 4.355 (0.83), 4.372 (0.98), 4.388 (0.77), 4.649 (16.00), 7.680 (0.58), 7.686 (0.77), 7.699 (1.02), 7.704 (1.35), 7.718 (0.63 ), 7.724 (1.34), 7.745 (1.11), 7.999 (2.73), 8.022 (2.68), 8.777 (6.49), 10.453 (1.61), 10.471 (1.53).

Example 69.

7- [3,3-bis- (Hydroxymethyl) azetidin-1 -yl] -1- (2-chloro-4,6-difluorophenyl) -N - [(1S) -1 -cyclopropyl2,2,2-trifluoroethyl ] -6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide (mixture of atropisomers).

1- (2-Chloro-4,6-difluorophenyl) -N - [(1S) -1-cyclo-propyl-2,2,2-trifluoroethyl] -6-fluoro-7- (2-oxa-6azaspiro [3.3] hept -6-yl) -4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide trifluoroacetate (mixture of atropisomers, 70.0 mg, 102 μmol) was placed in trifluoroacetic acid (640 μL, 8.3 mmol), mixed with 640 μl of water and 0.2 ml of acetonitrile and stirred for 4 days at room temperature. The reaction mixture was purified by preparative HPLC (RP18 columns, eluent: acetonitrile / water gradient with the addition of 0.1% trifluoroacetic acid). The product fractions were concentrated in vacuo, the residue was taken up in dichloromethane and washed twice with saturated aqueous sodium hydrogen carbonate solution. The combined aqueous phases were back-extracted once with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. Received 60 mg of the target compound (98% theory. V. 98% purity).

LCMS (Method 3): Rt = 1.91 min; MS (ESIpos): m / z = 591 [M + H] +.

Ή-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: -0.149 (0.88), -0.008 (7.82), 0.008 (6.52), 0.146 (0.86), 0.312 (0.99), 0.323 (1.77), 0.334 (2.13), 0.346 (1.93), 0.358 (1.22), 0.523 (1.69), 0.538 (1.80), 0.561 (1.93), 0.572 (2.02), 0.583 (1.74), 0.593 (1.49), 0.606 (1.08), 0.621 (0.83), 0.631 (1.13), 0.641 (1.55), 0.652 (1.82), 0.667 (1.60), 0.675 (1.19), 0.687 (0.69), 1.162 (0.44), 1.175 (0.80), 1.183 (1.16), 1.195 (1.99), 1.205 (1.55), 1.215 (1.96), 1.227 (1.22), 1.235 (1.13), 2.073 (0.77), 2.328 (1.16), 2.366 (0.80), 2.523 (4.37), 2.670 (1.30), 2.710

- 85 038451 (0.94), 3.465 (15.72), 3.479 (16.00), 4.118 (0.91), 4.333 (0.66), 4.353 (1.33), 4.373 (1.77), 4.392 (1.35), 4.411 (0.64), 4.831 (5.11 ), 4.844 (12.10), 4.858 (5.06), 7.667 (1.27), 7.673 (1.82), 7.690 (2.10), 7.697 (3.45), 7.713 (3.43), 7.720 (3.87), 7.731 (2.57), 7.742 (1.71 ), 7.967 (6.38), 7.996 (6.33), 8.758 (14.51), 10.481 (4.03), 10.505 (3.90).

Example 70.

7- [3,3-bis- (Hydroxymethyl) azetidin-1 -yl] -1- (2-chloro-4,6-difluorophenyl) -N - [(1S) -1 -cyclopropyl2,2,2-trifluoroethyl ] -6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyrvdine-3-carboxyamvd (atropisomer 1).

mg 7- [3,3-bis- (hydroxymethyl) azetidin-1-yl] -1- (2-chloro-4,6-difluorophenyl) -N - [(1S) -1cyclopropyl-2,2,2-trifluoroethyl ] -6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide (mixture of atropisomers) was separated by chiral HPLC into atropisomers preparative HPLC: column

Daicel® Chiralpak OX-H, 5 μm, 250x20 mm; eluent: 80% n-heptane / 20% ethanol + 0.2% diethylamine; flow 20 ml / min; temperature: 23 ° C, indication: 220 nm). The product fractions were evaporated at 30 ° C.

Atropoisomer 1: 22 mg (> 99% stereochemical purity).

Rt = 4.16 min [analytical HPLC: Daicel® Chiralpak OX column, 1 ml / min; 3 μm, 50x4.6 mm;

solvent: 90% n-hexane / 20% ethanol + 0.2% diethylamine; detection: 220 nm].

LCMS (Method 3): Rt = 1.90 min; MS (ESIpos): m / z = 591 [M + H] ⁺ .

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: -0.149 (0.82), -0.008 (7.57), 0.008 (6.50), 0.146 (0.85), 0.312 (1.26), 0.322 (2.17), 0.335 (2.11), 0.346 (2.14), 0.561 (2.22), 0.571 (1.81), 0.582 (1.95), 0.652 (1.73), 0.664 (1.54), 1.099 (1.56), 1.214 (2.14), 1.226 (1.21), 1.234 (1.65), 0.358 (0.85), 0.508 (1.45), (1.59), 0.593 (1.32), 0.606 (0.80), (0.82), 1.118 (1.51), 1.135 (0.71), (1.13), 2.327 (1.56 ), 2.366 (0.91),

0.519 (2.22), 0.531 (1.98), 0.543

0.621 (1.15), 0.631 (1.15), 0.642

1.182 (1.26), 1.194 (2.14), 1.202

2.523 (4.89), 2.670 (1.54), 2.710 (0.91), 2.820 (0.41), 3.465 (15.78), 3.479 (16.00), 4.131 (0.93), 4.348 (1.13), 4.370 (1.92), 4.392 (1.84), 4.411 (0.99), 4.831 (5.19), 4.844 (12.24), 4.857 (5.10), 7.666 (1.29), 7.673 (1.92), 7.690 (2.17), 7.697 (3.49), 7.713 (3.60), 7.720 (3.95), 7.731 (2.66), 7.967 (7.27), 7.996 (7.03), 8.758 (15.86), 10.482 (4.56), 10.506 (4.42).

Example 71.

7- [3,3-bis- (Hydroxymethyl) azetidin-1 -yl] -1- (2-chloro-4,6-difluorophenyl) -N - [(1S) -1 -cyclopropyl2,2,2-trifluoroethyl ] -6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide (atropisomer 2).

mg 7- [3,3-bis- (hydroxymethyl) azetidin-1-yl] -1- (2-chloro-4,6-difluorophenyl) -N - [(1S) -1cyclopropyl-2,2,2-trifluoroethyl ] -6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide (mixture of atropisomers) was separated by chiral HPLC into atropisomers preparative HPLC: column

Daicel® Chiralpak OX-H, 5 μm, 250x20 mm; eluent: 80% n-heptane / 20% ethanol + 0.2% diethylamine; flow 20 ml / min; temperature: 23 ° C, indication: 220 nm). The product fractions were evaporated at 30 ° C.

Atropoisomer 2: 22 mg (> 98.5% stereochemical purity).

Rt = 6.25 min [analytical HPLC: Daicel® Chiralpak OX column, 1 ml / min; 3 μm, 50x4.6 mm; solvent: 90% n-hexane / 20% ethanol + 0.2% diethylamine; detection: 220 nm].

LCMS (Method 3): Rt = 1.90 min; MS (ESIpos): m / z = 591 [M + H] ⁺ .

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: -0.149 (0.93), -0.008 (8.98), 0.008 (6.74), 0.146 (0.86), 0.323 (1.38), 0.333 (2.14), 0.346 (2.11), 0.359 (1.59), 0.370 (0.79), 0.513 (1.52), 0.525 (2.14), 0.538 (1.90), 0.552 (1.76), 0.560 (1.66), 0.572 (2.11), 0.582 (1.80), 0.593 (1.66), 0.604 (1.35), 0.616 (0.90), 0.630 (1.00), 0.640 (1.17), 0.651 (1.83), 0.661 (1.73), 0.675 (1.62), 0.696 (0.55), 1.101 (1.42), 1.119 (2.80), 1.137 (1.35), 1.175 (0.90), 1.183 (1.31), 1.196 (2.18), 1.205 (1.56), 1.216 (2.11), 1.228 (1.24), 2.323 (1.42), 2.327 (1.83), 2.366 (1.52), 2.523 (5.46), 2.670 (1.73), 2.710 (1.35), 2.825 (0.59), 2.843 (0.59), 3.465 (15.86), 3.479 (16.00), 4.127 (0.90), 4.333 (1.14), 4.354 (1.90), 4.374 (1.87), 4.395 (1.00), 4.830 (5.36), 4.844 (12.75), 4.857 (5.22), 7.667 (1.24), 7.673 (1.90), 7.690 (2.14), 7.697 (3.46), 7.713 (3.52), 7.720 (3.84), 7.732 (2.63), 7.967 (7.02), 7.995 (6.88), 8.758 (15.14), 10.480 (4.53), 10.503 (4.32).

Example 72.

1- (2-Chloro-4,6-difluorophenyl) -N - [(1S) -1-cyclopropyl-2,2,2-trifluoroethyl] -6-fluoro-7 - {[(2S) -2hydroxypropyl] (methyl ) amino} -4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide (mixture of atropisomers).

7-Chloro-1- (2-chloro-4,6-difluorophenyl) -N - [(1S) -1-cyclopropyl-2,2,2-trifluoroethyl] -6-fluoro-4-oxo-1,4dihydro- 1,8-naphthyridine-3-carboxamide (mixture of atropisomers, purity 57%, 90.0 mg, 176 μmol) was placed in 1.8 ml of DMF, mixed with (2S) -1- (methylamino) propan-2-ol (31.4 mg, 353 µmol) and N, N-diisopropylethylamine (110 µl, 620 µmol) and stirred overnight at room temperature. The reaction solution was poured onto water, the resulting precipitate was stirred for about 30 minutes, then filtered off, washed with water and dried under high vacuum. The residue was purified using thick layer chromatography (solvent: cyclohexane / ethyl acetate = 2/1). Received 31 mg of the target compound (31% theory. V., Purity 98%).

LCMS (Method 3): Rt = 2.20 min; MS (ESIpos): m / z = 563 [M + H] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: -0.149 (0.69), -0.008 (7.05), 0.008 (5.36), 0.146 (0.72), 0.314 (1.84), 0.325 (3.49), 0.336 (4.05), 0.348 (3.84), 0.360 (2.56), 0.525 (3.62), 0.545 (3.56), 0.552 (3.49), 0.563 (3.49), 0.573 (4.02), 0.584 (3.59), 0.593 (3.12), 0.607 (2.03), 0.623 (1.53), 0.632 (2.09), 0.642 (2.90), 0.653

- 86 038451 (3.59), 0.667 (3.34), 0.676 (2.68), 0.807 (11.54), 0.822 (7.64), 1.165 (0.78), 1.178 (1.59), 1.185 (2.34), 1.198 (4.02), 1.207 (2.99) ), 1.218 (3.84), 1.230 (2.12), 1.238 (1.03), 2.524 (4.96), 2.670 (1.81), 2.710 (1.06), 3.011 (1.72), 3.681 (2.50), 4.339 (1.31), 4.359 (2.68 ), 4.378 (6.80), 4.735 (5.99), 4.743 (5.68), 7.690 (1.28), 7.697 (1.43), 1.250 (0.65), 2.073 (0.53), 2.328 (1.72), 2.366 (1.40), 3.175 (6.49 ), 3.422 (2.50), 3.447 (2.50), 3.470 (3.27), 4.397 (2.46), 4.418 (1.09), 4.723 (5.02), 4.730 (2.00), 7.708 (2.56), 7.713 (2.50), 7.721 (4.05 ), 7.736 (6.83), 7.743 (5.74), 7.757 (6.11), 7.995 (13.35), 8.029 (13.13), 8.791 (14.07), 8.795 (16.00), 10.460 (7.42), 10.484 (7.14).

Example 73.

1- (2-Chloro-4,6-difluorophenyl) -7 - [(3R, 4R) -3,4-dihydroxypyrrolidin-1-yl] -6-fluoro-N- (2-methylbutan2-yl) -4- oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide (mixture of atropisomers).

1- (2-Chloro-4,6-difluorophenyl) -7 - [(3R, 4R) -3,4-dihydroxypyrrolidin-1-yl] -6-fluoro-4-oxo-1,4-dihydro-1,8- naphthyridine-3-carboxylic acid (80.0 mg, 176 µmol) was added to 1.2 ml of DMF, mixed with HATU (80.1 mg, 211 µmol) and N, N-diisopropylethylamine (110 µl, 610 µmol) and stirred for 30 min at room temperature. Added 2-methylbutan-2-amine (18.4 mg, 211 μmol) and stirred overnight at room temperature. The reaction mixture was mixed with acetonitrile / water / trifluoroacetic acid and purified by preparative HPLC (RP18 columns, eluent: acetonitrile / water gradient with the addition of 0.1% trifluoroacetic acid). The product fractions were then concentrated in vacuo and the residue was extracted twice with dichloromethane. The combined phases were washed twice with saturated aqueous sodium hydrogen carbonate solution. The combined aqueous phases were back-extracted with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. Received 58 mg of the target compound (62% theory. V. 99% purity).

LCMS (Method 3): Rt = 1.82 min; MS (ESIpos): m / z = 525 [M + H] +.

Example 74.

N-tert-Butyl-1- (2-chloro-4,6-difluorophenyl) -7 - [(3R, 4R) -3,4-dihydroxypyrrolidin-1-yl] -6-fluoro-4oxo-1,4- dihydro-1,8-naphthyridine-3-carboxamide (mixture of atropisomers).

1- (2-Chloro-4,6-difluorophenyl) -7 - [(3R, 4R) -3,4-dihydroxypyrrolidin-1-yl] -6-fluoro-4-oxo-1,4-dihydro-1,8- naphthyridine-3-carboxylic acid (100.0 mg, 219 µmol) was placed in 3.1 ml of DMF, mixed with HATU (100 mg, 263 µmol) and N, N-diisopropylethylamine (130 µl, 770 µmol) and stirred for 30 min at room temperature. Added 2-methylpropan-2-amine (19.3 mg, 263 μmol) and stirred overnight at room temperature. The reaction mixture was mixed with acetonitrile / water / trifluoroacetic acid and purified by preparative HPLC (RP18 columns, eluent: acetonitrile / water gradient with the addition of 0.1% trifluoroacetic acid). The product fractions were then concentrated in vacuo and the residue was extracted twice with dichloromethane. The combined phases were washed twice with saturated aqueous sodium hydrogen carbonate solution. The combined aqueous phases were back-extracted with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. 86 mg of the target compound was obtained (76% theory, 99% purity).

LCMS (Method 3): Rt = 1.71 min; MS (ESIpos): m / z = 511 [M + H] +.

Example 75.

1- (3,5-Difluoropyridin-2-yl) -7 - [(3R, 4R) -3,4-dihydroxypyrrolidin-1-yl] -6-fluoro-N- (2-methylbutan2-yl) -4- oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide.

1- (3,5-Difluoropyridin-2-yl) -7 - [(3R, 4R) -3,4-dihydroxypyrrolidin-1-yl] -6-fluoro-4-oxo-1,4-dihydro-1,8- naphthyridine-3-carboxylic acid (57.0 mg, 135 μmol) was placed in 1.4 ml of DMF, mixed with HATU (61.6 mg, 162 μmol) and N, N-diisopropylethylamine (94 μL, 540 μmol) and stirred for 10 min at room temperature. temperature. The reaction mixture was mixed with 2-methylbutane-2-amine (24 μl, 200 μmol) and stirred for 2 h at room temperature, the reaction solution was mixed with acetonitrile / water / TFA and purified by preparative HPLC (RP18 columns, eluent: acetonitrile / water gradient with the addition of 0.1% trifluoroacetic acid). The product fractions were then concentrated in vacuo, the residue was brought to an alkaline medium with saturated aqueous sodium hydrogen carbonate solution, and extracted twice with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. 55 mg of the target compound was obtained (82% theoretical, 98% purity).

LCMS (Method 3): Rt = 1.63 min; MS (ESIpos): m / z = 492 [M + H] ⁺ .

Example 76.

- (3,5-Difluoropyridin-2-yl) -7 - [(3R, 4R) -3,4-dihydroxypyrrolidin-1-yl] -6-fluoro-N- (3-methylpentan-3-yl) -4 -oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide.

1- (3,5-Difluoropyridin-2-yl) -7 - [(3R, 4R) -3,4-dihydroxypyrrolidin-1-yl] -6-fluoro-4-oxo-1,4-dihydro-1,8- naphthyridine-3-carboxylic acid (57.0 mg, 135 μmol) was placed in 1.4 ml of DMF, mixed with HATU (61.6 mg, 162 μmol) and N, N-diisopropylethylamine (140 μL, 810 μmol) and stirred for 10 min at room temperature. temperature. The reaction mixture was mixed with 3-methylpentane-3-amine hydrochloride (27.9 mg, 202 μmol) and stirred for 2 h at room temperature. Reak

87 038451 The mixture was mixed with acetonitrile / water / trifluoroacetic acid and purified by preparative HPLC (RP18 columns, solvent: acetonitrile / water-gradient with the addition of 0.1% trifluoroacetic acid). Then, the product fractions were concentrated in vacuo, the residue was set alkaline with saturated aqueous sodium hydrogen carbonate solution and extracted twice with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. Received 51 mg of the target compound (74% theory. V. 98% purity).

LCMS (Method 3): Rt = 1.74 min; MS (ESIpos): m / z = 506 [M + H] +.

Example 77.

7 - [(3R, 4S) -3,4-Dihydroxypyrrolidin-1-yl] -N- (3-ethylpentan-3-yl) -6-fluoro-4-oxo-1- (2,4,6trifluorophenyl) - 1,4-dihydro-1,8-naphthyridine-3-carboxamide.

7 - [(3R, 4S) -3,4-Dihydroxypyrrolidin-1-yl] -6-fluoro-4-oxo-1- (2,4,6-mfluorophenyl) -1,4-dihydro1,8-naphthyridine- 3-carboxylic acid (75.0 mg, 81% purity, 138 μmol) was placed in 1.9 ml of DMF, mixed with 3-ethylpentane-3-amine (19.1 mg, 166 μmol), N, N-diisopropylethylamine (84 μL, 480 μmol) and HATU (63.1 mg, 166 μmol) and stirred for 4 h at room temperature. The reaction mixture was mixed with acetonitrile / water / trifluoroacetic acid and purified by preparative HPLC (RP18 columns, eluent: acetonitrile / water gradient with the addition of 0.1% trifluoroacetic acid). Then, the product fractions were concentrated in vacuo, the residue was set alkaline with saturated aqueous sodium hydrogen carbonate solution and extracted twice with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. Received 59 mg of the target compound (78% theory. V., Purity 98%).

LCMS (Method 5): Rt = 1.41 min; MS (ESIpos): m / z = 537 [M + H] +.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: -0.008 (1.80), 0.008 (1.47), 0.768 (6.83), 0.786 (16.00), 0.805 (7.41), 1.699 (1.98), 1.718 (6.06), 1.736 (5.80), 1.755 (1.82), 2.328 (0.52), 2.366 (0.40), 2.670 (0.59), 4.030 (0.92), 4.991 (0.91), 7.545 (1.37), 7.567 (2.66), 7.589 (1.38), 7.979 (2.75), 8.011 (2.73), 8.667 (4.92), 9.612 (2.83).

Example 78.

7 - [(3R, 4S) -3,4-Dihydroxypyrrolidin-1-yl] -6-fluoro-N- (3-methylpenman-3-yl) -4-oxo-1- (2,4,6trifluorophenyl) - 1,4-dihydro-1,8-naphthyridine-3-carboxamide.

7 - [(3R, 4S) -3,4-Dihydroxypyrrolidin-1-yl] -6-fluoro-4-oxo-1- (2,4,6-trifluorophenyl) -1,4-dihydro1,8-naphthyridine- 3-carboxylic acid (75.0 mg, 81% purity, 138 μmol) was placed in 1.9 ml of DMF, mixed with 3-methylpentane-3-amine hydrochloride (22.8 mg, 166 μmol), N, N-diisopropylethylamine (84 μl, 480 μmol) and HATU (63.1 mg, 166 μmol) and left stirring for 4 h at room temperature. The reaction mixture was mixed with acetonitrile / water / trifluoroacetic acid and purified by preparative HPLC (RP18 columns, eluent: acetonitrile / water gradient with the addition of 0.1% trifluoroacetic acid). Then, the product fractions were concentrated in vacuo, the residue was set alkaline with saturated aqueous sodium hydrogen carbonate solution and extracted twice with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. Received 63 mg of the target compound (85% theory. V. 98% purity).

LCMS (Method 5): Rt = 1.35 min; MS (ESIpos): m / z = 523 [M + H] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: -0.008 (1.46), 0.008 (1.29), 0.814 (6.64), 0.833 (15.52), 0.851 (7.27), 1.234 (0.50), 1.279 ( 16.00), 1.613 (0.42), 1.631 (1.48), 1.649 (1.89), 1.665 (2.44), 1.684 (1.96), 1.703 (0.49), 1.769 (0.57), 1.787 (2.03), 1.806 (2.32), 1.822 ( 1.86), 1.841 (1.35), 2.073 (8.37), 2.328 (0.49), 2.523 (1.67), 2.670 (0.52), 4.031 (1.20), 4.989 (1.19), 7.546 (1.83), 7.568 (3.46), 7.590 ( 1.84), 7.977 (3.61), 8.008 (3.53), 8.669 (6.19), 9.728 (3.98).

Example 79.

7 - [(3R, 4S) -3,4-Dihydroxypyrrolidin-1-yl] -6-fluoro-N- (2-methylbutan-2-yl) -4-oxo-1- (2,4,6trifluorophenyl) - 1,4-dihydro-1,8-naphthyridine-3-carboxamide.

7 - [(3R, 4S) -3,4-Dihydroxypyrrolidin-1-yl] -6-fluoro-4-oxo-1- (2,4,6-trifluorophenyl) -1,4-dihydro1,8-naphthyridine- 3-carboxylic acid (75.0 mg, 81% purity, 138 μmol) was placed in 1.9 ml of DMF, mixed with 2-methylbutane-2-amine (19 μl, 170 μmol), N, N-diisopropylethylamine (84 μl, 480 μmol) and HATU (63.1 mg, 166 μmol) and left stirring for 4 h at room temperature. The reaction mixture was mixed with acetonitrile / water / trifluoroacetic acid and purified by preparative HPLC (RP18 columns, eluent: acetonitrile / water gradient with the addition of 0.1% trifluoroacetic acid). Then, the product fractions were concentrated in vacuo, the residue was set alkaline with saturated aqueous sodium hydrogen carbonate solution and extracted twice with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. Received 63 mg of the target compound (88% theory. V., Purity 98%).

LCMS (Method 5): Rt = 1.29 min; MS (ESIpos): m / z = 509 [M + H] +.

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: -0.008 (0.76), 0.008 (0.52), 0.848 (1.75), 0.867 (4.17), 0.885

- 88 038451 (1.87), 1.341 (16.00), 1.703 (0.53), 1.722 (1.62), 1.740 (1.54), 1.759 (0.45), 2.073 (3.41), 2.518 (0.96), 2.523 (0.79), 4.032 (0.61 ), 4.989 (0.60), 5.754 (0.54), 7.547 (0.88), 7.569 (1.67), 7.591 (0.89), 7.970 (1.66), 8.001 (1.63), 8.673 (2.83), 9.810 (2.01).

Example 80.

N-tert-Butyl-7 - [(3R, 4S) -3,4-dihydroxypyrrolidin-1-yl] -6-fluoro-4-oxo-1- (2,4,6-trifluorophenyl) 1,4-dihydro -1,8-naphthyridine-3-carboxamide.

7 - [(3R, 4S) -3,4-Dihydroxypyrrolidin-1-yl] -6-fluoro-4-oxo-1- (2,4,6-trifluorophenyl) -1,4-dihydro1,8-naphthyridine- 3-carboxylic acid (75.0 mg, 81% purity, 138 μmol) was placed in 1.9 ml of DMF, mixed with 2-methylpropane-2-amine (17 μl, 170 μmol), N, N-diisopropylethylamine (84 μl, 480 μmol) and HATU (63.1 mg, 166 μmol) and left stirring over the weekend at room temperature. The reaction mixture was mixed with acetonitrile / water / trifluoroacetic acid and purified by preparative HPLC (RP18 columns, eluent: acetonitrile / water gradient with the addition of 0.1% trifluoroacetic acid). The product fractions were concentrated in vacuo, the residue was taken up in dichloromethane / a little methanol. The organic phases were washed twice with saturated aqueous sodium hydrogen carbonate solution. The combined aqueous phases were back-extracted once with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. Received 42 mg of the target compound (60% theory. V. 98% purity).

LCMS (Method 3): Rt = 1.72 min; MS (ESIpos): m / z = 495 [M + H] +.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 0.008 (1.47), 1.388 (16.00), 2.073 (1.33), 4.028 (0.44), 4.989 (0.44), 7.547 (0.61), 7.569 ( 1.21), 7.591 (0.63), 7.957 (1.13), 7.989 (1.12), 8.679 (2.13), 9.865 (1.33).

Example 81.

N - [(1S) -1-Cyclopropyl-2,2,2-trifluoroethyl] -6-fluoro-4-oxo-7- (piperazin-1-yl) -1- (2,4,6trifluorophenyl) -1, 4-dihydro-1,8-naphthyridine-3-carboxamide.

tert-Butyl-4- [6 - {[(1S) -1-cyclopropyl-2,2,2-trifluoroethyl] carbamoyl} -3-fluoro-5-oxo-8- (2,4,6trifluorophenyl) -5, 8-dihydro-1,8-naphthyridin-2-yl] piperazine-1-carboxylate (113 mg, 69% pure, 121 μmol) was placed in 0.72 ml of dichloromethane, mixed with trifluoroacetic acid (360 μL, 4.7 mmol) and stirred in for 1 hour at room temperature. The reaction mixture was concentrated in vacuo, mixed with acetonitrile / water / trifluoroacetic acid and purified by preparative HPLC (RP18 columns, eluent: methanol / water gradient with the addition of 0.1% trifluoroacetic acid). Then the product fractions were evaporated. The residue was taken up in ethyl acetate, the aqueous phase was made alkaline with saturated aqueous sodium hydrogen carbonate solution. The aqueous phase was extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. The starting material was then purified by thick layer chromatography (eluent: dichloromethane / 2M ammonia in methanol = 20/1). Received 43 mg of the target compound (65% theory. V., 99% purity).

LCMS (Method 3): Rt = 1.36 min; MS (ESIpos): m / z = 544 [M + H] ⁺ .

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: -0.149 (0.64), -0.008 (6.43), 0.008 (5.61), 0.146 (0.68), 0.319 (2.04), 0.329 (3.29), 0.342 (3.21), 0.353 (2.50), 0.365 (1.25), 0.504 (0.82), 0.516 (2.18), 0.528 (3.29), 0.541 (3.07), 0.550 (3.43), 0.568 (3.57), 0.578 (2.79), 0.589 (2.54), 0.599 (2.07), 0.613 (1.29), 0.628 (1.86), 0.638 (1.71), 0.648 (3.14), 0.659 (2.61), 0.665 (2.43), 0.671 (2.39), 0.680 (1.18), 0.693 (0.79), 1.170 (0.64), 1.182 (1.32), 1.190 (1.89), 1.202 (3.18), 1.211 (2.32), 1.223 (3.18), 1.235 (2.07), 1.243 (1.29), 1.256 (0.57), 2.073 (0.96), 2.328 (1.21), 2.367 (1.04), 2.524 (4.82), 2.663 (12.39), 2.675 (16.00), 2.687 (12.50), 2.710 (1.39), 3.440 (12.39), 3.452 (15.11), 3.464 (11.71), 4.333 (0.43), 4.353 (1.64), 4.374 (2.89), 4.395 (2.86), 4.415 (1.54), 5.754 (0.43), 7.555 (5.61), 7.577 (10.82), 7.599 (5.71), 8.060 (9.39), 8.094 (9.29), 8.876 (15.57), 10.387 (6.43), 10.411 (6.29).

Example 82.

N - [(1S) -1-Cyclopropyl-2,2,2-trifluoroethyl] -6-fluoro-7 - [(3S) -3-methylpiperazin-1-yl] -4-oxo-1- (2,4 , 6trifluorophenyl) -1,4-dihydro-1,8-naphthyridine-3-carboxamide.

tert-Butyl- (2S) -4- [6 - {[(1S) -1-cyclopropyl-2,2,2-trifluoroethyl] carbamoyl} -3-fluoro-5-oxo-8- (2,4,6trifluorophenyl ) -5,8-dihydro-1,8-naphthyridin-2-yl] -2-methylpiperazine-1-carboxylate (81.5 mg, 90% purity, 112 μmol) was placed in 0.66 ml of dichloromethane, mixed with trifluoroacetic acid (330 μl , 4.3 mmol) and stirred for 1 h at room temperature. The reaction solution was diluted with dichloromethane and washed three times with saturated sodium chloride aqueous solution. The combined aqueous phases were back-extracted with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. The reaction mixture was mixed with acetonitrile / water / trifluoroacetic acid and purified by preparative HPLC (RP18 columns, eluent: acetonitrile / water gradient with the addition of 0.1% trifluoroacetic acid). Then the product fractions were evaporated. The residue was taken up in ethyl acetate, the aqueous phase was made alkaline with saturated aqueous sodium hydrogen carbonate solution. The aqueous phase was extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. The starting material was then purified by thick layer chromatography (solvent: dichloromethane / 2N ammonia in methanol = 20/1). Received 26.3 mg of the target compound (40% theory. V., Purity 95%).

LCMS (Method 3): Rt = 1.40 min; MS (ESIpos): m / z = 558 [M + H] +.

Ή-NMR (400 MHz, DMSO-de) δ [ppm]: -0.149 (0.92), -0.008 (8.28), 0.008 (6.83), 0.146 (0.92), 0.320 (1.78), 0.330 (2.85), 0.342 ( 2.76), 0.354 (2.17), 0.365 (1.07), 0.516 (1.90), 0.527 (2.85), 0.540 (2.64), 0.549 (2.97), 0.568 (3.09), 0.578 (2.40), 0.588 (2.20), 0.599 ( 1.81), 0.613 (1.10), 0.628 (1.60), 0.638 (1.54), 0.648 (2.73), 0.659 (2.29), 0.664 (2.11), 0.670 (2.11), 0.680 (1.10), 0.693 (0.80), 0.837 ( 15.47), 0.852 (16.00), 0.919 (0.53), 1.169 (0.62), 1.182 (1.22), 1.190 (1.75), 1.202 (2.82), 1.210 (2.08), 1.222 (2.82), 1.234 (1.99), 1.242 ( 1.16), 1.255 (0.53), 2.119 (0.42), 2.302 (2.94), 2.323 (1.22), 2.328 (1.34), 2.366 (0.74), 2.524 (4.36), 2.573 (3.06), 2.605 (1.51), 2.666 ( 0.95), 2.670 (1.28), 2.675 (0.92), 2.711 (0.74), 2.805 (2.64), 2.834 (2.05), 2.965 (1.40), 2.972 (1.57), 2.998 (2.52), 3.027 (1.57), 3.869 ( 3.06), 3.896 (3.06), 3.972 (2.43), 4.004 (2.29), 4.355 (1.45), 4.375 (2.52), 4.397 (2.49), 4.417 (1.37), 7.577 (4.93), 7.599 (9.26), 7.622 ( 4.96), 7.630 (1.75), 8.053 (8.55), 8. 088 (8.37), 8.890 (14.58), 8.913 (0.50), 10.390 (5.67), 10.414 (5.34).

Example 83.

N - [(1S) -1-Cyclopropyl-2,2,2-trifluoroethyl] -6-fluoro-7- (2-oxa-6-azaspiro [3.3] hept-6-yl) -4-oxo-1 ( 2,4,6-trifluorophenyl) -1,4-dihydro-1,8-naphthyridine-3-carboxamide.

7-Chloro-N - [(1S) -1-cyclopropyl-2,2,2-trifluoroethyl] -6-fluoro-4-oxo-1- (2,4,6-trifluorophenyl) -1,4 dihydro-1, 8-naphthyridine-3-carboxamide (1.20 g, 2.43 mmol) was placed in 23 ml of DMF, mixed with ethanedic acid-2-oxa-6-azaspiro [3.3] heptane (1: 1) (644 mg, 3.40 mmol) and Ν, -Diisopropylethylamine (2.1 ml, 12 mmol) and stirred overnight at room temperature. The reaction solution was mixed with water and the precipitated solid was filtered off and dried under high vacuum. The starting material was purified by chromatography on silica gel (solvent: 100% dichloromethane to dichloromethane / methanol = 100/1). Received 1.0 g of the target compound (73% theory. V. 99% purity).

LCMS (Method 3): Rt = 2.20 min; MS (ESIpos): m / z = 557 [M + H] ⁺ .

Example 84.

7- [3,3-bis- (Hydroxymethyl) azetidin-1-yl] -N - [(1S) -1-cyclopropyl-2,2,2-trifluoroethyl] -6-fluoro-4oxo-1- (2, 4,6-trifluorophenyl) -1,4-dihydro-1,8-naphthyridine-3-carboxamide.

N - [(1S) -1-cyclopropyl-2,2,2-trifluoroethyl] -6-fluoro-7- (2-oxa-6-azaspiro [3.3] hept-6-yl) -4-oxo-1 ( 2,4,6-trifluorophenyl) -1,4-dihydro-1,8-naphthyridine-3-carboxamide (65.0 mg, 117 μmol) was placed in trifluoroacetic acid (730 μL, 9.5 mmol), mixed with 730 μL of water and 730 μl of acetonitrile and stirred for two days at room temperature. The reaction mixture was purified by preparative HPLC (RP18 columns, eluent: acetonitrile / water gradient with the addition of 0.1% trifluoroacetic acid). The product fractions were concentrated in vacuo, the residue was taken up in dichloromethane and washed twice with saturated aqueous sodium hydrogen carbonate solution. The combined aqueous phases were back-extracted with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. Received 45 mg of the target compound (66% theory. V. 99% purity).

LCMS (Method 3): Rt = 1.86 min; MS (ESIpos): m / z = 575 [M + H] ⁺ .

Ή-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: -0.149 (0.42), -0.008 (3.70), 0.008 (3.30), 0.146 (0.41), 0.316 (1.31), 0.326 (2.15), 0.338 (2.07), 0.350 (1.69), 0.362 (0.80), 0.510 (1.45), 0.521 (2.09), 0.534 (1.89), 0.545 (2.18), 0.553 (1.61), 0.564 (2.23), 0.575 (1.72), 0.585 (1.64), 0.595 (1.33), 0.609 (0.83), 0.624 (1.13), 0.634 (1.13), 0.645 (1.97), 0.655 (1.70), 0.668 (1.59), 1.163 (0.46), 1.175 (0.92), 1.183 (1.27), 1.195 (2.15), 1.204 (1.50), 1.215 (2.10), 1.228 (1.24), 1.236 (1.21), 2.074 (10.78), 2.328 (0.75), 2.366 (0.47), 2.670 (0.66), 2.710 (0.41), 3.475 (15.83), 3.488 (16.00), 4.130 (0.94), 4.349 (1.22), 4.369 (1.91), 4.390 (1.84), 4.410 (0.97), 4.835 (5.32), 4.848 (12.45), 4.861 (5.07), 5.754 (4.77), 7.532 (3.99), 7.554 (7.54), 7.576 (3.92), 7.963 (6.93), 7.992 (6.79), 8.808 (12.92), 10.463 (4.45), 10.487 (4.20).

Example 85.

tert-Butyl-4 - [({7 - [(3R, 4R) -3,4-dihydroxypyrrolidin-1-yl] -6-fluoro-4-oxo-1- (2,4,6-trifluorophenyl) -1 , 4-dihydro-1,8-naphthyridin-3-yl} carbonyl) amino] -3,3-difluoropiperidine-1-carboxylate.

7 - [(3R, 4R) -3,4-Dihydroxypyrrolidin-1-yl] -6-fluoro-4-oxo-1- (2,4,6-trifluorophenyl) -1,4-dihydro1,8-naphthyridine- 3-carboxylic acid (50.0 mg, 73% purity, 83.1 μmol) was placed in 1.2 ml of DMF, mixed with HATU (37.9 mg, 99.7 μmol) and Ν, Ν-diisopropylethylamine (36 μL, 210 μmol) and stirred for 30 min at room temperature. Added tert-butyl 4-amino-3,3 difluoropiperidine-1-carboxylate (23.6 mg, 99.7 μmol) and the mixture was left stirring for 2 h at room temperature. The reaction mixture was mixed with acetonitrile / water / trifluoroacetic acid and purified by preparative HPLC (RP18 columns, eluent: acetonitrile / water gradient with the addition of 0.1% trifluoroacetic acid). The product fractions were then concentrated in vacuo and the residue was extracted twice with dichloromethane. The combined phases were washed twice with saturated aqueous sodium hydrogen carbonate solution. The combined aqueous phases were back-extracted with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated in

- 90 038451 vacuum. Received 48 mg of the target compound (87% theory. V., 99% purity).

LCMS (Method 3): Rt = 1.81 min; MS (ESIpos): m / z = 658 [M + H] +.

Ή-NMR (400 MHz, DMSO-de) δ [ppm]: -0.008 (0.48), 1.157 (0.55), 1.175 (1.10), 1.193 (0.55), 1.427 (16.00), 1.988 (2.06), 4.021 (0.59 ), 4.038 (0.53), 5.192 (0.56), 7.572 (0.73), 7.995 (0.80), 8.026 (0.78), 8.807 (1.58), 10.314 (0.54), 10.337 (0.51).

Example 86.

Methyl-4 - [({7 - [(3R, 4R) -3,4-dihydroxypyrrolidin-1-yl] -6-fluoro-4-oxo-1- (2,4,6-trifluorophenyl) -1,4 dihydro -1,8-naphthyridin-3-yl} carbonyl) amino] bicyclo [2.2.1] heptane-1 -carboxylate.

7 - [(3R, 4R) -3,4-Dihydroxypyrrolidin-1-yl] -6-fluoro-4-oxo-1- (2,4,6-trifluorophenyl) -1,4-dihydro1,8-naphthyridine- 3-carboxylic acid (50.0 mg, 98% purity, 112 µmol) was placed in 1.6 ml of DMF, mixed with HATU (50.9 mg, 134 µmol) and Ν, Ν-diisopropylethylamine (49 µl, 280 µmol) and stirred for 30 min at room temperature. Methyl 4-aminobicyclo [2.2.1] heptane-1carboxylate (22.6 mg, 134 µmol) was added and left stirring for 2 h at room temperature. The reaction mixture was mixed with acetonitrile / water / trifluoroacetic acid and purified by preparative HPLC (RP18 columns, eluent: acetonitrile / water gradient with the addition of 0.1% trifluoroacetic acid). Then the product fractions were concentrated in a vacuum, the residue was extracted twice with dichloromethane. The combined phases were washed twice with saturated aqueous sodium hydrogen carbonate solution. The combined aqueous phases were back-extracted with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. Received 52 mg of the target compound (78% theory. V., 99% purity).

LCMS (Method 3): Rt = 1.68 min; MS (ESIpos): m / z = 591 [M + H] ⁺ .

¹ H-NMR (400 MHz, CHLOROFORM-d) δ [ppm]: -0.008 (0.56), 0.008 (0.54), 1.584 (6.18), 1.725 (0.82), 1.751 (1.60), 1.765 (1.06), 1.903 ( 0.99), 1.917 (1.54), 1.943 (0.96), 2.006 (0.84), 2.083 (0.44), 2.124 (3.16), 2.138 (3.63), 2.155 (4.94), 2.279 (1.00), 3.693 (16.00), 4.255 ( 2.00), 6.860 (1.01), 6.880 (1.82), 6.899 (1.04), 7.997 (1.62), 8.029 (1.61), 8.522 (3.08), 10.228 (2.05).

Example 87.

7 - [(3R, 4R) -3,4-Dihydroxypyrrolidin-1-yl] -N- (3-ethylpentan-3-yl) -6-fluoro-4-oxo-1- (2,4,6trifluorophenyl) - 1,4-dihydro-1,8-naphthyridine-3-carboxamide.

7 - [(3R, 4R) -3,4-Dihydroxypyrrolidin-1-yl] -6-fluoro-4-oxo-1- (2,4,6-trifluorophenyl) -1,4-dihydro1,8-naphthyridine- 3-carboxylic acid (50.0 mg, 73% purity, 83.1 μmol) was placed in 1.2 ml of DMF, mixed with HATU (37.9 mg, 99.7 μmol) and Ν, Ν-diisopropylethylamine (36 μL, 210 μmol) and stirred for 30 min at room temperature. temperature. Added 3-ethylpentan-3-amine (11.5 mg, 99.7 μmol) and stirred overnight at room temperature. The reaction mixture was mixed with acetonitrile / water / trifluoroacetic acid and purified by preparative HPLC (RP18 columns, eluent: acetonitrile / water gradient with the addition of 0.1% trifluoroacetic acid). The product fractions were then concentrated in vacuo and the residue was extracted twice with ethyl acetate. The combined phases were washed twice with saturated aqueous sodium hydrogen carbonate solution. The combined aqueous phases were back-extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. Received 36 mg of the target compound (80% theory. V., 99% purity).

LCMS (Method 3): Rt = 1.99 min; MS (ESIpos): m / z = 537 [M + H] +.

¹ H-NMR (400 MHz, DMSO-de) δ [ppm]: -0.008 (0.97), 0.008 (0.75), 0.770 (6.80), 0.789 (16.00), 0.807 (7.33), 1.702 (1.95), 1.720 ( 5.99), 1.739 (5.74), 1.757 (1.74), 2.524 (0.69), 3.918 (0.49), 5.191 (1.51), 7.549 (1.11), 7.571 (1.93), 7.592 (1.09), 7.991 (2.75), 8.023 ( 2.69), 8.671 (4.76), 9.621 (2.85).

Example 88.

7 - [(3R, 4R) -3,4-Dihydroxypyrrolidin-1-yl] -6-fluoro-N- (3-methylpentan-3-yl) -4-oxo-1- (2,4,6trifluorophenyl) - 1,4-dihydro-1,8-naphthyridine-3-carboxamide.

7 - [(3R, 4R) -3,4-Dihydroxypyrrolidin-1-yl] -6-fluoro-4-oxo-1- (2,4,6-trifluorophenyl) -1,4-dihydro1,8-naphthyridine- 3-carboxylic acid (40.0 mg, 73% purity, 66.5 μmol) was placed in 0.93 DMF, mixed with HATU (30.3 mg, 79.8 μmol) and Ν, Ν-diisopropylethylamine (29 μL, 170 μmol) and stirred for 30 min at room temperature ... 3-methylpentane-3-amine hydrochloride (11.0 mg, 79.8 μmol) was added and stirred for 2 h at room temperature. The reaction mixture was mixed with acetonitrile / water / trifluoroacetic acid and purified by preparative HPLC (RP18 columns, eluent: acetonitrile / water gradient with the addition of 0.1% trifluoroacetic acid). Then the product fractions were concentrated in a vacuum, the residue was extracted twice with dichloromethane. The combined phases were washed twice with saturated aqueous sodium hydrogen carbonate solution. The combined aqueous phases were back-extracted with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. Received 29 mg of the target compound (83% theory. V., 99% purity).

LCMS (Method 3): Rt = 1.88 min; MS (ESIpos): m / z = 523 [M + H] +.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 0.008 (2.16), 0.817 (6.77), 0.835 (15.54), 0.854 (7.44),

- 91 038451

1.282 (16.00), 1.616 (0.41), 1.634 (1.39), 1.652 (1.86), 1.668 (2.36), 1.687 (1.89), 1.705 (0.53), 1.773 (0.62), 1.791 (2.07), 1.809 (2.44), 1.826 (1.91), 1.844 (1.39), 3.908 (0.77), 5.190 (2.41), 7.550 (1.66), 7.572 (3.01), 7.593 (1.62), 7.990 (3.59), 8.022 (3.54), 8.673 (6.67), 9.737 (4.26).

Example 89.

7 - [(3R, 4R) -3,4-Dihydroxypyrrolidin-1-yl] -6-fluoro-N- (2-methylbutan-2-yl) -4-oxo-1- (2,4,6trifluorophenyl) - 1,4-dihydro-1,8-naphthyridine-3-carboxamide.

7 - [(3R, 4R) -3,4-Dihydroxypyrrolidin-1-yl] -6-fluoro-4-oxo-1- (2,4,6-trifluorophenyl) -1,4-dihydro1,8-naphthyridine- 3-carboxylic acid (50.0 mg, 73% purity, 83.1 μmol) was placed in 1.2 mL of DMF, mixed with HATU (37.9 mg, 99.7 μmol) and N, N-diisopropylethylamine (36 μL, 210 μmol) and stirred for 30 min at room temperature. temperature. Added 2-methylbutan-3-s (12 μl, 100 μmol) and stirred for 2 h at room temperature. The reaction mixture was mixed with acetonitrile / water / trifluoroacetic acid and purified by preparative HPLC (RP18 columns, eluent: acetonitrile / water gradient with the addition of 0.1% trifluoroacetic acid). The product fractions were then concentrated in vacuo and the residue was extracted twice with ethyl acetate. The combined phases were washed twice with saturated aqueous sodium hydrogen carbonate solution. The combined aqueous phases were back-extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. Received 34 mg of the target compound (80% theory. V. 99% purity).

LCMS (Method 3): Rt = 1.76 min; MS (ESIpos): m / z = 509 [M + H] +.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 0.008 (1.67), 0.851 (1.89), 0.869 (4.29), 0.888 (1.90), 1.343 (16.00), 1.706 (0.62), 1.724 ( 1.70), 1.743 (1.61), 1.761 (0.47), 3.909 (0.41), 5.186 (1.22), 7.551 (0.86), 7.573 (1.45), 7.593 (0.83), 7.982 (1.87), 8.014 (1.83), 8.676 ( 3.26), 9.818 (2.08).

Example 90.

N-tert-Butyl-7 - [(3R, 4R) -3,4-dihydroxypyrrolidin-1-yl] -6-fluoro-4-oxo-1- (2,4,6-trifluorophenyl) 1,4-dihydro -1,8-naphthyridine-3-carboxamide.

7 - [(3R, 4R) -3,4-Dihydroxypyrrolidin-1-yl] -6-fluoro-4-oxo-1- (2,4,6-trifluorophenyl) -1,4-dihydro1,8-naphthyridine- 3-carboxylic acid (60.0 mg, 73% purity, 99.7 μmol) was placed in 1.4 ml of DMF, mixed with HATU (45.5 mg, 120 μmol) and N, N-diisopropylethylamine (43 μL, 250 μmol) and stirred for 30 min at room temperature. temperature. Added 2-methylpropan-3-amine (8.75 mg, 120 μmol) and stirred for 2 h at room temperature. The reaction mixture was mixed with acetonitrile / water / trifluoroacetic acid and purified by preparative HPLC (RP18 columns, eluent: acetonitrile / water gradient with the addition of 0.1% trifluoroacetic acid). Then the product fractions were concentrated in a vacuum, the residue was extracted twice with dichloromethane. The combined phases were washed twice with saturated aqueous sodium hydrogen carbonate solution. The combined aqueous phases were back-extracted with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. Received 26 mg of the target compound (52% theory. V., 99% purity).

LCMS (Method 3): Rt = 1.66 min; MS (ESIpos): m / z = 495 [M + H] +.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 0.008 (1.87), 1.245 (0.76), 1.260 (0.86), 1.275 (0.48), 1.390 (16.00), 5.185 (0.79), 7.551 ( 0.52), 7.573 (0.92), 7.594 (0.53), 7.970 (1.13), 8.002 (1.11), 8.682 (2.04), 9.872 (1.36).

Example 91.

7 - [(3R, 4S) -3,4-Dihydroxypyrrolidin-1-yl] -6-fluoro-4-oxo-N- (4,4,4-trifluoro-2-methylbutan-2-yl) -1 ( 2,4,6-trifluorophenyl) -1,4-dihydro-1,8-naphthyridine-3-carboxamide.

According to AAV1, 80.0 mg (182 μmol) 7 - [(3R, 4S) -3,4-dihydroxypyrrolidin-1-yl] -6fluoro-4-oxo-1- (2,4,6-trifluorophenyl) -1.4 -dihydro-1,8-naphthyridine-3-carboxylic acid with 45.3 mg (255 μmol) 4,4,4-trifluoro-2-methylbutan-2-amine hydrochloride in the presence of 83.1 mg (219 μmol) HATU and 95 μL (550 μmol) DIPEA in 730 μL DMF. The starting material was purified by preparative HPLC (column: acetonitrile / water / 0.1% formic acid). This gave 88.9 mg (87% theory, 100% purity) of the title compound.

LCMS (Method 3): Rt = 1.84 min; MS (ESIpos): m / z = 563 [M + H] +.

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 10.08 (s, 1H), 8.72 (s, 1H), 7.98 (d, 1H), 7.53-7.61 (m, 2H), 4.875.10 ( m, 2H), 3.83-4.11 (m, 3H), 3.48-3.69 (m, 1H), 3.12-3.27 (m, 1H), 2.87-3.09 (m, 3H), 1.48 (s, 6H).

Example 92.

7 - [(3R, 4S) -3,4-Dihydroxypyrrolidin-1-yl] -6-fluoro-4-oxo-N- [3,3,4,4,4-pentafluorobutan-2-yl] -1 ( 2,4,6-trifluorophenyl) -1,4-dihydro-1,8-naphthyridine-3-carboxamide (mixture of diastereoisomers).

According to AAV1, 150 mg (341 μmol) 7 - [(3R, 4S) -3,4-dihydroxypyrrolidin-1-yl] -6fluoro-4-oxo-1- (2,4,6-trifluorophenyl) -1,4 -dihydro-1,8-naphthyridine-3-carboxylic acid with 95.4 mg (478 μmol) 3,3,4,4,4-pentafluorobutan-2-amine hydrochloride (racemate) in the presence of 156 mg (410 μmol) HATU and 180 μl (1.00 mmol) DIPEA in 1.4 μl DMF. The starting material was purified by preparative HPLC (column: acetonitrile / water / 0.1% formic acid). Received 149 mg

- 92 038451 (75% theory, 100% purity) of the title compound.

LCMS (Method 3): Rt = 1.87 min; MS (ESIpos): m / z = 585 [M + H] +.

1H-NMR (400 MHz, DMSO <) δ [ppm]: 10.46 (d, 1H), 8.84 (s, 1H), 8.00 (d, 1H), 7.53-7.61 (m, 2H), 4.89-5.12 (m , 3H), 3.85-4.12 (m, 3H), 3.47-3.70 (m, 1H), 2.91-3.28 (m, 2H), 1.39 (d, 3H).

146 mg of the title compound (mixture of diastereoisomers) was separated into diastereoisomers by preparative HPLC (preparative HPLC: Daicel Chiralcel OX-H column, 5 μm, 250x30 mm; eluent: 80% n-heptane, 20% ethanol; temperature: 25 ° C ; flow: 40 ml / min; UV indication: 265 nm).

Received (as elution from the column) 56.0 mg of diastereoisomer 1 (99% de) Rt = 6.40 min and 55.8 mg of diastereoisomer 2 (98% de) Rt = 8.57 min.

[Analytical HPLC: Daicel OX-3 column, 3 μm, 50x4.6 mm; eluent: 80% isohexane, 20% ethanol; UV indication: 220 nm].

Diastereoisomer 1 was further purified by preparative HPLC (column: acetonitrile / water / 0.1% formic acid) to give 41.0 mg (21% theory, 100% purity) of the title compound from Example 93.

Diastereoisomer 2 was further purified by preparative HPLC (column: acetonitrile / water / 0.1% formic acid) to give 42.0 mg (21% theory, 100% purity) of the title compound from Example 94.

Example 93.

7 - [(3R, 4S) -3,4-dihydroxypyrrolidin-1-yl] -6-fluoro-4-oxo-N- [3,3,4,4,4-pentafluorobutan-2-yl] -1 ( 2,4,6-trifluorophenyl) -1,4-dihydro-1,8-naphthyridine-3-carboxamide (diastereoisomer 1).

LCMS (Method 3): Rt = 1.89 min; MS (ESIpos): m / z = 585 [M + H] +.

¹ H-NMR (400 MHz, DMSO <) δ [ppm]: 10.46 (d, 1H), 8.84 (s, 1H), 8.00 (d, 1H), 7.54-7.61 (m, 2H), 4.91-5.10 ( m, 3H), 3.84-4.12 (m, 3H), 3.43-3.67 (m, 1H), 3.12-3.28 (m, 1H), 2.88-3.11 (m, 1H), 1.39 (d, 3H).

Example 94.

7 - [(3R, 4S) -3,4-Dihydroxypyrrolidin-1-yl] -6-fluoro-4-oxo-N- [3,3,4,4,4-pentafluorobutan-2-yl] -1 ( 2,4,6-trifluorophenyl) -1,4-dihydro-1,8-naphthyridine-3-carboxamide (diastereoisomer 2).

LCMS (Method 3): Rt = 1.89 min; MS (ESIpos): m / z = 585 [M + H] +.

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 10.46 (d, 1H), 8.84 (s, 1H), 8.00 (d, 1H), 7.54-7.61 (m, 2H), 4.92-5.09 (m, 3H), 3.85-4.11 (m, 3H), 3.42-3.68 (m, 1H), 3.12-3.28 (m, 1H), 2.92-3.11 (m, 1H), 1.39 (d, 3H).

Example 95.

7 - [(3R, 4S) -3,4-Dihydroxypyrrolidin-1-yl] -6-fluoro-4-oxo-N- [1- (trifluoromethoxy) butan-2-yl] -1 (2,4,6 -trifluorophenyl) -1,4-dihydro-1,8-naphthyridine-3-carboxamide (mixture of diastereoisomers).

According to AAV1, 120 mg (273 μmol) 7 - [(3R, 4S) -3,4-dihydroxypyrroludin-1-yl] -6fluoro-4-oxo-1- (2,4,6-trifluorophenyl) -1,4 -dihydro-1,8-naphthyridine-3-carboxylic acid with 74.0 mg (382 μmol) 1- (trifluoromethoxy) butan-2-amine hydrochloride (racemate) in the presence of 125 mg (328 μmol) HATU and 140 μL (820 mmol) DIPEA in 1.1 ml DMF. The starting material was purified by preparative HPLC (column: acetonitrile / water / 0.1% formic acid). This gave 103 mg (65% theory, 100% purity) of the title compound.

LCMS (Method 1): Rt = 0.99 min; MS (ESIpos): m / z = 579 [M + H] +.

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 9.99 (br d, 1H), 8.76 (s, 1H), 8.00 (d, 1H), 7.53-7.61 (m, 2H), 4.79- 5.20 (m, 2H), 4.11-4.23 (m, 3H), 3.77-4.10 (m, 3H), 3.43-3.74 (m, 1H), 2.85-3.26 (m, 2H), 1.52-1.73 (m, 2H ), 0.94 (t, 3H).

100 mg of the title compound (mixture of diastereoisomers) was separated into diastereoisomers by preparative HPLC (preparative HPLC: Chiralpak AD-H column, 5 μm, 250x30 mm; eluent: 80% n-heptane, 20% ethanol; temperature: 25 ° C ; flow: 40 ml / min; UV indication: 265 nm).

Received (as elution from the column) 23.6 mg of diastereoisomer 1 (99% de) R _t = 10.77 min and 13.5 mg (9% theoretical, 100% purity) of diastereoisomer 2 from Example 97 (98% de) R _t = 12.40 minutes

[Analytical HPLC: Chiraltek AD-3 column, 3 μm; eluent: 80% isohexane, 20% ethanol; UV indication: 220 nm].

Diastereoisomer 1 was further purified by preparative HPLC (column: acetonitrile / water / 0.1% formic acid) to give 4.30 mg (3% theory, 100% purity) of the title compound from Example 96.

Example 96.

7 - [(3R, 4S) -3,4-Dihydroxypyrrolidin-1-yl] -6-fluoro-4-oxo-N- [1- (trifluoromethoxy) butan-2-yl] -1 (2,4,6 -trifluorophenyl) -1,4-dihydro-1,8-naphthyridine-3-carboxamide (diastereoisomer 1).

LCMS (Method 3): Rt = 1.87 min; MS (ESIpos): m / z = 579 [M + H] +.

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 9.98 (br d, 1H), 8.76 (s, 1H), 8.00 (d, 1H), 7.54-7.60 (m, 2H), 4.91- 5.07 (m, 2H), 4.13-4.22 (m, 3H), 3.82-4.10 (m, 3H), 3.44-3.66 (m, 1H), 3.12-3.29 (m, 1H), 2.93-3.11 (m, 1H ), 1.63-1.72 (m, 1H), 1.53-1.63 (m, 1H), 0.94 (t, 3H).

- 93 038451

Example 97.

7 - [(3R, 4S) -3,4-Dihydroxypyrrolidin-1-yl] -6-fluoro-4-oxo-N- [1- (trifluoromethoxy) butan-2-yl] -1 (2,4,6 -trifluorophenyl) -1,4-dihydro-1,8-naphthyrvdine-3-carboxyamvd (diastereoisomer 2).

LCMS (Method 3): Rt = 1.87 min; MS (ESIpos): m / z = 579 [M + H] +.

¹ H-NMR (400 MHz, DMSO-de) δ [ppm]: 9.99 (br d, 1H), 8.76 (s, 1H), 8.00 (d, 1H), 7.53-7.61 (m, 2H), 4.90- 5.08 (m, 2H), 4.13-4.23 (m, 3H), 3.79-4.10 (m, 3H), 3.45-3.69 (m, 1H), 3.11-3.27 (m, 1H), 2.86-3.11 (m, 1H ), 1.53-1.72 (m, 2H), 0.94 (t, 3H).

Example 98.

7 - [(3R, 4S) -3,4-Dihydroxypyrrolidin-1-yl] -6-fluoro-4-oxo-N - [(2S) -1,1,1-trifluorobutan-2-yl] -1 ( 2,4,6-trifluorophenyl) -1,4-dihydro-1,8-naphthyridine-3-carboxamide.

According to AAV1, 50.0 mg (114 μmol) 7 - [(3R, 4S) -3,4-dihydroxypyrrolidin-1-yl] -6fluoro-4-oxo-1- (2,4,6-trifluorophenyl) -1.4 -dihydro-1,8-naphthyridine-3-carboxylic acid with 26.1 mg (159 μmol) (2S) -1,1,1-fluorobutan-2-amine hydrochloride in the presence of 51.9 mg (137 μmol) HATU and 59 μL (340 μmol) DIPEA in 460 μL DMF. The starting material was purified by preparative HPLC (column: acetonitrile / water / 0.1% formic acid). This gave 47.2 mg (76% theory, 100% purity) of the title compound.

LCMS (Method 1): Rt = 0.98 min; MS (ESIpos): m / z = 549 [M + H] +.

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: 10.33 (d, 1H), 8.84 (s, 1H), 8.00 (d, 1H), 7.54-7.61 (m, 2H), 4.84-5.23 (m, 2H), 4.67-4.83 (m, 1H), 3.81-4.16 (m, 3H), 3.42-3.70 (m, 2H), 2.95-3.14 (m, 1H), 1.83-1.93 (m, 1H) , 1.58-1.70 (m, 1H), 0.97 (t, 3H).

Example 99.

7 - [(3R, 4S) -3,4-Dihydroxypyrrolidin-1-yl] -6-fluoro-N - [(2R) -3-methylbutan-2-yl] -4-oxo-1- (2,4 , 6trifluorophenyl) -1,4-dihydro-1,8-naphthyridine-3-carboxamide.

According to AAV1, 50.0 mg (114 μmol) 7 - [(3R, 4S) -3,4-dihydroxypyrrolidin-1-yl] -6fluoro-4-oxo-1- (2,4,6-trifluorophenyl) -1.4 -dihydro-1,8-naphthyridine-3-carboxylic acid with 13.9 mg (159 μmol) (2R) -3-methylbutan-2-amine in the presence of 51.9 mg (137 μmol) HATU and 59 μL (340 μmol) DIPEA in 460 μl of DMF. The starting material was purified by preparative HPLC (column: acetonitrile / water / 0.1% formic acid). This gave 21.6 mg (37% theory, 100% purity) of the title compound.

LCMS (Method 3): Rt = 1.74 min; MS (ESIpos): m / z = 509 [M + H] +.

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: 9.87 (d, 1H), 8.71 (s, 1H), 8.00 (d, 1H), 7.53-7.60 (m, 2H), 4.885.10 (m, 2H), 3.80-4.16 (m, 4H), 3.47-3.72 (m, 1H), 3.12-3.27 (m, 1H), 2.88-3.11 (m, 1H), 1.72-1.81 (m, 1H) , 1.10 (d, 3H), 0.93 (d, 3H), 0.91 (d, 3H).

Example 100.

7 - [(3R, 4S) -3,4-Dihydroxypyrrolidin-1-yl] -6-fluoro-N - [(2S) -3-methylbutan-2-yl] -4-oxo-1- (2,4 , 6trifluorophenyl) -1,4-dihydro-1,8-naphthyridine-3-carboxamide.

According to AAV1, 50.0 mg (114 μmol) 7 - [(3R, 4S) -3,4-dihydroxypyrrolidin-1-yl] -6fluoro-4-oxo-1- (2,4,6-trifluorophenyl) -1.4 -dihydro-1,8-naphthyridine-3-carboxylic acid with 13.9 mg (159 μmol) (2S) -3-methylbutan-2-amine in the presence of 51.9 mg (137 μmol) HATU and 59 μL (340 μmol) DIPEA in 460 μl of DMF. The starting material was purified by preparative HPLC (column: acetonitrile / water / 0.1% formic acid). This gave 52.0 mg (90% theory, 100% purity) of the title compound.

LCMS (Method 3): Rt = 1.74 min; MS (ESIpos): m / z = 509 [M + H] +.

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: 9.87 (d, 1H), 8.71 (s, 1H), 7.99 (d, 1H), 7.53-7.60 (m, 2H), 4.795.23 (m, 2H), 3.81-4.10 (m, 4H), 3.44-3.71 (m, 1H), 2.86-3.23 (m, 2H), 1.72-1.81 (m, 1H), 1.10 (d, 3H), 0.93 (br d, 3H), 0.91 (br d, 3H).

Example 101.

N - [(1S) -1-Cyclopropyl-2,2,2-trifluoroethyl] -7 - [(3R, 4S) -3,4-dihydroxypyrrolidin-1-yl] -6-fluoro-4oxo-1- (2 , 4,6-trifluorophenyl) -1,4-dihydro-1,8-naphthyridine-3-carboxamide.

According to AAV1, 50.0 mg (114 μmol) 7 - [(3R, 4S) -3,4-dihydroxypyrrolidin-1-yl] -6fluoro-4-oxo-1- (2,4,6-trifluorophenyl) -1.4 -dihydro-1,8-naphthyridine-3-carboxylic acid with 28.0 mg (159 μmol) (1S) -1-cyclopropyl-2,2,2-trifluoroethanamine hydrochloride in the presence of 51.9 mg (137 μmol) HATU and 59 μL (340 μmol) DIPEA in 460 μL DMF The starting material was purified by preparative HPLC (column: acetonitrile / water / 0.1% formic acid). This gave 36.9 mg (58% theory, 100% purity) of the title compound.

LCMS (Method 3): Rt = 1.85 min; MS (ESIpos): m / z = 561 [M + H] +.

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: 10.47 (d, 1H), 8.83 (s, 1H), 8.01 (d, 1H), 7.53-7.61 (m, 2H), 4.91-5.09 (m, 2H), 4.33-4.43 (m, 1H), 3.86-4.14 (m, 3H), 3.39-3.67 (m, 1H), 3.13-3.27 (m, 1H), 2.92-3.12 (m, 1H) , 1.16-1.25 (m, 1H), 0.50-0.69 (m, 3H), 0.29-0.37 (m, 1H).

Example 102.

7 - [(3R, 4S) -3,4-Dihydroxypyrrolidin-1-yl] -6-fluoro-N - [(2S) -1-methoxy-3-methylbutan-2-yl] -4-oxo 94 038451

1- (2,4,6-trifluorophenyl) -1,4-dihydro-1,8-naphthyrvdine-3-carboxyamide.

According to AAV1, 30.0 mg (68.3 μmol) 7 - [(3R, 4S) -3,4-dihydroxypyrrolidin-1-yl] -6fluoro-4-oxo-1- (2,4,6-trifluorophenyl) -1.4 -dihydro-1,8-naphthyridine-3-carboxylic acid with 11.2 mg (95.6 μmol) (2S) -1-methoxy-3-methylbutαn-2-amine in the presence of 31.2 mg (81.9 μmol) HATU and 36 μL (200 μmol ) DIPEA in 270 μl DMF. The starting material was purified by preparative HPLC (column: acetonitrile / water / 0.1% formic acid). This gave 32.1 mg (87% theory, 100% purity) of the title compound.

LCMS (Method 3): Rt = 1.64 min; MS (ESIpos): m / z = 539 [M + H] ⁺ .

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 9.93 (d, 1H), 8.72 (s, 1H), 8.00 (d, 1H), 7.53-7.61 (m, 2H), 4.825. 15 (m, 2H), 3.81-4.14 (m, 4H), 3.50-3.73 (m, 1H), 3.34-3.49 (m, 3H), 3.13-3.24 (m, 1H), 2.88-3.10 (m, 1H ), 1.87-1.97 (m, 1H), 0.92 (d, 6H).

Example 103.

7 - [(3R, 4S) -3,4-Digyroxypyrroligin-1-yl] -N- (2,4-dimethylpentan-3-yl) -6-fluoro-4-oxo-1- (2,4,6trifluorophenyl ) -1,4-dihydro-1,8-naphthyridine-3-carboxamide.

According to AAV1, 30.0 mg (68.3 μmol) 7 - [(3R, 4S) -3,4-dihydroxypyrroligin-1-yl] -6fluoro-4-oxo-1- (2,4,6-trifluorophenyl) -1.4 -dihydro-1,8-naphthyridine-3-carboxylic acid with 11.0 mg (95.6 μmol) 2,4-dimethylpentan-3-amine in the presence of 31.2 mg (81.9 μmol) HATU and 36 μL (200 μmol) DIPEA in 270 μL DMF ... The starting material was purified by preparative HPLC (column: acetonitrile / water / 0.1% formic acid). This gave 29.1 mg (79% theory, 100% purity) of the title compound.

LCMS (Method 3): Rt = 1.94 min; MS (ESIpos): m / z = 537 [M + H] +.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 9.76 (d, 1H), 8.72 (s, 1H), 8.02 (d, 1H), 7.53-7.60 (m, 2H), 4.915. 07 (m, 2H), 3.80-4.15 (m, 3H), 3.48-3.74 (m, 2H), 2.89-3.28 (m, 2H), 1.80-1.90 (m, 2H), 0.88 (dd, 12H).

Example 104.

7 - [(3R, 4S) -3,4-Digyroxypyrroligin-1-yl] -6-fluoro-N- [2-methylpenman-3-yl] -4-oxo-1- (2,4,6trifluorophenyl) - 1,4-dihydro-1,8-naphthyridine-3-carboxamide (mixture of diastereoisomers).

According to AAV1, 100 mg (228 μmol) 7 - [(3R, 4S) -3,4-dihydroxypyrrolidin-1-yl] -6fluoro-4-oxo-1- (2,4,6-trifluorophenyl) -1,4 -dihydro-1,8-naphthyridine-3-carboxylic acid with 32.2 mg (319 μmol) 2-methylpentan-3-amine in the presence of 104 mg (273 μmol) HATU and 120 μL (680 μmol) DIPEA in 920 μL DMF. The starting material was purified by preparative HPLC (column: acetonitrile / water / 0.1% formic acid). This gave 68.5 mg (58% theory, 100% purity) of the title compound.

LCMS (Method 3): Rt = 1.85 min; MS (ESIpos): m / z = 523 [M + H] +.

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 9.77 (d, 1H), 8.71 (s, 1H), 8.00 (d, 1H), 7.53-7.61 (m, 2H), 4.905.09 ( m, 2H), 3.86-4.16 (m, 3H), 3.72-3.85 (m, 1H), 3.41-3.69 (m, 1H), 3.13-3.28 (m, 1H), 2.90-3.12 (m, 1H), 1.77-1.87 (m, 1H), 1.51-1.62 (m, 1H), 1.35-1.47 (m, 1H), 0.84-0.92 (m, 9H).

65.0 mg of the title compound (mixture of diastereoisomers) was separated into diastereoisomers by preparative HPLC (preparative HPLC: Daicel Chiralcel OX-H column, 5 μm, 250x20 mm; eluent: 80% n-heptane, 20% ethanol; temperature: 23 ° C ; flow: 20 ml / min; UV indication: 220 nm).

Received (as elution from the column) 26.1 mg (22% theoretical, 100% purity) of diastereoisomer 1 from Example 105 (99% de) Rt = 11.82 min and 32.0 mg (27% theoretical, 100% purity ) diastereoisomer 2 from Example 106 (99% de) Rt = 15.94 min.

[Analytical HPLC: Chiraltek OX-3 column, 3 µm; eluent: 80% n-heptane, 20% ethanol; UV indication: 220 nm].

Example 105.

7 - [(3R, 4S) -3,4-Digyroxypyrroligin-1-yl] -6-fluoro-N- [2-methylpenman-3-yl] -4-oxo-1- (2,4,6trifluorophenyl) - 1,4-dihydro-1,8-naphthyridine-3-carboxamide (diastereoisomer 1).

LCMS (Method 3): Rt = 1.89 min; MS (ESIpos): m / z = 523 [M + H] +.

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 9.77 (d, 1H), 8.71 (s, 1H), 8.00 (d, 1H), 7.53-7.60 (m, 2H), 4.915.07 (m, 2H), 3.85-4.15 (m, 3H), 3.76-3.83 (m, 1H), 3.43-3.64 (m, 1H), 3.11-3.28 (m, 1H), 2.92-3.10 (m, 1H) , 1.77-1.86 (m, 1H), 1.51-1.61 (m, 1H), 1.36-1.47 (m, 1H), 0.84-0.92 (m, 9H).

Example 106.

7 - [(3R, 4S) -3,4-Digyroxypyrroligin-1-yl] -6-fluoro-N- [2-methylpenman-3-yl] -4-oxo-1- (2,4,6trifluorophenyl) - 1,4-dihydro-1,8-naphthyridine-3-carboxamide (diastereoisomer 2).

LCMS (Method 3): Rt = 1.89 min; MS (ESIpos): m / z = 523 [M + H] +.

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 9.77 (d, 1H), 8.71 (s, 1H), 8.00 (d, 1H), 7.48-7.66 (m, 2H), 4.885.11 ( m, 2H), 3.86-4.15 (m, 3H), 3.76-3.83 (m, 1H), 3.44-3.69 (m, 1H), 3.13-3.29 (m, 1H), 2.87-3.11 (m, 1H), 1.76-1.86 (m, 1H), 1.51-1.62 (m, 1H), 1.29-1.47 (m, 1H), 0.84-0.93 (m, 9H).

Example 107.

6-Fluoro-7 - [(3S) -3-hydroxypyrroligin-1-yl] -4-oxo-N- (4,4,4-trifluoro-2-methylbutan-2-yl) -1- (2,4 , 6

- 95 038451 trifluorophenyl) -1,4-dihydro-1,8-naphthyridine-3-carboxamide.

According to AAV1, 50.0 mg (118 μmol) of 6-fluoro-7 - [(3S) -3-hydroxypyrrolidin-1-yl] -4oxo-1- (2,4,6-trifluorophenyl) -1,4-dihydro-1 , 8-naphthyridine-3-carboxylic acid with 23.1 mg (130 μmol) 4,4,4-trifluoro-2-methylbutan-2-amine hydrochloride in the presence of 53.9 mg (142 μmol) HATU and 82 μL (470 μmol) DIPEA in 750 μl DMF. The starting material was purified by preparative HPLC (column: acetonitrile / water / 0.1% formic acid). This gave 51.0 mg (79% theory, 100% purity) of the title compound.

LCMS (Method 3): Rt = 2.06 min; MS (ESIpos): m / z = 547 [M + H] +.

Ή-NMR (400 MHz, DMSO-de) δ [ppm]: 10.09 (s, 1H), 8.72 (s, 1H), 7.98 (d, 1H), 7.56 (t, 2H), 4.95-5.04 (m, 1H), 4.18-4.37 (m, 1H), 3.34-4.01 (m, 3H), 3.06-3.27 (m, 1H), 2.95 (q, 2H), 1.72-1.98 (m, 2H), 1.48 (s, 6H).

Example 108.

N - [(1S) -1-Cyclopropyl-2,2,2-trifluoroethyl] -6-fluoro-7 - [(3S) -3-hydroxypyrrolidin-1-yl] -4-oxo-1 (2,4, 6-trifluorophenyl) -1,4-dihydro-1,8-naphthyridine-3-carboxamide.

According to AAV1, 50.0 mg (118 μmol) of 6-fluoro-7 - [(3S) -3-hydroxypyrrolidin-1-yl] -4oxo-1- (2,4,6-trifluorophenyl) -1,4-dihydro-1 , 8-naphthyridine-3-carboxylic acid with 22.8 mg (130 μmol) (1S) -1-cyclopropyl-2,2,2-trifluoroethanamine hydrochloride in the presence of 53.9 mg (142 μmol) HATU and 82 μL (470 μmol) DIPEA in 750 μl DMF. The starting material was purified by preparative HPLC (column: acetonitrile / water / 0.1% formic acid). This gave 50.3 mg (78% theory, 100% purity) of the title compound.

LCMS (Method 3): Rt = 2.07 min; MS (ESIpos): m / z = 545 [M + H] +.

Ή-NMR (400 MHz, DMSO-de) δ [ppm]: 10.48 (d, 1H), 8.83 (s, 1H), 8.01 (d, 1H), 7.53-7.60 (m, 2H), 4.97-5.04 ( m, 1H), 4.21-4.43 (m, 2H), 3.34-4.03 (m, 3H), 3.01-3.29 (m, 1H), 1.74-1.98 (m, 2H), 1.16-1.25 (m, 1H), 0.50-0.69 (m, 3H), 0.30-0.37 (m, 1H).

Example 109.

6-Fluoro-7 - [(3S) -3-hydroxypyrrolidin-1-yl] -4-oxo-N- [1- (trifluoromethoxy) butan-2-yl] -1- (2,4,6trifluorophenyl) -1 , 4-dihydro-1,8-naphthyridine-3-carboxamide (mixture of diastereoisomers).

According to AAV1, 100 mg (236 μmol) of 6-fluoro-7 - [(3S) -3-hydroxypyrrolidin-1-yl] -4oxo-1- (2,4,6-trifluorophenyl) -1,4-dihydro-1 , 8-naphthyridine-3-carboxylic acid with 50.3 mg (260 μmol) 1- (trifluoromethoxy) butan-2-amine hydrochloride (racemate) in the presence of 108 mg (283 μmol) HATU and 160 μL (940 μmol) DIPEA in 1.5 ml DMF. The starting material was purified by preparative HPLC (column: acetonitrile / water / 0.1% formic acid). 89.3 mg (67% theory, 100% purity) of the title compound was obtained.

LCMS (Method 3): Rt = 2.08 min; MS (ESIpos): m / z = 563 [M + H] +.

Ή-NMR (400 MHz, DMSO-d6) δ [ppm]: 10.00 (br d, 1H), 8.75 (s, 1H), 8.00 (d, 1H), 7.56 (br t, 2H), 4.955.04 ( m, 1H), 4.24-4.35 (m, 1H), 4.12-4.24 (m, 3H), 3.33-4.07 (m, 3H), 3.02-3.29 (m, 1H), 1.74-2.00 (m, 2H), 1.55-1.73 (m, 2H), 0.94 (t, 3H).

.0 mg of the title compound (mixture of diastereoisomers) was separated into diastereoisomers by preparative HPLC (preparative HPLC: Daicel Chiralcel IE column, 5 μm, 250x20 mm; eluent: 85% n-heptane, 15% ethanol + 0.2% DEA; temperature: 23 ° C; flow: 20 ml / min; UV indication: 220 nm).

Received (as elution from the column) 22.6 mg (17% of theory, 95% purity) of diastereoisomer 1 from Example 110 (99% de) Rt = 11.90 min and 24.7 mg (19% of theory, 95% purity ) diastereoisomer 2 from Example 111 (93% de) Rt = 13.32 min.

[Analytical HPLC: Daicel Chiralpak IE-3 column, 3 μm, 50x4.6 mm; eluent: 90% n-heptane, 10% ethanol + 0.2% DEA; flow: 1.0 ml / min; UV indication: 220 nm].

Example 110.

6-Fluoro-7 - [(3S) -3-hydroxypyrrolidin-1-yl] -4-oxo-N- [1- (trifluoromethoxy) butan-2-yl] -1- (2,4,6trifluorophenyl) -1 , 4-dihydro-1,8-naphthyridine-3-carboxamide (diastereoisomer 1).

LCMS (Method 3): Rt = 2.08 min; MS (ESIpos): m / z = 563 [M + H] +.

Ή-NMR (400 MHz, DMSO-d6) δ [ppm]: 10.00 (d, 1H), 8.75 (s, 1H), 8.00 (d, 1H), 7.56 (br t, 2H), 4.965.03 (m , 1H), 4.23-4.36 (m, 1H), 4.13-4.22 (m, 3H), 3.36-4.04 (m, 2H), 2.96-3.29 (m, 1H), 1.74-2.00 (m, 2H), 1.54 -1.73 (m, 2H), 0.94 (t, 3H).

Example 111.

6-Fluoro-7 - [(3S) -3-hydroxypyrrolidin-1-yl] -4-oxo-N- [1- (trifluoromethoxy) butan-2-yl] -1- (2,4,6trifluorophenyl) -1 , 4-dihydro-1,8-naphthyridine-3-carboxamide (diastereoisomer 2).

LCMS (Method 3): Rt = 2.08 min; MS (ESIpos): m / z = 563 [M + H] +.

Ή-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 10.00 (d, 1H), 8.75 (s, 1H), 8.00 (d, 1H), 7.53-7.59 (m, 2H), 4.96-5.03 (m, 1H), 4.23-4.35 (m, 1H), 4.13-4.22 (m, 3H), 3.33-4.01 (m, 3H), 3.05-3.29 (m, 1H), 1.73-1.99 (m, 2H) , 1.54-1.72 (m, 2H), 0.94 (t, 3H).

Example 112.

6-Fluoro-7 - [(3S) -3-hydroxypyrrolidin-1-yl] -4-oxo-N- [3,3,4,4,4-pentafluorobutan-2-yl] -1- (2,4 , 6

- 96 038451 trifluorophenyl) -1,4-dihydro-1,8-naphthyridine-3-carboxamide (mixture of diastereoisomers).

According to AAV1, 100 mg (236 μmol) of 6-fluoro-7 - [(3S) -3-hydroxypyrrolidin-1-yl] -4oxo-1- (2,4,6-trifluorophenyl) -1,4-dihydro-1 , 8-naphthyridine-3-carboxylic acid with 51.9 mg (260 μmol) 3,3,4,4,4-pentafluorobutan-2-amine hydrochloride (racemate) in the presence of 108 mg (283 μmol) HATU and 160 μL (940 μmol ) DIPEA in 1.5 ml DMF. The starting material was purified by preparative HPLC (column: acetonitrile / water / 0.1% formic acid). 107 mg (80% theory, 100% purity) of the title compound was obtained.

LCMS (Method 3): Rt = 2.10 min; MS (ESIpos): m / z = 569 [M + H] +.

¹ H -NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 10.47 (d, 1H), 8.84 (s, 1H), 8.00 (d, 1H), 7.56 (t, 2H), 4.95-5.08 ( m, 2H), 4.19-4.37 (m, 1H), 3.34-4.06 (m, 3H), 3.01-3.28 (m, 1H), 1.73-1.98 (m, 2H), 1.39 (d, 3H).

105 mg of the title compound (mixture of diastereoisomers) was separated by chiral SFC into diastereoisomers (preparative SFC: Chiralpak AD columns, 250x20 mm; eluent: 80% carbon dioxide, 20% isopropanol; temperature: 40 ° C; flow: 60 ml / min; UV indication: 210 nm).

Received (as elution from the column) 39.2 mg (29% of theory., 100% purity) of diastereoisomer 1 from Example 113 (99% de) R _t = 2.07 min and 32.8 mg (25% of theory., 100% purity) of diastereoisomer 2 from Example 114 (99% de) R _t = 2.59 min.

[Analytical SFC: columns AD; eluent: 80% carbon dioxide, 20% isopropanol; flow: 3.0 ml / min; UV indication: 210 nm].

Example 113.

6-Fluoro-7 - [(3S) -3-hydroxypyrrolidin-1-yl] -4-oxo-N- [3,3,4,4,4-pentafluorobutan-2-yl] -1- (2,4 , 6trifluorophenyl) -1,4-dihydro-1,8-naphthyridine-3-carboxamide (diastereoisomer 1).

LCMS (Method 3): Rt = 2.11 min; MS (ESIpos): m / z = 569 [M + H] +.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 10.47 (d, 1H), 8.84 (s, 1H), 8.00 (d, 1H), 7.57 (br t, 2H), 4.955.08 (m, 2H), 4.21-4.37 (m, 1H), 3.36-4.05 (m, 3H), 3.01-3.27 (m, 1H), 1.72-1.98 (m, 2H), 1.39 (d, 3H).

Example 114.

6-Fluoro-7 - [(3S) -3-hydroxypyrrolidin-1-yl] -4-oxo-N- [3,3,4,4,4-pentafluorobutan-2-yl] -1- (2,4 , 6trifluorophenyl) -1,4-dihydro-1,8-naphthyridine-3-carboxamide (diastereoisomer 2).

LCMS (Method 3): Rt = 2.11 min; MS (ESIpos): m / z = 569 [M + H] +.

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 10.47 (d, 1H), 8.84 (s, 1H), 8.00 (d, 1H), 7.53-7.60 (m, 2H), 4.96-5.07 (m, 2H), 4.26-4.34 (m, 1H), 3.34-3.98 (m, 3H), 3.00-3.26 (m, 1H), 1.70-2.01 (m, 2H), 1.39 (d, 3H).

Example 115.

6-Fluoro-7 - [(3S) -3-hydroxypyrrolidin-1-yl] -4-oxo-N - [(2S) -1,1,1-trifluorobutαn-2-yl] -1- (2,4 , 6trifluorophenyl) -1,4-dihydro-1,8-naphthyridine-3-carboxamide.

According to AAV1, 50.0 mg (118 μmol) of 6-fluoro-7 - [(3S) -3-hydroxypyrrolidin-1-yl] -4oxo-1- (2,4,6-trifluorophenyl) -1,4-dihydro-1 , 8-naphthyridine-3-carboxylic acid with 21.3 mg (130 μmol) (2S) -1,1,1-trifluorobutan-2-amine hydrochloride in the presence of 53.9 mg (142 μmol) HATU and 82 μL (470 μmol) DIPEA in 750 μl DMF. The starting material was purified by preparative HPLC (column: acetonitrile / water / 0.1% formic acid). This gave 46.8 mg (74% theory, 100% purity) of the title compound.

LCMS (Method 3): Rt = 2.05 min; MS (ESIpos): m / z = 533 [M + H] +.

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 10.34 (d, 1H), 8.83 (s, 1H), 8.00 (d, 1H), 7.53-7.61 (m, 2H), 4.96-5.05 (m, 1H), 4.68-4.79 (m, 1H), 4.19-4.39 (m, 1H), 3.33-4.04 (m, 3H), 3.02-3.28 (m, 1H), 1.72-1.97 (m, 3H) , 1.58-1.70 (m, 1H), 0.97 (t, 3H).

Example 116.

6-Fluoro-7 - [(3S) -3-hydroxypyrrolidin-1-yl] -N- [2-methylpentan-3-yl] -4-oxo-1- (2,4,6-trifluorophenyl) -1, 4-dihydro-1,8-naphthyridine-3-carboxamide (mixture of diastereoisomers).

According to AAV1, 100 mg (236 μmol) of 6-fluoro-7 - [(3S) -3-hydroxypyrrolidin-1-yl] -4oxo-1- (2,4,6-trifluorophenyl) -1,4-dihydro-1 , 8-naphthyridine-3-carboxylic acid with 35.8 mg (260 μmol) 2-methylpentan-3-amine hydrochloride (racemate) in the presence of 108 mg (283 μmol) HATU and 160 μL (940 μmol) DIPEA in 1.5 ml DMF. The starting material was purified by preparative HPLC (column: acetonitrile / water / 0.1% formic acid). This gave 90.1 mg (75% theory, 100% purity) of the title compound.

LCMS (Method 3): Rt = 2.10 min; MS (ESIpos): m / z = 507 [M + H] +.

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 9.78 (d, 1H), 8.71 (s, 1H), 8.00 (d, 1H), 7.56 (br t, 2H), 4.96-5.03 ( m, 1H), 4.20-4.38 (m, 1H), 3.35-4.05 (m, 4H), 3.01-3.30 (m, 1H), 1.73-1.98 (m, 3H), 1.51-1.62 (m, 1H), 1.361.47 (m, 1H), 0.84-0.92 (m, 9H).

99.0 mg of the title compound (mixture of diastereoisomers) was separated into diastereoisomers by preparative HPLC (preparative HPLC: Daicel Chiralcel AY-H column, 5 μm, 250x20 mm; eluent: 70% n-heptane, 30% ethanol + 0.2% DEA; temperature : 60 ° C; flow: 15 ml / min; UV indication: 260 nm).

- 97 038451

Received (as elution from the column) 21.0 mg (17% theoretical, 100% purity) of diastereoisomer 1 from Example 117 (97% de) Rt = 4.45 min and 23.0 mg (19% theoretical, 100% purity ) diastereoisomer 2 from Example 118 (76% de) Rt = 7.56 min.

[Analytical HPLC: Daicel Chiralpak AY-H column, 5 μm, 250x4.6 mm; eluent: 70% isohexane, 30% ethanol + 0.2% DEA; temperature: 60 ° C; flow: 1.0 ml / min; UV indication: 260 nm].

Example 117.

6-Fluoro-7 - [(3S) -3-hydroxypyrroluidin-1-yl] -N- [2-methylnentan-3-yl] -4-oxo-1- (2,4,6-trifluorophenyl) -1, 4-dihydro-1,8-naphthyridine-3-carboxamide (diastereoisomer 1).

LCMS (Method 3): Rt = 2.10 min; MS (ESIpos): m / z = 507 [M + H] ⁺ .

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 9.78 (d, 1H), 8.71 (s, 1H), 8.00 (d, 1H), 7.53-7.59 (m, 2H), 4.985. 01 (m, 1H), 4.26-4.32 (m, 1H), 3.36-4.10 (m, 4H), 2.99-3.27 (m, 1H), 1.76-1.94 (m, 3H), 1.52-1.60 (m, 1H ), 1.37-1.45 (m, 1H), 0.84-0.92 (m, 9H).

Example 118.

6-Fluoro-7 - [(3S) -3-hydroxypyrroludin-1-yl] -N- [2-methylpentan-3-yl] -4-oxo-1- (2,4,6-trifluorophenyl) -1, 4-dihydro-1,8-naphthyridine-3-carboxamide (diastereoisomer 2).

LCMS (Method 3): Rt = 2.11 min; MS (ESIpos): m / z = 507 [M + H] +.

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: 9.78 (d, 1H), 8.71 (s, 1H), 8.00 (d, 1H), 7.53-7.60 (m, 2H), 4.965.02 (m, 1H), 4.24-4.34 (m, 1H), 3.33-4.08 (m, 3H), 3.07-3.29 (m, 1H), 1.75-1.96 (m, 3H), 1.51-1.63 (m, 1H) , 1.36-1.47 (m, 1H), 0.83-0.92 (m, 9H).

Example 119.

6-Fluoro-7 - [(3S) -3-hydroxypyrroludin-1-yl] -N - [(2S) -3-methylbutan-2-yl] -4-oxo-1- (2,4,6trifluorophenyl) - 1,4-dihydro-1,8-naphthyridine-3-carboxamide.

According to AAV1, 50.0 mg (118 μmol) of 6-fluoro-7 - [(3S) -3-hydroxypyrrolidin-1-yl] -4oxo-1- (2,4,6-trifluorophenyl) -1,4-dihydro-1 , 8-naphthyridine-3-carboxylic acid with 11.3 mg (130 μmol) (2S) -3-methylbutan-2-amine in the presence of 53.9 mg (142 μmol) HATU and 62 μL (350 μmol) DIPEA in 750 μL DMF. The starting material was purified by preparative HPLC (column: acetonitrile / water / 0.1% formic acid). This gave 45.2 mg (78% theory, 100% purity) of the title compound.

LCMS (Method 3): Rt = 1.99 min; MS (ESIpos): m / z = 493 [M + H] +.

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 9.88 (d, 1H), 8.70 (s, 1H), 7.99 (d, 1H), 7.56 (br t, 2H), 4.95-5.03 (m , 1H), 4.19-4.37 (m, 1H), 3.33-4.10 (m, 4H), 3.01 -3.26 (m, 1H), 1.70-1.96 (m, 3H), 1.10 (d, 3H), 0.88-0.95 (m, 6H).

Example 120.

6-Fluoro-7 - [(3S) -3-hydroxypyrroluidin-1-yl] -N - [(2R) -3 -methylbutan-2-yl] -4-oxo-1- (2,4,6trifluorophenyl) - 1,4-dihydro-1,8-naphthyridine-3-carboxamide.

According to AAV1, 50.0 mg (118 μmol) of 6-fluoro-7 - [(3S) -3-hydroxypyrrolidin-1-yl] -4oxo-1- (2,4,6-trifluorophenyl) -1,4-dihydro-1 , 8-naphthyridine-3-carboxylic acid with 11.3 mg (130 μmol) (2R) -3-methylbutan-2-amine in the presence of 53.9 mg (142 μmol) HATU and 62 μL (350 μmol) DIPEA in 750 μL DMF. The starting material was purified by preparative HPLC (column: acetonitrile / water / 0.1% formic acid). This gave 45.8 mg (79% theory, 100% purity) of the title compound.

LCMS (Method 3): Rt = 1.99 min; MS (ESIpos): m / z = 493 [M + H] +.

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 9.88 (d, 1H), 8.70 (s, 1H), 7.99 (d, 1H), 7.56 (br t, 2H), 4.96-5.03 (m , 1H), 4.21-4.37 (m, 1H), 3.36-4.11 (m, 4H), 3.02 -3.28 (m, 1H), 1.71-1.97 (m, 3H), 1.10 (d, 3H), 0.88-0.96 (m, 6H).

Example 121.

6-Fluoro-7 - [(3S) -3-hydroxypyrroluidin-1-yl] -N - [(2R) -1-methoxy-3-methylbutan-2-yl] -4-oxo-1- (2,4 , 6trifluorophenyl) -1,4-dihydro-1,8-naphthyridine-3-carboxamide.

According to AAV1, 50.0 mg (118 μmol) of 6-fluoro-7 - [(3S) -3-hydroxypyrrolidin-1-yl] -4oxo-1- (2,4,6-trifluorophenyl) -1,4-dihydro-1 , 8-naphthyridine-3-carboxylic acid with 20.0 mg (130 μmol) (2R) -1-methoxy-3-methylbutan-2-amine hydrochloride in the presence of 53.9 mg (142 μmol) HATU and 62 μL (350 μmol) DIPEA in 750 μl DMF The starting material was purified by preparative HPLC (column: acetonitrile / water / 0.1% formic acid). This gave 45.5 mg (74% theory, 100% purity) of the title compound.

LCMS (Method 3): Rt = 1.88 min; MS (ESIpos): m / z = 523 [M + H] +.

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 9.94 (d, 1H), 8.72 (s, 1H), 8.00 (d, 1H), 7.52-7.60 (m, 2H), 4.945.05 ( m, 1H), 4.29 (br s, 1H), 3.96-4.03 (m, 1H), 3.50-3.94 (m, 2H), 3.34-3.49 (m, 3H), 3.27 (s, 3H), 2.90-3.24 (m, 1H), 1.74-1.99 (m, 3H), 0.92 (d, 6H).

- 98 038451

Example 122.

N- (2,4-Dimethylpenman-3-yl) -6-fluoro-7 - [(3S) -3-hydroxypyrrolidin-1-yl] -4-oxo-1- (2,4,6trifluorophenyl) -1, 4-dihydro-1,8-naphthyridine-3-carboxamide.

According to AAV1, 50.0 mg (118 μmol) of 6-fluoro-7 - [(3S) -3-hydroxypyrrolidin-1-yl] -4oxo-1- (2,4,6-trifluorophenyl) -1,4-dihydro-1 , 8-naphthyridine-3-carboxylic acid with 15.0 mg (130 μmol) 2,4-dimethylpentan-3-amine in the presence of 53.9 mg (142 μmol) HATU and 62 μL (350 μmol) DIPEA in 750 μL DMF. The starting material was purified by preparative HPLC (column: acetonitrile / water / 0.1% formic acid). This gave 50.7 mg (82% theory, 100% purity) of the title compound.

LCMS (Method 3): Rt = 2.19 min; MS (ESIpos): m / z = 521 [M + H] +.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 9.77 (d, 1H), 8.72 (s, 1H), 8.01 (d, 1H), 7.56 (br t, 2H), 4.96-5.03 (m, 1H), 4.21-4.36 (m, 1H), 3.37-3.98 (m, 4H), 3.01-3.27 (m, 1H), 1.74-1.96 (m, 4H), 0.88 (dd, 12H).

Example 123.

7 - [(3R, 4S) -3,4-Dihydroxypyrrolidin-1-yl] -6-fluoro-4-oxo-N- [1,1,1-trifluoro-3-methylbutan-2-yl] -1 ( 2,4,6-trifluorophenyl) -1,4-dihydro-1,8-naphthyridine-3-carboxamide (mixture of diastereoisomers).

According to AAV1, 100 mg (228 μmol) 7 - [(3R, 4S) -3,4-dihydroxypyrrolidin-1-yl] -6fluoro-4-oxo-1- (2,4,6-trifluorophenyl) -1,4 -dihydro-1,8-naphthyridine-3-carboxylic acid with 36.4 mg (250 μmol, 97% purity) 1,1,1-trifluoro-3-methylbutan-2-amine (racemate) in the presence of 104 mg (273 μmol) HATU and 160 μl (910 mmol) DIPEA in 2.0 ml DMF. The starting material was purified by preparative HPLC (column: acetonitrile / water / 0.1% formic acid). This gave 52.0 mg (41% theory, 100% purity) of the title compound.

LCMS (Method 3): Rt = 1.94 min; MS (ESIpos): m / z = 563 [M + H] +.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 10.53 (d, 1H), 8.84 (s, 1H), 8.04 (d, 1H), 7.58 (br t, 2H), 4.925.08 (m, 2H), 4.71-4.81 (m, 1H), 3.86-4.12 (m, 3H), 3.47-3.68 (m, 1H), 2.88-3.25 (m, 2H), 2.18-2.30 (m, 1H) , 1.02 (d, 3H), 0.96 (d, 3H).

Example 124.

7 - [(3R, 4S) -3,4-Dihydroxypyrrolidin-1-yl] -6-fluoro-4-oxo-N- (1,1,1-trifluoro-2-methylpropan-2-yl) 1- ( 2,4,6-trifluorophenyl) -1,4-dihydro-1,8-naphthyridine-3-carboxamide.

According to AAV1, 50.0 mg (114 μmol) 7 - [(3R, 4S) -3,4-dihydroxypyrrolidin-1-yl] -6fluoro-4-oxo-1- (2,4,6-trifluorophenyl) -1.4 -dihydro-1,8-naphthyridine-3-carboxylic acid with 15.9 mg (125 μmol) 1,1,1-trifluoro-2-methylpropan-2-amine in the presence of 51.9 mg (137 μmol) HATU and 59 μL (340 mmol ) DIPEA in 1.0 ml DMF. The starting material was purified by preparative HPLC (column: acetonitrile / water / 0.1% formic acid). This gave 45.0 mg (72% theory, 100% purity) of the title compound.

LCMS (Method 3): Rt = 1.87 min; MS (ESIpos): m / z = 549 [M + H] +.

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 10.55 (s, 1H), 8.77 (s, 1H), 8.01 (d, 1H), 7.54-7.61 (m, 2H), 4.895.10 (m, 2H), 3.79-4.14 (m, 3H), 3.44-3.67 (m, 1H), 3.12-3.28 (m, 1H), 2.87-3.12 (m, 1H), 1.63 (s, 6H).

Example 125.

6-Fluoro-7 - [(3S) -3-hydroxypyrrolidin-1-yl] -4-oxo-N- (1,1,1-mrifluoro-2-methylpropan-2-yl) -1- (2,4 , 6trifluorophenyl) -1,4-dihydro-1,8-naphthyridine-3-carboxamide.

According to AAV1, 20.0 mg (47.2 μmol) 6-fluoro-7 - [(3S) -3-hydroxypyrrolidin-1-yl] -4oxo-1- (2,4,6-trifluorophenyl) -1,4-dihydro-1 , 8-naphthyridine-3-carboxylic acid with 6.60 mg (52.0 μmol) 1,1,1-trifluoro-2-methylpropan-2-amine in the presence of 21.6 mg (56.7 μmol) HATU and 25 μL (140 μmol) DIPEA in 420 μl of DMF. The starting material was purified by preparative HPLC (column: acetonitrile / water / 0.1% formic acid). This gave 18.0 mg (72% theory, 100% purity) of the title compound.

LCMS (Method 1): Rt = 1.10 min; MS (ESIpos): m / z = 533 [M + H] +.

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 10.56 (s, 1H), 8.77 (s, 1H), 8.01 (d, 1H), 7.53-7.61 (m, 2H), 4.965.03 (m, 1H), 4.20-4.35 (m, 1H), 3.37-4.07 (m, 3H), 2.98-3.26 (m, 1H), 1.74-2.00 (m, 2H), 1.63 (s, 6H).

Example 126.

6-Fluoro-7 - [(3 S) -3-hydroxypyrrolidin-1-yl] -4-okco-N- [1,1,1-trifluoro-3-methylbutan-2-yl] -1- (2, 4,6trifluorophenyl) -1,4-dihydro-1,8-naphthyridine-3-carboxamide (mixture of diastereoisomers)

According to AAV1, 65.0 mg (154 μmol) of 6-fluoro-7 - [(3S) -3-hydroxypyrrolidin-1-yl] -4oxo-1- (2,4,6-trifluorophenyl) -1,4-dihydro-1 , 8-naphthyridine-3-carboxylic acid with 24.6 mg (169 μmol, 97% purity) 1,1,1-trifluoro-3-methylbutan-2-amine (racemate) in the presence of 70.1 mg (184 μmol) HATU and 80 μL (460 μmol) DIPEA in 1.3 ml DMF. The starting material was purified by preparative HPLC (column: acetonitrile / water / 0.1% formic acid). This gave 54.0 mg (64% theory, 99% purity) of the title compound.

LCMS (Method 3): Rt = 2.16 min; MS (ESIpos): m / z = 547 [M + H] +.

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 10.54 (d, 1H), 8.84 (s, 1H), 8.04 (d, 1H), 7.54-7.60 (m, 2H), 4.97-5.04 ( m, 1H), 4.71-4.82 (m, 1H), 4.24-4.36 (m, 1H), 3.33-4.10 (m, 3H), 2.97-3.27 (m, 1H), 2.20-2.28 (m,

- 99 038451

1H), 1.71-2.00 (m, 2H), 1.03 (d, 3H), 0.96 (d, 3H).

Example 127.

1- (3,5-Difluoropyridin-2-yl) -6-fluoro-7 - [(3S) -3-hydroxypyrrolidin-1-yl] -4-oxo-N- [3,3,4,4,4 pentafluorobutane -2-yl] -1,4-dihydro-1,8-naphthyridine-3-carboxamide (mixture of diastereoisomers).

According to AAV1, 100 mg (246 μmol) of 1- (3,5-difluoropyridin-2-yl) -6-fluoro-7 - [(3S) -3hydroxypyrrolidin-1-yl] -4-oxo-1,4-dihydro -1,8-naphthyridine-3-carboxylic acid with 54.0 mg (271 μmol) 3,3,4,4,4-pentafluorobutan-2-amine hydrochloride (racemate) in the presence of 112 mg (295 μmol) HATU and 170 μL ( 980 μmol) DIPEA in 2.2 ml DMF. The starting material was purified by preparative HPLC (column: acetonitrile / water / 0.1% formic acid). This gave 100 mg (74% theory, 100% purity) of the title compound.

LCMS (Method 3): Rt = 1.98 min; MS (ESIpos): m / z = 552 [M + H] ⁺ .

¹ H-NMR (400 MHz, DMSO-de) δ [ppm]: 10.46 (d, 1H), 8.83 (d, 1H), 8.61 (d, 1H), 8.30-8.37 (m, 1H), 8.00 (d , 1H), 4.93-5.09 (m, 2H), 4.20-4.39 (m, 1H), 3.35-4.06 (m, 3H), 3.01-3.28 (m, 1H), 1.73-1.98 (m, 2H), 1.39 (br d, 3H).

98.0 mg of the title compound (mixture of diastereoisomers) was separated into diastereoisomers by preparative HPLC (preparative HPLC: Daicel Chiralpak IE column, 5 μm, 250x20 mm; eluent: 70% n-heptane, 30% ethanol + 0.2% DEA; temperature: 35 ° C; flow: 15 ml / min; UV indication: 265 nm).

Received (as elution from the column) 46.0 mg of diastereoisomer 1 (99% de) Rt = 8.64 min and 47.0 mg of diastereoisomer 2 (99% de) Rt = 12.08 min.

[Analytical HPLC: Daicel Chiralpak IE column, 5 μm, 250x4.6 mm; eluent: 70% n-heptane, 30% ethanol + 0.2% DEA; temperature: 35 ° C; flow: 1.0 ml / min; UV indication: 265 nm].

Diastereoisomer 1 was further purified by preparative HPLC (column: acetonitrile / water / 0.1% formic acid) to give 40.0 mg (30% theory, 100% purity) of the title compound from Example 128.

Diastereoisomer 2 was further purified by preparative HPLC (column: acetonitrile / water / 0.1% formic acid) to give 42.0 mg (31% theory, 100% purity) of the title compound from Example 129.

Example 128.

1- (3,5-Difluoropyridin-2-yl) -6-fluoro-7 - [(3S) -3-hydroxypyrrolidin-1-yl] -4-oxo-N- [3,3,4,4,4 pentafluorobutane -2-yl] -1,4-dihydro-1,8-naphthyridine-3-carboxamide (diastereoisomer 1).

LCMS (Method 3): Rt = 1.97 min; MS (ESIpos): m / z = 552 [M + H] +.

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 10.46 (d, 1H), 8.83 (d, 1H), 8.60-8.63 (m, 1H), 8.31-8.37 (m, 1H), 8.00 ( d, 1H), 4.95-5.08 (m, 2H), 4.22-4.36 (m, 1H), 3.36-4.04 (m, 3H), 2.95-3.27 (m, 1H), 1.73-1.96 (m, 2H), 1.39 (br d, 3H).

Example 129.

1- (3,5-Difluoropyridin-2-yl) -6-fluoro-7 - [(3S) -3-hydroxypyrrolidin-1-yl] -4-oxo-N- [3,3,4,4,4 pentafluorobutane -2-yl] -1,4-dihydro-1,8-naphthyridine-3-carboxamide (diastereoisomer 2).

LCMS (Method 3): Rt = 1.97 min; MS (ESIpos): m / z = 552 [M + H] +.

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 10.46 (br d, 1H), 8.83 (d, 1H), 8.61 (d, 1H), 8.30-8.38 (m, 1H), 8.00 ( d, 1H), 4.93-5.10 (m, 2H), 4.22-4.37 (m, 1H), 3.36-4.07 (m, 3H), 2.96-3.29 (m, 1H), 1.73-1.98 (m, 2H), 1.39 (br d, 3H).

Example 130.

N- (2,6-Dichlorophenyl) -7 - [(3R, 4R) -3,4-dihydroxypyrrolidin-1-yl] -6-fluoro-4-oxo-1- (2,4,6trifluorophenyl) -1, 4-dihydro-1,8-naphthyridine-3-carboxamide.

According to AAV3 255 mg (494 μmol) 7-chloro-N- (2,6-dichlorophenyl) -6-fluoro-4-oxo-1 (2,4,6-trifluorophenyl) -1,4-dihydro-1, 8-naphthyridine-3-carboxamide with 75.8 mg (543 μmol) (3R, 4R) -pyrrolidine-3,4-diol hydrochloride and 300 μl (1.70 mmol) of Ν, Ν-diisopropylethylamine in 5 ml of dimethylformamide. The starting material was diluted with a small amount of acetonitrile and purified by preparative HPLC (column: acetonitrile / water / 0.1% formic acid). This gave 216 mg (75% theory, 100% purity) of the title compound.

LCMS (Method 3): Rt = 1.82 min; MS (ESIpos): m / z = 583 [M + H] +.

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 0.947 (0.79), 1.257 (3.15), 2.328 (0.67), 2.366 (0.53), 2.671 (0.73), 2.710 (0.55), 2.731 (4.61 ), 2.890 (5.57), 3.054 (1.06), 3.705 (0.95), 3.912 (1.83), 4.029 (1.36), 5.216 (3.69), 7.360 (2.39), 7.380 (4.91), 7.400 (3.33), 7.562 (3.25 ), 7.581 (16.00), 7.601 (11.10), 7.952 (0.78), 8.062 (4.69), 8.093 (4.59), 8.929 (8.31), 11.845 (8.05).

Example 131.

N- [1- (2-Chlorophenyl) -2,2,2-trifluoroethyl] -7 - [(3R, 4R) -3,4-dihydroxypyrrolidin-1-yl] -6-fluoro-4oxo-1 - (2 , 4,6-trifluorophenyl) -1,4-dihydro-1,8-naphthyridine-3-carboxamide (mixture of diastereoisomers).

According to AAV1, 100 mg (228 μmol) 7 - [(3R, 4R) -3,4-dihydroxypyrrolidin-1-yl] -6fluoro-4-oxo-1- (2,4,6-trifluorophenyl) -1,4 -dihydro-1,8-naphthyridine-3-carboxylic acid with 52.5 mg

- 100 038451 (250 μmol) 1- (2-chlorophenyl) -2,2,2-trifluoroethanamine (racemate) in the presence of 104 mg (273 μmol)

HATU and 120 μl (680 mmol) DIPEA in 1.4 ml DMF. The starting material was purified by preparative HPLC (column: acetonitrile / water / 0.1% formic acid). Received 104 mg (71% theory.,

98% purity) of the title compound.

LCMS (Method 1): Rt = 1.09 min; MS (ESIpos): m / z = 631 [M + H] +.

Ή-NMR (400 MHz, DMSO-de) δ [ppm]: -0.149 (0.55), -0.008 (5.54), 0.146 (0.64), 2.074 (0.71), 2.329 (1.11), 2.367 (0.95), 2.671 ( 1.20), 2.711 (0.93), 3.064 (1.11), 3.696 (1.09), 3.897 (2.04), 4.021 (1.60), 5.203 (4.37), 6.404 (0.75), 6.423 (2.53), 6.445 (3.43), 6.465 ( 2.39), 7.484 (1.62), 7.499 (4.37), 7.503 (4.83), 7.517 (4.54), 7.522 (4.79), 7.533 (3.68), 7.551 (7.45), 7.566 (7.05), 7.589 (4.65), 7.607 ( 12.96), 7.627 (7.80), 8.050 (8.75), 8.082 (8.62), 8.861 (16.00), 11.447 (5.70), 11.470 (5.39).

Example 132.

N- (2,6-Dichlorobenzyl) -7 - [(3R, 4R) -3,4-dihydroxypyrrolidin-1-yl] -6-fluoro-4-oxo-1- (2,4,6-trifluorophenyl) - 1,4-dihydro-1,8-naphthyridine-3-carboxamide.

According to AAV1, 100 mg (228 μmol) 7 - [(3R, 4R) -3,4-dihydroxypyrrolidin-1-yl] -6fluoro-4-oxo-1- (2,4,6-trifluorophenyl) -1,4 -dihydro-1,8-naphthyridine-3-carboxylic acid with 44.1 mg (250 μmol) 11- (2,6-dichlorophenyl) methanamine in the presence of 104 mg (273 μmol) HATU and 120 μL (680 mmol) DIPEA in 1.4 ml DMF The starting material was purified by preparative HPLC (column: acetonitrile / water / 0.1% formic acid). This gave 121 mg (89% theory, 100% purity) of the title compound.

LCMS (Method 1): Rt = 1.00 min; MS (ESIpos): m / z = 597 [M + H] ⁺ .

Ή-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: -0.149 (0.53), -0.008 (5.53), 0.008 (3.79), 0.146 (0.53), 2.367 (0.81), 2.519 (3.30), 2.524 (2.91), 2.711 (0.74), 3.046 (0.63), 3.671 (0.60), 3.903 (1.44), 4.809 (10.37), 4.823 (10.16), 5.181 (4.47), 7.379 (3.42), 7.398 (5.05), 7.401 (5.23), 7.420 (5.84), 7.525 (16.00), 7.545 (12.28), 7.569 (5.33), 7.591 (3.09), 7.953 (7.16), 7.985 (6.98), 8.782 (12.02), 10.219 (2.47), 10.232 (4.91), 10.245 (2.14).

Example 133.

6-Chloro-N- (2,6-dichlorophenyl) -1- (2,4-difluorophenyl) -4-oxo-1,4-dihydro-1,8-naphthyridine-3carboxamide.

A solution of 79.4 mg (490 mmol ) 2,6-dichloroaniline in 1.0 ml of DMF and then 19.6 mg (490 μmol) of sodium hydride (60% in mineral oil) was added. Stirred for 2 hours at room temperature. The reaction was terminated by the addition of water, acetonitrile and formic acid and the starting material was purified by preparative HPLC (column: acetonitrile / water / 0.1% formic acid). This gave 36.0 mg (16% theory, 93% purity) of the title compound.

LCMS (Method 1): Rt = 1.24 min; MS (ESIpos): m / z = 480 [M + H] ⁺ .

Ή-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 11.41 (s, 1H), 9.02 (s, 1H), 8.92 (d, 1H), 8.81 (d, 1H), 7.85-7.94 (m , 1H), 7.57-7.67 (m, 3H), 7.32-7.44 (m, 2H).

Example 134.

6-chloro-N- [1- (2-chlorophenyl) -2,2,2-trifluoroethyl] -1- (2,4-difluorophenyl) -4-oxo-1,4-dihydro-1,8 naphthyridine-3- carboxamide (racemate)

According to AAV1, 150 mg (446 μmol) of 6-chloro-1- (2,4-difluorophenyl) -4-oxo-1,4-dihydro1,8-naphthyridine-3-carboxylic acid was converted with 140 mg (668 μmol) 1- (2-chlorophenyl) -2,2,2-trifluoroethanamine (racemate) in the presence of 203 mg (535 μmol) HATU and 230 μl (1.30 mmol) DIPEA in 1.5 ml DMF. The starting material was purified by preparative HPLC (column: acetonitrile / water / 0.1% formic acid). This gave 197 mg (83% theory, 99% purity) of the title compound.

LCMS (Method 1): Rt = 1.37 min; MS (ESIpos): m / z = 528 [M + H] ⁺ .

Ή-NMR (400 MHz, DMSO-d6) δ [ppm]: 11.03 (d, 1H), 8.96 (s, 1H), 8.90 (d, 1H), 8.80 (d, 1H), 7.74-7.91 (m, 1H), 7.48-7.67 (m, 5H), 7.31-7.41 (m, 1H), 6.43-6.53 (m, 1H).

Example 135.

6-Chloro-1- (2,4-difluorophenyl) -4-oxo-N- [1- (trifluoromethoxy) propan-2-yl] -1,4-dihydro-1,8 naphthyridine-3-carboxamide (racemate).

According to AAV1, 150 mg (446 μmol) of 6-chloro-1- (2,4-difluorophenyl) -4-oxo-1,4-dihydro1,8-naphthyridine-3-carboxylic acid was converted with 120 mg (668 μmol) 1- (trifluoromethoxy) propan-2-amine hydrochloride (racemate) in the presence of 203 mg (535 μmol) HATU and 310 μl (1.30 mmol) DIPEA in 1.5 ml DMF. The starting material was purified by preparative HPLC (column: acetonitrile / water / 0.1% formic acid). This gave 159 mg (77% theory, 100% purity) of the title compound.

LCMS (Method 1): Rt = 1.21 min; MS (ESIpos): m / z = 462 [M + H] ⁺ .

Ή-NMR (400 MHz, DMSO-d6) δ [ppm]: 9.69 (d, 1H), 8.86-8.89 (m, 2H), 8.73 (d, 1H), 7.81-7.89 (m, 1H), 7.62 ( ddd, 1H), 7.33-7.39 (m, 1H), 4.33-4.42 (m, 1H), 4.16-4.23 (m, 2H), 1.27 (d, 3H).

- 101 038451

Example 136.

1- (2-Chloro-4,6-difluorophenyl) -7 - [(3R, 4R) -3,4-dihydroxypyrrolidin-1-yl] -6-fluoro-4-oxo-N- [1,1,1 trifluoro -3-methylbutan-2-yl] -1,4-dihydro-1,8-naphthyridine-3-carboxamide (mixture of diastereoisomers).

According to AAV1, 200 mg (83% purity, 364 μmol) 1- (2-chloro-4,6-difluorophenyl) -7 [(3R, 4R) -3,4-dihydroxypyrrolidin-1-yl] -6-fluoro- 4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid with 58.3 mg (97%, 401 μmol) 1,1,1-trifluoro-3-methylbutan-2-amine in the presence of 166 mg ( 437 μmol) HATU and 190 μl (1.10 mmol) DIPEA in 3.2 ml DMF The starting product was purified by preparative HPLC (column: acetonitrile / water / 0.1% formic acid). This gave 210 mg (100% theory, 100% purity) of the title compound.

LCMS (Method 3): Rt = 1.95 min; MS (ESIpos): m / z = 579 [M + H] +.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: -0.149 (0.42), 0.008 (3.45), 0.146 (0.45), 0.953 (9.63), 0.962 (10.81), 0.969 (10.83), 0.979 (9.65), 1.019 (9.50), 1.025 (9.91), 1.036 (10.14), 1.042 (9.33), 2.224 (1.64), 2.234 (1.74), 2.241 (2.15), 2.251 (2.15), 2.267 (1.51), 2.285 (0.65), 2.711 (0.54), 2.732 (2.24), 2.891 (2.92), 3.015 (1.51), 4.747 (1.32), 4.769 (1.91), 4.789 (1.28), 5.201 (1.74), 7.719 (2.68), 7.728 (2.97), 7.734 (3.17), 7.742 (0.59), 2.328 (0.63), 2.367 (0.54), 2.524 (2.19), 2.670 (0.96), 3.225 (0.99), 3.687 (1.01), 3.893 (1.99), 4.013 (5.09), 5.754 (5.44), 7.688 (0.85), 7.695 (1.33), 7.710 (3.82), 7.751 (3.28), 7.765 (2.51), 8.041 (7.79), 8.073 (7.68), 8.802 (16.00), 10.536 (3.12), 10.545 (3.29), 10.561 (3.10), 10.569 (3.09).

Example 137.

7 - [(3R, 4S) -3,4-Dihydroxypyrrolidin-1-yl] -6-fluoro-4-oxo-N- [1,1,1-trifluoro-3-methylbutan-2-yl] -1 ( 2,4,6-trifluorophenyl) -1,4-dihydro-1,8-naphthyridine-3-carboxamide (diastereoisomer 1).

52.0 mg 7 - [(3R, 4S) -3,4-dihydroxypyrrolidin-1-yl] -6-fluoro-4-oxo-N- [1,1,1-trifluoro-3-methylbutan2-yl] -1- (2,4,6-trifluorophenyl) -1,4-dihydro-1,8-naphthyridine-3-carboxamide (mixture of diastereoisomers) was separated into diastereoisomers by preparative HPLC (preparative HPLC: column

Daicel Chiralcel OX-H, 5 μm, 250x20 mm; eluent: 80% n-heptane / 20% ethanol; flow 15 ml / min; temperature: 25 ° C, indication: 210 nm).

Diastereoisomer 1: 19.5 mg (> 99% ee).

Rt = 1.30 min [HPLC: Daicel OX-3 columns; 3 μm, 50x4.6 mm; eluent: 80% isohexane / 20% ethanol; indication: 220 nm].

Diastereoisomer 1 was further purified by preparative HPLC (column: acetonitrile / water / 0.1% formic acid) and 14.0 mg (100% purity) of the title compound was purified.

LCMS (Method 3): Rt = 1.96 min; MS (ESIpos): m / z = 563 [M + H] ⁺ .

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: -0.149 (0.79), -0.008 (7.62), 0.008 (5.42), 0.146 (0.71), 0.953 (15.75), 0.970 (16.00), 1.017 (13.54), 1.034 (13.74), 2.203 (0.62), 2.221 (1.58), 2.230 (1.66), 2.237 (2.09), 2.247 (2.12), 2.254 (1.55), 2.264 (1.47), 2.328 (1.13), 2.366 (1.21), 2.523 (4.06), 2.670 (1.19), 2.710 (1.24), 3.036 (0.62), 3.406 (0.90), 3.583 (0.68), 3.803 (0.45), 3.821 (0.45), 4.034 (2.34), 4.738 (1.24), 4.747 (1.35), 4.761 (1.83), 4.770 (1.89), 4.783 (1.30), 4.793 (1.19), 5.004 (2.00), 7.556 (3.89), 7.577 (7.37), 7.600 (3.87), 8.025 (7.37), 8.057 (7.37), 8.845 (13.43), 10.514 (4.94), 10.540 (4.77).

Example 138.

7 - [(3R, 4S) -3,4-Dihydroxypyrrolidin-1-yl] -6-fluoro-4-oxo-N- [1,1,1-trifluoro-3-methylbutan-2-yl] -1 ( 2,4,6-trifluorophenyl) -1,4-dihydro-1,8-naphthyridine-3-carboxamide (diastereoisomer 2).

52.0 mg 7 - [(3R, 4S) -3,4-dihydroxypyrrolidin-1-yl] -6-fluoro-4-oxo-N- [1,1,1-trifluoro-3-methylbutan2-yl] -1- (2,4,6-trifluorophenyl) -1,4-dihydro-1,8-naphthyridine-3-carboxamide (mixture of diastereoisomers) was separated into diastereoisomers by preparative HPLC (preparative HPLC: Daicel Chiralcel OX-H column, 5 μm, 250x20 mm; eluent: 80% n-heptane / 20% ethanol; flow 15 ml / min; temperature: 25 ° C, indication: 210 nm).

Diastereoisomer 2: 21.5 mg (90.4% ee).

Rt = 1.77 min [HPLC: Daicel OX-3 columns; 3 μm, 50x4.6 mm; eluent: 80% isohexane / 20% ethanol; indication: 220 nm].

Diastereoisomer 2 was further purified by preparative HPLC (column: acetonitrile / water / 0.1% formic acid) and 15.0 mg (100% purity) of the title compound was purified.

LCMS (Method 3): Rt = 1.97 min; MS (ESIpos): m / z = 563 [M + H] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: -0.149 (0.48), -0.008 (4.54), 0.008 (3.45), 0.146 (0.46), 0.930 (3.74), 0.949 (12.03), 0.953 (15.89), 0.970 (16.00), 1.017 (13.01), 1.034 (13.22), 2.204 (0.59), 2.221 (1.53),

2.231 (1.58), 2.238 (2.01), 2.248 (2.01), 2.255 (1.48), 2.264 (1.41), 2.281 (0.53), 2.328 (0.69), 2.367 (0.75),

2.451 (0.77), 2.468 (2.26), 2.524 (2.47), 2.671 (0.75), 2.711 (0.78), 3.023 (0.62), 3.594 (0.64), 3.951 (0.80),

4.039 (2.22), 4.738 (1.17), 4.747 (1.32), 4.761 (1.74), 4.771 (1.76), 4.784 (1.25), 4.793 (1.16), 5.006 (1.69),

7.556 (3.68), 7.578 (6.92), 7.600 (3.70), 8.026 (7.19), 8.057 (7.07), 8.266 (0.77), 8.846 (12.46), 10.515 (4.82), 10.540 (4.65).

- 102 038451

Example 139.

6-Fluoro-7 - [(3 S) -3-hydroxypyrrolidin-1-yl] -4-okco-N- [1,1,1-trifluoro-3-methylbutan-2-yl] -1 - (2, 4,6trifluorophenyl) -1,4-dihydro-1,8-naphthyridine-3-carboxamide (diastereoisomer 1).

54.0 mg 6-fluoro-7 - [(3 S) -3-hydroxypyrrolidin-1-yl] -4-okco-N- [1,1,1-trifluoro-3-methylbutan-2-yl] -1 (2 , 4,6-trifluorophenyl) -1,4-dihydro-1,8-naphthyridine-3-carboxamide (mixture of diastereoisomers) was separated into diastereoisomers by preparative HPLC (preparative HPLC: Daicel Chiralpak ID column, 5 μm, 250x20 mm; eluent : 70% n-heptane / 30% isopropanol; flow 15 ml / min; temperature: 25 ° C, indication: 270 nm).

Diastereoisomer 1: 21.5 mg (> 99% ee).

Rt = 2.20 min [HPLC: Daicel IE-3 columns; 3 μm, 50x4.6 mm; eluent: 80% isohexane / 20% isopropanol; detection: 220 nm].

LCMS (Method 1): Rt = 1.13 min; MS (ESIpos): m / z = 547 [M + H] +.

¹ H-NMR (400 MHz, DMSO-06) δ [ppm]: -0.149 (0.42), -0.008 (3.86), 0.008 (3.14), 0.955 (15.68), 0.971 (16.00), 1.018 (13.42), 1.036 (13.72), 1.234 (0.52), 1.814 (0.98), 2.205 (0.64), 2.222 (1.58), 2.231 (1.64), 2.239 (2.10), 2.248 (2.10), 2.255 (1.60), 2.265 (1.50), 2.282 (0.54), 2.328 (0.88), 2.366 (0.72), 2.524 (2.80), 2.670 (0.94), 2.710 (0.76), 3.841 (0.46), 4.299 (1.22), 4.739 (1.24), 4.748 (1.36), 4.762 (1.78), 4.771 (1.82), 4.785 (1.30), 4.794 (1.20), 5.015 (1.18), 7.549 (2.90), 7.570 (5.35), 7.591 (3.08), 8.024 (7.85), 8.056 (7.69), 8.843 (13.18), 10.526 (4.95), 10.551 (4.79).

Example 140.

6-Fluoro-7 - [(3 S) -3-hydroxypyrrolidin-1-yl] -4-okco-N- [1,1,1-trifluoro-3-methylbutan-2-yl] -1 - (2, 4,6trifluorophenyl) -1,4-dihydro-1,8-naphthyridine-3-carboxamide (diastereoisomer 2).

54.0 mg 6-fluoro-7 - [(3 S) -3-hydroxypyrrolidin-1-yl] -4-okco-N- [1,1,1-trifluoro-3-methylbutan-2-yl] -1 (2 , 4,6-trifluorophenyl) -1,4-dihydro-1,8-naphthyridine-3-carboxamide (mixture of diastereoisomers) was separated into diastereoisomers by preparative HPLC (preparative HPLC: Daicel Chiralpak ID column, 5 μm, 250x20 mm; eluent : 70% n-heptane / 30% isopropanol; flow 15 ml / min; temperature: 25 ° C, indication: 270 nm).

Diastereoisomer 2: 19.5 mg (96.8% ee).

Rt = 3.41 min [HPLC: Daicel IE-3 columns; 3 μm, 50x4.6 mm; eluent: 80% isohexane / 20% isopropanol; detection: 220 nm].

LCMS (Method 1): Rt = 1.14 min; MS (ESIpos): m / z = 547 [M + H] ⁺ .

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.008 (2.57), 0.858 (0.51), 0.954 (15.74), 0.971 (16.00), 1.018 (13.62), 1.035 (13.86), 1.233 (0.75 ), 1.827 (1.03), 2.204 (0.66), 2.222 (1.61), 2.232 (1.70), 2.239 (2.10), 2.248 (2.14), 2.255 (1.59), 2.265 (1.52), 2.282 (0.58), 2.329 (0.88 ), 2.367 (0.58), 2.670 (0.86), 2.711 (0.56), 3.814 (0.49), 4.294 (1.27), 4.739 (1.29), 4.748 (1.37), 4.763 (1.82), 4.771 (1.85), 4.786 (1.26) ), 4.794 (1.24), 5.008 (2.70), 7.549 (4.18), 7.571 (7.89), 7.593 (4.22), 8.025 (7.63), 8.057 (7.57), 8.843 (13.71), 10.527 (4.93), 10.552 (4.78 ).

Example 141.

- (2-Chloro-4,6-difluorophenyl) -N- (1,1-difluoro-2-methylpropan-2-yl) -7 - [(3R, 4R) -3,4-dihydroxypyrrolidin-1-yl] -6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide (mixture of atropisomers)

F

According to AAV1, 100 mg (83% purity, 182 μmol) 1- (2-chloro-4,6-difluorophenyl) -7 [(3R, 4R) -3,4-dihydroxypyrrolidin-1-yl] -6-fluoro- 4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid with 30.1 mg (97% purity, 200 μmol) 11,1-difluoro-2-methylpropan-2-amine hydrochloride in the presence of 83.1 mg ( 219 μmol) HATU and 130 μl (730 μmol) DIPEA in 1.6 ml DMF. The starting material was purified by preparative HPLC (column: acetonitrile / water / 0.1% formic acid). 97.0 mg (97% theory, 100% purity) of the title compound was obtained.

LCMS (Method 3): Rt = 1.80 min; MS (ESIpos): m / z = 547 [M + H] ⁺ .

¹ H-NMR (400 MHz, DMSO- <1 ₆ ) δ [ppm]: 10.25 (s, 1H), 8.70 (s, 1H), 8.01 (d, 1H), 7.68-7.79 (m, 2H), 6.256 .58 (m, 1H), 5.19 (br s, 2H), 3.79-4.06 (m, 3H), 3.56-3.78 (m, 1H), 3.12-3.28 (m, 1H), 2.93-3.11 (m, 1H ), 1.43 (s, 6H).

Example 142.

- (2-Chloro-4,6-difluorophenyl) -N- (1,1-difluoro-2-methylpropan-2-yl) -7 - [(3R, 4R) -3,4-dihydroxypyrrolidin-1-yl] -6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide (atropisomer 1).

97.0 mg 1- (2-chloro-4,6-difluorophenyl) -N- (1,1-difluoro-2-methylpropan-2-yl) -7 - [(3R, 4R) -3,4-dihydroxypyrrolidine-1 -yl] -6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide (mixture of atropisomers)

- 103 038451 was separated by chiral HPLC into atropisomers (preparative HPLC: Daicel column

Chiralpak IA, 5 μm, 250x20 mm; eluent: 75% n-heptane / 25% isopropanol + 0.2% DEA; flow 15 ml / min;

temperature: 35 ° C, indication: 220 nm).

Atropoisomer 1: 34.4 mg (> 99% ee).

R _t = 9.05 min [HPLC: Daicel Chiralpak IA columns, 1 ml / min; 5 microns, 250x4.6 mm; eluent: 80% n-heptane / 20% isopropanol + 0.2% DEA; indication: 235 nm].

LCMS (Method 3): _Rt = 1.76 min; MS (ESIpos): m / z = 547 [M + H] ⁺ .

Ή NMR (400 MHz, DMSO ^) δ ppm 10.25 (s, 1H), 8.70 (s, 1H), 8.01 (d, 1H), 7.68 -7.77 (m, 2H), 6.226.58 (m, 1H), 5.19 (br s, 2H), 3.79-4.08 (m, 3H), 3.59-3.78 (m, 1H), 3.15-3.28 (m, 1H), 2.89-3.10 (m, 1H), 1.44 (s, 6H) ...

Example 143.

1- (2-Chloro-4,6-difluorophenyl) -N- (1,1-difluoro-2-methylpropan-2-yl) -7 - [(3R, 4R) -3,4-dihydroxypyrrolidin-1-yl ] -6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide (atropisomer 2).

97.0 mg 1- (2-chloro-4,6-difluorophenyl) -N- (1,1-difluoro-2-methylpropan-2-yl) -7 - [(3R, 4R) -3,4-dihydroxypyrrolidine-1 -yl] -6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide (mixture of atropisomers) was separated by chiral HPLC into atropisomers (preparative HPLC: Daicel Chiralpak IA column, 5 μm, 250x20 mm; eluent: 75% n-heptane / 25% isopropanol + 0.2% DEA; flow 15 ml / min; temperature: 35 ° C, indication: 220 nm).

Atropoisomer 2: 5.50 mg (> 99% ee).

R _t = 13.64 min [HPLC: Daicel Chiralpak IA columns, 1 ml / min; 5 microns, 250x4.6 mm; eluent: 80% n-heptane / 20% isopropanol + 0.2% DEA; indication: 235 nm].

LCMS (Method 3): Rt = 1.76 min; MS (ESIpos): m / z = 547 [M + H] ⁺ .

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 10.25 (s, 1H), 8.70 (s, 1H), 8.01 (d, 1H), 7.67-7.77 (m, 2H), 6.256. 58 (m, 1H), 5.14-5.24 (m, 2H), 3.78-4.08 (m, 3H), 3.57-3.77 (m, 1H), 3.12-3.27 (m, 1H), 2.92-3.11 (m, 1H ), 1.43 (s, 6H).

Example 144.

7 - [(3R, 4R) -3,4-Dihydroxypyrrolidin-1-yl] -6-fluoro-N- (1,1,1,3,3,3-hexafluoropropan-2-yl) -4-oxo 1 (2,4,6-trifluorophenyl) -1,4-dihydro-1,8-naphthyridine-3-carboxamide

F

According to AAV3, 80.0 mg (153 μmol) of 7-chloro-6-fluoro-N- (1,1,1,3,3,3-hexafluoropropane-2yl) -4-oxo-1- (2,4,6- trifluorophenyl) -1,4-dihydro-1,8-naphthyridine-3-carboxamide with 23.5 mg (169 μmol) (3R, 4R) -pyrrolidine-3,4-diol hydrochloride and 93 μL (540 μmol) DIPEA in 1.5 ml DMF. The starting material was purified by preparative HPLC (column: acetonitrile / water / 0.1% formic acid). This gave 88.0 mg (98% theory, 100% purity) of the title compound.

LCMS (Method 3): Rt = 1.91 min; MS (ESIpos): m / z = 589 [M + H] ⁺ .

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.149 (0.63), -0.008 (5.64), 0.008 (4.87), 0.146 (0.63), 2.073 (0.88), 2.328 (0.91), 2.367 (0.67), 2.670 (0.95), 2.711 (0.67), 3.081 (1.16), 3.708 (1.16), 3.903 (2.10), 4.025 (1.68), 5.208 (3.85), 6.280 (0.49), 6.297 (1.23), 6.316 (1.75), 6.340 (1.86), 6.358 (1.23), 7.569 (3.78), 7.590 (6.79), 7.611 (3.78), 8.033 (8.96), 8.065 (8.79), 8.969 (16.00), 11.296 (5.95), 11.321 (5.67).

Example 145.

1- (3,5-Difluoropyridin-2-yl) -7 - [(3R, 4R) -3,4-dihydroxypyrrolidin-1-yl] -6-fluoro-N- (1,1,1,3,3 , 3hexafluoropropan-2-yl) -4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide

F

According to AAV3, 249 mg (493 μmol) of 7-chloro-1- (3,5-difluoropyridin-2-yl) -6-fluoro-N (1,1,1,3,3,3-hexafluoropropan-2-yl ) -4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide with 75.8 mg (543 μmol) (3R, 4R) -pyrrolidine-3,4-diol hydrochloride and 300 μL (1.70 mmol) DIPEA in 5 ml of DMF. The starting material was purified by preparative HPLC (column: acetonitrile / water / 0.1% formic acid). Received 197 mg (70% theory.rev., 100% purity) of the title compound

- 104 038451 ny.

LCMS (Method 3): Rt = 1.79 min; MS (ESIpos): m / z = 572 [M + H] ⁺ .

¹ H-NMR (400 MHz, DMSO-a ₆ ) δ [ppm]: -0.150 (0.81), 0.146 (0.81), 0.950 (1.31), 0.966 (1.16), 2.327 (1.26), 2.367 (1.26), 2.670 (1.46), 2.710 (1.26), 3.060 (0.86), 3.717 (0.96), 3.905 (2.68), 4.017 (1.92), 5.118 (0.91), 5.207 (3.43), 6.309 (1.56), 6.328 (2.32), 6.351 (2.37), 6.369 (1.56), 8.034 (6.06), 8.066 (6.21), 8.340 (2.37), 8.346 (2.78), 8.367 (4.74), 8.384 (2.47), 8.390 (2.68), 8.633 (8.98), 8.933 (16.00), 11.291 (7.32), 11.317 (7.07).

Example 146.

6-Fluoro-7- (morpholin-4-yl) -4-oxo-N- [3,3,4,4,4-pentafluorobutan-2-yl] -1- (2,4,6-trifluorophenyl) - 1,4dihydro-1,8-naphthyridine-3-carboxamide (racemate)

According to AAV1, 100 mg (236 μmol) -fluoro-7- (morpholin-4-yl) -4-oxo-1- (2,4,6trifluorophenyl) -1,4-dihydro-1,8-naphthyridine-3- carboxylic acid with 51.9 mg (260 µmol) 3,3,4,4,4 pentafluorobutan-2-amine hydrochloride (racemate) in the presence of 108 mg (283 µmol) HATU and 120 µl (710 µmol) DIPEA in 2.3 ml DMF. The starting material was purified by preparative HPLC (column: acetonitrile / water / 0.1% formic acid). This gave 86.0 mg (64% theory, 100% purity) of the title compound.

LCMS (Method 3): Rt = 2.33 min; MS (ESIpos): m / z = 569 [M + H] +.

¹ H-NMR (400 MHz, DMSO-06) δ [ppm]: -0.149 (1.35), -0.008 (14.16), 0.008 (14.02), 0.146 (1.44), 1.389 (12.85), 1.407 (12.72), 1.988 (0.85), 2.327 (2.07), 2.366 (1.84), 2.523 (7.64), 2.670 (2.20), 2.710 (1.84), 3.506 (8.45), 3.517 (14.92), 3.529 (14.38), 3.596 (15.28), 3.608 (16.00), 3.619 (9.17), 3.741 (0.58), 4.038 (0.40), 5.015 (1.39), 5.034 (1.35), 7.550 (5.12), 7.572 (9.75), 7.594 (5.12), 8.103 (8.94), 8.137 (8.76), 8.711 (0.49), 8.907 (15.60), 10.344 (5.26), 10.368 (5.17).

Example 147.

N - [(1S) -Cyclopropyl-2,2,2-trifluoroethyl] -6-fluoro-7- (morpholin-4-yl) -4-oxo-1- (2,4,6-trifluorophenyl) 1,4 -dihydro-1,8-naphthyridine-3-carboxamide

According to AAV1, 80.0 mg (189 μmol) of 6-fluoro-7- (morpholin-4-yl) -4-oxo-1- (2,4,6trifluorophenyl) -1,4-dihydro-1,8-naphthyridine-3 β-carboxylic acid with 36.5 mg (208 μmol) (1S) -cyclopropyl-2,2,2-trifluoroethanamine hydrochloride in the presence of 86.2 mg (227 μmol) HATU and 99 μL (570 μmol) DIPEA in 1.8 ml DMF. The starting material was purified by preparative HPLC (column: acetonitrile / water / 0.1% formic acid). This gave 91.9 mg (89% theory, 100% purity) of the title compound.

LCMS (Method 3): Rt = 2.33 min; MS (ESIpos): m / z = 545 [M + H] ⁺ .

1H-NMR (400 MHz, DMSO-a ₆ ) δ [ppm]: -0.149 (0.68), -0.008 (8.06), 0.008 (4.92), 0.146 (0.68), 0.320 (1.83), 0.330 (2.93), 0.343 (2.81), 0.354 (2.06), 0.366 (1.15), 0.508 (0.77), 0.521 (1.90), 0.532 (2.93), 0.545 (2.88), 0.551 (3.23), 0.570 (3.35), 0.579 (2.48), 0.590 (2.25), 0.600 (1.83), 0.614 (1.12), 0.630 (1.52), 0.640 (1.50), 0.650 (3.00), 0.660 (2.32), 0.667 (2.08), 0.672 (2.01), 0.686 (1.10), 0.694 (0.68), 1.172 (0.59), 1.185 (1.19), 1.193 (1.64), 1.205 (2.76), 1.214 (2.11), 1.225 (2.69), 1.237 (1.52), 1.246 (1.01), 1.258 (0.45), 2.073 (1.10), 2.328 (0.82), 2.367 (0.94), 2.524 (3.40), 2.670 (0.91), 2.710 (1.01), 3.509 (8.88), 3.520 (15.46), 3.532 (14.62), 3.549 (1.52), 3.600 (15.77), 3.612 (16.00), 3.622 (9.04), 4.353 (1.50), 4.374 (2.60), 4.396 (2.48), 4.415 (1.36), 7.550 (5.06), 7.573 (9.77), 7.595 (5.15), 7.603 (1.62), 8.112 (8.78), 8.146 (8.62), 8.896 (14.52), 10.361 (5.67), 10.384 (5.51).

- 105 038451

Example 148.

6-Fluoro-7- (morpholin-4-yl) -4-oxo-N- [1,1,1,2,2-pentafluoropentan-3-yl] -1 - (2,4,6-trifluorophenyl) - 1,4dihydro-1,8-naphthyridine-3-carboxamide (racemate)

F

According to AAV1, 100 mg (236 μmol) of 6-fluoro-7- (morpholin-4-yl) -4-oxo-1- (2,4,6trifluorophenyl) -1,4-dihydro-1,8-naphthyridine-3 -carboxylic acid with 55.5 mg (260 μmol) 1,1,1,2,2 pentafluoropentan-3-amine hydrochloride (racemate) in the presence of 108 mg (283 μmol) HATU and 120 μL (710 μmol) DIPEA in 2.3 ml DMF. The starting material was purified by preparative HPLC (column: acetonitrile / water / 0.1% formic acid). This gave 108 mg (78% theory, 100% purity) of the title compound.

LCMS (Method 3): Rt = 2.42 min; MS (ESIpos): m / z = 583 [M + H] ⁺ .

¹ H-NMR (400 MHz, DMSO-06) δ [ppm]: -0.149 (1.17), -0.008 (10.68), 0.008 (8.97), 0.146 (1.22), 0.943 (7.08), 0.962 (16.00), 0.980 (7.66), 1.157 (0.90), 1.175 (1.80), 1.193 (0.95), 1.234 (0.41), 1.624 (0.86), 1.642 (1.22), 1.650 (1.13), 1.659 (1.44), 1.669 (1.31), 1.677 (1.26), 1.685 (1.44), 1.703 (0.99), 1.907 (1.44), 1.988 (3.20), 2.328 (1.35), 2.366 (1.89), 2.523 (5.00), 2.670 (1.58), 2.710 (1.94), 3.508 (6.76), 3.519 (12.21), 3.531 (11.85), 3.547 (1.58), 3.597 (12.57), 3.610 (12.94), 3.620 (7.35), 4.021 (0.81), 4.038 (0.72), 4.831 (0.86), 4.857 (1.08), 4.883 (1.08), 4.907 (0.86), 7.551 (4.01), 7.573 (7.80), 7.595 (4.10), 8.113 (6.94), 8.147 (6.85), 8.914 (11.67), 10.266 (4.42), 10.291 (4.28).

Example 149.

6-Fluoro-7- (morpholin-4-yl) -4-oxo-N- (1,1,1-trifluoro-2-methylpropan-2-yl) -1 - (2,4,6-trifluorophenyl) 1 , 4-dihydro-1,8-naphthyridine-3-carboxamide

F

According to AAV1, 80.0 mg (189 μmol) of 6-fluoro-7- (morpholin-4-yl) -4-oxo-1- (2,4,6trifluorophenyl) -1,4-dihydro-1,8-naphthyridine-3 -carboxylic acid with 34.0 mg (208 μmol) 1,1,1-trifluoro-2-methylpropan-2-amine hydrochloride in the presence of 86.2 mg (227 μmol) HATU and 99 μL (570 μmol) DIPEA in 1.8 ml DMF. The starting material was purified by preparative HPLC (column: acetonitrile / water / 0.1% formic acid). This gave 87.6 mg (87% theory, 100% purity) of the title compound.

LCMS (Method 3): Rt = 2.34 min; MS (ESIpos): m / z = 533 [M + H] +.

¹ H-NMR (400 MHz, DMSO-06) δ [ppm]: -0.008 (2.83), 0.008 (2.66), 1.636 (16.00), 2.073 (1.35), 2.670 (0.47), 2.710 (0.42), 3.504 ( 2.00), 3.514 (3.57), 3.526 (3.45), 3.596 (3.60), 3.609 (3.83), 3.619 (2.21), 7.552 (1.12), 7.574 (2.09), 7.596 (1.15), 8.115 (1.92), 8.149 ( 1.92), 8.840 (3.18), 10.452 (2.69).

Example 150.

N- (1,1-Difluoro-2-methylpropan-2-yl) -6-fluoro-7- (morpholin-4-yl) -4-oxo-1- (2,4,6-trifluorophenyl) -1, 4dihydro-1,8-naphthyridine-3-carboxamide

F

According to AAV1, 80.0 mg (189 μmol) of 6-fluoro-7- (morpholin-4-yl) -4-oxo-1- (2,4,6trifluorophenyl) -1,4-dihydro-1,8-naphthyridine-3 -carboxylic acid with 30.3 mg (208 μmol) 1,1-difluoro-2methylpropan-2-amine hydrochloride in the presence of 86.2 mg (227 μmol) HATU and 99 μL (570 μmol) DIPEA in 1.8 ml DMF. The starting material was purified by preparative HPLC (column: acetonitrile / water / 0.1% formic acid). This gave 128 mg (col., 100% pure) of the title compound.

- 106 038451

LCMS (Method 1): _Rt = 1.17 min; MS (ESIpos): m / z = 515 [M + H] +.

1H-NMR (400 MHz, DMSO-de) δ [ppm]: 0.008 (2.62), 1.439 (16.00), 2.073 (1.40), 2.328 (0.43), 2.670 (0.45), 3.500 (2.43), 3.510 (4.30) , 3.522 (4.05), 3.595 (4.20), 3.607 (4.50), 3.618 (2.59), 6.277 (0.88), 6.419 (1.63), 6.562 (0.74), 7.550 (1.32), 7.572 (2.49), 7.594 (1.34) , 8.095 (2.20), 8.129 (2.19), 8.817 (3.74), 10.135 (2.90).

Example 151.

6-Fluoro-7- (morpholin-4-yl) -4-oxo-N - [(2S) -1,1,1-trifluorobutan-2-yl] -1 - (2,4,6-trifluorophenyl) - 1,4dihydro-1,8-naphthyridine-3-carboxamide

F

According to AAV1, 80.0 mg (189 μmol) of 6-fluoro-7- (morpholin-4-yl) -4-oxo-1- (2,4,6trifluorophenyl) -1,4-dihydro-1,8-naphthyridine-3 -carboxylic acid with 34.0 mg (208 μmol) (2S) -1,1,1 trifluorobutan-2-amine hydrochloride in the presence of 86.2 mg (227 μmol) HATU and 99 μL (570 μmol) DIPEA in 1.8 ml DMF. The starting material was purified by preparative HPLC (column: acetonitrile / water / 0.1% formic acid). This gave 83.0 mg (82% theory, 100% purity) of the title compound.

LCMS (Method 1): _Rt = 1.20 min; MS (ESIpos): m / z = 533 [M + H] +.

¹ H-NMR (400 MHz, DMSO-de) δ [ppm]: 0.951 (7.27), 0.969 (16.00), 0.988 (7.90), 1.611 (1.05), 1.629 (1.46), 1.635 (1.29), 1.646 (1.77) ), 1.654 (1.58), 1.664 (1.52), 1.671 (1.69), 1.689 (1.27), 1.835 (0.42), 1.854 (1.32), 1.864 (1.52), 1.872 (1.57), 1.882 (1.75), 1.889 (1.54 ), 1.899 (1.38), 1.907 (1.15), 1.917 (0.96), 2.074 (0.67), 3.510 (8.13), 3.520 (14.34), 3.532 (13.50), 3.549 (1.33), 3.600 (14.03), 3.612 (14.78 ), 3.622 (8.39), 4.742 (1.52), 4.762 (1.43), 7.554 (4.14), 7.576 (8.01), 7.598 (4.19), 8.107 (6.29), 8.141 (6.26), 8.906 (11.53), 10.220 (4.83 ), 10.244 (4.71).

Example 152.

1- (3,5-Difluoropyridin-2-yl) -6-fluoro-7- [(3 S) -3-hydroxypyrrolidin-1-yl] -4-oxo-N - [(2S) -1,1, 1trifluorobutan-2-yl] -1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to AAV1, 45.0 mg (111 μmol) 1- (3,5-difluoropyridin-2-yl) -6-fluoro-7 - [(3S) -3 hydroxypyrrolidin-1-yl] -4-oxo-1,4- dihydro-1,8-naphthyridine-3-carboxylic acid with 19.9 mg (122 μmol) (2S) -1,1,1-trifluorobutan-2-amine hydrochloride in the presence of 50.5 mg (133 μmol) HATU and 77 μL (440 μmol ) DIPEA in 1.0 ml DMF. The starting material was purified by preparative HPLC (column: acetonitrile / water / 0.1% formic acid). This gave 42.0 mg (74% theory, 100% purity) of the title compound.

LCMS (Method 3): _Rt = 1.95 min; MS (ESIpos): m / z = 516 [M + H] +.

1H-NMR (400 MHz, DMSO-de) δ [ppm]: -0.149 (1.48), -0.008 (16.00), 0.008 (9.38), 0.146 (1.14), 0.959 (6.81), 0.975 (6.86), 0.992 ( 2.91), 1.637 (1.30), 1.883 (2.23), 2.328 (1.72), 2.523 (6.83), 2.670 (1.32), 3.342 (1.11), 4.303 (1.46), 4.741 (1.40), 4.995 (2.89), 5.004 ( 2.91), 7.988 (5.03), 8.020 (5.01), 8.315 (1.59), 8.321 (1.72), 8.342 (2.65), 8.365 (1.51), 8.617 (5.62), 8.837 (15.23), 10.328 (3.10), 10.353 ( 2.89).

Example 153.

N - [(1S) -1-Cyclopropyl-2,2,2-trifluoroethyl] -1- (3,5-difluoropyridin-2-yl) -6-fluoro-7 - [(3S) -3-hydroxypyrrolidine-1 -yl] -4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to AAV1, 45.0 mg (111 μmol) 1- (3,5-difluoropyridin-2-yl) -6-fluoro-7 - [(3S) -3-107 038451 gvdroxypyrrolvdin-1-yl] -4-oxo-1 , 4-dihydro-1,8-naphthyrvdine-3-carboxylic acid with 21.4 mg (122 μmol) (1S) -1-cyclopropyl-2,2,2-trifluoroethanamine hydrochloride in the presence of 50.5 mg (133 μmol) HATU and 77 μL (440 μmol) DIPEA in 1.0 ml DMF. The starting material was purified by preparative HPLC (column: acetonitrile / water / 0.1% formic acid). This gave 45.0 mg (77% theory, 100% purity) of the title compound.

LCMS (Method 3): Rt = 1.97 min; MS (ESIpos): m / z = 528 [M + H] +.

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.149 (1.00), 0.008 (9.61), 0.147 (1.11), 0.339 (2.15), 0.537 (2.19), 1.200 (2.37), 1.220 (2.40 ), 1.894 (1.33), 2.073 (6.17), 2.328 (2.12), 2.523 (6.89), 2.670 (2.26), 2.710 (1.15), 4.295 (1.69), 4.394 (2.30), 4.412 (2.37), 4.994 (3.62 ), 7.994 (6.31), 8.026 (6.39), 8.318 (2.08), 8.339 (3.55), 8.356 (1.79), 8.611 (6.67), 8.828 (16.00), 10.464 (2.69), 10.481 (2.76).

Example 154.

- (3,5-Difluoropyridin-2-yl) -6-fluoro-7 - [(3 S) -3-hydroxypyrrolidin-1-yl] -4-oxo-N- (1,1,1-trifluoro2-methylpropane -2-yl) -1,4-dihydro-1,8-naphthyridine-3-carboxamide

F

According to AAV1, 45.0 mg (111 μmol) 1- (3,5-difluoropyridin-2-yl) -6-fluoro-7 - [(3S) -3hydroxypyrrolidin-1-yl] -4-oxo-1,4-dihydro -1,8-naphthyridine-3-carboxylic acid with 15.5 mg (122 μmol) 1,1,1-trifluoro-2-methylpropan-2-amine in the presence of 50.5 mg (133 μmol) HATU and 58 μL (330 μmol) DIPEA in 1.0 ml of DMF. The starting material was purified by preparative HPLC (column: acetonitrile / water / 0.1% formic acid). This gave 42.0 mg (74% theory, 100% purity) of the title compound.

LCMS (Method 3): Rt = 1.94 min; MS (ESIpos): m / z = 516 [M + H] +.

¹ H-NMR (400 MHz, DMSO-a _b ) δ ppm: 10.56 (s, 1H), 8.78 (s, 1H), 8.61 (d, 1H), 8.30 -8.37 (m, 1H), 8.01 (d, 1H), 4.99 (br d, 1H), 4.20-4.38 (m, 1H), 3.35-4.05 (m, 1H), 3.00-3.28 (m, 1H), 1.72-1.97 (m, 2H), 1.63 (s , 6H).

Example 155.

7 - [(3R, 4S) -3,4-Dihydroxypyrrolidin-1-yl] -6-fluoro-4-oxo-N - [(2R) -1,1,1-trifluorobutan-2-yl] -1 ( 2,4,6-trifluorophenyl) -1,4-dihydro-1,8-naphthyridine-3-carboxamide

According to AAV1, 30.0 mg (68.3 μmol) 7 - [(3R, 4S) -3,4-dihydroxypyrrolidin-1-yl] -6fluoro-4-oxo-1- (2,4,6-trifluorophenyl) -1.4 -dihydro-1,8-naphthyridine-3-carboxylic acid with 13.4 mg (81.9 μmol) (2R) -1,1,1-trifluorobutan-2-amine hydrochloride in the presence of 31.2 mg (81.9 μmol) HATU and 42 μL (240 μmol) DIPEA in 1.0 ml DMF. The starting material was mixed with aqueous 1N hydrochloric acid and acetonitrile and purified by preparative HPLC (column: acetonitrile / water / 0.1% formic acid). This gave 29.5 mg (78% theory, 99% purity) of the title compound.

LCMS (Method 3): Rt = 1.84 min; MS (ESIpos): m / z = 549 [M + H] +.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: -0.008 (1.76), 0.008 (1.54), 0.949 (7.24), 0.967 (16.00), 0.985 (7.83), 1.603 (1.05), 1.621 (1.44), 1.628 (1.26), 1.638 (1.72), 1.646 (1.56), 1.656 (1.48), 1.663 (1.68), 1.681 (1.24), 1.831 (0.43), 1.850 (1.28), 1.859 (1.50), 1.868 (1.50), 1.878 (1.72), 1.884 (1.52), 1.894 (1.32), 1.903 (1.14), 1.913 (0.97), 2.328 (0.55), 2.367 (0.41), 2.524 (1.78), 2.671 (0.57), 2.711 (0.41), 3.027 (0.59), 3.212 (0.67), 3.589 (0.59), 4.036 (2.41), 4.733 (1.44), 4.753 (1.34), 5.003 (2.13), 7.555 (3.93), 7.577 (7.42), 7.599 (3.91), 7.988 (7.40), 8.019 (7.36), 8.838 (12.76), 10.322 (5.21), 10.346 (4.97).

Example 156.

7 - [(3 S, 4S) -3,4-Dihydroxypyrrolidin-1-yl] -6-fluoro-4-oxo-N - [(2R) -1,1,1-trifluorobutan-2-yl] -1 (2,4,6-trifluorophenyl) -1,4-dihydro-1,8-naphthyridine-3-carboxamide

- 108 038451

According to AAV1, 30.0 mg (68.3 μmol) 7 - [(3S, 4S) -3,4-dihydroxypyrrolidin-1-yl] -6fluoro-4-oxo-1- (2,4,6-trifluorophenyl) -1.4 -dihydro-1,8-naphthyridine-3-carboxylic acid with 13.4 mg (81.9 μmol) (2R) -1,1,1-trifluorobutan-2-amine hydrochloride in the presence of 31.2 mg (81.9 μmol) HATU and 42 μL (240 μmol) DIPEA in 690 μL DMF. The original product was mixed with aqueous 1N. hydrochloric acid and acetonitrile and purified by preparative HPLC (column: acetonitrile / water / 0.1% formic acid). This gave 30.6 mg (81% theory, 99% purity) of the title compound.

LCMS (Method 3): Rt = 1.78 min; MS (ESIpos): m / z = 549 [M + H] +.

¹ H-NMR (400 MHz, DMSO-0 ₆ ) δ [ppm]: -0.149 (0.47), 0.146 (0.47), 0.951 (7.20), 0.969 (16.00), 0.987 (7.86), 1.604 (1.09), 1.622 (1.40), 1.639 (1.71), 1.647 (1.56), 1.664 (1.67), 1.683 (1.25), 1.851 (1.21), 1.860 (1.56), 1.868 (1.48), 1.879 (1.67), 1.896 (1.36), 1.913 (0.93), 2.328 (1.48), 2.366 (1.21), 2.523 (4.71), 2.669 (1.44), 2.710 (1.13), 3.070 (0.86), 3.698 (0.86), 3.906 (1.75), 4.735 (1.52), 5.203 (3.70), 7.559 (3.04), 7.579 (5.37), 7.599 (2.92), 7.999 (8.02), 8.031 (7.82), 8.840 (14.75), 10.329 (5.14), 10.353 (4.87).

Example 157.

6-Bromo-7 - [(3R, 4R) -3,4-dihydroxypyrrolidin-1-yl] -4-oxo-N- [1,1,1,2,2-pentafluoropentan-3-yl] -1 ( 2,4,6-trifluorophenyl) -1,4-dihydro- 1,8-naphthyridine-3-carboxamide (mixture of diastereoisomers)

F

To a solution of 242 mg (417 μmol) 7 - [(3R, 4R) -3,4-dihydroxypyrrolidin-1-yl] -4-oxo-N- [1,1,1,2,2pentafluoropentan-3-yl] - 1 - (2,4,6-trifluorophenyl) -1,4-dihydro-1,8-naphthyridine-3-carboxamide in 5.0 ml of acetonitrile at room temperature was added 160 mg (896 μmol) of 1-bromopyrrolidine-2,5-dione (NBS) and 10.0 mg (60.9 μmol) 2,2 '- (E) -diazene-1,2-diyl-bis- (2-methylpropanenitrile (AIBN). Stirred for 1 h at 60 ° C. The reaction mixture was cooled , concentrated (in vacuo) to half volume and purified by preparative HPLC (column: acetonitrile / water / 0.1% formic acid) to give 103 mg (37% theory, 100% purity) of the title compound.

LCMS (Method 3): Rt = 2.08 min; MS (ESIpos): m / z = 659 [M + H] +.

¹ H-NMR (400 MHz, DMSO-0 ₆ ) δ [ppm]: -0.149 (0.81), -0.008 (6.76), 0.008 (6.78), 0.146 (0.81), 0.943 (7.54), 0.961 (16.00), 0.979 (8.14), 1.620 (1.01), 1.656 (1.75), 1.664 (1.68), 1.682 (1.66), 1.699 (1.15), 1.920 (1.87), 2.111 (0.55), 2.328 (1.01), 2.367 (0.85), 2.524 (3.23), 2.671 (1.01), 2.711 (0.76), 3.733 (1.22), 3.929 (8.99), 4.826 (1.18), 4.851 (1.54), 4.877 (1.54), 4.901 (1.13), 5.188 (2.81), 7.567 (3.67), 7.588 (6.46), 7.608 (3.46), 8.473 (13.99), 8.881 (15.40), 10.242 (5.19), 10.266 (5.10).

Example 158.

6-Bromo-7 - [(3R, 4R) -3,4-dihydroxypyrrolidin-1-yl] -4-oxo-N- [3,3,4,4,4-pentafluorobutan-2-yl] -1 ( 2,4,6-trifluorophenyl) -1,4-dihydro- 1,8-naphthyridine-3-carboxamide (mixture of diastereoisomers)

F

To a solution of 239 mg (422 μmol) 7 - [(3R, 4R) -3,4-dihydroxypyrrolidin-1-yl] -4-oxo-N- [3,3,4,4,4pentafluorobutan-2-yl] - 1- (2,4,6-trifluorophenyl) -1,4-dihydro-1,8-naphthyridine-3-carboxamide in 7.1 ml of acetonitrile at room temperature was added 161 mg (907 μmol) of 1-bromopyrrolidine-2,5-dione (NBS) and 10.0 mg (60.9 μmol) AIBN. Stirred for 1 h at 60 ° C. The reaction mixture was cooled, concentrated (in vacuo) to half volume and purified by preparative HPLC (column: acetonitrile / water / 0.1% formic acid). This gave 175 mg (64% theory, 100% purity) of the title compound.

LCMS (Method 3): Rt = 1.98 min; MS (ESIpos): m / z = 645 [M + H] +.

1H-NMR (400 MHz, DMSO-0 ₆ ) δ [ppm]: -0.149 (0.50), -0.008 (4.75), 0.146 (0.50), 1.386 (15.73), 1.404 (16.00), 2.074 (4.75), 2.329 (0.69), 2.367 (0.52), 2.671 (0.69), 2.711 (0.53), 3.421 (1.36), 3.734 (1.34), 3.930 (9.47), 4.966 (0.78), 4.986 (1.47), 5.008 (1.78), 5.028 (1.79), 5.052 (1.47), 5.073 (0.82), 5.185 (9.07), 7.565 (3.88), 7.586 (6.91), 7.607 (3.78), 8.453 (1.24), 8.462 (11.09), 8.466 (10.96), 8.876 (15.27), 9.513 (0.44), 9.518 (0.44), 10.318 (5.44), 10.342 (5.29).

- 109 038451

Example 159.

6-Bromo-7 - [(3R, 4R) -3,4-dihydroxypyrrolidin-1-yl] -4-oxo-N- (1,1,1-trifluoro-2-methylpropan-2-yl) 1 - ( 2,4,6-trifluorophenyl) - 1,4-dihydro- 1,8-naphthyridine-3-carboxamide

To a solution of 272 mg (513 μmol) 7 - [(3R, 4R) -3,4-dihydroxypyrrolidin-1-yl] -4-oxo-N- (1,1,1trifluoro-2-methylpropan-2-yl) - 1- (2,4,6-trifluorophenyl) -1,4-dihydro-1,8-naphthyridine-3-carboxamide in 8.0 ml of acetonitrile at room temperature was added 196 mg (1.10 mmol) of 1-bromopyrrolidine-2,5dione (NBS ) and 10.0 mg (60.9 μmol) AIBN. Stirred for 1 h at 60 ° C. The reaction mixture was cooled, concentrated (in vacuo) to half volume and purified by preparative HPLC (column: acetonitrile / water / 0.1% formic acid). This gave 128 mg (41% theory, 100% purity) of the title compound.

LCMS (Method 3): Rt = 1.95 min; MS (ESIpos): m / z = 609 [M + H] ⁺ .

¹ H-NMR (400 MHz, DMSO-66) δ [ppm]: -0.008 (2.95), 0.008 (2.81), 1.632 (16.00), 2.523 (1.40), 3.928 (1.71), 5.176 (2.24), 5.184 ( 2.24), 7.567 (0.69), 7.587 (1.17), 7.607 (0.66), 8.463 (0.44), 8.473 (4.19), 8.807 (3.19), 10.425 (2.53).

Example 160.

6-Bromo-N - [(1S) -1 -cyclopropyl-2,2,2-trifluoroethyl] -7- [(3R, 4R) -3,4-dihydroxypyrrolidin-1 -yl] -4oxo-1- (2 , 4,6-trifluorophenyl) -1,4-dihydro-1,8-naphthyridine-3-carboxamide

To a solution of 100 mg (184 μmol) N - [(1S) -1-cyclopropyl-2,2,2-trifluoroethyl] -7 - [(3R, 4R) -3,4-dihydroxypyrrolidin-1-yl] -4-oxo 1- (2,4,6-trifluorophenyl) -1,4-dihydro-1,8-naphthyridine-3carboxamide in 6.7 ml of acetonitrile at room temperature was added 39 mg (219 μmol) of 1 bromopyrrolidine-2,5-dione (NBS) and 3.00 mg (18.4 μmol) AIBN. The mixture was stirred for 4 h at 60 ° C, then another 15 mg (84.3 μmol) of NBS was added and the solution was stirred overnight at 60 ° C. The reaction mixture was cooled, concentrated (in vacuo) to half volume and purified by preparative HPLC (column: acetonitrile / water / 0.1% formic acid). 90.0 mg (79% theory, 100% purity) of the title compound was obtained.

LCMS (Method 3): _Rt = 1.02 min; MS (ESIpos): m / z = 621 [M + H] ⁺ .

¹ H-NMR (400 MHz, DMSO-bb) δ [ppm]: 0.342 (4.23), 0.556 (5.62), 0.660 (4.02), 1.219 (3.63), 3.424 (2.52), 3.736 (2.56), 3.933 (12.28 ), 4.382 (3.45), 5.188 (16.00), 7.587 (8.46), 8.473 (9.13), 8.863 (9.13), 10.338 (4.81), 10.361 (5.05).

Example 161.

6-Fluoro-7- (2-oxa-6-azaspiro [3.3] hept-6-yl) -4-oxo-N- [1,1,1,2,2-pentafluoropentan-3-yl] -1- (2,4,6trifluorophenyl) -1,4-dihydro- 1,8-naphthyridine-3-carboxamide (racemate)

•

-Chloro-6-fluoro-4-oxo-N- [1,1,1,2,2-pentafluoropentan-3-yl] -1 - (2,4,6-trifluorophenyl) -1,4-dihydro-1 , 8naphthyridine-3-carboxamide (racemate, 282 mg, 531 μmol) was placed in 3.6 ml of DMF, mixed with ethanedic acid-2-oxa-6-azaspiro [3.3] heptane (1: 1) (141 mg, 743 μmol) and N , N-diisopropylethylamine (560 μL, 3.2 mmol) and stirred for 2 h at room temperature. Once again, ethanedic acid-2-oxa-6-azaspiro [3.3] heptane (1: 1) (30.1 mg, 159 µmol) and N, N-diisopropylethylamine (93 µl, 530 µmol) were added and stirred overnight at room temperature. The mixture was mixed with water and the precipitated solid was filtered off and then purified through silica gel (solvent:

- 110 038451 cyclohexane / ethyl acetate = 2/1). Received 199 mg of the target compound (62% theory. V. 98% purity).

LCMS (Method 3): _Rt = 2.35 min; MS (ESIpos): m / z = 595 [M + H] +.

'H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: -0.149 (0.56), 0.146 (0.63), 0.935 (3.05), 0.953 (6.63), 0.971 (3.23), 1.235 (0.77), 1.630 (0.56), 1.647 (0.70), 1.656 (0.65), 1.673 (0.63), 1.692 (0.45), 1.915 (0.59), 2.085 (0.97), 2.327 (0.90), 2.366 (1.04), 2.670 (0.99), 2.710 (1.06), 4.209 (0.47), 4.656 (16.00), 4.843 (0.56), 4.870 (0.50), 7.542 (1.67), 7.565 (3.27), 7.587 (1.69), 7.991 (2.57), 8.020 (2.57), 8.844 (4.63), 10.339 (1.90), 10.364 (1.85).

Example 162.

6-Fluoro-7- (2-oxa-6-azaspiro [3.3] hept-6-yl) -4-oxo-N- [3,3,4,4,4-pentafluorobutan-2-yl] -1- (2,4,6trifluorophenyl) -1,4-dihydro-1,8-naphthyridine-3-carboxamide (racemate)

•

7-Chloro-6-fluoro-4-oxo-N- [3,3,4,4,4-pentafluorobutan-2-yl] -1- (2,4,6-trifluorophenyl) -1,4-dihydro- 1,8 naphthyridine-3-carboxamide (racemate, 250 mg, 482 μmol) was placed in 3.3 ml of DMF, mixed with ethanedic acid-2-oxa-6-azaspiro [3.3] heptane (1: 1) (128 mg, 675 μmol) and Ν, Ν-diisopropylethylamine 500 μl, 2.9 mmol) and stirred for 2 h at room temperature. Once again, ethanedic acid-2-oxa-6-azaspiro [3.3] heptane (1: 1) (27.4 mg, 145 µmol) and, Ν-diisopropylethylamine (84 µl, 480 µmol) were added and stirred overnight at room temperature. The reaction mixture was mixed with water and the precipitated solid was filtered off. The solid was purified using a silica gel column (solvent: cyclohexane / ethyl acetate = 2/1). Received 165 mg of the target compound (58% theory. V., 99% purity).

LCMS (Method 3): _Rt = 2.26 min; MS (ESIpos): m / z = 581 [M + H] +.

'H-NMR (400 MHz, DMSO- ₆ ) δ [ppm]: -0.008 (2.46), 0.008 (2.00), 1.379 (4.40), 1.397 (4.88), 2.524 (1.24), 2.670 (0.42), 4.654 (16.00), 5.001 (0.45), 5.022 (0.45), 7.541 (1.69), 7.563 (3.22), 7.586 (1.72), 7.982 (2.85), 8.011 (2.85), 8.838 (4.94), 10.417 (1.91), 10.441 (1.84).

Example 163.

6-Fluoro-7- (2-oxa-6-azaspiro [3.3] hept-6-yl) -4-oxo-N- (3,3,4,4,4-pentafluoro-2-methylbutan-2-yl ) -1 (2,4,6-trifluorophenyl) -1,4-dihydro-1,8-naphthyridine-3-carboxamide

•

7-Chloro-6-fluoro-4-oxo-N- (3,3,4,4,4-pentafluoro-2-methylbutan-2-yl) -1 - (2,4,6-trifluorophenyl) -1, 4-dihydro-1,8-naphthyridine-3-carboxamide (300 mg, 564 μmol) was placed in 5.4 ml of DMF, mixed with ethanedic acid-2-oxa-6-azaspiro [3.3] heptane (1: 2) (97.6 mg, 338 μmol ) and, Ν-diisopropylethylamine (490 μL, 2.8 mmol) and then stirred for 3 h at room temperature. The reaction solution was poured onto water, and a fine precipitate was formed. Then the aqueous suspension was acidified with 1N. hydrochloric acid. The residue was washed well with water and dried under high vacuum. Received 340 mg of the target compound (94% theory. V., Purity 93%).

LCMS (Method 3): _Rt = 2.32 min; MS (ESIpos): m / z = 595 [M + H] ⁺ .

'H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: -0.008 (2.38), 0.008 (2.11), 1.674 (15.31), 2.328 (0.46), 2.524 (1.28), 2.670 (0.46), 4.653 (16.00), 7.541 (1.72), 7.563 (3.03), 7.585 (1.72), 8.001 (3.03), 8.030 (3.00), 8.774 (5.32), 10.529 (3.97).

Example 164.

7 - [(3R, 4R) -3,4-Dihydroxypyrrolidin-1-yl] -6-fluoro-4-oxo-N- (3,3,4,4,4-pentafluoro-2-methylbutane-2yl) - 1 - (2,4,6-trifluorophenyl) -1,4-dihydro-1,8-naphthyridine-3-carboxamide

- 111 038451

7 - [(3R, 4R) -3,4-Dihydroxypyrrolidin-1-yl] -6-fluoro-4-oxo-1- (2,4,6-trifluorophenyl) -1,4-dihydro1,8-naphthyridine- 3-carboxylic acid (30.0 mg, 68.3 μmol) was added to 0.47 ml of DMF. HATU (31.2 mg, 81.9 μmol), N, N-diisopropylethylamine (59 μl, 340 μmol) and 3,3,4,4,4-pentafluoro-2-methylbutane-2amine hydrochloride (1: 1) (19.0 mg, 88.8 μmol ) was added to the solution and stirred overnight at room temperature. The mixture was then mixed with water and the pH was adjusted to neutral with 1M hydrochloric acid. The precipitated solid was filtered off, put in acetonitrile / water / trifluoroacetic acid and purified by preparative HPLC (RP18 columns, eluent: acetonitrile / water gradient with 0.1% trifluoroacetic acid). The product fractions were concentrated in vacuo, the residue was taken up in dichloromethane and washed twice with saturated aqueous sodium hydrogen carbonate solution. The combined aqueous phases were back-extracted with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. Received 31 mg of the target compound (75% theory. V., 99% purity).

LCMS (Method 1): Rt = 1.04 min; MS (ESIpos): m / z = 599 [M + H] +.

1H-NMR (400 MHz, DMSO-de) δ [ppm]: 1.680 (16.00), 3.903 (0.72), 4.012 (0.50), 5.198 (1.65), 7.555 (1.28), 7.576 (2.37), 7.597 (1.30) , 8.014 (2.65), 8.045 (2.62), 8.778 (4.80), 10.565 (4.02).

Example 165.

7 - [(3R, 4R) -3,4-Dihydroxypyrrolidin-1-yl] -6-fluoro-4-oxo-1- (2,4,6-trifluorophenyl) -N- (2,3,3trimethylbutane-2 -yl) -1,4-dihydro-1,8-naphthyridine-3-carboxamide

F

7 - [(3R, 4R) -3,4-dihydroxypyrrolidin-1-yl] -6-fluoro-4-oxo-1 - (2,4,6-trifluorophenyl) -1,4-dihydro-1,8naphthyridine- 3-carboxylic acid (60.0 mg, 137 μmol) was added to 0.93 ml of DMF. HATU (62.3 mg, 164 μmol), Ν, Ν-diisopropylethylamine (71 μL, 410 μmol) and 2,3,3-trimethylbutan-2-amine (20.5 mg, 178 μmol) were added to the solution and the mixture was stirred for 2.5 h at room temperature. Then the reaction mixture was mixed with acetonitrile / water / trifluoroacetic acid and purified by preparative HPLC (RP18 columns, eluent: acetonitrile / water-gradient with the addition of 0.1% trifluoroacetic acid). The product fractions were concentrated in vacuo, the residue was taken up in dichloromethane and washed twice with saturated aqueous sodium hydrogen carbonate solution. The combined aqueous phases were reextracted twice with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated. Received 34 mg of the target compound (47% theory. V., Purity 95%).

LCMS (Method 1): Rt = 1.04 min; MS (ESIpos): m / z = 537 [M + H] ⁺ .

1H-NMR (400 MHz, DMSO-de) δ [ppm]: -0.008 (0.57), 1.039 (16.00), 1.411 (11.99), 7.551 (0.52), 7.573 (0.93), 7.594 (0.52), 8.034 (1.09 ), 8.066 (1.08), 8.678 (1.90), 10.097 (1.36).

Example 166.

- [3,3-bis- (Hydroxymethyl) azetidin-1-yl] -6-fluoro-4-oxo-N- (3,3,4,4,4-pentafluoro-2-methylbutane-2yl) -1 - (2,4,6-trifluorophenyl) -1,4-dihydro-1,8-naphthyridine-3-carboxamide

F

6-Fluoro-7- (2-oxa-6-azaspiro [3.3] hept-6-yl) -4-oxo-N- (3,3,4,4,4-pentafluoro-2-methylbutan-2-yl ) -1 (2,4,6-trifluorophenyl) -1,4-dihydro-1,8-naphthyridine-3-carboxamide (100 mg, 93% purity, 156 μmol) was placed in 1 ml of acetonitrile, mixed with 1 ml of water and 1 ml of trifluoroacetic acid and stirred for 2 days at room temperature. The mixture was purified by preparative HPLC (RP18 columns, eluent: acetonitrile / water gradient with the addition of 0.1% trifluoroacetic acid). The product fractions were concentrated in vacuo, the residue was taken up in dichloromethane / a little methanol and washed twice with saturated aqueous sodium hydrogen carbonate solution. The combined aqueous phases were reextracted twice with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. Received 66 mg of the target compound (68% theory. V., Purity 98%).

LCMS (Method 3): Rt = 1.98 min; MS (ESIpos): m / z = 613 [M + H] ⁺ .

- 112 038451 ¹ H-NMR (400 MHz, DMSO ^) δ [ppm]: 1.676 (16.00), 3.471 (7.03), 3.484 (7.17), 4.127 (0.45), 4.834 (2.20), 4.847 (5.01), 4.861 (2.14), 7.532 (1.56), 7.553 (2.96), 7.575 (1.60), 7.973 (2.48), 8.001 (2.43), 8.754 (4.63), 10.561 (3.80).

Example 167.

7 - [(3R, 4R) -3,4-Dihydroxypyrrolidin-1-yl] -6-fluoro-4-oxo-N - [(1S) -1-phenylethyl] -1- (2,4,6trifluorophenyl) - 1,4-dihydro-1,8-naphthyridine-3-carboxamide

F

7 - [(3R, 4R) -3,4-Dihydroxypyrrolidin-1-yl] -6-fluoro-4-oxo-1- (2,4,6-trifluorophenyl) -1,4-dihydro1,8-naphthyridine- 3-carboxylic acid (150 mg, 341 μmol) was added to 3.0 ml of DMF. HATU (156 mg, 410 μmol), N, N-diisopropylethylamine (300 μL, 1.7 mmol) and (1S) -1-phenylethanamine (53 μL, 410 μmol) were added to the solution and the mixture was stirred for 2 days at room temperature. The reaction mixture was mixed with acetonitrile / water / trifluoroacetic acid and purified by preparative HPLC (RP18 columns, eluent: acetonitrile / water gradient with the addition of 0.1% trifluoroacetic acid). The product fractions were combined and freed from acetonitrile, the residue was made alkaline with saturated aqueous sodium hydrogen carbonate solution and extracted three times with dichloromethane. The combined phases were washed with saturated aqueous sodium hydrogen carbonate solution. The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. 159 mg of the target compound was obtained (84% theoretical, 98% purity).

LCMS (Method 3): Rt = 1.74 min; MS (ESIpos): m / z = 543 [M + H] +.

¹ H-NMR (400 MHz, DMSO-66) δ [ppm]: -0.008 (1.38), 0.008 (1.36), 1.486 (14.29), 1.503 (14.41), 2.328 (0.50), 2.671 (0.55), 3.058 ( 0.57), 3.675 (0.57), 3.908 (1.33), 5.126 (0.59), 5.143 (2.31), 5.162 (3.54), 5.180 (4.40), 5.195 (4.16), 7.244 (1.38), 7.261 (3.28), 7.273 ( 1.45), 7.278 (2.64), 7.282 (1.66), 7.341 (3.02), 7.361 (8.77), 7.379 (16.00), 7.384 (11.89), 7.401 (3.16), 7.405 (1.95), 7.545 (3.57), 7.567 ( 6.49), 7.588 (3.54), 7.992 (6.78), 8.023 (6.63), 8.726 (12.10), 10.325 (4.28), 10.345 (4.11).

Example 168.

7- [3,3-bis- (Hydroxymethyl) αzetidin-1-yl] -6-fluoro-4-oxo-N- [3,3,4,4,4-pentafluorobutan-2-yl] -1 (2 , 4,6-trifluorophenyl) -1,4-dihydro- 1,8-naphthyridine-3-carboxamide (racemate)

F

6-Fluoro-7- (2-oxa-6-αzaspiro [3.3] hept-6-yl) -4-oxo-N- [3,3,4,4,4-pentafluorobutan-2-yl] -1- (2,4,6trifluorophenyl) -1,4-dihydro-1,8-naphthyridine-3-carboxamide (racemate, 165 mg, 284 μmol) was placed in 1.8 ml of trifluoroacetic acid, mixed with 1.8 ml of water and 1.8 ml of acetonitrile and stirred within 2 days at room temperature. The reaction mixture was purified by preparative HPLC (RP18 columns, eluent: acetonitrile / water gradient with the addition of 0.1% trifluoroacetic acid). The product fractions were concentrated in vacuo, the residue was taken up in dichloromethane and washed twice with saturated aqueous sodium hydrogen carbonate solution. The combined aqueous phases were back-extracted with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. Received 140 mg of the target compound (82% theory. V. 99% purity).

LCMS (Method 3): _Rt = 1.91 min; MS (ESIpos): m / z = 599 [M + H] ⁺ .

¹ H-NMR (400 MHz, DMSOC) δ [ppm]: -0.149 (0.50), -0.008 (4.12), 0.008 (3.62), 0.146 (0.50), 1.177 (0.47), 1.234 (1.73), 1.381 (9.75 ), 1.398 (9.79), 2.328 (0.67), 2.367 (0.63), 2.524 (2.11), 2.670 (0.78), 2.711 (0.73), 3.472 (15.61), 3.485 (16.00), 4.124 (0.93), 4.835 (4.98 ), 4.848 (11.73), 4.862 (4.96), 4.958 (0.48), 4.981 (0.84), 5.004 (0.99), 5.023 (1.01), 5.047 (0.86), 5.067 (0.48), 5.754 (2.05), 7.532 (3.90 ), 7.554 (7.40), 7.576 (3.99), 7.954 (6.69), 7.983 (6.62), 8.819 (12.01), 10.450 (4.38), 10.474 (4.27).

Example 169.

7- [3,3-bis- (Hydroxymethyl) αzetidin-1-yl] -6-fluoro-4-oxo-N- [3,3,4,4,4-pentafluorobutan-2-yl] -1 (2 , 4,6-trifluorophenyl) -1,4-dihydro-1,8-naphthyridine-3-carboxamide (enantiomer A).

mg 7- [3,3-bis- (hydroxymethyl) azetidin-1-yl] -6-fluoro-4-oxo-N- [3,3,4,4,4-pentafluorobutan-2-yl] 1- ( 2,4,6-trifluorophenyl) -1,4-dihydro-1,8-naphthyridine-3-carboxamide (racemate) was separated by chiral HPLC into enantiomers (preparative HPLC: Daicel® Chiralpak AD-H column, 5 μm, 250x20 mm; eluent: 70% n-heptane / 30% isopropanol; flow: 19 ml / min; temperature: 25 ° C, indication:

- 113 038451

240 nm).

Enantiomer A: 66 mg (> 99% ee).

R _t = 4.45 min [HPLC: Daicel® Chiralcel OD-H column, 1 ml / min; 5 microns, 250x4.6 mm; eluent: 70% n-heptane / 30% isopropanol; indication: 240 nm].

Example 170.

7- [3,3-bis- (Hydroxymethyl) αzetidin-1-yl] -6-fluoro-4-oxo-N- [3,3,4,4,4-pentafluorobutan-2-yl] -1 (2 , 4,6-trifluorophenyl) -1,4-dihydro-1,8-naphthyridine-3-carboxamide (enantiomer B).

mg 7- [3,3-bis- (hydroxymethyl) azetidin-1-yl] -6-fluoro-4-oxo-N- [3,3,4,4,4-pentafluorobutan-2-yl] 1- ( 2,4,6-trifluorophenyl) -1,4-dihydro-1,8-naphthyridine-3-carboxamide (racemate) was separated by chiral HPLC into enantiomers (preparative HPLC: Daicel® Chiralpak AD-H column, 5 μm, 250x20 mm; eluent: 70% n-heptane / 30% isopropanol; flow: 19 ml / min; temperature: 25 ° C, indication: 240 nm).

Enantiomer B: 68 mg (> 99% ee).

R _t = 5.99 min [HPLC: Daicel® Chiralcel OD-H column, 1 ml / min; 5 microns, 250x4.6 mm; eluent: 70% n-heptane / 30% isopropanol; indication: 240 nm].

Example 171.

7- [3,3-bis- (Hydroxymethyl) αzetidin-1-yl] -6-fluoro-4-oxo-N- [1,1,1,2,2-pentafluoropentan-3-yl] -1 (2 , 4,6-trifluorophenyl) -1,4-dihydro-1,8-naphthyridine-3-carboxamide (racemate)

F

6-Fluoro-7- (2-oxa-6-azaspiro [3.3] hept-6-yl) -4-oxo-N- [1,1,1,2,2-pentafluoropentan-3-yl] -1- (2,4,6trifluorophenyl) -1,4-dihydro-1,8-naphthyridine-3-carboxamide (racemate, 199 mg, 335 μmol) was placed in 2.1 ml of trifluoroacetic acid, mixed with 2.1 ml of water and 2.1 ml of acetonitrile and stirred within 2 days at room temperature. The reaction mixture was purified by preparative HPLC (RP18 columns, eluent: acetonitrile / water gradient with the addition of 0.1% trifluoroacetic acid). The product fractions were evaporated in vacuo, the residue was taken up in dichloromethane and washed twice with saturated aqueous sodium hydrogen carbonate solution. The combined aqueous phases were back-extracted with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. Received 140 mg of the target compound (82% theory. V. 99% purity).

LCMS (Method 3): _Rt = 1.91 min; MS (ESIpos): m / z = 599 [M + H] +.

¹ H-NMR (400 MHz, DMSO-66) δ [ppm]: -0.149 (0.50), -0.008 (4.12), 0.008 (3.62), 0.146 (0.50), 1.177 (0.47), 1.234 (1.73), 1.381 (9.75), 1.398 (9.79), 2.328 (0.67), 2.367 (0.63), 2.524 (2.11), 2.670 (0.78), 2.711 (0.73), 3.472 (15.61), 3.485 (16.00), 4.124 (0.93), 4.835 (4.98), 4.848 (11.73), 4.862 (4.96), 4.958 (0.48), 4.981 (0.84), 5.004 (0.99), 5.023 (1.01), 5.047 (0.86), 5.067 (0.48), 5.754 (2.05), 7.532 (3.90), 7.554 (7.40), 7.576 (3.99), 7.954 (6.69), 7.983 (6.62), 8.819 (12.01), 10.450 (4.38), 10.474 (4.27).

Example 169.

7- [3,3-bis- (Hydroxymethyl) αzetidin-1-yl] -6-fluoro-4-oxo-N- [3,3,4,4,4-pentafluorobutan-2-yl] -1 (2 , 4,6-trifluorophenyl) -1,4-dihydro-1,8-naphthyridine-3-carboxamide (enantiomer A).

mg 7- [3,3-bis- (hydroxymethyl) azetidin-1-yl] -6-fluoro-4-oxo-N- [3,3,4,4,4-pentafluorobutan-2-yl] 1- ( 2,4,6-trifluorophenyl) -1,4-dihydro-1,8-naphthyridine-3-carboxamide (racemate) was separated by chiral HPLC into enantiomers (preparative HPLC: Daicel® Chiralpak AD-H column, 5 μm, 250x20 mm; eluent: 70% n-heptane / 30% isopropanol; flow: 19 ml / min; temperature: 25 ° C, indication: 240 nm).

Enantiomer A: 66 mg (> 99% ee).

R _t = 4.45 min [HPLC: Daicel® Chiralcel OD-H column, 1 ml / min; 5 microns, 250x4.6 mm; eluent: 70% n-heptane / 30% isopropanol; indication: 240 nm].

Example 170.

7- [3,3-bis- (Hydroxymethyl) αzetidin-1-yl] -6-fluoro-4-oxo-N- [3,3,4,4,4-pentafluorobutan-2-yl] -1 (2 , 4,6-trifluorophenyl) -1,4-dihydro-1,8-naphthyridine-3-carboxamide (enantiomer B) mg 7- [3,3-bis- (hydroxymethyl) azetidin-1-yl] -6-fluoro -4-oxo-N- [3,3,4,4,4-pentafluorobutan-2-yl] 1- (2,4,6-trifluorophenyl) -1,4-dihydro-1,8-naphthyridine-3- carboxamide (racemate) was separated by chiral HPLC into enantiomers (preparative HPLC: Daicel® Chiralpak AD-H column, 5 μm, 250x20 mm; eluent: 70% n-heptane / 30% isopropanol; flow: 19 ml / min; temperature: 25 ° C, indication: 240 nm).

Enantiomer B: 68 mg (> 99% ee).

R _t = 5.99 min [HPLC: Daicel® Chiralcel OD-H column, 1 ml / min; 5 microns, 250x4.6 mm; eluent: 70%

- 114 038451 n-heptane / 30% isopropanol; indication: 240 nm].

Example 171.

7- [3,3-bis- (Hydroxymethyl) azetidin-1-yl] -6-fluoro-4-oxo-N - [1,1,1,2,2-pentafluoropentan-3-yl] -1 ( 2,4,6-trifluorophenyl) -1,4-dihydro- 1,8-naphthyridine-3-carboxamide (racemate)

F

6-Fluoro-7- (2-oxa-6-αzaspiro [3.3] hept-6-yl) -4-oxo-N- [1,1,1,2,2-pentafluoropentan-3 -yl] -1 - (2,4,6trifluorophenyl) -1,4-dihydro-1,8-naphthyridine-3-carboxamide (racemate, 199 mg, 335 μmol) was placed in 2.1 ml of trifluoroacetic acid, mixed with 2.1 ml of water and 2.1 ml of acetonitrile and stirred within 2 days at room temperature. The reaction mixture was purified by preparative HPLC (RP18 columns, eluent: acetonitrile / water gradient with the addition of 0.1% trifluoroacetic acid). The product fractions were concentrated in vacuo, the residue was taken up in dichloromethane and washed twice with saturated aqueous sodium hydrogen carbonate solution. The combined aqueous phases were back-extracted with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated. Received 168 mg of the target compound (81% theory. V., 99% purity).

LCMS (Method 3): _Rt = 1.98 min; MS (ESIpos): m / z = 613 [M + H] +.

¹ H-NMR (400 MHz, DMSOC) δ [ppm]: 0.008 (2.65), 0.939 (6.29), 0.957 (14.00), 0.975 (6.81), 1.157 (2.65), 1.175 (5.29), 1.193 (2.72), 1.235 (0.88), 1.615 (0.76), 1.632 (1.09), 1.640 (0.98), 1.649 (1.31), 1.658 (1.20), 1.667 (1.11), 1.675 (1.24), 1.694 (0.90), 1.917 (1.16), 1.989 (9.69), 2.329 (0.43), 2.670 (0.50), 2.711 (0.40), 3.473 (15.68), 3.486 (16.00), 4.003 (0.99), 4.021 (2.61), 4.039 (2.63), 4.057 (1.15), 4.133 (0.97), 4.838 (5.71), 4.851 (12.52), 4.864 (5.69), 4.897 (0.77), 7.533 (3.62), 7.555 (6.94), 7.577 (3.68), 7.585 (1.23), 7.964 (5.89), 7.993 (5.83), 8.826 (10.47), 10.373 (4.13), 10.397 (3.99).

Example 172.

7- [3,3-bis- (Hydroxymethyl) azetidin-1-yl] -6-fluoro-4-oxo-N - [1,1,1,2,2-pentafluoropentan-3-yl] -1 ( 2,4,6-trifluorophenyl) -1,4-dihydro-1,8-naphthyridine-3-carboxamide (enantiomer A).

209 mg 7- [3,3-bis- (hydroxymethyl) azetidin-1-yl] -6-fluoro-4-oxo-N- [1,1,1,2,2-pentafluoropentan-3 yl] -1- (2,4,6-trifluorophenyl) -1,4-dihydro-1,8-naphthyridine-3-carboxamide (racemate) was separated by chiral HPLC into enantiomers (preparative HPLC: Daicel® Chiralpak AD-H column, 5 μm, 250x20 mm; eluent: 90% n-heptane / 10% ethanol; flow: 19 ml / min; temperature: 25 ° C, indication: 240 nm).

Enantiomer A: 84 mg (98.5% ee).

R _t = 14.72 min [HPLC: Daicel® Chiralpak AD-H column, 1 ml / min; 5 microns, 250x4.6 mm; eluent: 90% n-heptane / 10% ethanol; indication: 240 nm].

Example 173.

7- [3,3-bis- (Hydroxymethyl) azetidin-1-yl] -6-fluoro-4-oxo-N - [1,1,1,2,2-pentafluoropentan-3-yl] -1 ( 2,4,6-trifluorophenyl) -1,4-dihydro-1,8-naphthyridine-3-carboxamide (enantiomer B).

209 mg 7- [3,3-bis- (hydroxymethyl) azetidin-1-yl] -6-fluoro-4-oxo-N- [1,1,1,2,2-pentafluoropentan-3 yl] -1- (2,4,6-trifluorophenyl) -1,4-dihydro-1,8-naphthyridine-3-carboxamide (racemate) was separated by chiral HPLC into enantiomers (preparative HPLC: Daicel® Chiralpak AD-H column, 5 μm, 250x20 mm; eluent: 90% n-heptane / 10% ethanol; flow: 19 ml / min; temperature: 25 ° C, indication: 240 nm).

Enantiomer B: 75 mg (96.8% ee).

Rt = 17.24 min [HPLC: Daicel® Chiralpak AD-H column, 1 ml / min; 5 microns, 250x4.6 mm; eluent: 90% n-heptane / 10% ethanol; indication: 240 nm].

Example 174.

6-Fluoro-7- [3- (hydroxymethyl) piperazin-1-yl] -4-oxo-N- [1,1,1,2,2-pentafluoropentan-3-yl] -1- (2,4, 6trifluorophenyl) -1,4-dihydro- 1,8-naphthyridine-3-carboxamide (mixture of diastereoisomers)

tert-Butyl-4- [3-fluoro-5-oxo-6 - {[1,1,1,2,2-pentafluoropentan-3-yl] carbamoyl} -8- (2,4,6-trifluorophenyl) - 5,8-dihydro-1,8-naphthyridin-2-yl] -2- (hydroxymethyl) piperazine-1-carboxylate (mixture of diastereo-115 038451 isomers, 204 mg, 287 μmol) was placed in 1.6 ml of dichloromethane, mixed with trifluoroacetic acid (780 μL, 10 mmol) and stirred for 1.5 h at room temperature. The dichloromethane was evaporated and the residue was purified by preparative HPLC (RP18 columns, solvent: acetonitrile / water gradient with the addition of 0.1% trifluoroacetic acid). The product fractions were evaporated, the residue was taken up in dichloromethane / a little methanol and washed twice with saturated aqueous sodium hydrogen carbonate solution. The combined aqueous phases were reextracted twice with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. We obtained 63 mg of the target compound (48% of theory, purity 96%) as a mixture of a diastereoisomeric mixture of two diastereoisomers.

LCMS (Method 3): _Rt = 1.55 min; MS (ESIpos): m / z = 612 [M + H] +.

¹ H-NMR (400 MHz, DMSO-06) δ [ppm]: -0.149 (0.55), -0.008 (4.61), 0.008 (4.48), 0.146 (0.55), 0.943 (7.10), 0.961 (16.00), 0.980 (7.69), 1.142 (0.40), 1.622 (0.93), 1.640 (1.25), 1.647 (1.10), 1.656 (1.48), 1.666 (1.36), 1.675 (1.28), 1.683 (1.48), 1.701 (1.02), 1.924 (1.29), (3.33), 2.604 (1.48), 2.637 (2.57), 2.668 (3.19), 2.694 (1.65), (1.32), 2.997 (2.27), 3.025 (1.22), 3.145 (1.00), 3.159 (1.89) ), (2.01), 3.228 (3.54), 3.241 (2.90), 3.254 (1.74), 3.268 (1.00), (2.43), 4.599 (3.14), 4.612 (6.76), 4.625 (3.03), 4.829 (0.86),

2.086 (2.96), 2.324 (2.65), 2.368 (0.70), 2.574

2.711 (0.60), 2.842 (2.77), 2.872 (2.22), 2.971

3.172 (2.80), 3.186 (3.63), 3.200 (1.94), 3.214

3.952 (2.22), 3.984 (2.08), 4.040 (2.55), 4.071

4.856 (1.10), 4.881 (1.12), 4.906 (0.83), 5.755 (1.89), 7.513 (1.39), 7.541 (4.86), 7.564 (4.85), 7.592 (1.36), 8.058 (7.61), 8.092 (7.46), 8.894 (13.63), 10.304 (4.75), 10.329 (4.58).

Example 175.

N- (1 S) -1 -cyclopropyl-2,2,2-trifluoroethyl] -7 - [(3R, 4R) -3,4-dihydroxypyrrolidin-1 -yl] -6-fluoro-1 (4-fluoro- 2,6-dimethylphenyl) -4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide

7-Chloro-N - [(1S) -1-cyclopropyl-2,2,2-trifluoroethyl] -6-fluoro-1- (4-fluoro-2,6-dimethylphenyl) -4-oxo-1,4dihydro- 1,8-naphthyridine-3-carboxamide (80.0 mg, 165 μmol) was placed in 1.6 ml of DMF, (3R, 4R) -pyrrolidine-3,4-diol hydrochloride (25.3 mg, 181 μmol) was added and mixed with N, N- diisopropylethylamine (0.17 ml, 0.99 mmol) and stirred overnight at room temperature. The reaction solution was mixed with acetonitrile / water / trifluoroacetic acid. The formed precipitate was filtered off and dried under high vacuum. 76 mg of the target compound was obtained (84% theoretical, 99% purity).

LCMS (Method 3): _Rt = 1.86 min; MS (ESIpos): m / z = 553 [M + H] +.

¹ H-NMR (400 MHz, DMSO-66) δ [ppm]: 0.324 (0.76), 0.334 (1.15), 0.347 (1.18), 0.358 (0.93), 0.370 (0.45), 0.503 (0.84), 0.514 (1.21 ), 0.527 (1.01), 0.537 (0.84), 0.548 (0.87), 0.567 (1.07), 0.578 (1.01), 0.588 (0.93), 0.600 (0.76), 0.612 (0.48), 0.625 (0.56), 0.635 (0.65 ), 0.646 (1.01), 0.656 (0.98), 0.670 (0.90), 1.174 (0.48), 1.183 (0.70), 1.194 (1.18), 1.203 (0.87), 1.215 (1.12), 1.227 (0.67), 1.235 (0.59 ), 1.940 (16.00), 1.951 (15.83), 2.328 (0.42), 2.670 (0.45), 3.883 (0.67), 4.342 (0.62), 4.363 (1.04), 4.384 (1.04), 4.404 (0.56), 5.171 (2.64 ), 7.164 (4.63), 7.188 (4.66), 8.009 (3.34), 8.041 (3.28), 8.429 (7.55), 10.623 (2.41), 10.646 (2.30).

Example 176.

N - [(1S) -1-Cyclopropyl-2,2,2-trifluoroethyl] -6-fluoro-7- [2- (hydroxymethyl) -4-methylpiperazin-1-yl] 4-oxo-1 - (2, 4,6-trifluorophenyl) -1,4-dihydro-1,8-naphthyridine-3-carboxamide (mixture of diastereoisomers)

7-Chloro-N - [(1S) -1-cyclopropyl-2,2,2-trifluoroethyl] -6-fluoro-4-oxo-1- (2,4,6-trifluorophenyl) -1,4 dihydro-1, 8-naphthyridine-3-carboxamide (100 mg, 203 μmol) was placed in 2 ml of DMF, mixed with [4-methylpiperazin-2-yl] methanol (30.5 mg, 95% pure, 223 μmol) and N, N-diisopropylethylamine ( 0.177 ml, 1.01 mmol) and stirred for 3 h at room temperature. The reaction mixture was mixed with acetonitrile / water / trifluoroacetic acid and purified by preparative HPLC (RP18 columns, eluent: acetonitrile / water gradient with the addition of 0.1% trifluoroacetic acid). The product fractions were combined and purified from acetonitrile. Established an alkaline environment in

- 116 038451 residue with saturated, aqueous sodium hydrogen carbonate solution and extracted three times with dichloromethane. The combined phases were washed with saturated aqueous sodium hydrogen carbonate solution.

The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. The fraction was purified again by thick layer chromatography (eluent: dichloromethane / methanol = 10/1).

Received 48 mg of the target compound (39% theory. V., Purity 98%) as a mixture of a diastereoisomeric mixture of two diastereoisomers.

LCMS (Method 3): _Rt = 1.38 min; MS (ESIpos): m / z = 588 [M + H] +.

¹ H-NMR (500 MHz, DMSO-66) δ [ppm]: -0.007 (1.35), 0.006 (0.98), 0.335 (0.88), 0.340 (0.92), 0.345 (0.84), 0.350 (0.72), 0.519 ( 0.80), 0.529 (1.19), 0.539 (1.05), 0.547 (0.88), 0.555 (0.82), 0.571 (0.99), 0.579 (0.93), 0.588 (0.79), 0.597 (0.67), 0.633 (0.54), 0.642 ( 0.71), 0.650 (0.98), 0.654 (0.82), 0.659 (0.97), 0.662 (0.95), 0.670 (0.94), 0.676 (0.47), 0.679 (0.47), 1.188 (0.47), 1.195 (0.69), 1.204 ( 1.16), 1.211 (0.85), 1.220 (1.14), 1.230 (0.71), 1.236 (0.54), 1.837 (0.54), 1.844 (0.67), 1.861 (1.09), 1.867 (1.10), 1.884 (0.69), 1.891 ( 0.56), 1.989 (0.93), 1.996 (1.01), 2.012 (1.03), 2.019 (0.90), 2.113 (16.00), 2.516 (1.06), 2.520 (0.93), 2.524 (0.85), 2.697 (1.08), 2.719 ( 1.00), 2.830 (1.56), 2.853 (1.45), 3.028 (0.41), 3.051 (0.73), 3.076 (0.41), 3.594 (1.65), 3.606 (2.39), 3.618 (1.66), 3.784 (0.85), 3.811 ( 0.80), 4.261 (0.89), 4.359 (0.58), 4.376 (0.98), 4.393 (0.95), 4.409 (0.52), 4.700 (0.98), 4.710 (1.87), 4.720 (0.93), 7.518 (0.66), 7.541 ( 1.37), 7.552 (0.92), 7.564 (1.39), 7. 586 (0.64), 8.032 (4.28), 8.060 (4.10), 8.869 (7.42), 10.394 (2.60), 10.413 (2.45).

Example 177.

N - [(1R) -1-Cyclopropyl-2,2,2-trifluoroethyl] -6-fluoro-1- (4-fluoro-2,6-dimethylphenyl) -7 - [(4S) -4hydroxy-2-oxopyrrolidine -1 -yl] -4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide

F

Potassium carbonate (34.1 mg, 0.28 mmol) was added and heated in a vessel. Palladium (II) acetate (4 mg, 0.02 mmol) and 9,9-dimethyl-4,5-bis- (diphenylphosphino) xanthene (16 mg, 0.03 mmol) were added under argon and mixed with degassed dioxane (1.8 mL). The mixture was stirred for 30 minutes at room temperature. Added 7-chloro-N - [(1R) -1-cyclopropyl-2,2,2-trifluoroethyl] -6-fluoro-1- (4-fluoro2,6-dimethylphenyl) -4-oxo-1,4-dihydro -1,8-naphthyridine-3-carboxamide (80.0 mg, 165 μmol) and (4S) -4hydroxypyrrolidin-2-one (20.0 mg, 198 μmol) and stirred overnight at 80 ° C. The reaction solution was mixed with acetonitrile / TFA / water, and a solid precipitated out. The reaction mixture was extracted twice with dichloromethane. The residue was purified using a silica gel column (solvent: dichloromethane / methanol = 30/1). The residue was freed from dichloromethane and purified again by thick layer chromatography (eluent: dichloromethane / methanol = 20/1). A total of 7 mg of the target compound was obtained (8% theoretical, 99% purity).

LCMS (Method 3): Rt = 1.88 min; MS (ESIpos): m / z = 551 [M + H] ⁺ .

¹ H-NMR (400 MHz, DMSO-66) δ [ppm]: -0.008 (2.34), 0.008 (1.96), 0.348 (1.04), 0.361 (0.95), 0.372 (0.65), 0.383 (0.41), 0.541 ( 0.62), 0.553 (0.94), 0.569 (1.18), 0.586 (1.28), 0.596 (0.84), 0.607 (0.75), 0.617 (0.61), 0.644 (0.46), 0.653 (0.48), 0.664 (1.03), 0.674 ( 0.74), 0.681 (0.68), 1.141 (1.13), 1.207 (0.41), 1.216 (0.57), 1.228 (1.04), 1.236 (1.08), 1.248 (1.04), 1.260 (0.64), 1.268 (0.44), 1.948 ( 15.80), 1.952 (16.00), 2.117 (0.51), 2.278 (1.13), 2.326 (1.59), 2.523 (1.30), 2.808 (1.25), 2.824 (1.27), 2.852 (1.11), 2.868 (1.11), 3.338 ( 1.55), 3.704 (1.16), 3.717 (1.45), 3.731 (1.26), 3.744 (1.08), 4.358 (1.48), 4.379 (1.07), 4.399 (0.86), 4.420 (0.46), 5.318 (3.02), 5.327 ( 2.97), 7.181 (2.48), 7.204 (2.52), 8.530 (2.92), 8.554 (2.87), 8.690 (7.03), 10.281 (1.93), 10.304 (1.87).

Example 178.

7 - [(3S, 4S) -3,4-Dihydroxypyrrolidin-1-yl] -6-fluoro-4-oxo-N - [(2S) -1,1,1-trifluorobutan-2-yl] -1 ( 2,4,6-trifluorophenyl) -1,4-dihydro-1,8-naphthyridine-3-carboxamide

F

7 - [(3S, 4S) -3,4-Dihydroxypyrrolidin-1-yl] -6-fluoro-4-oxo-1- (2,4,6-trifluorophenyl) -1,4-dihydro-1,8naphthyridine- 3-carboxylic acid (30.0 mg, 68.3 mmol) was dissolved in 0.7 ml of DMF, HATU (31 mg, 0.08 mmol) and DIPEA (42 μl, 0.24 mmol) were added and stirred for 30 min at room temperature. (S) -1,1,1-trifluoro-2-butylamine hydrochloride (13.4 mg, 81.9 μmol) was added and stirred for min at room temperature. The mixture was mixed with 0.5 ml of 1N. hydrochloric acid and 1 ml acetonitrile and purified by preparative HPLC (RP18 columns, eluent: acetonitrile / water gradient).

Received 24.3 mg (99% purity, 64% theory. V.) Of the target compound.

LCMS (Method 3): _Rt = 1.78 min; MS (ESIpos): m / z = 549 [M + H] +.

¹ H-NMR (400 MHz, DMSO-6) δ [ppm]: -0.008 (2.33), 0.008 (2.22), 0.950 (7.18), 0.969 (16.00), 0.987 (7.85), 1.604 (1.08), 1.622 ( 1.42), 1.629 (1.29), 1.639 (1.73), 1.647 (1.54), 1.657 (1.50), 1.664 (1.69), 1.682 (1.29), 1.851 (1.31), 1.861 (1.48), 1.869 (1.52), 1.879 ( 1.73), 1.886 (1.50), 1.895 (1.33), 1.904 (1.12), 1.914 (0.95), 2.328 (0.76), 2.367 (0.82), 2.524 (3.03), 2.670 (0.85), 2.711 (0.87), 3.073 ( 0.80), 3.695 (0.85), 3.904 (1.80), 4.014 (1.23), 4.734 (1.42), 4.755 (1.35), 5.201 (4.80), 7.558 (3.87), 7.580 (6.82), 7.601 (3.79), 7.999 ( 7.53), 8.031 (7.41), 8.841 (12.89), 10.329 (5.19), 10.353 (5.00).

Example 179.

N - [(1S) -1-Cyclopropyl-2,2,2-trifluoroethyl] -6-fluoro-7 - [3- (hydroxymethyl) -4-methylpiperazin-1 -yl] 4-oxo-1 - (2, 4,6-trifluorophenyl) -1,4-dihydro- 1,8-naphthyridine-3-carboxamide (mixture of diastereoisomers) n ₃ c- * O but-4

F.

-Χλορ-Ν - [(1S) -1 -cyclopropyl-2,2,2-trifluoroethyl] -6-fluoro-4-oxo-1 - (2,4,6-trifluorophenyl) -1,4 dihydro-1,8 -naphthyridine-3-carboxamide (100 mg, 203 μmol) was placed in 2 ml of DMF, mixed with [1-methylpiperazin-2-yl] methanol dihydrochloride (47.6 mg, 95% purity, 223 μmol) and N, N-diisopropylethylamine (0.25 ml, 1.42 mmol) and stirred for 3 h at room temperature. The reaction mixture was mixed with acetonitrile / water / trifluoroacetic acid and purified by preparative HPLC (RP18 columns, eluent: acetonitrile / water gradient with the addition of 0.1% trifluoroacetic acid). The product fractions were combined and purified from acetonitrile. The residue was alkaline with saturated aqueous sodium hydrogen carbonate solution and extracted three times with dichloromethane. The combined phases were washed with saturated aqueous sodium hydrogen carbonate solution. The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. The fraction was purified again by thick layer chromatography (eluent: dichloromethane / methanol = 10/1). Received 80 mg of the target compound (66% theory. V., Purity 98%).

LCMS (Method 3): Rt = 1.37 min; MS (ESIpos): m / z = 588 [M + H] ⁺ .

¹ H-NMR (400 MHz, DMSO-66) δ [ppm]: -0.008 (2.54), 0.008 (2.44), 0.320 (0.70), 0.330 (1.13), 0.343 (1.11), 0.354 (0.86), 0.366 ( 0.43), 0.517 (0.75), 0.528 (1.13), 0.541 (1.03), 0.550 (1.17), 0.569 (1.20), 0.579 (0.95), 0.589 (0.86), 0.600 (0.71), 0.614 (0.44), 0.629 ( 0.61), 0.638 (0.58), 0.649 (1.05), 0.659 (0.90), 0.665 (0.84), 0.671 (0.81), 0.685 (0.41), 1.183 (0.45), 1.191 (0.64), 1.203 (1.10), 1.212 ( 0.80), 1.223 (1.09), 1.235 (0.67), 1.244 (0.41), 1.932 (0.57), 1.940 (0.71), 1.948 (0.92), 1.957 (0.94), 1.965 (0.73), 1.973 (0.61), 2.079 ( 0.61), 2.101 (1.15), 2.108 (1.16), 2.130 (0.70), 2.137 (0.62), 2.179 (16.00), 2.524 (0.77), 2.697 (1.34), 2.727 (1.23), 2.849 (0.99), 2.874 ( 1.10), 2.882 (1.17), 2.907 (0.98), 3.107 (0.61), 3.134 (1.08), 3.162 (0.62), 3.212 (0.61), 3.228 (0.90), 3.241 (1.15), 3.254 (1.03), 3.270 ( 0.72), 3.481 (0.67), 3.492 (0.98), 3.504 (0.87), 3.520 (0.82), 3.531 (0.54), 3.949 (0.97), 3.978 (0.88), 4.146 (1.17), 4.179 (1.10), 4.355 ( 0.56), 4.376 (1.00), 4.397 (0.97), 4. 417 (0.50), 4.505 (1.26), 4.518 (2.74), 4.531 (1.23), 7.499 (0.64), 7.528 (1.83), 7.540 (0.75), 7.551 (1.81), 7.580 (0.61), 8.071 (3.31), 8.105 (3.22), 8.876 (5.71), 10.386 (2.30), 10.410 (2.21).

Example 180.

1- (2-Chloro-4,6-difluorophenyl) -7- (dimethylamino) -6-fluoro-N- (1,1,1,3,3,3-hexafluoropropan-2-yl) -4oxo-1, 4-dihydro-1,8-naphthyridine-3-carboxamide

7-Chloro-1- (2-chloro-4,6-difluorophenyl) -6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid (250 mg, 642 μmol), 1,1,1,3,3,3-hexafluoropropan-2-amine (118 mg, 707 μmol) and N, N-diisopropylethylamine (340 μL, 1.9 mmol) were placed in 6.5 ml of ethyl acetate, mixed with T3P- solution (2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinate 2,4,6-trioxide) (1.5 ml, 50% purity, 2.6 mmol) and stirred overnight at 80 ° C. 1,1,1,3,3,3-118 038451 hexafluoropropan-2-amine (53.6 mg, 321 mmol), Ν, Ν-diisopropylethylamine (57 μl, 0.32 mmol) and T3P solution (2.4.6 -tripropyl-1,3,5,2,4,6-trioxatriphosphinate 2,4,6-trioxide) (188 μl, 50% purity, 325 μmol) and stirred overnight at 80 ° C. 1,1,1,3,3,3-hexafluoropropane-2amine (60 mg, 359 μmol) and T3P solution (2,4,6-tripropyl-1,3,5,2,4,6- trioxatriphosphinan 2,4,6-trioxide) (750 μL, 50% purity, 1.3 mmol) to the reaction mixture and stirred at 80 ° C. The mixture was poured onto water and ethyl acetate and the phases were separated. The aqueous phase was extracted once more with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and evaporated on a rotary evaporator. The residue was purified by preparative HPLC (RP18 columns, eluent: acetonitrile / water + 0.1% formic acid gradient). The fractions containing the product were pooled and lyophilized. The starting material was purified again by preparative HPLC (RP18 column, eluent: acetonitrile / water + 2% formic acid gradient). Received 4 mg (100% purity, 1% theory. V.) Of the target compound.

LCMS (Method 3): Rt = 1.33 min; MS (ESIpos): m / z = 547 [M + H] +.

¹ H-NMR (400 MHz, DMSO-66) δ [ppm]: 0.008 (2.86), 2.328 (0.40), 2.367 (0.43), 3.019 (16.00), 3.023 (15.23), 6.302 (0.75), 6.320 (0.99 ), 6.345 (1.00), 6.363 (0.65), 7.699 (1.01), 7.706 (1.39), 7.722 (1.62), 7.729 (2.54), 7.745 (2.44), 7.752 (2.62), 7.762 (1.88), 7.773 (1.09 ), 8.037 (4.69), 8.071 (4.62), 8.948 (8.99), 11.276 (3.01), 11.301 (2.88).

Example 181.

7- (3,4-Dihydroxypiperidin-1-yl) -6-fluoro-4-oxo-N- (3,3,4,4,4-pentafluorobutan-2-yl) -1- (2,4,6trifluorophenyl ) -1,4-dihydro-1,8-naphthyridine-3-carboxamide (mixture of diastereoisomers)

-Chloro-6-fluoro-4-oxo-N- (3,3,4,4,4-pentafluorobutan-2-yl) -1 - (2,4,6-trifluorophenyl) -1,4-dihydro-1 , 8naphthyridine-3-carboxamide (150 mg, 290 μmol) (pure enantiomers) was placed in 2.9 ml of N, N-dimethylformamide and mixed with trans-piperidine-3,4-diol hydrochloride (49.0 mg, 319 μmol) and N, N- diisopropylethylamine (230 μl, 1.3 mmol). The reaction mixture was stirred for 8 h at 55 ° C. The reaction mixture was cooled and diluted with acetonitrile and purified by preparative RP-HPLC (column: Reprosil 125x30; 10 μl, flow: 50 ml / min, acetonitrile / water, 0.1% formic acid). The solvent was evaporated off under vacuum and the residue was dried under high vacuum. This gave 105 mg (61% theory, 100% purity) of the title compound.

LCMS (Method 3): Rt = 1.93 min; MS (ESIpos): m / z = 599 [M + H] +.

¹ H-NMR (400 MHz, DMSO-66) δ [ppm]: -0.149 (0.69), -0.008 (6.10), 0.008 (6.04), 0.146 (0.75), 1.230 (1.66), 1.389 (12.14), 1.406 (12.23), 1.771 (1.42), 1.782 (1.57), 1.791 (1.57), 1.814 (1.30), 2.329 (0.82), 2.367 (0.63), 2.671 (0.91), 2.711 (0.63), 3.292 (4.47), 3.350 (2.26), 3.367 (1.51), 3.447 (2.63), 3.530 (1.48), 3.549 (1.69), 3.773 (2.87), 3.806 (2.51), 4.892 (7.52), 4.901 (7.61), 4.970 (0.63), 4.999 (7.34), 5.010 (8.15), 5.034 (1.30), 5.058 (1.12), 7.554 (4.32), 7.576 (7.67), 7.597 (4.26), 8.022 (8.51), 8.057 (8.39), 8.889 (16.00), 10.392 (5.55), 10.416 (5.37).

Example 182.

7- (3,4-Dihydroxypiperidin-1-yl) -6-fluoro-4-oxo-N- (3,3,4,4,4-pentafluorobutan-2-yl) -1- (2,4,6trifluorophenyl ) -1,4-dihydro-1,8-naphthyridine-3-carboxamide (diastereoisomer 1).

105 mg 7- (3,4-dihydroxypiperidin-1-yl) -6-fluoro-4-oxo-N- (3,3,4,4,4-pentafluorobutan-2-yl) -1 (2,4, 6-trifluorophenyl) -1,4-dihydro-1,8-naphthyridine-3-carboxamide (mixture of diastereoisomers) was separated into diastereoisomers by preparative HPLC (preparative HPLC: Daicel® Chiralpak IF column, 5 μm, 250x20 mm; eluent: 80% n-heptane / 20% ethanol; flow 15 ml / min; temperature: 25 ° C, indication: 210 nm).

Diastereoisomer 1: 46.5 mg (> 99% de).

R _t = 1.411 min [HPLC: Daicel® Chiralpak ID-3 columns, 1 ml / min; 3 μm, 50x4.6 mm; eluent: 80% isohexane / 20% ethanol; indication: 220 nm].

The resulting material was purified once more by preparative HPLC HPLC (column: Reprosil 125x30; 10 μl, flow: 50 ml / min, acetonitrile / water, 0.1% formic acid). The solvent was evaporated off under vacuum and the residue was dried under high vacuum. This gave 36 mg (21% theory, 100% purity) of the title compound.

LCMS (Method 3): _Rt = 1.92 min; MS (ESIpos): m / z = 599 [M + H] ⁺ .

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.149 (0.88), -0.008 (7.15), 0.008 (7.01), 0.146 (0.88), 1.205 (1.69), 1.230 (1.76), 1.238 (1.66), 1.389 (13.36), 1.406 (13.46), 1.762 (1.52), 1.771 (1.66), 1.781 (1.80), 1.804

- 119 038451 (1.52), 1.814 (1.37), 2.324 (0.74), 2.328 (1.02), 2.666 (0.81), 2.670 (1.13), 2.675 (0.85), 2.711 (0.39), 3.272 (4.09), 3.283 (4.58 ), 3.351 (2.54), 3.368 (1.73), 3.419 (1.06), 3.445 (3.03), 3.527 (1.62), 3.548 (1.80), 3.571 (1.27), 3.773 (3.07), 3.778 (3.24), 3.805 (2.85 ), 4.890 (8.88), 4.899 (8.92), 4.969 (0.70), 4.997 (9.23), 5.007 (9.73), 5.033 (1.41), 5.057 (1.16), 5.077 (0.60), 7.555 (4.44), 7.577 (7.72 ), 7.598 (4.37), 8.023 (9.59), 8.057 (9.41), 8.889 (16.00), 10.392 (6.13), 10.415 (5.89).

Example 183.

7- (3,4-Dihydroxypiperidin-1-yl) -6-fluoro-4-oxo-N- (3,3,4,4,4-pentafluorobutan-2-yl) -1- (2,4,6trifluorophenyl ) -1,4-dihydro-1,8-naphthyridine-3-carboxamide (diastereoisomer 2).

105 mg 7- (3,4-dihydroxypiperidin-1-yl) -6-fluoro-4-oxo-N- (3,3,4,4,4-pentafluorobutan-2-yl) -1 (2,4, 6-trifluorophenyl) -1,4-dihydro-1,8-naphthyridine-3-carboxamide (mixture of diastereoisomers) was separated into diastereoisomers by preparative HPLC (preparative HPLC: Daicel® Chiralpak IF column, 5 μm, 250x20 mm; eluent: 80% n-heptane / 20% ethanol; flow 15 ml / min; temperature: 25 ° C, indication: 210 nm).

Diastereoisomer 2: 46.7 mg (98.6% de).

Rt = 1.818 min [HPLC: Daicel® Chiralpak IF-3 columns, 1 ml / min; 3 μm, 50x4.6 mm; eluent: 80% isohexane / 20% ethanol; indication: 220 nm].

The resulting material was purified once more by preparative HPLC HPLC (column: Reprosil 125x30; 10 μl, flow: 50 ml / min, acetonitrile / water, 0.1% formic acid). The solvent was evaporated off under vacuum and the residue was dried under high vacuum. This gave 38 mg (22% theory, 100% purity) of the title compound.

LCMS (Method 1): Rt = 1.00 min; MS (ESIpos): m / z = 599 [M + H] +.

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.149 (0.53), -0.008 (4.75), 0.008 (4.93), 0.146 (0.53), 1.141 (1.14), 1.205 (1.62), 1.229 (1.72), 1.388 (13.04), 1.405 (13.14), 1.771 (1.42), 1.781 (1.62), 1.791 (1.77), 1.814 (1.42), 1.824 (1.34), 2.117 (0.53), 2.328 (1.19), 2.670 (1.21), 3.270 (3.77), 3.292 (4.95), 3.348 (2.43), 3.365 (1.69), 3.448 (2.91), 3.530 (1.54), 3.552 (1.79), 3.774 (3.24), 3.800 (2.86), 4.891 (8.24), 4.901 (8.32), 4.999 (8.47), 5.009 (9.30), 5.034 (1.34), 5.058 (1.19), 5.077 (0.66), 7.554 (4.73), 7.576 (8.44), 7.598 (4.65), 8.022 (9.48), 8.056 (9.15), 8.889 (16.00), 10.391 (5.79), 10.415 (5.69).

Example 184.

6-Fluoro-7 - [(2R) -2- (hydroxymethyl) pyrrolidin-1-yl] -4-oxo-N- (3,3,4,4,4-pentafluorobutan-2-yl) -1 (2 , 4,6-trifluorophenyl) -1,4-dihydro-1,8-naphthyridine-3-carboxamide (pure enantiomers)

7-Chloro-6-fluoro-4-oxo-N- [3,3,4,4,4-pentafluorobutan-2-yl] -1- (2,4,6-trifluorophenyl) -1,4-dihydro- 1,8 naphthyridine-3-carboxamide (70.0 mg, 135 μmol) (pure enantiomers) was taken up in 1.4 ml of N, N-dimethylformamide and mixed with (2R) -pyrrolidin-2-ylmethanol (15.0 mg, 149 μmol) and N, N -diisopropylethylamine (82 μl, 470 μmol). The reaction mixture was stirred for 8 h at 55 ° C. The reaction mixture was cooled and diluted with acetonitrile and purified by preparative RP-HPLC (column: Reprosil 125x30; 10 μl, flow: 50 ml / min, acetonitrile / water, 0.1% formic acid). The solvent was evaporated off under vacuum and the residue was dried under high vacuum. This gave 51 mg (65% theory, 100% purity) of the title compound.

LCMS (Method 1): Rt = 1.17 min; MS (ESIpos): m / z = 583 [M + H] +.

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (3.44), 0.008 (3.51), 0.146 (0.41), 1.386 (13.38), 1.403 (13.45), 1.811 (3.37), 1.927 ( 3.17), 2.329 (0.89), 2.367 (0.93), 2.670 (0.96), 2.711 (0.96), 3.263 (2.00), 3.276 (3.17), 3.290 (3.65), 3.598 (0.62), 4.634 (0.62), 4.966 ( 0.65), 4.986 (1.17), 5.009 (1.38), 5.029 (1.34), 5.053 (1.17), 5.073 (0.62), 7.500 (1.51), 7.525 (6.09), 7.548 (6.23), 7.573 (1.62), 7.982 ( 8.77), 8.015 (8.57), 8.846 (16.00), 10.451 (5.85), 10.474 (5.68).

Example 185.

6-Fluoro-7 - [(2R) -2- (hydroxymethyl) piperidin-1-yl] -4-oxo-N- (3,3,4,4,4-pentafluorobutan-2-yl) -1 (2 , 4,6-trifluorophenyl) -1,4-dihydro-1,8-naphthyridine-3-carboxamide (pure enantiomers)

7-Chloro-6-fluoro-4-oxo-N- (3,3,4,4,4-pentafluorobutan-2-yl) -1- (2,4,6-trifluorophenyl) -1,4-dihydro- 1.8

- 120 038451 naphthyridine-3-carboxamide (70.0 mg, 135 μmol) (pure enantiomers) were placed in 1.4 ml

Ν, Ν-dimethylformamide and mixed with (2R) -piperidin-2-ylmethanol (17.1 mg, 149 μmol) and

N, N-diisopropylethylamine (82 μl, 470 μmol). The reaction mixture was stirred for 18 h at 55 ° C. The reaction mixture was cooled and diluted with acetonitrile and purified by preparative RP-HPLC (column: Reprosil 125x30; 10 μl, flow: 50 ml / min, acetonitrile / water, 0.1% formic acid). The solvent was evaporated off under vacuum and the residue was dried under high vacuum. Received mg (58% theory. Y., 99% purity) of the title compound.

LCMS (Method 3): Rt = 1.22 min; MS (ESIpos): m / z = 597 [M + H] ⁺ .

¹ H-NMR (400 MHz, DMSO-66) δ [ppm]: -0.149 (0.42), -0.008 (3.95), 0.008 (4.02), 0.146 (0.46), 1.388 (14.45), 1.406 (14.10), 1.470 (2.22), 1.520 (3.70), 1.529 (4.02), 1.549 (6.66), 1.577 (2.64), 1.721 (2.29), 1.741 (2.15), 2.328 (1.06), 2.367 (1.02), 2.671 (1.02), 2.711 (0.99), 2.919 (1.27), 2.949 (2.36), 2.981 (1.27), 3.475 (1.13), 3.492 (1.83), 3.503 (2.85), 3.518 (3.10), 3.533 (2.15), 3.558 (1.37), 3.574 (2.36), 3.587 (2.04), 3.852 (2.15), 3.885 (1.97), 4.287 (2.43), 4.660 (3.42), 4.673 (7.47), 4.687 (3.31), 4.967 (0.63), 4.988 (1.16), 5.010 (1.34), 5.030 (1.37), 5.055 (1.16), 5.076 (0.67), 7.533 (1.73), 7.546 (4.16), 7.553 (4.83), 7.569 (4.83), 7.576 (4.30), 7.589 (1.69), 7.996 (9.37), 8.031 (9.13), 8.870 (16.00), 10.399 (5.92), 10.423 (5.67).

Example 186.

6-Fluoro-7- [4-hydroxy-4- (hydroxymethyl) piperidin-1-yl] -4-oxo-N- [3,3,4,4,4-pentafluorobutane-2yl] -1 - (2, 4,6-trifluorophenyl) -1,4-dihydro-1,8-naphthyridine-3-carboxamide (pure enantiomers)

7-Chloro-6-fluoro-4-oxo-N- [3,3,4,4,4-pentafluorobutan-2-yl] -1- (2,4,6-trifluorophenyl) -1,4-dihydro- 1,8 naphthyridine-3-carboxamide (70.0 mg, 135 μmol) (pure enantiomers) was taken up in 1.4 ml of N, N-dimethylformamide and mixed with 4- (hydroxymethyl) piperidine-4-olhydrochloride (24.9 mg, 149 μmol) and N, N-diisopropylethylamine (110 μL, 610 μmol). The reaction mixture was stirred for 8 h at 55 ° C. The reaction mixture was cooled and diluted with acetonitrile and purified by preparative RP-HPLC (column: Reprosil 125x30; 10 μl, flow: 50 ml / min, acetonitrile / water, 0.1% formic acid). The solvent was evaporated off under vacuum and the residue was dried under high vacuum. This gave 55 mg (66% theory, 100% purity) of the title compound.

LCMS (Method 3): Rt = 1.99 min; MS (ESIpos): m / z = 613 [M + H] ⁺ .

¹ H-NMR (400 MHz, DMSO- ₆ ) δ [ppm]: -0.149 (0.92), -0.008 (8.27), 0.008 (7.14), 0.146 (0.92), 1.311 (4.72), 1.345 (6.17), 1.388 (13.79), 1.405 (13.76), 1.504 (2.72), 1.534 (4.37), 1.567 (2.07), 2.328 (1.00), 2.367 (1.00), 2.670 (1.00), 2.711 (0.89), 3.142 (11.28), 3.156 (11.34), 3.249 (2.98), 3.280 (5.93), 3.891 (4.66), 3.923 (4.28), 4.324 (14.08), 4.562 (3.31), 4.576 (7.56), 4.590 (3.25), 4.968 (0.65), 4.989 (1.15), 5.009 (1.39), 5.033 (1.45), 5.055 (1.18), 5.076 (0.65), 7.558 (5.37), 7.580 (10.13), 7.603 (5.34), 8.036 (9.12), 8.070 (8.86), 8.886 (16.00), 10.389 (6.11), 10.413 (5.85).

Example 187.

7- [4,4-bis- (Hydroxymethyl) piperidin-1-yl] -6-fluoro-4-oxo-N- (3,3,4,4,4-pentafluorobutan-2-yl) -1 (2 , 4,6-trifluorophenyl) -1,4-dihydro-1,8-naphthyridine-3-carboxamide (pure enantiomers)

F

7-Chloro-6-fluoro-4-oxo-N- (3,3,4,4,4-pentafluorobutan-2-yl) -1- (2,4,6-trifluorophenyl) -1,4-dihydro- 1,8 naphthyridine-3-carboxamide (70.0 mg, 135 μmol) (pure enantiomers) was taken up in 1.4 ml of N, N-dimethylformamide and mixed with piperidine-4,4-diyldimethanol hydrochloride (27.0 mg, 149 μmol) and N, N-diisopropylethylamine (110 μl, 610 μmol). The reaction mixture was stirred for 8 h at 55 ° C. The reaction mixture was cooled, diluted with acetonitrile and purified by preparative RP-HPLC (column: Reprosil 125x30; 10 μl, flow: 50 ml / min, acetonitrile / water, 0.1% formic acid). The solvent was evaporated off under vacuum and the residue was dried under high vacuum. This gave 45 mg (53% theory, 100% purity) of the title compound.

LCMS (Method 3): Rt = 2.02 min; MS (ESIpos): m / z = 626 [M + H] ⁺ .

1H-NMR (400 MHz, DMSO-66) δ [ppm]: -0.149 (0.58), 0.008 (4.01), 0.146 (0.58), 1.347 (6.26), 1.361 (7.91), 1.375 (6.74), 1.387 (9.36) ), 1.404 (8.55), 2.328 (0.61), 2.367 (0.68), 2.671 (0.66), 2.710 (0.68), 3.271 (14.94), 3.285 (16.00), 3.507 (5.81), 3.520 (7.20), 4.405 (4.49 ), 4.419 (9.86), 4.432 (4.11), 4.967 (0.48), 4.988

- 121 038451 (0.76), 5.009 (0.91), 5.031 (0.89), 5.054 (0.76), 7.555 (3.37), 7.577 (6.24), 7.600 (3.27), 8.020 (5.48), 8.055 (5.27), 8.873 (9.38 ), 10.399 (3.85), 10.424 (3.63).

Example 188.

6-Fluoro-N- (1,1,1,3,3,3-hexafluoropropan-2-yl) -7 - [(2R) -2- (hydroxymethyl) piperidin-1-yl] -4-oxo-1 (2,4,6-trifluorophenyl) -1,4-dihydro-1,8-naphthyridine-3-carboxamide

7-Chloro-6-fluoro-N- (1,1,1,3,3,3-hexafluoropropan-2-yl) -4-oxo-1- (2,4,6-trifluorophenyl) -1,4- dihydro1,8-naphthyridine-3-carboxamide (50.0 mg, 95.8 μmol) was placed in 1 ml of DMF, mixed with (2R) -piperidin-2-ylmethanol (12.1 mg, 105 μmol) and N, N-diisopropylethylamine (58 μl, 340 μmol) and stirred for 8 h at 55 ° C. The reaction mixture was cooled and purified by preparative HPLC (RP18 columns, eluent: acetonitrile / water gradient supplemented with 0.1% formic acid). The product fractions were combined and evaporated. 43 mg of the target compound was obtained (74% theoretical, 100% purity).

LCMS (Method 3): Rt = 2.37 min; MS (ESIpos): m / z = 601 [M + H] ⁺ .

¹ H-NMR (400 MHz, DMSO-06) δ [ppm]: 1.378 (1.60), 1.476 (2.24), 1.534 (3.84), 1.555 (6.73), 1.725 (2.33), 1.743 (2.24), 2.328 (1.90 ), 2.366 (0.52), 2.670 (2.12), 2.710 (0.80), 2.930 (1.23), 2.960 (2.27), 2.992 (1.32), 3.494 (1.75), 3.506 (2.83), 3.520 (3.01), 3.535 (1.97 ), 3.578 (2.30), 3.866 (2.09), 3.899 (1.97), 4.298 (2.43), 4.679 (2.73), 4.692 (5.59), 4.705 (2.76), 6.325 (1.75), 6.347 (1.84), 7.547 (1.75) ), 7.567 (4.82), 7.583 (4.88), 7.604 (1.81), 8.034 (8.97), 8.068 (8.60), 8.541 (0.64), 8.995 (16.00), 11.231 (5.71), 11.256 (5.44).

Example 189.

6-Fluoro-N- (1,1,1,3,3,3-hexafluoropropan-2-yl) -7- [4-hydroxy-4- (hydroxymethyl) piperidin-1-yl] -4oxo-1- ( 2,4,6-trifluorophenyl) -1,4-dihydro-1,8-naphthyridine-3-carboxamide

7-Chloro-6-fluoro-N- (1,1,1,3,3,3-hexafluoropropan-2-yl) -4-oxo-1- (2,4,6-trifluorophenyl) -1,4- dihydro1,8-naphthyridine-3-carboxamide (50.0 mg, 95.8 μmol) was placed in 1 ml of DMF, mixed with 4- (hydroxymethyl) piperidine-4-olhydrochloride (18.6 mg, 95% purity, 105 μmol) and N, N- diisopropylethylamine (75 μL, 430 μmol) and stirred for 8 h at 55 ° C. The reaction mixture was cooled and purified by preparative HPLC (RP18 columns, eluent: acetonitrile / water gradient supplemented with 0.1% formic acid). The product fractions were combined and evaporated. Received 30 mg of the target compound (50% theory. V., Purity 100%).

LCMS (Method 3): Rt = 2.05 min; MS (ESIpos): m / z = 617 [M + H] +.

¹ H-NMR (400 MHz, DMSO- ₆ ) δ [ppm]: -0.149 (0.46), -0.008 (5.62), 0.008 (3.80), 0.146 (0.44), 1.320 (4.64), 1.353 (5.97), 1.505 (2.67), 1.515 (3.07), 1.538 (4.37), 1.546 (4.30), 1.570 (2.28), 1.580 (1.92), 2.329 (0.77), 2.671 (0.81), 3.146 (11.34), 3.160 (11.17), 3.262 (3.24), 3.291 (7.90), 3.569 (0.46), 3.907 (4.70), 3.940 (4.16), 4.332 (14.24), 4.565 (3.63), 4.579 (8.00), 4.593 (3.38), 6.307 (1.30), 6.331 (1.78), 6.348 (1.80), 6.367 (1.23), 7.573 (5.26), 7.595 (9.59), 7.617 (5.06), 8.073 (9.13), 8.107 (8.75), 9.009 (16.00), 11.219 (5.76), 11.244 (5.41).

Example 190.

1- (3,5-Difluoropyridin-2-yl) -6-fluoro-N- (1,1,1,3,3,3-hexafluoropropan-2-yl) -7 - [(2R) -2- ( hydroxymethyl) piperidin-1-yl] -4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide

7-Chloro-1- (3,5-difluoropyridin-2-yl) -6-fluoro-N- (1,1,1,3,3,3-hexafluoropropan-2-yl) -4-oxo-1, 4-dihydro-1,8-naphthyridine-3-carboxamide (50.0 mg, 99.1 μmol) was placed in 1 ml of DMF, mixed with (2R) -piperidin-2-ylmethanol (12.6 mg, 109 μmol) and N, N-diisopropylethylamine (8.6 μl,

- 122 038451 μmol) and stirred for 8 h at 55 ° C. (2R) -piperidin-2-ylmethanol (19.4 mg, 50 μmol) and N, N-diisopropylethylamine (8.6 μL, 50 μmol) were added again and stirred at 55 ° C. The reaction mixture was cooled and purified by preparative HPLC (RP18 columns, eluent:

acetonitrile / water gradient with addition of 0.1% formic acid). The product fractions were combined and evaporated. Received 37 mg of the target compound (63% theory. V., 99% purity).

LCMS (Method 3): Rt = 2.26 min; MS (ESIpos): m / z = 584 [M + H] +.

¹ H-NMR (400 MHz, DMSO-66) δ [ppm]: -0.149 (0.99), -0.008 (7.81), 0.008 (7.07), 0.146 (0.93), 1.339 (1.30), 1.525 (9.67), 1.545 (8.81), 1.616 (2.67), 1.647 (2.17), 1.745 (3.97), 2.328 (1.86), 2.367 (0.68), 2.670 (1.98), 2.711 (0.68), 2.921 (2.17), 2.954 (1.61), 3.002 (1.74), 3.031 (0.99), 3.473 (1.74), 3.489 (3.22), 3.500 (6.02), 3.515 (7.75), 3.529 (6.20), 3.581 (2.54), 3.859 (4.59), 3.892 (4.28), 4.286 (3.16), 4.660 (3.10), 4.697 (4.90), 6.300 (1.05), 6.317 (2.67), 6.335 (3.78), 6.360 (3.91), 6.378 (2.60), 6.397 (0.99), 8.037 (9.92), 8.071 (10.23), 8.339 (4.53), 8.357 (4.09), 8.629 (16.00), 8.635 (15.32), 8.956 (9.80), 11.224 (12.84), 11.250 (12.34).

Example 191.

- [4,4-bis- (Hydroxymethyl) piperidin-1 -yl] -6-fluoro-N- (1,1,1,3,3,3-hexafluoropropan-2-yl) -4-oxo-1 (2,4,6-trifluorophenyl) -1,4-dihydro-1,8-naphthyridine-3-carboxamide

7-Chloro-6-fluoro-N- (1,1,1,3,3,3-hexafluoropropan-2-yl) -4-oxo-1- (2,4,6-trifluorophenyl) -1,4- dihydro1,8-naphthyridine-3-carboxamide (50.0 mg, 95.8 μmol) was placed in 1 ml of DMF, mixed with piperidine-4,4-diyldimethanol hydrochloride (20.2 mg, 95% pure, 105 μmol) and N, N-diisopropylethylamine (75 μl, 430 μmol) and stirred for 8 h at 55 ° C. The reaction mixture was cooled and purified by preparative HPLC (RP18 columns, eluent: acetonitrile / water gradient supplemented with 0.1% formic acid). The product fractions were combined and evaporated. Received 52 mg of the target compound (85% theory. V., 100% purity).

LCMS (Method 3): Rt = 2.07 min; MS (ESIpos): m / z = 631 [M + H] ⁺ .

¹ H-NMR (400 MHz, DMSO-66) δ [ppm]: 1.354 (7.76), 1.368 (10.28), 1.382 (8.05), 2.328 (1.17), 2.670 (1.30), 3.276 (15.51), 3.285 (16.00 ), 3.520 (7.34), 3.534 (9.74), 4.423 (5.58), 6.287 (0.42), 6.304 (1.10), 6.329 (1.52), 6.347 (1.61), 6.365 (1.05), 7.571 (4.40), 7.592 (8.22 ), 7.614 (4.45), 8.058 (7.63), 8.092 (7.49), 8.996 (13.58), 11.232 (5.36), 11.258 (5.09).

Example 192.

6-Fluoro-7 - [3-hydroxy-3 - (hydroxymethyl) piperidin-1 -yl] -4-oxo-N- [3,3,4,4,4-pentafluorobutane-2yl] -1 - (2, 4,6-trifluorophenyl) -1,4-dihydro-1,8-naphthyridine-3-carboxamide (mixture of diastereoisomers)

7-Chloro-6-fluoro-4-oxo-N- [3,3,4,4,4-pentafluorobutan-2-yl] -1- (2,4,6-trifluorophenyl) -1,4-dihydro- 1,8 naphthyridine-3-carboxamide (100 mg, 94% purity, 182 μmol) (pure enantiomers) were placed in 2 ml of DMF, mixed with 3- (hydroxymethyl) piperidin-3-ol (26.2 mg, 200 μmol) and Ν, -Diisopropylethylamine (110 μL, 640 μmol) and stirred for 18 h at room temperature. The reaction mixture was purified by preparative HPLC (RP18 columns, eluent: acetonitrile / water gradient with the addition of 0.1% formic acid). The product fractions were evaporated. Received 88 mg of the target compound (79% theory. V., 100% purity).

LCMS (Method 3): _Rt = 2.03 min; MS (ESIpos): m / z = 613 [M + H] +.

1H-NMR (400 MHz, DMSO-66) δ [ppm]: -0.149 (1.00), -0.008 (14.16), 0.008 (7.76), 0.146 (0.94), 1.273 (2.39), 1.387 (15.20), 1.404 ( 15.48), 1.599 (1.18), 1.628 (4.19), 1.655 (4.40), 2.328 (1.52), 2.670 (1.59), 2.901 (1.97), 3.105 (1.39), 3.132 (4.12), 3.149 (6.34), 3.164 ( 4.43), 3.177 (1.49), 3.192 (1.28), 3.770 (2.53), 3.803 (2.25), 3.834 (2.81), 3.868 (2.35), 4.241 (10.29), 4.655 (3.15), 4.669 (6.20), 4.683 ( 2.84), 4.988 (1.25), 5.013 (1.42), 5.032 (1.42), 5.056 (1.18), 7.556 (3.71), 7.566 (4.71), 7.579 (4.68), 7.598 (2.01), 7.971 (7.48), 8.005 ( 7.34), 8.875 (16.00), 10.424 (5.44), 10.447 (5.23).

- 123 038451

Example 193.

6-Fluoro-7 - [(2S, 3S) -3-hydroxy-2- (hydroxymethyl) pyrrolidin-1-yl] -4-oxo-N- (3,3,4,4,4-pentafluoro-2methylbutane- 2-yl) -1 - (2,4,6-trifluorophenyl) -1,4-dihydro-1,8-naphthyridine-3-carboxamide

7-Chloro-6-fluoro-4-oxo-N- (3,3,4,4,4-pentafluoro-2-methylbutan-2-yl) -1- (2,4,6-trifluorophenyl) -1, 4-dihydro-1,8-naphthyridine-3-carboxamide (100 mg, 188 μmol) was placed in 1.9 ml of DMF, mixed with (2S, 3S) -2- (hydroxymethyl) pyrrolidine-3-olhydrochloride (37.6 mg, 244 μmol) and Ν, Ν-diisopropylethylamine (150 μL, 850 μmol) and stirred for 12 h at 55 ° C. The reaction mixture was cooled and purified by preparative HPLC (RP18 columns, eluent: acetonitrile / water gradient with the addition of 0.1% formic acid). The product fractions were combined and evaporated. Received 93 mg of the target compound (81% theory. V., 100% purity).

LCMS (Method 3): Rt = 2.08 min; MS (ESIpos): m / z = 613 [M + H] +.

1H-NMR (400 MHz, DMSO-06) δ [ppm]: -0.008 (3.03), 0.008 (2.80), 1.681 (16.00), 1.953 (1.23), 1.969 (1.25), 2.073 (0.51), 3.478 (1.10 ), 4.273 (0.92), 5.176 (1.16), 5.185 (1.14), 7.531 (1.06), 7.550 (1.89), 7.570 (1.10), 7.993 (2.68), 8.026 (2.62), 8.783 (5.55), 10.556 (4.22 ).

Example 194.

6-Fluoro-7 - [(2S, 3S) -3-hydroxy-2- (hydroxymethyl) pyrrolidin-1-yl] -4-oxo-N- [3,3,4,4,4-pentafluorobutane-2- yl] -1- (2,4,6-trifluorophenyl) -1,4-dihydro-1,8-naphthyridine-3-carboxamide (pure enantiomers)

7-Chloro-6-fluoro-4-oxo-N- [3,3,4,4,4-pentafluorobutan-2-yl] -1- (2,4,6-trifluorophenyl) -1,4-dihydro- 1,8 naphthyridine-3-carboxamide (80.0 mg, 155 μmol) was placed in 1.5 ml of DMF, mixed with (2S, 3S) -2 (hydroxymethyl) pyrrolidine-3-olhydrochloride (30.9 mg, 201 μmol) and N, N-diisopropylethylamine (120 μL, 700 μmol) and stirred for 12 h at 55 ° C. The reaction mixture was cooled and purified by preparative HPLC (RP18 columns, eluent: acetonitrile / water gradient with the addition of 0.1% formic acid). The product fractions were combined and evaporated. Received 75 mg of the target compound (81% theory. V., 100% purity).

LCMS (Method 3): _Rt = 1.98 min; MS (ESIpos): m / z = 599 [M + H] +.

1H-NMR (400 MHz, DMSO-06) δ [ppm]: -0.149 (1.46), -0.008 (11.75), 0.008 (11.23), 0.146 (1.43), 1.386 (12.95), 1.403 (13.01), 1.953 ( 3.41), 1.970 (3.44), 2.328 (1.14), 2.367 (0.42), 2.670 (1.17), 2.711 (0.42), 3.481 (3.05), 4.272 (2.50), 4.964 (0.62), 4.986 (1.10), 5.006 ( 1.33), 5.028 (1.30), 5.051 (1.14), 5.072 (0.58), 5.185 (2.82), 7.531 (2.89), 7.552 (5.16), 7.569 (2.86), 7.976 (7.30), 8.008 (7.08), 8.032 ( 0.42), 8.848 (16.00), 10.446 (5.71), 10.470 (5.52).

Example 195.

- [4,4-bis- (Hydroxymethyl) piperidin-1 -yl] -1- (3,5-difluoropyridin-2-yl) -6-fluoro-N- (1,1,1,3,3, 3hexafluoropropan-2-yl) -4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide

7-Chloro-1- (3,5-difluoropyridin-2-yl) -6-fluoro-N- (1,1,1,3,3,3-hexafluoropropan-2-yl) -4-oxo-1, 4-dihydro-1,8-naphthyridine-3-carboxamide (50.0 mg, 99.1 μmol) was placed in 1 ml of DMF, mixed with piperidine-4,4-diyldimethanol hydrochloride (20.8 mg, 95% purity, 109 μmol) and, Ν-diisopropylethylamine (78 μl, 450 μmol) and stirred overnight at 55 ° C. The reaction mixture was cooled and purified by preparative HPLC (RP18 columns, eluent: acetonitrile / water gradient with the addition of 0.1% formic acid). The product fractions were combined and evaporated. Received 36 mg of the target compound (59% theory. V. 99% purity).

LC-MS (Method 3): R _t = 1.96 min; MS (ESIpos): m / z = 614 [M + H] +.

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.364 (0.66), 1.378 (1.01), 1.393 (0.69), 3.278 (1.57), 3.291

- 124 038451 (1.64), 3.312 (16.00), 3.529 (0.79), 4.413 (0.47), 4.427 (1.05), 4.440 (0.47), 8.061 (0.74), 8.095 (0.72), 8.636 (0.86), 8.642 (0.82) ), 8.958 (1.64), 11.226 (0.46), 11.251 (0.44).

Example 196.

6-Fluoro-N- (1,1,1,3,3,3-hexafluoropropan-2-yl) -7- (2-oxa-6-azaspiro [3.3] hept-6-yl) -4-oxo 1- (2,4,6trifluorophenyl) -1,4-dihydro-1,8-naphthyridine-3-carboxamide

7-Chloro-6-fluoro-N- (1,1,1,3,3,3-hexafluoropropan-2-yl) -4-oxo-1 - (2,4,6-trifluorophenyl) -1,4- dihydro1,8-naphthyridine-3-carboxamide (100 mg, 100% purity, 192 μmol) was placed in 2.1 ml of DMF, mixed with ethanedic acid-2-oxa-6-azaspiro [3.3] heptane (1: 2) (71.8 mg, 249 μmol) and, Ν-diisopropylethylamine (120 μL, 670 μmol) and stirred for 18 h at 55 ° C. The reaction solution was left over the weekend at room temperature. Then purified by preparative HPLC (RP18 columns, eluent: acetonitrile / water gradient with addition of 0.1% formic acid). The product fractions were combined and evaporated. 89 mg of the target compound was obtained (79% theoretical, 99% purity).

LCMS (Method 3): Rt = 2.31 min; MS (ESIpos): m / z = 585 [M + H] +.

¹ H-NMR (400 MHz, DMSO-66) δ [ppm]: -0.008 (2.33), 0.008 (2.26), 4.656 (16.00), 6.297 (0.41), 6.316 (0.57), 6.339 (0.61), 7.556 ( 1.64), 7.578 (2.94), 7.600 (1.63), 8.020 (2.85), 8.049 (2.83), 8.965 (4.77), 11.258 (1.92), 11.284 (1.84).

Example 197.

1- (3,5-Difluoropyridin-2-yl) -6-fluoro-N- (1,1,1,3,3,3-hexafluoropropan-2-yl) -7 - [(2R) -2- ( hydroxymethyl) pyrrolidin-1-yl] -4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide

F

О О F — I— F

7-Chloro-1 - (3,5-difluoropyridin-2-yl) -6-fluoro-N- (1,1,1,3,3,3-hexafluoropropan-2-yl) -4-oxo-1, 4-dihydro-1,8-naphthyridine-3-carboxamide (50.0 mg, 99.1 μmol) was labeled in 1 ml of DMF, mixed with (2R) -pyrrolidin-2-ylmethanol (11 μl, 99% purity, 110 μmol) and N, N- diisopropylethylamine (60 μl, 350 μmol) and stirred overnight at 55 ° C. The reaction mixture was cooled and purified by preparative HPLC (RP18 columns, eluent: acetonitrile / water gradient supplemented with 0.1% formic acid). The product fractions were combined, purified from solvent and lyophilized. This gave 30 mg (52% theory, 98% purity) of the title compound.

LCMS (Method 3): Rt = 2.17 min; MS (ESIpos): m / z = 570 [M + H] ⁺ .

¹ H-NMR (400 MHz, DMSO-66) δ [ppm]: -0.149 (1.37), 0.146 (1.76), 1.820 (7.75), 1.934 (7.70), 2.328 (2.31), 2.670 (2.69), 2.711 ( 0.66), 3.160 (2.09), 3.576 (1.54), 4.710 (1.43), 6.309 (2.91), 6.328 (4.23), 6.352 (4.40), 6.369 (2.97), 8.021 (10.28), 8.054 (10.17), 8.284 ( 2.97), 8.309 (3.30), 8.335 (3.68), 8.353 (1.87), 8.557 (1.87), 8.612 (16.00), 8.939 (11.22), 8.954 (9.68), 11.287 (12.70), 11.312 (12.10).

Example 198.

1- (3,5-Difluoropyridin-2-yl) -6-fluoro-N- (1,1,1,3,3,3-hexafluoropropan-2-yl) -7- [4-hydroxy-4 (hydroxymethyl ) piperidin-1-yl] -4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide

7-Chloro-1 - (3,5-difluoropyridin-2-yl) -6-fluoro-N- (1,1,1,3,3,3-hexafluoropropan-2-yl) -4-oxo-1, 4-dihydro-1,8-naphthyridine-3-carboxamide (50.0 mg, 99.1 μmol) was labeled in 1 ml of DMF, mixed with 4- (hydroxymethyl) piperidine-4-olhydrochloride (19.2 mg, 95% purity, 109 μmol) and N, N-diisopropylethylamine (78 μl, 450 μmol) and stirred overnight at 55 ° C. The reaction mixture was cooled and purified by preparative HPLC (RP18 columns, solvent: aceto-125 038451 nitrile / water gradient with 0.1% formic acid). The product fractions were combined and purified from the solvent. The residue was purified by chromatography on silica gel (eluent: dichloromethane after ethyl acetate). The fractions containing the product were combined, evaporated and lyophilized overnight from acetonitrile / water. Received 22.3 mg (37% theory.,

99% pure) of the title compound.

LCMS (Method 1): _Rt = 1.02 min; MS (ESIpos): m / z = 600 [M + H] ⁺ .

¹ H-NMR (400 MHz, DMSO-de) δ [ppm]: -0.149 (0.70), -0.008 (6.17), 0.008 (5.68), 0.146 (0.70), 1.235 (0.55), 1.284 (0.76), 1.298 (1.40), 1.312 (1.56), 1.347 (3.39), 1.383 (2.11), 1.491 (1.10), 1.524 (1.89), 1.543 (1.89), 1.566 (1.92), 1.598 (0.89), 2.041 (1.13), 2.328 (1.01), 2.366 (0.43), 2.670 (1.13), 2.710 (0.52), 3.147 (10.11), 3.162 (10.20), 3.233 (1.01), 3.266 (2.08), 3.912 (2.81), 4.329 (12.64), 4.564 (2.93), 4.578 (6.81), 4.592 (2.96), 6.318 (0.98), 6.343 (1.50), 6.360 (1.59), 6.379 (1.04), 8.076 (7.76), 8.110 (7.60), 8.354 (1.74), 8.360 (2.05), 8.382 (3.11), 8.399 (1.92), 8.405 (2.02), 8.638 (8.98), 8.645 (8.52), 8.969 (16.00), 11.212 (5.31), 11.238 (5.07).

Example 199.

6-Fluoro-N- (1,1,1,3,3,3-hexafluoropropan-2-yl) -7 - [(2R) -2- (hydroxymethyl) pyrrolidin-1-yl] -4-oxo-1 (2,4,6-trifluorophenyl) -1,4-dihydro-1,8-naphthyridine-3-carboxamide

7-Chloro-6-fluoro-N- (1,1,1,3,3,3-hexafluoropropan-2-yl) -4-oxo-1- (2,4,6-trifluorophenyl) -1,4- dihydro1,8-naphthyridine-3-carboxamide (50.0 mg, 95.8 μmol) was placed in 1 ml of DMF, mixed with (2R) -pyrrolidin-2-ylmethanol (11 μl, 99% purity, 110 μmol) and Ν, Ν-diisopropylethylamine (58 μl, 340 μmol) and stirred for 8 h at 55 ° C. The reaction mixture was cooled and purified by preparative HPLC (RP18 columns, eluent: acetonitrile / water gradient supplemented with 0.1% formic acid). The product fractions were combined and purified from the solvent. The residue was purified once more by preparative HPLC (RP18 columns, eluent: acetonitrile / water gradient with the addition of 0.1% formic acid). The product fractions were combined and purified from the solvent. The residue was purified by chromatography on silica gel (ethyl acetate-cyclohexane gradient). After evaporation, the residue was purified once more by preparative HPLC (RP18 columns, eluent: acetonitrile / water gradient supplemented with 0.1% formic acid). The fractions containing the product were combined, evaporated and lyophilized overnight from acetonitrile / water. This gave 14.2 mg (25% theory, 99% purity) of the title compound.

LCMS (Method 3): _Rt = 2.27 min; MS (ESIpos): m / z = 587 [M + H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.149 (0.99), 0.146 (0.93), 1.821 (3.92), 1.933 (3.51), 2.328 (1.13), 2.367 (0.90), 2.670 (1.25 ), 2.711 (0.87), 3.346 (1.19), 3.603 (0.64), 4.641 (0.64), 6.299 (1.39), 6.317 (2.03), 6.341 (2.15), 6.360 (1.36), 7.518 (1.74), 7.540 (6.68 ), 7.563 (6.85), 7.587 (1.92), 8.020 (8.68), 8.052 (8.57), 8.974 (16.00), 11.291 (6.45), 11.316 (6.16).

Example 200.

6-Fluoro-7- [6-hydroxy-1,4-diazepan-1-yl] -4-oxo-N- [3,3,4,4,4-pentafluorobutan-2-yl] -1- (2 , 4,6trifluorophenyl) -1,4-dihydro-1,8-naphthyridine-3-carboxamide (mixture of diastereoisomers)

1,4-Diazepan-6-oldihydrobromide (37.6 mg, 135 µmol) was added to 0.26 ml of DMF and Ν, Ν-diisopropylethylamine (170 µl, 970 µmol). 7-chloro-6-fluoro-4-oxo-N- (3,3,4,4,4-pentafluorobutane-2yl) -1- (2,4,6-trifluorophenyl) -1,4-dihydro-1, 8-naphthyridine-3-carboxamide (pure enantiomers) (100 mg, 193 μmol) was dissolved in 0.79 ml of DMF and slowly added dropwise to the first mixture and stirred overnight at room temperature. The reaction mixture was diluted with acetonitrile, water and trifluoroacetic acid and purified by preparative HPLC (RP18 columns, eluent: acetonitrile / water gradient with the addition of 0.1% trifluoroacetic acid). The combined product fractions were evaporated. The residue was dissolved in dichloromethane and washed twice with saturated aqueous sodium hydrogen carbonate solution. The combined aqueous phases were reextracted twice with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated. Received 37 mg of the target compound (32% theory. V. 99% purity).

- 126 038451

LCMS (Method 3): Rt = 1.43 min; MS (ESIpos): m / z = 598 [M + H] +.

Ή-NMR (400 MHz, DMSO-66) δ [ppm]: -0.149 (1.01), -0.008 (8.78), 0.008 (8.35), 0.146 (1.01), 0.853 (0.86), 1.234 (1.21), 1.387 ( 11.18), 1.404 (11.23), 2.156 (0.61), 2.328 (1.59), 2.366 (0.56), 2.570 (3.81), 2.670 (4.29), 2.697 (1.59), 3.627 (1.89), 3.854 (1.84), 3.878 ( 1.67), 4.729 (1.49), 4.989 (0.98), 5.010 (1.09), 5.033 (1.14), 5.754 (11.43), 7.541 (3.56), 7.547 (3.63), 7.564 (4.21), 7.584 (1.51), 7.993 ( 7.97), 8.027 (7.80), 8.868 (16.00), 10.414 (4.90), 10.438 (4.79).

Example 201.

N- [1-Cyclopropyl-2,2,3,3,3-pentafluoropropyl] -7- [(3R, 4R) -3,4-dihydroxypyrrolidin-1 -yl] -6fluoro-4-oxo-1 - (2 , 4,6-trifluorophenyl) -1,4-dihydro-1,8-naphthyridine-3-carboxamide (enantiomer 1)

F

7-Chloro-N- [1-cyclopropyl-2,2,3,3,3-pentafluoropropyl] -6-fluoro-4-oxo-1- (2,4,6-trifluorophenyl) -1,4 dihydro-1, 8-naphthyridine-3-carboxamide (enantiomer 1) (100 mg, 184 μmol) was added to 1 ml of DMF. Added (3R, 4R) -pyrrolidine-3,4-diol hydrochloride (30.8 mg, 221 μmol), mixed with

N, N-diisopropylethylamine (160 μl, 920 μmol) and stirred overnight at room temperature. The reaction mixture was mixed with water / acetonitrile / trifluoroacetic acid and purified by preparative HPLC (RP18 columns, eluent: acetonitrile / water gradient with the addition of 0.1% trifluoroacetic acid). The combined product fractions were evaporated. The residue was dissolved in dichloromethane and a small amount of methanol and washed twice with saturated aqueous sodium hydrogen carbonate solution. The combined aqueous phases were reextracted twice with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated. Received 103 mg of the target compound (90% theory. V., Purity 98%).

Enantiomer 1: ee> 97%.

R _t = 7.703 min [analytical HPLC: Daicel® Chiralpak IA column, 5 μm, 250x4.6 mm; 1 ml / min, 30 ° C; eluent: 80% isohexane / 20% ethanol; indication: 220 nm].

LCMS (Method 1): _Rt = 1.06 min; MS (ESIpos): m / z = 611 [M + H] ⁺ .

¹ H-NMR (400 MHz, DMSOA) δ [ppm]: -0.149 (0.56), -0.008 (4.36), 0.008 (4.16), 0.146 (0.52), 0.308 (0.79), 0.320 (1.84), 0.332 (2.92 ), 0.345 (3.15), 0.357 (2.45), 0.369 (1.11), 0.486 (0.86), 0.497 (2.37), 0.509 (3.34), 0.521 (2.94), 0.533 (2.22), 0.545 (1.02), 0.566 (1.01 ), 0.576 (1.14), 0.587 (2.39), 0.599 (2.71), 0.609 (2.26), 0.620 (1.96), 0.633 (1.13), 0.650 (1.29), 0.670 (2.35), 0.683 (2.68), 0.696 (2.09 ), 0.717 (0.67), 1.207 (0.50), 1.219 (1.14), 1.227 (1.75), 1.240 (2.91), 1.249 (2.16), 1.260 (2.69), 1.272 (1.47), 1.281 (0.95), 2.328 (0.94 ), 2.367 (0.61), 2.670 (0.98), 2.711 (0.58), 3.066 (1.02), 3.700 (1.05), 3.906 (2.19), 4.022 (1.54), 4.434 (0.67), 4.457 (1.66), 4.479 (2.15 ), 4.501 (2.09), 4.522 (1.69), 4.545 (0.63), 5.202 (4.77), 7.556 (3.48), 7.577 (6.29), 7.597 (3.48), 8.011 (9.15), 8.043 (8.99), 8.838 (16.00 ), 10.542 (6.29), 10.566 (6.04).

Example 202.

N- [1-Cyclopropyl-2,2,3,3,3-pentafluoropropyl] -7- [(3R, 4R) -3,4-dihydroxypyrrolidin-1 -yl] -6fluoro-4-oxo-1 - (2 , 4,6-trifluorophenyl) -1,4-dihydro-1,8-naphthyridine-3-carboxamide (enantiomer 2)

F

7-Chloro-N- [1-cyclopropyl-2,2,3,3,3-pentafluoropropyl] -6-fluoro-4-oxo-1- (2,4,6-trifluorophenyl) -1,4 dihydro-1, 8-naphthyridine-3-carboxamide (enantiomer 2) (100 mg, 184 μmol) was added to 1 ml of DMF. (3R, 4R) -pyrrolidine-3,4-diol hydrochloride (30.8 mg, 221 μmol) and N, N-diisopropylethylamine (160 μL, 920 μmol) were added and the mixture was stirred overnight at room temperature. The reaction mixture was mixed with water / acetonitrile / trifluoroacetic acid and purified by preparative HPLC (RP18 columns, eluent: acetonitrile / water gradient with the addition of 0.1% trifluoroacetic acid). The combined product fractions were evaporated. The residue was dissolved in dichloromethane and a small amount of methanol and washed twice with saturated aqueous sodium hydrogen carbonate solution. The combined aqueous phases were reextracted twice with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated. Received 105 mg of the target compound (92% theory. V., Purity 98%).

Enantiomer 2: ee> 96.5%.

- 127 038451

Rt = 6.54 min [analytical HPLC: Daicel® Chiralpak IA column, 5 μm, 250x4.6 mm; 1 ml / min,

30 ° C; eluent: 80% isohexane / 20% ethanol; indication: 220 nm].

LCMS (Method 1): Rt = 1.06 min; MS (ESIpos): m / z = 611 [M + H] ⁺ .

¹ H-NMR (400 MHz, DMSO-66) δ [ppm]: -0.149 (0.68), 0.146 (0.64), 0.308 (0.75), 0.321 (1.88), 0.333 (2.90), 0.345 (3.19), 0.357 ( 2.48), 0.369 (1.09), 0.487 (0.83), 0.499 (2.31), 0.511 (3.27), 0.523 (2.86), 0.534 (2.19), 0.547 (1.02), 0.566 (0.95), 0.588 (2.37), 0.600 ( 2.70), 0.609 (2.25), 0.621 (1.97), 0.634 (1.13), 0.650 (1.24), 0.671 (2.36), 0.684 (2.66), 0.696 (2.08), 0.718 (0.67), 1.206 (0.50), 1.227 ( 1.70), 1.239 (2.83), 1.249 (2.23), 1.260 (2.64), 1.271 (1.51), 1.293 (0.42), 2.328 (0.94), 2.367 (0.42), 2.671 (0.99), 2.710 (0.41), 3.074 ( 1.03), 3.691 (1.09), 3.903 (2.19), 4.017 (1.59), 4.432 (0.64), 4.455 (1.67), 4.477 (2.14), 4.498 (2.12), 4.520 (1.69), 4.544 (0.63), 5.203 ( 5.43), 7.555 (4.56), 7.577 (8.29), 7.598 (4.45), 8.012 (8.76), 8.044 (8.61), 8.838 (16.00), 10.543 (6.02), 10.568 (5.80).

Example 203.

N- (1,1-Dicyclopropyl-2,2,2-trifluoroethyl) -7 - [(3R, 4R) -3,4-dihydroxypyrrolidin-1-yl] -6-fluoro-4oxo-1- (2,4 , 6-trifluorophenyl) -1,4-dihydro-1,8-naphthyridine-3-carboxamide

7-Χλορ-Ν- (1,1-dicyclopropyl-2,2,2-trifluoroethyl) -6-fluoro-4-oxo-1- (2,4,6-trifluorophenyl) -1,4 dihydro-1,8- naphthyridine-3-carboxamide (70.0 mg, 131 μmol) was added to 0.7 ml of DMF. (3R, 4R) -pyrrolidine-3,4-diol hydrochloride (22.0 mg, 157 μmol) and N, N-diisopropylethylamine (110 μL, 660 μmol) were added and stirred overnight at room temperature. The reaction mixture was mixed with water / acetonitrile / trifluoroacetic acid and purified by preparative HPLC (RP18 columns, eluent: acetonitrile / water gradient with the addition of 0.1% trifluoroacetic acid). The combined product fractions were evaporated. The residue was dissolved in dichloromethane and a small amount of methanol and washed twice with saturated aqueous sodium hydrogen carbonate solution. The combined aqueous phases were reextracted twice with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated. Received 71 mg of the target compound (88% theory. V., Purity 98%).

LCMS (Method 1): Rt = 1.04 min; MS (ESIpos): m / z = 601 [M + H] +.

¹ H-NMR (400 MHz, DMSO-66) δ [ppm]: -0.149 (0.68), -0.008 (5.38), 0.008 (4.77), 0.146 (0.65), 0.458 (1.16), 0.469 (2.08), 0.481 (3.81), 0.493 (4.94), 0.505 (5.07), 0.516 (3.30), 0.527 (2.52), 0.552 (1.70), 0.564 (3.47), 0.578 (4.05), 0.586 (5.38), 0.600 (4.90), 0.608 (3.68), 0.622 (4.87), 0.633 (4.05), 0.645 (5.89), 0.658 (4.94), 0.672 (1.97), 0.685 (2.55), 0.699 (4.87), 0.710 (5.55), 0.723 (4.26), 0.733 (2.72), 0.747 (1.02), 1.175 (0.65), 1.518 (1.60), 1.533 (3.51), 1.540 (3.74), 1.553 (6.26), 1.567 (3.51), 1.574 (3.17), 1.589 (1.36), 1.988 (1.16), 2.086 (5.69), 2.328 (1.09), 2.367 (0.71), 2.670 (1.23), 2.711 (0.78), 3.072 (0.95), 3.684 (1.02), 3.901 (2.04), 4.021 (1.67), 5.198 (4.36), 5.754 (3.34), 7.553 (3.88), 7.575 (6.98), 7.595 (3.91), 8.034 (9.12), 8.066 (8.99), 8.776 (16.00), 9.878 (11.85).

Example 204.

N- [1-Cyclopropyl-2,2,3,3,3-pentafluoropropyl] -6-fluoro-7- (2-oxa-6-azaspiro [3.3] hept-6-yl) -4-oxo1- (2 , 4,6-trifluorophenyl) -1,4-dihydro-1,8-naphthyridine-3-carboxamide (enantiomer 1)

7-Chloro-N- [1-cyclopropyl-2,2,3,3,3-pentafluoropropyl] -6-fluoro-4-oxo-1- (2,4,6-trifluorophenyl) -1,4 dihydro-1, 8-naphthyridine-3-carboxamide (enantiomer 1) (150 mg, 276 µmol) was placed in 1.5 ml of DMF, mixed with N, N-diisopropylethylamine (480 µl, 2.8 mmol) and ethanedic acid-2-oxa-6azaspiro [3.3] heptane (1: 2) (59.6 mg, 207 μmol) at room temperature. The reaction solution was stirred overnight at room temperature. The reaction mixture was mixed with water / acetonitrile / trifluoroacetic acid and purified by preparative HPLC (RP18 columns, eluent: acetonitrile / water gradient with the addition of 0.1% trifluoroacetic acid). Received 160 mg of the target compound (94% theory. V. 98% purity).

LCMS (Method 1): Rt = 1.21 min; MS (ESIpos): m / z = 607 [M + H] +.

1H-NMR (400 MHz, DMSO-a ₆ ) δ [ppm]: -0.149 (0.97), -0.008 (7.80), 0.146 (0.88), 0.310 (0.64), 0.323

- 128 038451 (0.97), 0.335 (0.97), 0.346 (0.82), 0.493 (0.74), 0.504 (1.09), 0.517 (0.92), 0.528 (0.70), 0.580 (0.80), 0.593 (0.86), 0.680 (0.88 ), 1.222 (0.58), 1.234 (1.01), 1.254 (0.88), 2.073 (9.20), 2.327 (1.58), 2.366 (0.74), 2.670 (1.58), 2.710 (0.74), 4.272 (0.43), 4.446 (0.70 ), 4.468 (0.86), 4.489 (0.82), 4.511 (0.64), 4.655 (16.00), 7.541 (1.70), 7.563 (3.25), 7.585 (1.73), 7.999 (2.88), 8.027 (2.85), 8.833 (5.07 ), 10.507 (1.95), 10.531 (1.91).

Example 205.

7- [3,3-bis- (Hydroxymethyl) azetidin-1-yl] -N- [1-cyclopropyl-2,2,3,3,3-pentafluoropropyl] -6-fluoro-4oxo-1 - (2, 4,6-trifluorophenyl) -1,4-dihydro-1,8-naphthyridine-3-carboxamide (enantiomer 1)

Trifluoroacetic acid (1.5 ml, 20 mmol) was mixed with 1.5 ml of water and 1.5 ml of acetonitrile and stirred for 2 days at room temperature. The reaction mixture was purified by preparative HPLC (RP18 columns, eluent: acetonitrile / water gradient with the addition of 0.1% trifluoroacetic acid). The combined product fractions were evaporated. The residue was dissolved in dichloromethane and washed twice with saturated aqueous sodium hydrogen carbonate solution. The combined aqueous phases were reextracted twice with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated. A total of 115 mg of the target compound was obtained (73% theoretical, 98% purity).

LCMS (Method 3): Rt = 1.99 min; MS (ESIpos): m / z = 625 [M + H] +.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: -0.149 (0.47), 0.146 (0.44), 0.304 (0.53), 0.316 (1.31), 0.328 (2.04), 0.340 (2.20), 0.352 (1.72), 0.365 (0.74), 0.483 (0.59), 0.495 (1.58), 0.507 (2.26), 0.519 (1.97), 0.531 (1.51), 0.542 (0.72), 0.563 (0.67), 0.585 (1.65), 0.597 (1.87), 0.607 (1.59), 0.618 (1.38), 0.630 (0.76), 0.648 (0.85), 0.669 (1.65), 0.682 (1.90), 0.694 (1.43), 0.715 (0.46), 1.223 (1.12), 1.235 (1.99), 1.245 (1.56), 1.256 (1.80), 1.268 (1.01), 2.329 (0.50), 2.671 (0.54), 3.475 (15.57), 3.488 (16.00), 4.131 (1.02), 4.425 (0.49), 4.448 (1.17), 4.470 (1.51), 4.492 (1.47), 4.514 (1.19), 4.537 (0.49), 4.838 (4.89), 4.851 (11.09), 4.864 (4.84), 7.532 (3.57), 7.554 (6.85), 7.576 (3.60), 7.971 (5.68), 8.000 (5.62), 8.814 (10.62), 10.540 (4.12), 10.564 (3.97).

Example 206.

N- [1-Cyclopropyl-2,2,3,3,3-pentafluoropropyl] -6-fluoro-7- (2-oxa-6-azaspiro [3.3] hept-6-yl) -4-oxo1 - (2 , 4,6-trifluorophenyl) -1,4-dihydro-1,8-naphthyridine-3-carboxamide (enantiomer 2)

7-Chloro-N- [1-cyclopropyl-2,2,3,3,3-pentafluoropropyl] -6-fluoro-4-oxo-1- (2,4,6-trifluorophenyl) -1,4 dihydro-1, 8-naphthyridine-3-carboxamide (enantiomer 2) (150 mg, 276 µmol) was placed in 1.5 ml of DMF, mixed with N, N-diisopropylethylamine (480 µl, 2.8 mmol) and ethanedic acid-2-oxa-6azaspiro [3.3] heptane (1: 2) (59.6 mg, 207 μmol) at room temperature. The reaction solution was stirred overnight at room temperature. The reaction mixture was mixed with water / acetonitrile / trifluoroacetic acid and purified by preparative HPLC (RP18 columns, eluent: acetonitrile / water gradient with the addition of 0.1% trifluoroacetic acid). 155 mg of the target compound was obtained (91% theoretical, 98% purity).

LCMS (Method 1): Rt = 1.21 min; MS (ESIpos): m / z = 607 [M + H] +.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 0.311 (0.62), 0.323 (0.97), 0.335 (1.03), 0.347 (0.80), 0.494 (0.75), 0.505 (1.08), 0.517 ( 0.94), 0.529 (0.72), 0.580 (0.79), 0.592 (0.89), 0.601 (0.73), 0.613 (0.63), 0.646 (0.40), 0.667 (0.77), 0.680 (0.88), 0.692 (0.68), 1.222 ( 0.54), 1.234 (0.98), 1.245 (0.72), 1.255 (0.87), 1.267 (0.48), 2.073 (6.92), 4.423 (0.41), 4.447 (0.70), 4.468 (0.86), 4.490 (0.81), 4.512 ( 0.64), 4.656 (16.00), 7.541 (1.69), 7.563 (3.20), 7.585 (1.69), 7.999 (2.70), 8.028 (2.69), 8.833 (4.83), 10.508 (1.95), 10.532 (1.89).

Example 207.

7- [3,3-bis- (Hydroxymethyl) azetidin-1-yl] -N- [1-cyclopropyl-2,2,3,3,3-pentafluoropropyl] -6-fluoro-4oxo-1 - (2, 4,6-trifluorophenyl) -1,4-dihydro-1,8-naphthyridine-3-carboxamide (enantiomer 2)

- 129 038451 No. [1-Cyclopropyl-2,2,3,3,3-pentafluoropropyl] -6-fluoro-7- (2-oxa-6-azaspiro [3.3] hept-6-yl) -4-oxo1- (2,4,6-trifluorophenyl) -1,4-dihydro-1,8-naphthyridine-3-carboxamide (enantiomer 2) (145 mg, 239 μmol) was placed in 1.5 ml of trifluoroacetic acid, mixed with 1.5 ml of water and 1.5 ml of acetonitrile and stirred for 2 days at room temperature. The reaction mixture was purified by preparative HPLC (RP18 columns, eluent: acetonitrile / water gradient with the addition of 0.1% trifluoroacetic acid). The combined product fractions were evaporated. The residue was dissolved in dichloromethane and washed twice with saturated aqueous sodium hydrogen carbonate solution. The combined aqueous phases were reextracted twice with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated. A total of 109 mg of the target compound was obtained (72% theoretical, 98% purity).

LCMS (Method 3): _Rt = 1.99 min; MS (ESIpos): m / z = 625 [M + H] +.

¹ H-NMR (400 MHz, DMSO-06) δ [ppm]: -0.149 (1.39), -0.008 (10.57), 0.008 (10.54), 0.146 (1.26), 0.315 (1.31), 0.327 (2.02), 0.339 (2.27), 0.351 (1.72), 0.364 (0.76), 0.494 (1.61), 0.506 (2.27), 0.518 (1.97), 0.530 (1.58), 0.562 (0.68), 0.585 (1.64), 0.597 (1.88), 0.606 (1.56), 0.616 (1.37), 0.630 (0.76), 0.648 (0.85), 0.668 (1.64), 0.681 (1.91), 0.693 (1.47), 1.222 (1.17), 1.235 (2.13), 1.244 (1.56), 1.255 (1.86), 1.267 (1.01), 2.328 (1.50), 2.367 (0.98), 2.670 (1.31), 2.710 (0.82), 3.473 (15.78), 3.486 (16.00), 4.138 (1.01), 4.424 (0.46), 4.448 (1.17), 4.470 (1.53), 4.492 (1.50), 4.512 (1.15), 4.536 (0.49), 4.836 (5.16), 4.850 (11.96), 4.863 (5.00), 7.531 (3.88), 7.553 (7.18), 7.575 (3.74), 7.970 (6.53), 7.999 (6.39), 8.813 (11.85), 10.539 (4.31), 10.563 (4.01).

Example 208.

N- (1,1-Dicyclopropyl-2,2,3,3,3-pentafluoropropyl) -7 - [(3 R, 4R) -3,4-dihydroxypyrrolidin-1 -yl] -6fluoro-4-oxo-1 - (2,4,6-trifluorophenyl) -1,4-dihydro-1,8-naphthyridine-3-carboxamide

F

7-Chloro-N- (1,1-dicyclopropyl-2,2,3,3,3-pentafluoropropyl) -6-fluoro-4-oxo-1- (2,4,6-trifluorophenyl) 1,4-dihydro -1,8-naphthyridine-3-carboxamide (65.0 mg, 111 μmol) was added to 0.61 ml of DMF. (3R, 4R) -pyrrolidine-3,4-diol hydrochloride (18.6 mg, 134 μmol) and N, N-diisopropylethylamine (97 μL, 560 μmol) were added and stirred overnight at room temperature. The reaction solution was diluted with ethyl acetate and extracted twice with water and washed with a saturated sodium chloride aqueous solution. The organic phase was dried over sodium sulfate, filtered and concentrated. The residue was purified using thick layer chromatography (solvent: dichloromethane / methanol: 30/1). Received 39 mg of the target compound (52% theory. V., Purity 97%).

LCMS (Method 3): Rt = 2.11 min; MS (ESIpos): m / z = 651 [M + H] ⁺ .

¹ H-NMR (400 MHz, DMSO-06) δ [ppm]: -0.149 (1.39), -0.008 (11.73), 0.146 (1.28), 0.458 (1.22), 0.481 (3.72), 0.494 (5.46), 0.507 (4.88), 0.516 (3.66), 0.530 (2.18), 0.573 (1.63), 0.585 (3.57), 0.607 (5.78), 0.621 (5.05), 0.642 (5.31), 0.653 (4.70), 0.665 (6.04), 0.678 (4.62), 0.746 (2.09), 0.759 (4.73), 0.771 (5.69), 0.782 (4.94), 0.795 (3.37), 1.236 (0.41), 1.583 (1.57), 1.603 (4.07), 1.618 (6.21), 1.633 (3.80), 1.652 (1.34), 2.328 (1.48), 2.367 (1.02), 2.670 (1.48), 2.711 (0.96), 2.731 (2.90), 2.891 (3.72), 3.069 (1.13), 3.692 (1.13), 3.902 (2.38), 4.017 (1.66), 5.202 (4.79), 7.551 (4.24), 7.573 (7.64), 7.594 (4.18), 7.952 (0.46), 8.036 (9.03), 8.068 (8.94), 8.781 (16.00), 9.849 (11.73).

Example 209.

N- (1,1-Dicyclopropyl-2,2,2-trifluoroethyl) -6-fluoro-7- (2-oxa-6-azaspiro [3.3] hept-6-yl) -4-oxo-1 (2, 4,6-trifluorophenyl) -1,4-dihydro-1,8-naphthyridine-3-carboxamide

-Chloro-N- (1,1-dicyclopropyl-2,2,2-trifluoroethyl) -6-fluoro-4-oxo-1 - (2,4,6-trifluorophenyl) -1,4 dihydro-1,8-naphthyridine -3-carboxamide (110 mg, 206 μmol) was placed in 1.1 ml of DMF and mixed with N, N-diisopropylethylamine (360 μl, 2.1 mmol) and ethanedic acid-2-oxa-6-azaspiro [3.3] heptane (1: 2) (44.6 mg, 155 μmol) at room temperature. The reaction solution was stirred overnight at room temperature. The reaction mixture was mixed with water / acetonitrile / trifluoroacetic acid and purified by preparative HPLC (RP18

- 130 038451 columns, solvent: acetonitrile / water-gradient with the addition of 0.1% trifluoroacetic acid). The combined product fractions were evaporated. The residue was dissolved in dichloromethane and a small amount of methanol and washed twice with saturated aqueous sodium hydrogen carbonate solution. The combined aqueous phases were reextracted twice with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated. Received 103 mg of the target compound (83% theory. V., 99% purity).

LCMS (Method 1): _Rt = 1.24 min; MS (ESIpos): m / z = 597 [M + H] +.

¹ H-NMR (400 MHz, DMSO-66) δ [ppm]: 0.008 (1.29), 0.467 (0.73), 0.477 (1.28), 0.489 (1.66), 0.501 (1.73), 0.512 (1.08), 0.523 (0.83 ), 0.549 (0.55), 0.561 (1.16), 0.575 (1.38), 0.583 (1.83), 0.597 (2.14), 0.612 (1.47), 0.621 (1.72), 0.635 (2.11), 0.648 (1.72), 0.661 (0.65 ), 0.674 (0.87), 0.688 (1.65), 0.699 (1.84), 0.711 (1.41), 0.723 (0.91), 1.157 (0.53), 1.175 (1.07), 1.193 (0.55), 1.234 (0.46), 1.511 (0.59 ), 1.526 (1.23), 1.533 (1.33), 1.547 (2.25), 1.561 (1.23), 1.568 (1.10), 1.582 (0.48), 1.989 (1.96), 4.021 (0.56), 4.039 (0.57), 4.653 (16.00 ), 7.540 (1.63), 7.562 (3.02), 7.584 (1.63), 8.022 (2.63), 8.052 (2.62), 8.774 (4.75), 9.847 (3.87).

Example 210.

7- [3,3-bis- (Hydroxymethyl) azetidin-1-yl] -N- (1,1-dicyclopropyl-2,2,2-trifluoroethyl) -6-fluoro-4oxo-1 - (2,4, 6-trifluorophenyl) -1,4-dihydro-1,8-naphthyridine-3-carboxamide

F

N- (1,1-Dicyclopropyl-2,2,2-trifluoroethyl) -6-fluoro-7- (2-oxa-6-azaspiro [3.3] hept-6-yl) -4-oxo-1 (2, 4,6-trifluorophenyl) -1,4-dihydro-1,8-naphthyridine-3-carboxamide (101 mg, 169 μmol) was placed in 1.1 ml of trifluoroacetic acid, mixed with 1.1 ml of water and 1.1 ml of acetonitrile and stirred for 5 days at room temperature. The reaction mixture was purified by preparative HPLC (RP18 columns, eluent: acetonitrile / water gradient with the addition of 0.1% trifluoroacetic acid). The combined product fractions were evaporated. The residue was dissolved in dichloromethane and washed twice with saturated aqueous sodium hydrogen carbonate solution. The combined aqueous phases were reextracted twice with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated. Received 73 mg of the target compound (69% theory. V. 98% purity).

LCMS (Method 3): _Rt = 2.04 min; MS (ESIpos): m / z = 615 [M + H] +.

¹ H-NMR (400 MHz, DMSO-66) δ [ppm]: -0.150 (0.53), -0.008 (5.14), 0.008 (3.74), 0.146 (0.41), 0.477 (2.86), 0.490 (3.72), 0.501 (3.85), 0.523 (2.02), 0.549 (1.30), 0.560 (2.71), 0.575 (3.25), 0.583 (4.07), 0.597 (4.09), 0.617 (3.56), 0.638 (4.71), 0.651 (3.83), 0.664 (1.54), 0.679 (1.91), 0.693 (3.58), 0.704 (4.17), 0.716 (3.19), 0.727 (2.12), 1.233 (0.56), 1.398 (0.74), 1.513 (1.40), 1.528 (3.00), 1.535 (3.25), 1.549 (5.10), 1.563 (2.94), 1.570 (2.49), 1.584 (1.01), 2.073 (0.82), 2.328 (1.36), 2.366 (0.60), 2.670 (1.15), 2.710 (0.43), 3.472 (15.94), 3.485 (16.00), 4.119 (1.05), 4.834 (4.67), 4.847 (11.54), 4.861 (4.71), 7.530 (4.15), 7.551 (7.26), 7.573 (4.17), 7.992 (8.12), 8.021 (7.88), 8.752 (14.09), 9.875 (9.11).

Example 211.

N- (1,1-Dicyclopropyl-2,2,3,3,3-pentafluoropropyl) -6-fluoro-7- (2-oxa-6-azaspiro [3.3] hept-6-yl) -4oxo-1 - (2,4,6-trifluorophenyl) -1,4-dihydro-1,8-naphthyridine-3-carboxamide

7-Chloro-N- (1,1-dicyclopropyl-2,2,3,3,3-pentafluoropropyl) -6-fluoro-4-oxo-1- (2,4,6-trifluorophenyl) 1,4-dihydro -1,8-naphthyridine-3-carboxamide (100 mg, 171 μmol) was placed in 0.93 ml of DMF and mixed with N, N-diisopropylethylamine (300 μl, 1.7 mmol) and ethanedic acid-2-oxa-6-azaspiro [3.3] heptane (1: 2) (37.0 mg, 128 μmol) at room temperature. The reaction solution was stirred overnight at room temperature. The reaction mixture was mixed with water / acetonitrile / trifluoroacetic acid and purified by preparative HPLC (RP18 columns, eluent: acetonitrile / water gradient with the addition of 0.1% trifluoroacetic acid). The combined product fractions were evaporated. The residue was dissolved in dichloromethane and a small amount of methanol and washed twice with saturated aqueous sodium hydrogen carbonate solution. The combined aqueous phases were reextracted twice with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated. Received 78 mg of the target compound (70% theory.,

- 131 038451 99% purity).

LCMS (Method 1): _Rt = 1.29 min; MS (ESIpos): m / z = 647 [M + H] +.

1H-NMR (400 MHz, DMSO-a ₆ ) δ [ppm]: -0.149 (0.66), -0.023 (0.56), -0.008 (5.12), 0.008 (4.77), 0.146 (0.63), 0.476 (1.08), 0.489 (1.56), 0.503 (1.47), 0.524 (0.69), 0.569 (0.47), 0.581 (1.08), 0.603 (1.73), 0.617 (1.90), 0.628 (1.56), 0.640 (1.72), 0.654 (1.83), 0.666 (1.34), 0.733 (0.65), 0.747 (1.38), 0.759 (1.65), 0.769 (1.41), 0.783 (0.97), 1.175 (0.44), 1.234 (0.81), 1.575 (0.48), 1.596 (1.18), 1.611 (1.90), 1.625 (1.10), 1.988 (0.81), 2.328 (0.74), 2.366 (0.55), 2.523 (1.79), 2.665 (0.58), 2.670 (0.79), 2.710 (0.54), 4.653 (16.00), 7.538 (1.67), 7.559 (3.03), 7.581 (1.69), 8.025 (3.04), 8.054 (2.96), 8.777 (5.19), 9.818 (3.56).

Example 212.

- [3,3-bis- (Hydroxymethyl) azetidin-1-yl] -N- (1,1-dicyclopropyl-2,2,3,3,3-pentafluoropropyl) -6fluoro-4-oxo-1- ( 2,4,6-trifluorophenyl) -1,4-dihydro-1,8-naphthyridine-3-carboxamide o o γ A

F

N- (1,1-Dicyclopropyl-2,2,3,3,3-pentafluoropropyl) -6-fluoro-7- (2-oxa-6-azaspiro [3.3] hept-6-yl) -4oxo-1- (2,4,6-trifluorophenyl) -1,4-dihydro-1,8-naphthyridine-3-carboxamide (75.0 mg, 116 μmol) was placed in 0.73 ml of trifluoroacetic acid, mixed with 0.73 ml of water and 0.73 ml of acetonitrile and stirred within 5 days at room temperature. The reaction mixture was purified by preparative HPLC (RP18 columns, eluent: acetonitrile / water gradient with the addition of 0.1% trifluoroacetic acid). The combined product fractions were evaporated. The residue was dissolved in dichloromethane and a small amount of methanol and washed twice with saturated aqueous sodium hydrogen carbonate solution. The combined aqueous phases were reextracted twice with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated. Received 44 mg of the target compound (56% theory. V., Purity 98%).

LCMS (Method 3): _Rt = 2.16 min; MS (ESIpos): m / z = 665 [M + H] +.

¹ H-NMR (400 MHz, DMSO-a ₆ ) δ [ppm]: -0.150 (0.64), -0.008 (5.04), 0.008 (4.74), 0.146 (0.55), 0.491 (3.45), 0.504 (3.22), 0.526 (1.41), 0.582 (2.36), 0.604 (3.62), 0.618 (3.82), 0.645 (3.27), 0.658 (3.89), 0.671 (2.90), 0.752 (2.98), 0.764 (3.70), 0.776 (3.18), 1.235 (0.62), 1.599 (2.63), 1.614 (4.19), 1.627 (2.53), 2.328 (1.31), 2.368 (0.64), 2.670 (1.41), 2.710 (0.52), 3.471 (15.83), 3.484 (16.00), 4.132 (1.04), 4.835 (5.06), 4.849 (12.18), 4.862 (4.99), 7.528 (3.94), 7.551 (6.85), 7.572 (3.84), 7.995 (7.42), 8.024 (7.12), 8.757 (13.07), 9.846 (7.81).

Example 213.

6-Fluoro-7- (2-oxa-6-azaspiro [3.3] hept-6-yl) -4-oxo-N- [1,1,1,2,2-pentafluoro-4,4-dimethylpentane-3 -yl] 1- (2,4,6-trifluorophenyl) -1,4-dihydro-1,8-naphthyridine-3-carboxamide (enantiomer 1)

7-Chloro-6-fluoro-4-oxo-N- [1,1,1,2,2-pentafluoro-4,4-dimethylpentan-3-yl] -1 - (2,4,6-trifluorophenyl) - 1,4dihydro-1,8-naphthyridine-3-carboxamide (enantiomer 1) (150 mg, 268 μmol) was placed in 1.5 ml of DMF and mixed with N, N-diisopropylethylamine (470 μl, 2.7 mmol) and ethanedic acid-2-oxa -6azaspiro [3.3] heptane (1: 2) (57.9 mg, 201 µmol) at room temperature. The reaction solution was stirred overnight at room temperature. The reaction mixture was mixed with water / acetonitrile / trifluoroacetic acid and purified by preparative HPLC (RP18 columns, eluent: acetonitrile / water gradient with the addition of 0.1% trifluoroacetic acid). The combined product fractions were evaporated. The residue was dissolved in dichloromethane and washed twice with saturated aqueous sodium hydrogen carbonate solution. The combined aqueous phases were reextracted twice with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated. Received 123 mg of the target compound (72% theory. V. 98% purity).

LCMS (Method 1): Rt = 1.31 min; MS (ESIpos): m / z = 623 [M + H] +.

¹ H-NMR (400 MHz, DMSO-a ₆ ) δ [ppm]: 1.102 (16.00), 4.657 (10.77), 4.678 (0.51), 4.708 (0.42), 4.753 (0.44), 4.780 (0.42), 7.539 ( 1.26), 7.561 (2.36), 7.583 (1.24), 8.032 (2.26), 8.061 (2.18), 8.856 (4.05), 10.687 (1.25), 10.713 (1.19).

- 132 038451

Example 214.

7- [3,3-bis- (Hydroxymethyl) azetidin-1-yl] -6-fluoro-4-oxo-N- [1,1,1,2,2-pentafluoro-4,4dimethylpentan-3-yl ] -1 - (2,4,6-trifluorophenyl) -1,4-dihydro-1,8-naphthyridine-3-carboxamide (enantiomer 1)

6-Fluoro-7- (2-oxa-6-azaspiro [3.3] hept-6-yl) -4-oxo-N- [1,1,1,2,2-pentafluoro-4,4-dimethylpentane-3 -yl] 1- (2,4,6-trifluorophenyl) -1,4-dihydro-1,8-naphthyridine-3-carboxamide (enantiomer 1) (120 mg, 98% purity, 189 μmol) was mixed with 1.6 ml of acetonitrile , 1.6 ml of water and 1.6 ml of trifluoroacetic acid and stirred for 5 days at room temperature. The reaction mixture was immediately purified by preparative HPLC (RP18 columns, eluent: acetonitrile / water gradient with the addition of 0.1% trifluoroacetic acid). The combined product fractions were evaporated. The residue was dissolved in dichloromethane and a small amount of methanol and washed twice with saturated aqueous sodium hydrogen carbonate solution. The combined aqueous phases were reextracted twice with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated. A total of 102 mg of the target compound was obtained (83% theoretical, 98% purity).

LCMS (Method 1): Rt = 1.14 min; MS (ESIpos): m / z = 641 [M + H] +.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: -0.008 (1.02), 0.008 (0.91), 1.104 (16.00), 2.328 (0.56), 2.670 (0.54), 3.472 (5.03), 3.486 (5.11), 4.680 (0.43), 4.707 (0.43), 4.754 (0.46), 4.780 (0.45), 4.839 (1.68), 4.853 (4.05), 4.866 (1.67), 7.530 (1.27), 7.552 (2.42), 7.574 (1.30), 8.004 (2.43), 8.033 (2.39), 8.837 (4.32), 10.716 (1.34), 10.742 (1.24).

Example 215.

6-Fluoro-7- (2-oxa-6-azaspiro [3.3] hept-6-yl) -4-oxo-N - [1,1,1,2,2-pentafluoro-4,4-dimethylpentane-3 -yl] 1 - (2,4,6-trifluorophenyl) -1,4-dihydro-1,8-naphthyridine-3-carboxamide (enantiomer 2)

F

7-Chloro-6-fluoro-4-oxo-N- [1,1,1,2,2-pentafluoro-4,4-dimethylpentan-3-yl] -1 - (2,4,6-trifluorophenyl) - 1,4dihydro-1,8-naphthyridine-3-carboxamide (enantiomer 2) (150 mg, 268 μmol) was placed in 1.5 ml of DMF and mixed with N, N-diisopropylethylamine (470 μl, 2.7 mmol) and ethanedic acid-2-oxa -6azaspiro [3.3] heptane (1: 2) (57.9 mg, 201 µmol) at room temperature. The reaction solution was stirred for 4 hours at room temperature. The reaction mixture was mixed with water / acetonitrile / trifluoroacetic acid and purified by preparative HPLC (RP18 columns, eluent: acetonitrile / water gradient with the addition of 0.1% trifluoroacetic acid). The combined product fractions were evaporated. The residue was dissolved in dichloromethane and a small amount of methanol and washed twice with saturated aqueous sodium hydrogen carbonate solution. The combined aqueous phases were reextracted twice with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated. Got 122 mg of the target compound (72% theory. V. 98% purity).

LCMS (Method 1): Rt = 1.31 min; MS (ESIpos): m / z = 623 [M + H] +.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: -0.008 (0.66), 0.008 (0.52), 1.102 (16.00), 2.524 (0.75), 4.656 (10.99), 4.678 (0.52), 4.706 (0.46), 4.752 (0.45), 4.778 (0.43), 7.539 (1.20), 7.561 (2.29), 7.583 (1.22), 8.032 (2.18), 8.061 (2.14), 8.856 (3.81), 10.686 (1.28), 10.713 (1.22).

Example 216.

7- [3,3-bis- (Hydroxymethyl) azetidin-1-yl] -6-fluoro-4-oxo-N- [1,1,1,2,2-pentafluoro-4,4dimethylpentan-3-yl ] -1- (2,4,6-trifluorophenyl) -1,4-dihydro-1,8-naphthyridine-3-carboxamide (enantiomer 2)

- 133 038451

6-Fluoro-7- (2-oxa-6-azaspiro [3.3] hept-6-yl) -4-oxo-N - [1,1,1,2,2-pentafluoro-4,4-dimethylpentane-3 -yl] 1- (2,4,6-trifluorophenyl) -1,4-dihydro-1,8-naphthyridine-3-carboxamide (enantiomer 2) (120 mg, 98% purity, 189 μmol) was mixed with 1.6 ml of acetonitrile , 1.6 ml of water and 1.6 ml of trifluoroacetic acid and stirred for 5 days at room temperature. The reaction mixture was immediately purified by preparative HPLC (RP18 columns, solvent: acetonitrile / water gradient with the addition of 0.1% trifluoroacetic acid). The combined product fractions were evaporated. The residue was dissolved in dichloromethane and a small amount of methanol and washed twice with saturated aqueous sodium hydrogen carbonate solution. The combined aqueous phases were reextracted twice with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated. A total of 97 mg of the target compound was obtained (79% theoretical, 98% purity).

LCMS (Method 1): _Rt = 1.14 min; MS (ESIpos): m / z = 641 [M + H] +.

1H-NMR (400 MHz, DMSO-de) δ [ppm]: -0.008 (0.78), 0.008 (0.79), 1.105 (16.00), 3.473 (5.01), 3.486 (5.13), 4.681 (0.40), 4.707 (0.41 ), 4.754 (0.42), 4.781 (0.42), 4.839 (1.70), 4.853 (4.02), 4.866 (1.66), 7.530 (1.22), 7.552 (2.31), 7.574 (1.21), 8.004 (2.16), 8.033 (2.10 ), 8.838 (3.89), 10.716 (1.29), 10.742 (1.23).

Example 217.

7 - [(3R, 4R) -3,4-Dihydroxypyrrolidin-1-yl] -6-fluoro-4-oxo-N- [1,1,1,2,2-pentafluoro-4,4dimethylpentan-3-yl ] -1 - (2,4,6-trifluorophenyl) -1,4-dihydro-1,8-naphthyridine-3-carboxamide (enantiomer 1)

-Chloro-6-fluoro-4-oxo-N- [1,1,1,2,2-pentafluoro-4,4-dimethylpentan-3-yl] -1 - (2,4,6-trifluorophenyl) -1 , 4-dihydro-1,8-naphthyridine-3-carboxamide (enantiomer 1) (100 mg, 179 μmol) was added to 0.97 ml of DMF. (3R, 4R) -pyrrolidine-3,4-diol hydrochloride (29.9 mg, 214 μmol) and Ν, Ν-diisopropylethylamine (160 μL, 890 μmol) were added and the mixture was stirred for 4 h at room temperature. The reaction mixture was mixed with water / acetonitrile / trifluoroacetic acid and purified by preparative HPLC (RP18 columns, eluent: acetonitrile / water gradient with the addition of 0.1% trifluoroacetic acid). The combined product fractions were evaporated. The residue was dissolved in dichloromethane and a small amount of methanol and washed twice with saturated aqueous sodium hydrogen carbonate solution. The combined aqueous phases were reextracted twice with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated. The residue was purified using silica gel (solvent: isocratic: dichloromethane / methanol = 50/1). Received 69 mg of the target compound (60% theory. V., Purity 98%).

Enantiomer 1: de> 88%.

R _t = 5.356 min [analytical HPLC: Daicel® Chiralpak IA column, 5 μm, 250x4.6 mm; 1 ml / min, 70 ° C; eluent: 80% isohexane / 20% ethanol; indication: 220 nm].

LCMS (Method 1): _Rt = 1.12 min; MS (ESIpos): m / z = 627 [M + H] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: -0.008 (1.17), 0.008 (0.96), 1.109 (16.00), 2.523 (0.73), 3.903 (0.47), 4.761 (0.41), 4.787 ( 0.41), 5.205 (0.97), 7.554 (0.90), 7.576 (1.58), 7.596 (0.88), 8.044 (2.11), 8.076 (2.07), 8.861 (3.54), 10.720 (1.27), 10.747 (1.22).

Example 218.

7 - [(3R, 4R) -3,4-Dihydroxypyrrolidin-1-yl] -6-fluoro-4-oxo-N- [1,1,1,2,2-pentafluoro-4,4dimethylpentan-3-yl ] -1 - (2,4,6-trifluorophenyl) -1,4-dihydro-1,8-naphthyridine-3-carboxamide (enantiomer 2)

-Chloro-6-fluoro-4-oxo-N- [1,1,1,2,2-pentafluoro-4,4-dimethylpentan-3-yl] -1 - (2,4,6-trifluorophenyl) -1 , 4-dihydro-1,8-naphthyridine-3-carboxamide (enantiomer 2) (100 mg, 179 μmol) was added to 0.97 ml of DMF. (3R, 4R) -pyrrolidine-3,4-diol hydrochloride (29.9 mg, 214 μmol) and Ν, Ν-diisopropylethylamine (160 μL, 890 μmol) were added and stirred for 4 h at room temperature. The reaction mixture was mixed with water / acetonitrile / trifluoroacetic acid and purified by preparative HPLC (RP18 columns, eluent: acetonitrile / water gradient supplemented with 0.1% trifluoroacetic acid

- 134 038451 acids). The combined product fractions were evaporated. The residue was dissolved in dichloromethane and a small amount of methanol and washed twice with saturated aqueous sodium hydrogen carbonate solution. The combined aqueous phases were reextracted twice with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated. The residue was purified using silica gel (solvent: isocratic: dichloromethane / methanol = 50/1). Received 72 mg of the target compound (63% theory. V., Purity 98%).

Enantiomer 2: de> 88.5%.

Rt = 4.677 min [Analytical HPLC: Daicel® Chiralpak IA column, 5 μm, 250x4.6 mm; 1 ml / min, 70 ° C; eluent: 80% isohexane / 20% ethanol; indication: 220 nm].

LCMS (Method 1): Rt = 1.11 min; MS (ESIpos): m / z = 627 [M + H] ⁺ .

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (1.06), 0.008 (0.99), 1.109 (16.00), 2.074 (0.44), 2.523 (0.76), 3.912 (0.47), 4.713 ( 0.41), 4.760 (0.42), 4.788 (0.41), 5.208 (1.00), 7.554 (0.82), 7.575 (1.47), 7.595 (0.79), 8.044 (2.15), 8.076 (2.10), 8.861 (3.89), 10.720 ( 1.28), 10.746 (1.21).

Example 219.

7 - [(3R, 4R) -3,4-Dihydroxypyrrolidin-1-yl] -6-fluoro-4-oxo-1- (2,4,6-trifluorophenyl) -N - [(2R) -1,1 , 1trifluoropropan-2-yl] -1,4-dihydro-1,8-naphthyridine-3-carboxamide

II J ϋ ^{n HO} 'Q ^but o')

F

7 - [(3R, 4R) -3,4-Dihydroxypyrrolidin-1-yl] -6-fluoro-4-oxo-1- (2,4,6-trifluorophenyl) -1,4-dihydro1,8-naphthyridine- 3-carboxylic acid (100 mg, 228 μmol) was placed in 1.0 ml of DMF, mixed with HATU (95.2 mg, 250 μmol) and N, N-diisopropylethylamine (160 μl, 910 μmol) and (2R) -1.1 was added, 1trifluoropropane-2-amine (25 μl, 250 μmol). The reaction solution was stirred overnight at room temperature. The reaction mixture was mixed with acetonitrile / water / trifluoroacetic acid and purified by preparative HPLC (RP18 columns, eluent: acetonitrile / water gradient with the addition of 0.1% trifluoroacetic acid). The combined product fractions were evaporated. The residue was dissolved in dichloromethane and washed twice with saturated aqueous sodium hydrogen carbonate solution. The combined aqueous phases were reextracted twice with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated. Received 74 mg of the target compound (60% theory. V., Purity 98%).

LCMS (Method 1): Rt = 0.89 min; MS (ESIpos): m / z = 535 [M + H] ⁺ .

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: -0.008 (3.06), 0.008 (2.77), 1.365 (15.90), 1.383 (16.00), 2.328 (0.77), 2.366 (0.83), 2.670 (0.83), 2.710 (0.77), 3.068 (0.77), 3.690 (0.81), 3.899 (1.79), 4.009 (1.19), 4.861 (1.19), 4.881 (1.83), 4.902 (1.85), 4.921 (1.15), 4.939 (0.42), 5.196 (3.96), 7.556 (3.94), 7.578 (7.04), 7.599 (3.87), 7.988 (7.81), 8.020 (7.73), 8.837 (13.58), 10.382 (5.10), 10.405 (4.90).

Example 220.

7- (3R, 4R) -3,4-Dihydroxypyrrolidin-1-yl] -6-fluoro-4-oxo-N- (2,2,2-trifluoroethyl) -1- (2,4,6trifluorophenyl) -1 , 4-dihydro-1,8-naphthyridine-3-carboxamide

7 - [(3R, 4R) -3,4-Dihydroxypyrrolidin-1-yl] -6-fluoro-4-oxo-1- (2,4,6-trifluorophenyl) -1,4-dihydro1,8-naphthyridine- 3-carboxylic acid (80.0 mg, 182 μmol) was placed in 1.4 ml of DMF, mixed with HATU (83.1 mg, 219 μmol) and N, N-diisopropylethylamine (140 μL, 820 μmol) and 2,2,2-trifluoroethanamine ( 21.6 mg, 219 μmol). The reaction mixture was stirred for 2 hours at room temperature. The reaction mixture was mixed with acetonitrile / water / trifluoroacetic acid and purified by preparative HPLC (RP18 columns, eluent: acetonitrile / water gradient with the addition of 0.1% trifluoroacetic acid). The combined product fractions were evaporated. The residue was dissolved in dichloromethane and washed twice with saturated aqueous sodium hydrogen carbonate solution. The combined aqueous phases were reextracted twice with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated. The residue was purified using thick layer chromatography (solvent: dichloromethane / methanol = 10/1). Received 34 mg of the target compound (35% theory. V., Purity 98%).

- 135 038451

LCMS (Method 1): Rt = 0.83 min; MS (ESIpos): m / z = 521 [M + H] +.

1H-NMR (400 MHz, DMSO-06) δ [ppm]: 2.074 (1.03), 2.328 (0.64), 2.367 (0.59), 2.670 (0.55), 2.711 (0.56), 3.058 (0.83), 3.677 (0.89) , 3.902 (1.78), 4.192 (1.23), 4.217 (3.82), 4.233 (4.22), 4.241 (3.96), 4.257 (3.78), 4.282 (1.17), 5.196 (5.02), 7.556 (3.74), 7.578 (6.60) , 7.599 (3.65), 7.995 (8.81), 8.026 (8.46), 8.838 (16.00), 10.299 (2.67), 10.316 (5.50), 10.332 (2.37).

Example 221.

1- (2-Chloro-4,6-difluorophenyl) -7 - [(3R, 4R) -3,4-dihydroxypyrrolidin-1-yl] -6-fluoro-4-oxo-N- (2,2,2trifluoroethyl ) -1,4-dihydro- 1,8-naphthyridine-3-carboxamide (mixture of atropisomers)

1- (2-Chloro-4,6-difluorophenyl) -7 - [(3R, 4R) -3,4-dihydroxypyrrolidin-1-yl] -6-fluoro-4-oxo-1,4-dihydro-1,8- naphthyridine-3-carboxylic acid (mixture of atropisomers) (326 mg, 715 mmol) was placed in 3.1 ml of DMF, mixed with HATU (299 mg, 787 mmol) and N, N-diisopropylethylamine (500 μl, 2.9 mmol) and 2 was added, 2,2-trifluoroethanamine (62 μl, 790 μmol). The reaction solution was stirred for 3 days at room temperature. The reaction mixture was mixed with acetonitrile / water / trifluoroacetic acid and purified by preparative HPLC (RP18 columns, eluent: acetonitrile / water gradient with the addition of 0.1% trifluoroacetic acid). The combined product fractions were evaporated. The residue was dissolved in dichloromethane and washed twice with saturated aqueous sodium hydrogen carbonate solution. The combined aqueous phases were reextracted twice with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated. Received 200 mg of the target compound (49% theory. V., Purity 95%).

LCMS (Method 3): Rt = 1.59 min; MS (ESIpos): m / z = 537 [M + H] ⁺ .

¹ H-NMR (400 MHz, DMSO- ₆ ) δ [ppm]: -0.008 (1.90), 0.008 (1.89), 2.073 (6.60), 2.328 (0.43), 2.366 (0.46), 2.670 (0.51), 2.710 (0.49), 3.014 (0.51), 3.228 (0.52), 3.692 (0.57), 3.897 (1.15), 4.011 (0.80), 4.192 (0.87), 4.216 (2.57), 4.233 (2.83), 4.241 (2.64), 4.257 (2.58), 4.282 (0.79), 5.196 (3.43), 5.754 (16.00), 7.685 (0.54), 7.692 (0.86), 7.702 (0.91), 7.708 (0.98), 7.716 (1.72), 7.725 (1.81), 7.731 (1.85), 7.738 (2.30), 7.748 (2.06), 7.762 (1.52), 7.998 (5.32), 8.030 (5.29), 8.788 (10.64), 10.315 (1.72), 10.331 (3.64), 10.347 (1.65).

Example 222.

1- (2-Chloro-4,6-difluorophenyl) -7 - [(3R, 4R) -3,4-dihydroxypyrrolidin-1-yl] -6-fluoro-4-oxo-N- (2,2,2trifluoroethyl ) -1,4-dihydro-1,8-naphthyridine-3-carboxamide (atropisomer 1).

197 mg 1- (2-chloro-4,6-difluorophenyl) -7 - [(3R, 4R) -3,4-dihydroxypyrrolidin-1-yl] -6-fluoro-4-oxo-N (2,2, 2-trifluoroethyl) -1,4-dihydro-1,8-naphthyridine-3-carboxamide (mixture of atropisomers) was separated by chiral HPLC into atropisomers (preparative HPLC: Daicel® Chiralpak IA column, 5 μm, 250x20 mm; eluent: 75 % n-heptane / 25% isopropanol; flow 15 ml / min; temperature: 40 ° C, indication: 220 nm).

Atropoisomer 1: 84 mg (99% stereochemical purity)

Rt = 10.527 min [analytical HPLC: Daicel® Chiralpak IA columns, 1 ml / min; 5 microns, 250x4.6 mm; eluent: 80% n-heptane / 20% isopropanol + 0.2% DEA; indication: 235 nm].

LCMS (Method 3): Rt = 1.59 min; MS (ESIpos): m / z = 537 [M + H] ⁺ .

¹ H-NMR (400 MHz, DMSO-a ₆ ) δ [ppm]: -0.008 (0.86), 0.008 (0.79), 2.073 (16.00), 2.328 (0.48), 2.670 (0.47), 3.896 (0.71), 4.192 (0.56), 4.216 (1.54), 4.233 (1.68), 4.241 (1.55), 4.257 (1.50), 4.282 (0.44), 5.195 (1.82), 7.685 (0.64), 7.691 (0.96), 7.708 (1.10), 7.715 (1.58), 7.738 (2.03), 7.763 (1.24), 7.999 (3.81), 8.030 (3.71), 8.788 (8.47), 10.315 (1.09), 10.332 (2.20), 10.348 (0.96).

Example 223.

1- (2-Chloro-4,6-difluorophenyl) -7 - [(3R, 4R) -3,4-dihydroxypyrrolidin-1-yl] -6-fluoro-4-oxo-N- (2,2,2trifluoroethyl ) -1,4-dihydro-1,8-naphthyridine-3-carboxamide (atropisomer 2).

197 mg 1- (2-chloro-4,6-difluorophenyl) -7 - [(3R, 4R) -3,4-dihydroxypyrrolidin-1-yl] -6-fluoro-4-oxo-N (2,2, 2-trifluoroethyl) -1,4-dihydro-1,8-naphthyridine-3-carboxamide (mixture of atropisomers) was separated by chiral HPLC into atropisomers (preparative HPLC: Daicel® Chiralpak IA column, 5 μm, 250x20 mm; eluent: 75 % n-heptane / 25% isopropanol; flow 15 ml / min; temperature: 40 ° C, indication: 220 nm).

Atropoisomer 2: 84 mg (99% stereochemical purity)

Rt = 13.695 min [analytical HPLC: Daicel® Chiralpak IA columns, 1 ml / min; 5 microns, 250x4.6 mm; eluent: 80% n-heptane / 20% isopropanol + 0.2% DEA; indication: 235 nm].

LCMS (Method 3): Rt = 1.59 min; MS (ESIpos): m / z = 537 [M + H] ⁺ .

'H-NMR (400 MHz, DMSO-a6) δ [ppm]: -0.008 (0.69), 2.073 (16.00), 2.328 (0.42), 2.670 (0.40), 3.902

- 136 038451 (0.66), 4.192 (0.49), 4.216 (1.51), 4.233 (1.61), 4.241 (1.49), 4.257 (1.48), 4.281 (0.45), 5.196 (2.26), 7.695 (0.64), 7.702 (0.93 ), 7.717 (0.95), 7.725 (2.09), 7.730 (1.75), 7.740 (1.30), 7.751 (1.78), 7.761 (0.81), 7.998 (3.70), 8.030 (3.57), 8.789 (8.25), 10.315 (1.05 ), 10.331 (2.13), 10.347 (0.95).

Example 224.

1- (2-Chloro-4,6-difluorophenyl) -7 - [(3R, 4R) -3,4-dihydroxypyrrolidin-1-yl] -6-fluoro-4-oxo-N - [(2S) 1, 1,1-trifluoropropan-2-yl] -1,4-dihydro-1,8-naphthyridine-3-carboxamide (mixture of atropisomers)

- (2-Chloro-4,6-difluorophenyl) -7 - [(3R, 4R) -3,4-dihydroxypyrrolidin-1-yl] -6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine -3-carboxylic acid (mixture of atropisomers) (200 mg, 439 μmol) was placed in 1.9 ml of DMF, mixed with HATU (184 mg, 483 μmol) and N, N-diisopropylethylamine (310 μL, 1.8 mmol) and added (2S) -1,1,1-trifluoropropan-2-amine (48 μl, 480 μmol). The reaction solution was stirred overnight at room temperature. The reaction solution was mixed with water and stirred quickly. The precipitated solid was filtered off and dried under high vacuum. Received 240 mg of the target compound (97% theory. V. 98% purity).

LCMS (Method 3): Rt = 1.72 min; MS (ESIpos): m / z = 551 [M + H] ⁺ .

Ή-NMR (400 MHz, DMSO-06) δ [ppm]: 0.936 (16.00), 0.951 (15.00), 1.364 (9.71), 1.370 (9.62), 1.382 (9.80), 2.327 (1.73), 2.366 (1.96) , 2.409 (2.10), 2.669 (1.69), 2.690 (5.70), 2.710 (1.60), 2.961 (1.78), 3.889 (1.73), 4.880 (2.05), 5.196 (4.88), 7.715 (2.23), 7.749 (3.69) , 7.993 (7.79), 8.025 (7.52), 8.790 (11.94), 10.401 (4.06), 10.425 (4.33).

Example 225.

1- (2-Chloro-4,6-difluorophenyl) -7 - [(3R, 4R) -3,4-dihydroxypyrrolidin-1-yl] -6-fluoro-4-oxo-N - [(2S) 1, 1,1-trifluoropropan-2-yl] -1,4-dihydro-1,8-naphthyridine-3-carboxamide (atropisomer 1).

238 mg 1- (2-chloro-4,6-difluorophenyl) -7 - [(3R, 4R) -3,4-dihydroxypyrrolidin-1-yl] -6-fluoro-4-oxo-N [(2S) - 1,1,1-trifluoropropan-2-yl] -1,4-dihydro-1,8-naphthyridine-3-carboxamide (mixture of atropisomers) was separated by chiral HPLC into atropisomers (preparative HPLC: Daicel® Chiralcel OX-H column , 5 μm, 250x20 mm; eluent: 75% n-heptane / 25% isopropanol; flow 15 ml / min; temperature: 45 ° C, indication: 220 nm).

Atropoisomer 1: 82 mg (> 99% stereochemical purity).

Rt = 5.024 min [analytical HPLC: Daicel® Chiralpak OX-H column, 1 ml / min; 5 microns, 250x4.6 mm; eluent: 75% isohexane / 25% 2-propanol; detection: 220 nm; 30 ° C].

LCMS (Method 3): Rt = 1.71 min; MS (ESIpos): m / z = 551 [M + H] +.

Ή-NMR (400 MHz, DMSO-66) δ [ppm]: -0.008 (1.60), 0.008 (2.07), 1.365 (15.87), 1.382 (16.00), 2.328 (0.50), 2.670 (0.58), 2.710 (0.44 ), 3.008 (0.82), 3.226 (0.85), 3.685 (0.85), 3.897 (1.62), 4.007 (1.21), 4.842 (0.45), 4.861 (1.19), 4.880 (1.79), 4.901 (1.84), 4.920 (1.18 ), 4.939 (0.42), 5.196 (4.26), 7.684 (1.46), 7.691 (2.04), 7.707 (2.51), 7.714 (3.53), 7.730 (1.57), 7.738 (4.02), 7.749 (2.24), 7.765 (2.80 ), 7.771 (1.97), 7.994 (7.83), 8.026 (7.66), 8.790 (15.94), 10.404 (5.16), 10.427 (4.94).

Example 226.

1- (2-Chloro-4,6-difluorophenyl) -7 - [(3R, 4R) -3,4-dihydroxypyrrolidin-1-yl] -6-fluoro-4-oxo-N - [(2S) 1, 1,1-trifluoropropan-2-yl] -1,4-dihydro-1,8-naphthyridine-3-carboxamide (atropisomer 2).

238 mg 1- (2-chloro-4,6-difluorophenyl) -7 - [(3R, 4R) -3,4-dihydroxypyrrolidin-1-yl] -6-fluoro-4-oxo-N [(2S) - 1,1,1-trifluoropropan-2-yl] -1,4-dihydro-1,8-naphthyridine-3-carboxamide (mixture of atropisomers) was separated by chiral HPLC into atropisomers (preparative HPLC: Daicel® Chiralcel OX-H column , 5 μm, 250x20 mm; eluent: 75% n-heptane / 25% isopropanol; flow 15 ml / min; temperature: 45 ° C, indication: 220 nm).

Atropoisomer 2: 97 mg (> 99% stereochemical purity).

R _t = 5.970 min [analytical HPLC: Daicel® Chiralpak OX-H column, 1 ml / min; 5 microns, 250x4.6 mm; eluent: 75% isohexane / 25% 2-propanol; detection: 220 nm; 30 ° C].

LCMS (Method 3): Rt = 1.72 min; MS (ESIpos): m / z = 551 [M + H] +.

Ή-NMR (400 MHz, DMSO-a ₆ ) δ [ppm]: -0.008 (1.15), 0.008 (1.11), 1.371 (15.90), 1.388 (16.00), 3.040 (0.78), 3.214 (0.79), 3.687 ( 0.79), 3.892 (1.56), 4.007 (1.16), 4.842 (0.43), 4.861 (1.15), 4.881 (1.74), 4.901 (1.80), 4.920 (1.14), 4.938 (0.40), 5.197 (5.26), 7.696 ( 1.32), 7.703 (2.00), 7.719 (2.02), 7.726 (5.20), 7.740 (2.37), 7.750 (4.75), 7.761 (1.73), 7.993 (7.49), 8.025 (7.38), 8.788 (14.24), 10.401 ( 5.13), 10.425 (4.92).

Example 227.

1- (2-Chloro-4,6-difluorophenyl) -7 - [(3R, 4R) -3,4-dihydroxypyrrolidin-1-yl] -6-fluoro-4-oxo-N - [(2R) - 137 038451

1,1,1-trifluoropropan-2-yl] -1,4-dihydro- 1,8-naphthyridine-3-carboxamide (mixture of atropisomers)

F

1- (2-Chloro-4,6-difluorophenyl) -7 - [(3R, 4R) -3,4-dihydroxypyrrolidin-1-yl] -6-fluoro-4-oxo-1,4-dihydro-1,8- naphthyridine-3-carboxylic acid (mixture of atropisomers) (200 mg, 439 μmol) was placed in 1.9 ml of DMF, mixed with HATU (184 mg, 483 μmol) and N, N-diisopropylethylamine (310 μL, 1.8 mmol) and added (2R ) -1,1,1-trifluoropropan-2-amine (48 μl, 480 μmol). The reaction solution was stirred overnight at room temperature. The reaction solution was mixed with water and stirred quickly. The precipitated solid was filtered off and dried under high vacuum. Received 237 mg of the target compound (96% theory. V. 98% purity).

LCMS (Method 3): Rt = 1.72 min; MS (ESIpos): m / z = 551 [M + H] +.

¹ H-NMR (400 MHz, DMSO-06) δ [ppm]: 0.936 (16.00), 0.951 (14.58), 1.369 (6.83), 1.382 (6.68), 2.327 (0.76), 2.366 (0.73), 2.410 (2.10 ), 2.427 (2.17), 2.671 (0.62), 2.690 (1.63), 2.709 (0.51), 2.945 (1.23), 2.961 (1.57), 2.978 (1.45), 3.695 (0.70), 3.897 (1.41), 4.861 (0.87 ), 4.880 (1.32), 4.899 (1.29), 5.194 (3.33), 7.717 (1.99), 7.741 (2.83), 7.992 (3.63), 8.024 (3.64), 8.788 (6.15), 10.401 (2.85), 10.424 (2.73) ).

Example 228.

1- (2-Chloro-4,6-difluorophenyl) -7 - [(3R, 4R) -3,4-dihydroxypyrrolidin-1-yl] -6-fluoro-4-oxo-N - [(2R) 1, 1,1-trifluoropropan-2-yl] -1,4-dihydro-1,8-naphthyridine-3-carboxamide (atropoisomer 1).

235 mg 1- (2-chloro-4,6-difluorophenyl) -7 - [(3R, 4R) -3,4-dihydroxypyrrolidin-1-yl] -6-fluoro-4-oxo-N [(2R) - 1,1,1-trifluoropropan-2-yl] -1,4-dihydro-1,8-naphthyridine-3-carboxamide (mixture of atropisomers) was separated by chiral HPLC into atropisomers (preparative HPLC: Daicel® Chiralpak IE, 5 μm, 250x20 mm; eluent: 80% n-heptane / 20% ethanol; flow 15 ml / min; temperature: 40 ° C, indication: 220 nm).

Atropoisomer 1: 89.4 mg (> 99% stereochemical purity).

Rt = 6.076 min [analytical HPLC: Daicel® Chiralpak IE column, 1 ml / min; 5 microns, 250x4.6 mm; eluent: 80% isohexane / 20% ethanol; indication: 220 nm; temperature: 30 ° C].

LCMS (Method 3): Rt = 1.73 min; MS (ESIpos): m / z = 551 [M + H] ⁺ .

¹ H-NMR (400 MHz, DMSOC) δ [ppm]: -0.008 (1.70), 0.008 (1.45), 1.364 (14.98), 1.382 (15.05), 2.328 (0.41), 2.367 (0.45), 2.690 (1.41) , 2.711 (0.46), 3.032 (0.73), 3.212 (0.75), 3.686 (0.73), 3.899 (1.50), 4.005 (1.04), 4.842 (0.41), 4.861 (1.09), 4.880 (1.66), 4.900 (1.68) , 4.920 (1.05), 5.196 (4.33), 7.694 (1.34), 7.701 (2.01), 7.717 (2.15), 7.724 (4.15), 7.731 (3.32), 7.741 (2.73), 7.747 (3.08), 7.753 (3.30) , 7.763 (1.74), 7.993 (7.70), 8.024 (7.55), 8.790 (16.00), 10.402 (4.83), 10.425 (4.63).

Example 229.

1- (2-Chloro-4,6-difluorophenyl) -7 - [(3R, 4R) -3,4-dihydroxypyrrolidin-1-yl] -6-fluoro-4-oxo-N - [(2R) 1, 1,1-trifluoropropan-2-yl] -1,4-dihydro-1,8-naphthyridine-3-carboxamide (atropoisomer 2).

235 mg 1- (2-chloro-4,6-difluorophenyl) -7 - [(3R, 4R) -3,4-dihydroxypyrrolidin-1-yl] -6-fluoro-4-oxo-N [(2R) - 1,1,1-trifluoropropan-2-yl] -1,4-dihydro-1,8-naphthyridine-3-carboxamide (mixture of atropisomers) was separated by chiral HPLC into atropisomers (preparative HPLC: Daicel® Chiralpak IE, 5 μm, 250x20 mm; eluent: 80% n-heptane / 20% ethanol; flow 15 ml / min; temperature: 40 ° C, indication: 220 nm).

Atropoisomer 2: 95.7 mg (> 99% stereochemical purity).

Rt = 7.196 min [analytical HPLC: Daicel® Chiralpak IE column, 1 ml / min; 5 microns, 250x4.6 mm; eluent: 80% isohexane / 20% ethanol; indication: 220 nm; temperature: 30 ° C].

LCMS (Method 3): Rt = 1.73 min; MS (ESIpos): m / z = 551 [M + H] ⁺ .

1I-NMR (400 MHz, DMSO-06) δ [ppm]: -0.008 (1.62), 0.008 (1.41), 1.244 (0.79), 1.258 (0.97), 1.272 (0.54), 1.370 (15.93), 1.388 (16.00 ), 2.366 (0.45), 2.710 (0.46), 3.012 (0.80), 3.240 (0.83), 3.692 (0.82), 3.892 (1.67), 4.008 (1.18), 4.842 (0.44), 4.861 (1.18), 4.880 (1.76 ), 4.901 (1.80), 4.920 (1.17), 4.938 (0.42), 5.196 (3.63), 7.686 (1.44), 7.693 (2.00), 7.709 (2.44), 7.716 (3.55), 7.740 (4.63), 7.748 (2.20 ), 7.758 (2.62), 7.762 (2.72), 7.769 (1.86), 7.993 (7.82), 8.024 (7.71), 8.788 (15.55), 10.401 (5.16), 10.424 (4.94).

- 138 038451

Example 230.

7- [3,3-bis- (Hydroxymethyl) αzetidin-1-yl] -6-fluoroρ-N- (1,1,1,3,3,3-hexafluoroρpρopan-2-yl) -4-oxo-1 (2,4,6-trifluorophenyl) -1,4-dihydro-1,8-naphthyridine-3-carboxamide

6-Φτορ-Ν- (1,1,1,3,3,3-hexafluoropropan-2-yl) -7- (2-oxa-6-azaspiro [3.3] hept-6-yl) -4-oxo 1 - (2,4,6trifluorophenyl) -1,4-dihydro-1,8-naphthyridine-3-carboxamide (88.0 mg, 99% purity, 149 μmol) was placed in 930 μL of acetonitrile, mixed with 930 μL of water and 930 μL trifluoroacetic acid and stirred for 18 h at room temperature. The mixture was purified by preparative HPLC (column: acetonitrile / water / 0.1% formic acid). The product fractions were concentrated in vacuo, the residue was taken up in a small amount of dichloromethane and washed three times with saturated aqueous sodium hydrogen carbonate solution. The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. Received 56.0 mg of the target compound (62% theory. V., Purity 100%).

LCMS (Method 3): _Rt = 1.95 min; MS (ESIpos): m / z = 603 [M + H] +.

¹ H-NMR (400 MHz, DMSO-de) δ [ppm]: -0.149 (0.90), -0.008 (7.60), 0.008 (7.41), 0.146 (0.92), 1.157 (0.56), 1.175 (1.07), 1.193 (0.56), 1.989 (1.96), 2.328 (0.67), 2.367 (0.42), 2.671 (0.73), 2.711 (0.44), 3.475 (15.50), 3.489 (16.00), 4.021 (0.69), 4.039 (0.67), 4.142 (1.21), 4.842 (5.05), 4.855 (11.74), 4.868 (4.99), 6.294 (0.86), 6.312 (1.25), 6.336 (1.32), 6.354 (0.84), 7.546 (3.66), 7.568 (6.71), 7.590 (3.68), 7.991 (6.48), 8.020 (6.43), 8.945 (11.99), 11.295 (4.16), 11.320 (4.05).

Example 231.

N - [(1S) -1-Cyclopropyl-2,2,2-trifluoroethyl] -6-fluoro-4-oxo-7- (pyrrolidin-1-yl) -1 - (2,4,6-trifluorophenyl) - 1,4-dihydro-1,8-naphthyridine-3-carboxamide o o 4- ^F \ __ I ^F x / k / ^F XT

F

According to AAV3, 80.0 mg (162 μmol) of 7-chloroρ-N - [(1S) -1-cycloρopyl-2,2,2trifluoroethyl] -6-fluoro-4-oxo-1- (2,4,6-trifluorophenyl) -1,4-dihydro-1,8-naphthyridine-3-carboxamide with 27 μl (320 μmol) pyrrolidine and 110 μl (650 μmol) N, N-diisopropylethylamine in 1.0 ml dimethylformamide. The starting material was diluted with a small amount of acetonitrile and purified by preparative HPLC (column: acetonitrile / water / 0.1% formic acid). This gave 51.1 mg (59% theory, 96% purity) of the title compound.

LCMS (Method 5): Rt = 1.66 min; MS (ESIpos): m / z = 529 [M + H] ⁺ .

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: -0.149 (0.42), 0.146 (0.41), 0.319 (1.90), 0.329 (3.08), 0.342 (3.03), 0.353 (2.43), 0.365 (1.16), 0.500 (0.75), 0.512 (2.08), 0.523 (3.11), 0.536 (2.78), 0.547 (3.13), 0.555 (2.37), 0.566 (3.17), 0.576 (2.59), 0.587 (2.34), 0.597 (1.95), 0.611 (1.18), 0.626 (1.63), 0.636 (1.55), 0.647 (2.81), 0.657 (2.44), 0.663 (2.34), 0.670 (2.33), 0.682 (1.12), 0.691 (0.77), 1.166 (0.55), 1.178 (1.16), 1.187 (1.72), 1.198 (2.98), 1.208 (2.16), 1.219 (2.96), 1.231 (1.96), 1.239 (1.14), 1.252 (0.47), 1.840 (8.25), 2.329 (0.52), 2.671 (0.59), 4.334 (0.42), 4.353 (1.62), 4.374 (2.83), 4.396 (2.79), 4.416 (1.47), 7.536 (5.42), 7.558 (10.40), 7.580 (5.46), 7.975 (7.58), 8.007 (7.54), 8.821 (16.00), 10.476 (6.10), 10.500 (5.89).

Example 232.

6-Bromo-7 - [(3 S) -3-hydroxypyρρolidin-1 -yl] -4-okco-N - [3,3,4,4,4-pentafluorobutan-2-yl] -1- (2, 4,6trifluorophenyl) -1,4-dihydro- 1,8-naphthyridine-3-carboxamide (pure enantiomers)

To a solution of 4.99 g (9.07 mmol) 7 - [(3S) -3-hydroxypyρρolidin-1-yl] -4-oxo-N- [3,3,4,4,4-pentafluoroρbutan-2-yl] -1- (2,4,6-trifluorophenyl) -1,4-dihydro-1,8-naphthyridine-3-carboxamide (pure enantiomers) in 120 ml of acetonitrile at room temperature was added 3.47 g (19.5 mmol) of 1-bromopyrrolidine-2,5 - 139 038451 dione (NBS) and 41.0 mg (250 μmol) 2,2 '- (E) -diazene-1,2-diyl-bis- (2-methylpropanenitrile (AIBN). Stirred for 50 min at 60 ° C The reaction mixture was cooled, evaporated by half and poured onto water and dichloromethane The phases were separated and the organic phase was extracted twice with DCM The combined organic phases were washed with saturated sodium chloride solution, dried over sodium sulfate and concentrated.The starting product was purified using normal phase chromatography (cyclohexane Acetic acid ethyl ester gradient) 2.75 g (48% theory, 100% purity) of the title compound were obtained.

LCMS (Method 1): _Rt = 1.22 min; MS (ESIpos): m / z = 629 [M + H] +.

¹ H-NMR (400 MHz, DMSO-de) δ [ppm]: -0.008 (2.11), 0.008 (1.87), 1.386 (9.88), 1.403 (10.35), 1.793 (1.40), 1.849 (1.45), 1.861 ( 0.98), 1.872 (1.33), 2.074 (0.47), 2.328 (0.74), 2.670 (0.92), 3.461 (1.15), 3.580 (1.46), 4.271 (2.45), 4.980 (3.99), 4.987 (4.14), 5.029 ( 1.16), 5.052 (0.98), 7.550 (3.37), 7.573 (5.83), 7.594 (3.28), 8.456 (16.00), 8.871 (12.06), 10.322 (4.09), 10.346 (4.07).

Example 233.

7 - [(3R, 4R) -3,4-Dihydroxypyrrolidin-1-yl] -6-fluoro-N- [3-methyl-1- (trifluoromethoxy) butan-2-yl] -4oxo-1- (2, 4,6-trifluorophenyl) -1,4-dihydro-1,8-naphthyridine-3-carboxamide (mixture of diastereoisomers) n ₃ with ch ₃ oo ⁴ /

HOn ^^^ V

VJ ^F ^ / ^^ ^F but 1 J

F

7 - [(3R, 4R) -3,4-Dihydroxypyrrolidin-1-yl] -6-fluoro-4-oxo-1- (2,4,6-trifluorophenyl) -1,4-dihydro1,8-naphthyridine- 3-carboxylic acid (75.0 mg, 171 μmol) was placed in 1.3 ml of DMF, mixed with HATU (77.9 mg, 205 μmol) and Ν, Ν-diisopropylethylamine (130 μL, 770 μmol) and 3-methyl-1 (trifluoromethoxy) butane was added -2-amine hydrochloride (racemate) (42.5 mg, 205 μmol). The reaction mixture was stirred overnight at room temperature. The reaction solution was mixed with ethyl acetate and extracted three times with water, and the combined aqueous phases were reextracted twice with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and concentrated. The residue was mixed with acetonitrile / water / trifluoroacetic acid and purified by preparative HPLC (RP18 columns, eluent: acetonitrile / water gradient with the addition of 0.1% trifluoroacetic acid). The combined product fractions were evaporated. The residue was dissolved in dichloromethane and washed twice with saturated aqueous sodium hydrogen carbonate solution. The combined aqueous phases were reextracted twice with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated. 68.6 mg of the target compound was obtained (66% theoretical, 97% purity).

LCMS (Method 3): _Rt = 1.91 min; MS (ESIpos): m / z = 593 [M + H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (1.44), 0.008 (1.38), 0.960 (15.75), 0.977 (16.00), 1.939 (0.91), 1.956 (1.47), 1.973 (1.41 ), 1.989 (0.85), 2.328 (0.46), 2.524 (1.29), 2.670 (0.53), 3.073 (0.42), 3.679 (0.45), 3.915 (0.96), 4.115 (0.89), 4.128 (1.21), 4.146 (2.56 ), 4.170 (3.20), 4.181 (1.89), 4.200 (2.19), 4.214 (2.11), 4.225 (1.36), 4.239 (0.74), 5.196 (2.32), 7.553 (1.98), 7.575 (3.41), 7.596 (1.90 ), 8.014 (4.52), 8.045 (4.46), 8.768 (7.51), 10.088 (2.55), 10.109 (2.43).

Example 234.

6-Fluoro-7- (3-methyl-2,4-dioxo-1,3,7-triazaspiro [4.4] non-7-yl) -4-oxo-N- [3,3,4,4,4 -pentafluorobutan2-yl] -1- (2,4,6-trifluorophenyl) -1,4-dihydro-1,8-naphthyridine-3-carboxamide (mixture of diastereoisomers)

7-Chloro-6-fluoro-4-oxo-N- (3,3,4,4,4-pentafluorobutan-2-yl) -1- (2,4,6-trifluorophenyl) -1,4-dihydro- 1,8 naphthyridine-3-carboxamide (pure enantiomers) (30.0 mg, 57.9 μmol) was added to 0.32 ml of DMF. Added 3-methyl-1,3,7-triazaspiro [4.4] nonane-2,4-dione hydrochloride (racemate) (14.3 mg, 69.5 μmol), mixed with Ν, Ν-diisopropylethylamine (50 μL, 290 μmol) and stirred in overnight at room temperature. The reaction mixture was diluted with acetonitrile / water / trifluoroacetic acid and purified by preparative HPLC (RP18 columns, eluent: acetonitrile / water gradient with the addition of 0.1% trifluoroacetic acid). The combined product fractions were evaporated. The residue was dissolved in dichloromethane and washed twice with saturated aqueous sodium hydrogen carbonate solution. The combined aqueous phases were reextracted twice with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated. Received 35 mg of the target compound

- 140 038451 (90% theoretical, 97% purity).

LCMS (Method 3): _Rt = 2.01 min; MS (ESIpos): m / z = 651 [M + H] +.

1H-NMR (400 MHz, DMSO-06) δ [ppm]: -0.149 (0.51), -0.008 (4.35), 0.146 (0.48), 1.387 (4.65), 1.404 (4.66), 2.054 (0.50), 2.247 ( 0.51), 2.328 (0.89), 2.670 (0.90), 2.839 (16.00), 4.989 (0.42), 5.012 (0.48), 5.030 (0.50), 5.053 (0.42), 5.754 (2.25), 7.540 (1.30), 7.562 ( 2.34), 7.583 (1.26), 8.057 (2.81), 8.089 (2.79), 8.645 (3.24), 8.862 (4.26), 10.407 (2.00), 10.431 (1.94).

Example 235.

7- (2,4-Dioxo-1,3,7-triazaspiro [4.4] non-7-yl) -6-fluoro-4-oxo-N- [3,3,4,4,4-pentafluorobutane-2 -yl] -1 (2,4,6-trifluorophenyl) -1,4-dihydro- 1,8-naphthyridine-3 -carboxamide (mixture of diastereoisomers)

F

7-Chloro-6-fluoro-4-oxo-N- (3,3,4,4,4-pentafluorobutan-2-yl) -1- (2,4,6-trifluorophenyl) -1,4-dihydro- 1,8 naphthyridine-3-carboxamide (pure enantiomers) (75.0 mg, 145 μmol) was added to 0.79 ml of DMF. Added 1,3,7-triazaspiro [4.4] nonane-2,4-dione hydrochloride (racemate) (33.3 mg, 174 μmol), mixed with N, N-diisopropylethylamine (130 μL, 720 μmol) and stirred for two days at room temperature. The reaction mixture was diluted with acetonitrile / water / trifluoroacetic acid and purified by preparative HPLC (RP18 columns, eluent: acetonitrile / water gradient with the addition of 0.1% trifluoroacetic acid). The combined product fractions were evaporated. The residue was dissolved in dichloromethane and washed twice with saturated aqueous sodium hydrogen carbonate solution. The combined aqueous phases were reextracted twice with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated. Received 81 mg of the target compound (87% theory. V. 99% purity).

LCMS (Method 3): Rt = 1.88 min; MS (ESIpos): m / z = 637 [M + H] ⁺ .

Ή-NMR (400 MHz, DMSO-66) δ [ppm]: -0.064 (0.65), -0.008 (2.78), 0.008 (2.31), 1.235 (0.44), 1.387 (14.93), 1.404 (14.88), 2.063 ( 1.52), 2.236 (1.54), 2.324 (0.96), 2.328 (1.26), 2.367 (0.89), 2.523 (2.50), 2.670 (1.12), 2.675 (0.84), 2.710 (0.77), 3.589 (0.68), 4.967 ( 0.72), 4.989 (1.28), 5.012 (1.52), 5.031 (1.56), 5.056 (1.26), 5.075 (0.68), 7.545 (5.71), 7.567 (10.68), 7.589 (5.69), 8.053 (9.66), 8.085 ( 9.42), 8.390 (11.36), 8.865 (16.00), 10.409 (6.74), 10.433 (6.48), 10.876 (9.42).

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 person skilled in the art. The following application examples describe the biological action of the compounds according to the invention without limiting the invention to these examples.

- 141 038451

Abbreviations and acronyms:

Wmax Number of specific binding sites for radioligands CAFTY calcium-free Tyrode's solution SNO chinese hamster ovary CRE cAMP sensor DMEM Wednesday Eagle as modified by Dulbecco DMSO dimethyl sulfoxide FCS fetal calf serum FRET fluororesonance energy transfer GIRK1 / 4 G-protein-linked internal rectifying potassium channels, element 1/4 HEPES hydroxyethylpiperazine-ethanesulfonic acid HTRF time resolved homogeneous fluorescence K _d equilibrium dissociation constant Ki equilibrium inhibitor constant k _O ff dissociation rate k _on association speed nM nano-molar MEM minimal nutrient medium (Eagle's medium) MCL microliter MKM micro-molar ML milliliter mM millimolar mtClytin mitochondrial clitin min minutes NMS N-Me-scopolamine PAM positive allosteric modulator PEI polyethyleneimine Pen / Strep penicillin / streptomycin sec seconds

B-1. Functional test activation M2-GIRK1 / 4.

Both M2 receptor activation by orthosteric agonists alone and allosteric enhancement of orthosterically-induced activation by positive allosteric modulators (PAMCs) can be determined using the GIRK1 / 4 cellular function test. The binding of an orthosteric agonist (endogenous ligand: acetylcholine) to the M2 receptor results in receptor activation or a change in receptor conformation in terms of an equilibrium shift in favor of an active receptor conformation. The binding of an orthosteric agonist to the M2 receptor and thus its activation can be enhanced by positive allosteric modulators, which are associated not with the orthosteric binding site of agonists, but with a separate allosteric binding site.

A consequence of agonist-induced conformational changes in the M2 receptor is the activation of God proteins. Activation of the Ga subunit again leads to dissociation and, thus, to the release of Gβγ subunits from Ga subunits and activation of separate sequential signal transduction cascades. The released heterodimeric Gβγ complex is linked to the GIRK1 / 4 potassium channel and induces ligand-driven activation or channel opening (Reuveny et al., Nature, July 1994, 370, 143-146). Then, under physiological conditions, there is a selective release of potassium from the cell along the electrochemical gradient. The export of a positive charge leads to a decrease in the transmembrane potential and thus to an increased cell membrane potential. Therefore, the volume of increased membrane potential can be considered as the amount of activation of the M2 receptor.

The test cells are recombinant CHO-DUKX cells, which are transfected

142 038451 are located with cDNA encoded for the human M2 receptor as well as with cDNA encoded for two GIRK1 / 4 subunits (CHO-DUKX-M2-GIRK). Determination of transmembrane potential or relative changes in transmembrane potential depending on substance addition or M2 activation is carried out using a voltage sensitive dye (FLIPR Membrane Potential Assay Kit Blue, Molecular Devices # R8034) and measurement of cellular fluorescence using its own fluorescence imaging meter.

B-1.1. Determination of the allosteric grade of the test substances (EC ₅₀ value).

The test substances were dissolved in dimethyl sulfoxide (DMSO) at a concentration of 10 mM and serially diluted for exposure-dose-effect analysis in 10 steps for 1: 3.16 in DMSO. According to the desired test concentration, the substances were dissolved in the loaded buffer solution (composition: 0.6 ml of the FLIPR Membrane Potential Assay Kit Blue (10 mg / ml), 0.6 ml of Brilliant Black (10 mg / ml), 2 mM CaCl ₂ and 2 mM KCl ad 50 ml sodium gluconate-Tyrode's solution (PAA, # T21-155)) pre-diluted.

Cultured in MEM alpha medium (filled with 10% FCS, 2% glutamax, 1 mg / ml geniticin), reporter gene cells were seeded from 2000 cells (measured after 48 h) or 4000 cells (measured after 24 h) in 30 μl in 384 wells in μCLEAR / Black Greiner Microtiter Plates (# 781092) and incubated for 24 h or 48 h at 37 ° C. The seed medium consisted of MEM alpha medium (filled with 5% FCS, 2% glutamax, no geniticin).

For appropriate measurement, remove the medium and fill the cells for at least 6 min at room temperature with a voltage sensitive dye (30 μl loaded buffer solution per 384 wells). Then, a first measurement was made to determine the fluorescence for the transmembrane potential at rest for 5 s. After that, 10 μl of test substances diluted in a buffer solution were added, a second measurement was carried out to determine the transmembrane potential for 50 s. The cells were then mixed with 10 μl of agonist solution (acetylcholine dissolved in the loaded buffer). Acetylcholine was used at an appropriate concentration with an EC ₂₀ determined during a preliminary test. M2-mediated GIRK1 / 4 activation or hyperpolarization was then performed during the third measurement for 60 seconds.

The EC ₅₀ value (the size of the allosteric capacity of the test compound) and the efficacy (the size of the enhancement of the effect of acetylcholine at the concentration of acetylcholine EC ₂₀ ) were determined using the 4-parameter-logistic function (Hill function).

B-1.2. Definition of positive cooperativity (α-factor).

Test substances were dissolved in 10 mM DMSO and serially diluted for exposure-dose-effect analysis in 10 steps for 1: 3.16 in DMSO. According to the desired test concentration, the substances were dissolved in the loaded buffer solution (see above).

Cultured in MEM alpha medium (filled with 10% FCS, 2% glutamax, 1 mg / ml geniticin), reporter gene cells were seeded from 2000 cells (measured after 48 h) or 4000 cells (measured after 24 h) in 30 μl in 384 wells in μCL · EAR / Black Greiner microtiter plates (# 781092) and incubated for 24 or 48 h at 37 ° C. The seed medium consisted of MEM alpha medium (filled with 5% FCS, 2% glutamax, no geniticin).

For appropriate measurement, remove the medium and fill the cells for at least 6 min at room temperature with a voltage sensitive dye (30 μl loaded buffer solution per 384 wells). Then, a first measurement was made to determine the fluorescence for the transmembrane potential at rest for 5 s in 1 s increments. After that, 10 μl of test substances diluted in a buffer solution were added, a second measurement was carried out to determine the transmembrane potential for 50 s with 1 s increment.

The cells were then mixed with 10 μl of agonist solution (acetylcholine dissolved in the loaded buffer). In this case, in contrast to the EC ₅₀ determination of the test substances (see B-1.1), not only the concentration of acetylcholine is used, but also the concentration of the test substance is combined with the acetylcholine-8 exposure-dose-effect curve. For a series of dilutions of acetylcholine, the agonist was pre-diluted, starting at a maximum final concentration of 3 μM, sequentially, in steps 1: 3.16, in the loaded buffer solution according to the desired concentration. M2-mediated GIRK1 / 4 activation or hyperpolarization was then performed during the third measurement for 60 s in 1 s increments. The shift of the acetylcholine-exposure-dose-effect curve in the presence of increasing concentration of the test substance was analyzed using GraphPad PRISM (Allosteric EC ₅₀ shift) and quantified. At the same time, the established α-factor is a measure for enhancing and directing the allosteric effect, α-value> 1 reflects a decrease in the EC ₅₀ value or an increase in the ability of an agonist (acetylcholine) in the presence of an alloster, and thus means a positive cooperativity between ortoster (acetylcholine) and alloster (test substance). Positive cooperativity is a sign of a positive allosteric modulator, α-values <1 indicate negative cooperativity between orthoster and alloster

- 143 038451 and thus characterize negative allosteric modulators. α-values = 1 mean there is no cooperativity between the orthoster and alloster, i.e. the binding affinities of ortoster and alloster to the receptor do not affect each other. The larger the α-value, the greater the amount of cooperativity between the orthoster and alloster.

_{In the table below, the EC 50} values and efficiency values determined in this way are shown for the individual execution examples, as well as the α values from the essay (partly as averages from several independent individual determinations .______________________

No. Example ECso receptor activity [μmol / L] Efficiency [ %] Cooperative interaction (alpha factor) 1 0 021 92 35 2 0.0355 96 3 0 038 97 4 0 038 89 5 0 069 99 6 0.00617 94 58 7 0.00564 93 57 eight 0.0043 96 nine 0.00199 91 39 ten 0.00527 99 70 AND 0.0058 100 60 12 0:02 90 40 13 0.0062 94 49 fourteen 0.0055 100 49 15 0.00915 96 41 16 0.00845 99 42 17 0.0795 83 eighteen 0.0205 99 43 19 0 016 98 twenty 0 013 92 21 0 003 100 22 0:01 95 42 23 0.0055 100 41 24 0.00135 100 57 25 0.00405 95 45 26 0.00403 100 27 0.00258 92 28 0.00315 100 29 0.0025 100 thirty 0.0026 100 31 0.00415 100 37 32 0.0043 100 54 33 0.00175 100 50 34 0.0012 100 53

- 144 038451

35 0.0029 100 36 0 005 92 51 37 0 006 100 38 38 0.0101 100 39 0.0205 100 40 0.0023 98 41 0.0033 100 37 42 0 004 100 43 0.0075 100 44 012 100 45 0.00847 100 62 46 0 051 100 47 0 048 81 48 0.0018 78 42 49 0 068 74 50 0.0025 60 51 0 036 81 52 0.0013 83 53 0 016 100 thirty 54 0 025 100 thirty 55 0 025 96 56 0 035 100 57 0.0785 89 58 0 104 90 59 0.0915 97 60 0.0036 100 61 0.0022 94

- 145 038451

62 0.0041 88 63 0.0039 92 64 012 96 65 0:03 89 fourteen 66 0 035 92 67 0:01 95 68 0 032 92 69 0.0059 100 70 0.1 86 71 0.0042 94 26 72 UN 89 73 0.0027 94 74 0.0039 95 75 0 087 100 76 0 029 100 77 0.0016 100 78 0.0028 100 79 0.0093 99 80 0 024 100 81 0:15 87 82 0:14 65 83 0 044 94 84 0.00835 88 39 85 0 033 100 86 0 014 95 87 0.0014 100 88 0.0022 100

- 146 038451

89 0.00475 100 44 90 0.0185 95 thirty 91 0.0065 100 92 0.0066 100 93 012 100 94 0.0047 100 34 95 0.0155 100 96 0 016 96 97 0 013 97 98 0.0143 98 50 99 0.0355 96 100 0.0315 100 101 0.0135 100 102 0 295 92 103 0.0081 100 104 0 013 97 105 0.0075 97 106 0.0072 100 107 0.00355 92 108 0.0054 96 47 109 0.0077 100 110 0 019 100 111 0.0072 99 112 0.00425 100 33 FROM 0 002 100 35 114 0 007 94 115 0.00665 98 53

- 147 038451

116 0.0035 97 117 0.0069 99 118 0.0028 100 119 0.0087 100 120 0.0105 96 121 0 125 100 122 0.00355 100 123 0.0031 100 124 0018 100 125 012 97 126 0.0039 97 127 0 013 92 128 0.0098 90 129 0 066 95 130 0.0023 96 131 0.0046 100 132 0:01 99 133 1.6 81 134 1.83 55 135 2.61 75 136 0.0028 84 137 0.0033 91 138 0.0076 84 139 0.0034 100 140 0.0053 95 141 0.0034 97 142 0 039 99

- 148 038451

143 0.0015 94 40 144 0.0045 98 67 145 0.0112 100 86 146 012 100 147 0016 94 148 0.0187 96 149 0 021 92 150 0 024 93 151 0 024 100 152 0 053 100 153 0 048 99 154 0 097 100 155 OOP 100 156 OOP 100 157 0.0026 100 158 0.0037 100 159 0.0071 100 45 160 0.0073 100 38 163 0 025 93 164 0 002 100 45 165 0.0024 100 48 166 0.0044 100 31 167 0.0074 95 168 0 004 86 169 0.0038 99 34 170 0.0081 100 38 171 0.0013 95

- 149 038451

172 0.0033 94 35 173 0.0025 99 39 175 0 073 83 176 0:11 91 177 0:53 77 178 0 017 99 179 0 027 100 180 0.0085 86 181 0.0130 83 182 0.0088 100 27 183 0.0423 96 184 0.0045 90 24 185 0.0064 83 13 186 0.0058 87 twenty 187 0.0099 90 25 188 026 97 189 0:03 100 190 0.0835 100 191 0 048 100 192 0.1275 100 193 0.0325 100 194 0.0315 94 195 0 058 100 196 0 063 100 197 0 051 100 198 0 033 100 199 0 014 100

- 150 038451

200 201 0:12 0.0016 73 100 39 202 0 001 100 203 0 005 100 29 204 0017 97 205 0.0031 100 25 206 0:01 100 207 0.0033 100 24 208 0.0018 100 27 209 210 0.0021 100 26 211 212 0 002 100 28 213 0 013 100 214 0.0021 100 215 0.0086 100 216 0.0015 99 217 0.0009 100 39 218 0.0006 100 39 219 0.0165 91 220 0 080 85 221 0 031 85 222 0:55 61 223 026 86 224 0 010 96 225 0:11 82 226 0.0067 93 31 227 UN 94 228 0.0064 93 33 229 0:26 67 230 0.0097 97 36 231 0.0048 82 232 0 007 100 233 0.0023 100 234 0.0097 90 235 0 004 92

B-2. Functional test of Ca ²⁺ release using M2-Gα16 reporter gene cells.

Potentially agonistic as well as positive allosteric effects of test substances on the M2 receptor can be determined using a functional Ca ²⁺ release test. Activation of the M2 receptor by the binding of an orthosteric agonist (acetylcholine) or other substances with an agonist effect leads to a change in the receptor conformation, which in the endogenous state leads to the activation of the Gai protein. However, through the connection of the M2 receptor with the exogenously expressed promiscuous Gaq protein Ga 16, activation of the Ga 16 protein occurs after the activation of the M2 receptor, which, using a sequential signal transduction cascade, causes intracellular Ca ²⁺ release. Therefore, the volume of intracellular Ca ²⁺ mobilization in this case is

- 151 038451 can be considered as the size of the activation of the M2 receptor.

The test cells are a recombinant CHO cell line that is stably transfected with cDNA encoding the human M2 receptor and Gα16 protein, as well as cDNA encoding the mitochondrially expressed photoprotein clitin (mtClytin), (CHO mtClytin Ga16 M2).

Determination of intracellular ^{Ca 2+} release depending on substance addition or M2 activation is carried out using Ca ²⁺ -sensitive dye (Fluo-8) and measurement of cell fluorescence using FLIPR ^TETPA- Instrumentes (Molecular Devices).

B-2.1. Analysis of agonism.

Test substances were dissolved in 10 mM DMSO and serially diluted for exposure-dose-effect analysis in 10 steps for 1: 3.16 in DMSO. According to the desired test concentration, the substances were dissolved in a buffer solution of Fluo-8 (composition per 100 ml: diluted with 500 μl of probenecid, 2 ml of brilliant black (20 mg / ml), 440 μl of Fluo-8, 2 mM CaCl ₂ to 100 ml of CAFTY Tyrode's solution ( 130 mM NaCl, 5 mM KCl, 20 mM HEPES, 1 mM MgCG 5 mM \ aHCO _; pH 7.4)).

Cultured in MEM alpha medium (filled with 10% FCS, 2% glutamax) reporter gene cells were plated from 3000 cells in 30 μl of seeding medium in 384 wells in μCLEAR / Black Greiner microtiter plates (# 781092) and incubated for 24 h at 37 ° C. The seed medium consisted of MEM alpha medium (filled with 5% FCS, 2% glutamax). For appropriate measurement, the medium was removed and the cells were incubated after adding 20 μl of Fluo-8 buffer solution in 384 wells for 1 h at 37 ° C in an incubator. After addition of 10 μl per 384 wells of the diluted test substances, the cell fluorescence was measured for 5 min with 1 sec. The relative size of the maximum activation of the M2 receptor by the respective test substances was calculated by normalizing the test signal to the E _max concentration of the corresponding acetylcholine (3 μM) signal.

B-2.2. Determination of the positive allosteric effect of the modulator.

To determine the positive cooperativity of the test substances with respect to acetylcholine-mediated activation of the M2 receptor, only the reference agonist (acetylcholine) was added for a complete exposure-dose analysis. For this, acetylcholine was diluted, starting with a maximum final concentration of 1 μM in steps of 1: 3.16, sequentially in a buffer solution Fluo-8-. After adding 10 μl of agonist solution to 384 wells, the cell fluorescence was measured again for 5 min in 1 sec increments. The same essay plate was used as before for the analysis of M2 agonism. The shift of the acetylcholine-exposure-dose-response curve in the presence of increasing concentration of the test substance was analyzed using GraphPad PRISM (Allosteric EC ₅₀ shift) and quantified (see c.).

B-3. Selectivity test for human muscarinic acetylcholine receptors.

The potential agonistic effect, as well as the positive allosteric effect, of test substances on other human muscarinic acetylcholine receptors can be determined in the Ca ²⁺ release functional test (Eurofins; GPCRProfiler® Services in agonistic and allosteric mode for Mx Receptors; cat # HTS600GPCR).

The test cells are transfected with the appropriate Chem-1 or Chem-4 receptor cell lines (ChemiScreen ™ M1 Calcium-Optimized FLIPR cell lines, Eurofins; M1: HTS044C; ChemiScreen ™ calcium-optimized stable cell line of human recombinant M2 muscarinic receptor Eurofins, acetylcholine; M2: HTS115C; ChemiScreen ™ Human Recombinant M3 Muscarinic Acetylcholine Receptor Calcium Optimized Stable Cell Line, Eurofins; M3: HTS116C; ChemiScreen ™ Human Recombinant Muscarinic Acetylcholine Receptor M4 Calcium Optimized Stable Cell Line, Eurofins; FLIPScreen ™ Calcium Optimized Stable Cell Line, Eurofins; cell line, Eurofins; M5: HTS075C). Substances were tested using the FLIPR ^tetpa Molecular Devices instrument).

B-3.1. Analysis of agonism.

To determine the potential agonistic effect of the test substances, add the appropriate test substances with a final test concentration of 10 or 1 μM. Ca ²⁺ release or cellular fluorescence was measured after 180 seconds. _{The E max} value of the corresponding acetylcholine concentration was used as a positive control for normalizing the effects of substances on receptor activation.

After the end of the agonism experiment, the test plate (microplate) was incubated at 25 ° C for 7 minutes. After an incubation period, a positive allosteric assay of the modulator was initiated.

B-3.2. Allosteric analysis of the modulator.

To study the positive or negative allosteric effects of the test substances on other muscarinic acetylcholine receptors, as well as the M2 receptor itself, each concentration

- 152 038451 substances are combined with an action-acetylcholine-dose-effect curve in 8 stages. After the addition of the agonist solution, the cell fluorescence was measured again for 180 seconds. The shift in the exposure-acetylcholine-dose-effect curve (maximum shift in the EC ₅₀ -value of acetylcholine) was analyzed using GraphPad PRISM (sigmoidal dose-response curve (variable slope) -EC ₅₀ ) and quantified. Then the coefficients of allosteric shift for the M2 receptor and the M4 receptor were formed, which in turn are the values for the corresponding selectivity

B-4. In vitro test M2 PAM Gi.

To characterize the test substances for positive allosteric modulation of the human M2 receptor, carbachol-induced inhibition of cAMP uplift by forskolin was measured in CHO cells recombinantly expressed by the M2 receptor, which additionally express the luciferase gene under the control of a cAMP sensitive element (CRE): 3000 cells in 25 μl complete medium (DMEM F12 PAN medium, 10% FCS, 1.35 mM Na-pyruvate, 20 mM Hepes, 4 mM glutamax, 2% sodium bicarbonate, 1% Pen / Strep, 1% 100x minor amino acids) were seeded into the holes of a 384 microtiter plate (Greiner , TC Platte, black with a transparent bottom) and incubated at 37 ° C, 5% CO2 for 24 h.Before measurement, the medium was replaced with 30 μL of measurement medium (Optimem) and incubated at 37 ° C, 5% CO2 for 10 min ... The test substance was previously prepared in DMSO at various concentrations (initial concentration 10 mm, dilution factor 3.16) in the form of a dose-effect curve and diluted 1:50 with calcium-free Tyrode's solution, 2 mM CaCl ₂ , 0.01% BSA. 10 μl of a diluted substance solution was added to the cells and incubated at 37 ° C, 5% CO2 for 10 min. The M2 receptor was activated by adding 10 μl of carbachol at various concentrations in calcium-free Tyrode's solution, 2 mM CaCl ₂ and incubated at 37 ° C, 5% CO ₂ for 5 min. Adenylcyclase was activated by adding 10 μl of 1 μM (final concentration) forskolin in calcium-free Tyrode's solution, 2 mM CaCl ₂ and incubated at 37 ° C, 5% CO ₂ for 5 hours. After removing the cell liquid fraction and adding 20 μl of Luci / Triton buffer solution (1: 1), the luminescence was determined in a luminometer for 60 s.

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.

Luci / Triton buffer solution (1: 1): Luci buffer solution (20 mM tricine, pH 7.8, 2.67 mM magnesium sulfate, 0.1 mM EDTA, 4 mM DTT, 270 μM coenzyme A, 470 μM D-luciferin, 530 μM ATP) 1: 1 was mixed with Triton buffer solution (25 mM Tris aq. Hydrochloric acid, pH 7.8, 25 mM Na ₂ HPO ₄ , 2 mM dithiothreitol, 3% Triton X-100, 10% glycerol).

The EC ₅₀ value was determined using the 4-parameter-logistics function (Hill's function).

B-5. Competitive FRET test for binding of human M2 and M4 receptors.

The direct binding of test substances to the M2 receptor as well as the enhancement of binding (increased affinity) of the natural agonist of acetylcholine to the M2 receptor in the presence of the test substances (positive allosteric effect) was determined using a FRET-based binding assay (HTRF Tag-lite® binding assay. Cisbio). To control the selectivity, the binding of the test substances to the structurally related M4 receptor was studied in a similar way. The HTRF Tag-lite® assay is a homogeneous binding assay based on the competitive binding of a fluorescent ligand (probe) and an unlabeled test substance to a receptor that is expressed on living cells. Derivatization of the receptor takes place on its side with a fluorescent dye donor (terbium cryptate), thus, after activation of the donor dye, a FRET signal arises between the receptor and the probe (acceptor) if the probe is bound to the receptor. A telenzepine derivative was used as an acceptor probe, which was conjugated with a fluorescent dye HTRF (red ligand; L0040RED). Therefore, the probe is bound at the conserved orthosteric junction of both the M2 and M4 receptors. The allosteric junction of the M2 receptor was characterized by X-ray crystallography and immediately postulated above the orthosteric junction pocket (Kruse et al., Nature, 2013, 504, 101-106). Therefore, both coupling of unlabeled orthosteric agonists (acetylcholine) to an orthosteric junction and coupling of allosteric modulators (test substances) to an allosteric junction result in concentration-dependent competitive displacement of the probe and thus a decrease in the FRET-based fluorescent signal.

All binding tests were performed on a white 384 microtiter plate (small-sized plate) with a total volume of 20 μl. HTRF measurements were performed using a PHERAstar instrument (BMG Labtech). SNAPed-M2-expressing cells (C1TT1M2) or SNAPed-M4-expressing cells (C1TT1M4), which were labeled with a fluorophore donor (Lumi4Tb; CELLCUST), were used to test the compound of the muscarinic M2 or M4 receptor. Cells were incubated with an acceptor probe in Tag-lite binding buffer solution (LABMED) in the presence of the test substance or acetylcholine. Then, the fluorescence signal was measured at a wavelength of 665 m 620 nm, and the HTRF (signal at 665 nm / signal at 620 nm) was determined. The relative specific signal was determined by subtracting the HTRF coefficient of the negative control (only Tag-lite buffer solution without

- 153 038451 probes).

B-5.1. Binding of Test Substances.

To determine the binding of the test substances to the M2 or M4 receptor in the presence of an orthosteric agonist, a dose-response analysis of the test substances was performed in the competitive format of the M2-Tag-lite® or M4-Tag-lite® binding assay. Test substances were dissolved in 10 mM DMSO and diluted serially for dose-response analysis in 1: 3.16 steps in DMSO. The maximum concentration of the test substances corresponds to 10 μM. The molar concentration of the test substance, which contributes to the half-maximum decrease in the HTRF signal relative to the maximum and the remaining HTRF signal at a higher concentration of substances (EC ₅₀ -binding value), was determined using GraphPad PRISM (dose-response response). At the same time, the strength of the competition effect was determined by calculating the maximum acceptance of a specific HTRF signal at higher concentrations of the substance (% max. Competition).

B-5.2. Binding of test substances in an allosteric mode.

To study the allosteric modulation of the M2 receptor using the test compounds, firstly, a dose-response analysis of the test substances was performed in a competitive format of the M2-Tag-lite®- or M4-Tag-lite® binding assay in the presence of an acetylcholine concentration _{corresponding to the EC 20 value,} which was determined in a separate exposure-acetylcholine-dose-response assay in 11 steps (3 μM). Test substances were dissolved in 10 mM DMSO and serially diluted for exposure-dose-effect analysis in 10 steps for 1: 3.16 in DMSO. The maximum concentration of the test substances corresponds to 10 μM. The molar concentration of the test substance, which contributes to the half-maximum decrease in the HTRF signal relative to the maximum and the remaining HTRF signal at a higher concentration of substances in the presence of the corresponding EC ₂₀ concentration of acetylcholine (EC ₅₀ binding value), was determined using GraphPad PRISM (dose-response response). At the same time, the strength of the competition effect was determined by calculating the maximum acceptance of a specific HTRF signal at higher concentrations of the substance (% max. Competition).

To study the enhancement of the binding of acetylcholine to the M2 or M4 receptor, secondly, we additionally performed the effect-dose-effect analysis of acetylcholine in 11 stages in a competitive format of the M2-Tag-lite®- or M4-Tag-lite® binding assay in the presence of 1 μM or 10 μM test substance. The shift in the acetylcholine-dose-response curve (maximum shift in the EC ₅₀ -value of acetylcholine) was analyzed using GraphPad PRISM (dose-response response) and quantified.

B-6. Radioligand binding assay for human M2 receptors.

The allosteric mechanism of action of the test substances can be investigated in more detail using the test of binding of various radioligands and quantified. Binding of the alloster to the allosteric binding site of the M2 receptor in the case of positive cooperativity leads to an increase in the binding affinity of the orthosteric ligand for the M2 receptor. An increase in the affinity of the orthosteric ligand binding by the alloster in the tertiary complex consisting of the orthoster, alloster, and M2 receptor again returns to modulation of the orthoster binding kinetics. In this case, the alloster can change the rate of association and / or dissociation of the orthoster at the M2 receptor. At the same time, a decrease in the dissociation rate reflects the stabilization of the tertiary complex and, therefore, is also accompanied by a decrease in the dissociation constant of the orthosteric ligand under equilibrium conditions (Lazareno, Determination of Allosteric Interactions Using Radioligand-Binding Techniques in Methods in Molecular Biology, vol. 259, Receptor Signal Transduction Protocols, 2nd ed .; Kostenis and Mohr, Trends Pharmacol Sci 1996,17 (8), 280-283).

B-6.1. Binding test of ³ H-oxotremorine-M radioligand under equilibrium conditions.

To test and quantify the effect of test substances on the binding affinity of an orthosteric agonist for the M2 receptor, a radioligand binding assay under equilibrium conditions can be performed. The binding of the radiolabeled agonist of the M2 receptor ³ H-oxotremorin-M to the M2 receptor ^{is determined for various concentrations of 3} H-oxotremorin-M in the binding equilibrium (Croy et al., Mol. Pharmacol. 2014, 86, 106-115) ... Based on the specific amount of the radioactive agonist bound to the M2 receptor, depending on the concentration of the agonist (represented graphically in the form of the so-called Langmuir isotherm), one can then calculate, first, the dissociation constant of the equilibrium K _{d of the} agonist as a quantitative measure of its binding affinity for the M2 receptor, and secondly, the concentration or number of specific binding sites of the radioligand (agonist) B _max in the absence or presence of various concentrations of test substances (positive allosteric modulators) (Hulme and Trevethick, Brit. J. Pharmacol. 2010 , 161, 1219-1237.).

The radioligand binding assay for the M2 receptor (Euroscreen, FAST-O261B) was performed using D-labeled oxotremorine-M (NET671) as an agonist. The binding of the agonist to the M2 receptor was performed on a 96 microtiter plate (Master Block, Greiner, 786201) in a binder buffer solution (sodium / potassium phosphate buffer solution, pH 7.4) in triplicate. For this on the compo

- 154 038451 incubates M2-membrane extracts (20 μg protein / 96 wells) with different concentrations of radioactive agonist (0.2-100 nM) separately or in the presence of 1 or 10 μM test substance or binding buffer solution separately with a total volume of 0.1 ml for 60 min at 37 ° C. The nonspecific compound of ³ H-labeled oxotremorine-M with the membrane was determined by co-incubation with N-Me-scopolamine (NMS), an orthosteric M2 receptor antagonist, with a 200-fold excess. Then the samples were filtered until the binding reaction was stopped through a GF / C filter (Perkin Elmer, 6005174), which was pre-wetted with a 0.5% polyethyleneimine solution (PEI-), for 2 hours at room temperature. The filter was washed six times with 0.5 ml ice-cold wash buffer (10 mM sodium / potassium phosphate buffer, pH 7.4) and then added 50 μl of Microscint 20 scintillation solution (Packard) per formulation. The samples were then incubated for 15 minutes on an orbital shaker until the radioactivity was determined using a TopCount ™ instrument - (1 min / rev).

The test substances were dissolved in 10 mM DMSO and then diluted to the final test concentration in DMSO to give a 100-fold dilution of the DMSO solution used in the binder buffer.

The Kd value as well as the B _max ^{value 3 of} I-oxotremorine-M for the M2 receptor was determined using a one-site specific binding model (Croy et al., Mol. Pharmacol. 2014, 86, 106-115).

B-6.2. Displacement test of 3H-NMS radioligand under equilibrium conditions.

Further, to test and quantify the effect of test substances on the binding affinity of an orthosteric agonist for the M2 receptor, a competitive radioligand binding assay under equilibrium conditions can be additionally performed. At the same time, the binding of the antigonist radioligand ³ HN-Me-scopolamine (3H-NMS) to the M2 receptor was determined in the absence or in the presence of various concentrations of the non-radiolabeled agonist oxotremorin-M (Croy et al., Mol. Pharmacol. 2014, 86, 106 -115; Schober et al., Mol. Pharmacol. 2014, 86, 116-123). A radioactively labeled probe (antigonist) and an unlabeled agonist compete for binding to the orthosteric junction of the M2 receptor. Therefore, the displacement ability of the radiolabeled probe serves as a measure of the agonist binding affinity for the receptor and can be quantified using the Cheng-Prusoff equation as the equilibrium inhibitor constant (Ki-value) (Cheng and Prusoff, Biochem. Pharmacol. 1973, 22 ( 23), 3099-3108). To further investigate the allosteric effect of the test substances, their effect on the Ki-value of oxotremorine-M was determined.

Compound inhibition assay of M2 receptor antagonists (Euroscreen, FAST-0261B) was performed on a 96 microtiter plate (Master Block, Greiner, 786201) in binding buffer solution (50 mM Tris buffer pH 7.4, 1 mM EDTA, 10 μg / ml saponin) with 3H-NMS as M2 receptor antagonists. To equilibrate the compound, M2 membrane extracts (20 μg protein / 96 wells) are incubated on the composition with a certain concentration of radiolabeled antagonist (0.5 nM) alone or in the presence of various concentrations of unlabeled agonists (oxotremorin-M; 0.001 nM-1 mM) with or without 1 or 10 μM test substance or binder buffer, separately in a total volume of 0.1 ml for 2 h at 25 ° C. The nonspecific compound ^{3 of the} I-labeled NMS with the membrane was determined by co-incubation with non-radioactively labeled acetylcholine, with a 200-fold excess. Then, the samples were filtered until the binding reaction stopped through a GF / C filter (Perkin Elmer, 6005174), which was pre-wetted with a 0.5% PEI solution, for 2 h at room temperature. The filter was washed six times with 0.5 ml ice-cold wash buffer (10 mM sodium / potassium phosphate buffer pH 7.4) and then added 50 μl of Microscint 20 scintillation solution (Packard) per formulation. The samples were then incubated for 15 minutes on an orbital shaker until the radioactivity was determined using a TopCount ™ instrument - (1 min / rev).

The test substances were dissolved in 10 mM DMSO and then diluted to the final test concentration in DMSO to give a 100-fold dilution of the DMSO solution used in the binder buffer.

The Ki-value was quantified in the absence or presence of the test substance using the Cheng-Prusoff equation (Cheng and Prusoff, Biochem. Pharmacol. 1973, 22 (23), 30993108). At the same time, the IC5 ₀ -value of the substances was established according to one of the four parameters contained in the logical equation, and the Kd-value of NMS was determined in the radioligand binding test under equilibrium conditions (Schober et al., Mol. Pharmacol. 2014, 86, 116-123) ...

B-6.3. Test of kinetics of dissociation of ³ H-oxotremorine-M.

The kinetic radioligand binding assay can investigate the dissociation kinetics of a radiolabeled ³ H-oxotremorine-M agonist for the M2 receptor in the presence or absence of a test substance. With this, it is possible to determine the effect of the allosteric activity of the tested substances on the dissociation constant (koff-rate) of the M2 agonist and, therefore, to characterize the mechanism of allosteric activity of the tested substances (Lazareno, Determination of Allosteric

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Interactions Using Radioligand-Binding Techniques in Methods in Molecular Biology, vol. 259, Receptor Signal

Transduction Protocols, 2 ^nd ed .; Schrage et al., Biochem. Pharmacol, 2014, 90, 307-319.).

A radioligand dissociation binding assay for the M2 receptor (Euroscreen, FAST-0261B) was performed using ³ H-labeled oxotremorine-M (NET671) as an agonist. The binding reaction was carried out in binder buffer (sodium / potassium phosphate buffer, pH 7.4) on a 96 microtiter plate (Master Block, Greiner, 786201). For this, M2-membrane extracts (20 μg protein / 96 wells) with a certain concentration of radioactive agonist (9.65 nM) are incubated on the composition separately or in the presence of 1 or 10 μM of the test substance or binding buffer solution separately for 60 min at 37 ° C. C. Then NMS was added in 200-fold excess at different time points (one time point per composition) and the compositions were incubated in a total volume of 0.1 ml at 37 ° C. Then, the samples were filtered until the binding reaction stopped through a GF / C filter (Perkin Elmer, 6005174), which was pre-wetted with a 0.5% PEI solution, for 2 h at room temperature. The filter was washed six times with 0.5 ml ice-cold wash buffer (10 mM sodium / potassium phosphate buffer, pH 7.4) and then added 50 μl of Microscint 20 scintillation solution (Packard) per formulation. The samples were then incubated for 15 min on an orbital shaker until the radioactivity was determined using a TopCountTM- instrument (1 min / rev).

The test substances were dissolved in 10 mM DMSO and then diluted to the final test concentration in DMSO to give a 100-fold dilution of the DMSO solution used in the binder buffer.

The k _off value was determined using a one phase exponential dissociation decay model (Hulme and Trevethick, Brit. J. Pharmacol. 2010, 161, 1219-1237; Kostenis and Mohr, Trends Pharmacol. Sci. 1996, 17 (8), 280- 283).

B-6.4. ³ H-M2-PAM binding test.

The binding affinity of the human M2 receptor test substances can be determined directly by using radioactively labeled test substances as probes. For this, positive allosteric test substances are radioactively labeled using tritiations (3H-M2-PAM).

Using the radioligand binding test under equilibrium conditions, it is possible to determine, firstly, the dissociation constant of equilibrium K _{d of a} positively allosteric test substance ( ³ H-M2-PAM) as a quantitative value of its binding affinity for the M2 receptor, and, secondly, the amount of specific Bmax radioligand binding sites in the presence or absence of an orthosteric agonist (acetylcholine) (Hulme and Trevethick, Brit. J. Pharmacol. 2010, 161, 1219-1237; Schober et al., Mol. Pharmacol. 2014, 86, 116-123) ... For the ³ H-M2-PAM binding assay under equilibrium conditions, samples of the cell membranes of the M2 receptor (CHO-S / hM2, 200 μg) were incubated in an incubation buffer solution (10 mM Tris / HCl pH 7.4, 2 mM MgCl2, 120 mM NaCl, protease inhibitors, 0.3% BSA) together with respectively two different concentrations of the allosteric radioligand 3H-M2-PAM (0.5-4000 nM) with or without acetylcholine (100 μm) for 1 h at 4 ° C. Non-specific binding was determined by the addition of excess non-radioactively labeled allosteric ligand (M2-PAM) (10 μm). To terminate the binding reaction, the samples were filtered through a Brandel filter system and washed with stop buffer (50 mM Tris / HCl pH 7.4, 500 mM NaCl, 0.3% BSA). The filter was pre-wetted with a 0.3% PEI solution. The K _d - and B _max values of the allosteric radioligand were determined based on a one-site specific binding model (GraphPad Prism).

Using the competitive ³ H-M2-PAM binding assay, the affinity of unlabeled allosteric test substances for the binding site of the ³ H-M2-PAM radioligand to the M2 receptor can be determined (Croy et al., Mol. Pharmacol. 2014, 86, 106-115; Schober et al., Mol. Pharmacol. 2014, 86, 116123). Radioactively labeled probe ³ H-M2-PAM) and an unlabeled allosteric test substance compete for binding to the allosteric junction site of the M2 receptor. Therefore, the displacement ability of the radiolabeled probe serves as a measure of the allosteric binding affinity of the test substances for the receptor and can be quantified using the Cheng-Prusoff equation as the equilibrium inhibitor constant (Ki-value) (Cheng and Prusoff, Biochem. Pharmacol. 1973, 22 (23), 3099-3108). In this case, the displacement of the radiolabeled allosteric probe is determined with or without an orthosteric agonist (acetylcholine). ^{The 3} H-M2-PAM competitive binding assay was performed similarly to the above described ³ H-M2-PAM equilibrium binding assay. At the same time, membrane formulations containing the M2 receptor were incubated with 1 nM ³ H-M2-PAM and various concentrations of unlabeled test substance with or without acetylcholine (100 μm). The Ki-value was determined in the absence or presence of acetylcholine using the Cheng-Prusoff equation (Cheng and Prusoff, Biochem. Pharmacol. 1973, 22 (23), 30993108).

B-7. Effects of test substances on acetylcholine-mediated GIRKI / 4-channel flows in rat primary atrial cardiomyocytes.

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Substances were tested according to one of the literature-described local potential clamping protocols for electrophysiological measurement of acetylcholine-induced GIRK1 / 4 membrane fluxes in natural rat atrial myocytes (Cheng and Prusoff, Biochem. Pharmacol.

1973, 22 (23), 3099-3108 see, for example, Beckmann and Rinne et al., Cell. Physiol. Biochem. 2008, 21, 259268).

First, a curve of acetylcholine-exposure-dose in the presence of a test substance (DMSO-control) for GIRK1 / 4 activity was determined by perfusing test solutions with an increase in the concentration of acetylcholine and measuring the formed membrane fluxes. Measurement of backflows or change in membrane fluxes for the added concentration of ACh in this case was about 10-20 s. After applying the maximum concentration of ACh within the DWK row, the solution is perfused with atropine (10 μM), accompanied by the washing of the solution of substances, to ensure M2 selectivity and reversibility of M2 activation. Changes in membrane fluxes were recorded accordingly. In this case, for each concentration of acetylcholine, the corresponding measured flux with the maximum acetylcholine-induced membrane flux (I / IMax) was normalized. The acetylcholine-exposure-dose curve contains five different concentrations (1, 10, 100 nM, 1, 10 μM). The EC ₅₀ value was determined using the 4-parameter-logistics function (Hill's function).

To determine the allosteric effect of test substances on the M2 receptor, an acetylcholine-exposure-dose curve was determined for GIRK1 / 4 membrane flux in the presence of a constant concentration of the corresponding test substance (eg 1 μM). For this, after preincubating the cell with the test substance for about 20 s and measuring the membrane fluxes, the test substance, which had the same concentration of substances and certain concentrations of ACh, was perfused for about 10-20 s and the membrane fluxes were measured. After applying the maximum concentration of acetylcholine within a series of measurements, the solution is again perfused with atropine (10 μM) in order to control the M2-selectivity of the effect of the substances. Similarly, determine the EC ₅₀ value in the presence of the test substance using the 4-parameter-logistics function (Hill's function) (see above).

The shift in the acetylcholine-exposure-dose curve was determined and quantified by changing the EC ₅₀ value for acetylcholine in the presence or absence of the test substance.

B-8. Effects of test substances on an isolated perfused rat heart.

Male Wistar rats (species: HsdCpb: WU) weighing 200-250 g were anesthetized with Narcoren (100 mg / kg. After opening the chest, the heart was dissected, excised and attached to the Langendorff apparatus by cannulating the aorta. The heart was perfused with Krebs buffer solution) -Henseleit (saturated with gases at 95% O2 and 5% CO ₂ , pH 7.4, 35 ° C) with the following composition in mmol / l: NaCl 118; KCl 3; NaHCO ₃ 22; KH ₂ PO ₄ 1.2; magnesium sulfate 1.2; CaCl ₂ 1.8; glucose 10; pyruvate Na 2 with 9 ml / min constant flow To obtain the force of heart contractions, a thin synthetic balloon, fixed on a PE tourniquet, filled with water, is introduced through the opening in the left atrial appendage. The balloon was connected to a pressure transducer The end-diastole pressure was set at 5-10 mmHz using the balloon volume The data was amplified with a bridge amplifier and recorded on a computer using LabChart Software (ADInstruments).

To study the allosteric effect of the test substances, hearts were perfused with the addition of 300 nmol / L of the test substance. After 15 minutes, carbachol is added cumulatively with increasing concentration of the perfusion solution. The resulting decrease in heart rate was compared as an exposure-dose curve with the effect on hearts that were treated with a vehicle instead of the test substance. Carbachol-exposure-dose shift was analyzed using GraphPad PRISM (sigmoidal dose-response function) and quantified.

B-9. Effects of test substances on heart rate in anesthetized rats.

Male (WI) WU Br rats, breeder Charles River, were initially anesthetized with 4-5% isoflurane inhalation for approximately 3 minutes. Then carried out inhalation maintenance anesthesia with 1.5% isoflurane. For this, the anesthetized animals were fixed on their backs on a heated operating table. The depth of anesthesia was checked using visual control and Babinsky intermediate reflexes.

For administration of the test substance, intravenous access to the jugular vein was provided. A skin incision was then made longitudinally from the cranial to the caudal point, and both the cervical musculature and the salivary gland were removed. The right common carotid artery was presented and tourniquets were applied both proximally and distally. Using microinstrumentation, a TIP catheter (1.2F) was inserted into a vessel to measure blood pressure and heart rate.

At first, both parameters were recorded for 10 min in the basal state without the addition of a substance. The test substances were dissolved in a suitable mixture of solvents and then injected at different dosages according to each group of animals through the jugular vein using an infusion pump for 5 minutes. The group receiving the solvent was considered control under the same test conditions. Measurement of arterial blood pressure, as well as heart rate

- 157 038451 contractions under the conditions of the introduction of the substance were carried out for 20 minutes. Data were recorded using the PowerLab system (ADinstruments) and evaluated using the LabChart software (ADinstruments).

B-10. Radio telemetry measurement of blood pressure and heart rate in awake rats.

For the measurement described below in awake rats, a commercially available telemetry system from Data Sciences International DSI, USA was used. The system consists of three main components: (1) an implantable transmitter (PhysioTel® telemetry transmitter), (2) a receiver (PhysioTel® receiver), which are connected via a multiplexer (DSI communication matrix) to (3) a computer for data collection. The telemetry device makes it possible to continuously collect information about blood pressure, heart rate and body movements from awake animals in their normal habitat.

Studies were conducted on adult female rats (Wistar Unilever / WU strain or spontaneously hypertensive rats / SHR) weighing> 200 g. The test animals were housed separately with an implanted transmitter in Makrolon® type III cages. They have access to regular food and water. The day / night rhythm in the research laboratory was established by changing the room lighting.

Transmitter implantation.

Used telemetry transmitters (for example, PA-C40, HD-S10, DSI) were implanted in the test animals at least 14 days before the start of the first experiment under aseptic conditions by surgery. For implantation, awake animals were euthanized with isoflurane anesthesia (IsoFlo®, Abbott, administration 5%, content 2%), their abdomen was shaved and disinfected. After opening the abdomen along the white line (Linea alba), a fluid-filled measuring system catheter was inserted above the bifurcation cranially into the descending aorta and secured with tissue adhesive (Vetbond ™, 3M). The body of the transmitter is intraperitoneally fixed on the muscles of the abdominal wall and the wound is closed in layers. An antibiotic (Ursocycline® 10%, 60 mg / kg subcutaneously, 0.06 ml / 100g body weight, Serumwerk Bernburg LLC (Bernburg), Germany), as well as an analgesic (Rimadil®, 4 mg / kg subcutaneously, Pfizer , Germany).

Substances and solutions.

Unless otherwise indicated, the test substances were given orally to each group of animals (M = 6). According to the applied volume of 2 ml / kg body weight, the test substances were dissolved in a suitable solvent mixture. The group of animals that are treated with solvents is called the control group.

Test progress.

The measuring telemetry device was positioned for 24 animals. Each prepared rat living in the device has its own receiving antenna (RPC-1 receiver 1010, DSI). The implanted transmitters were activated by an externally built-in excitation switch and switched to transmission during a preliminary assessment of the experiment process. The emitted signals can be captured online using the data acquisition system (Dataquest ™ A.R.T. for Windows, DSI or Ponemah, DSI) and processed accordingly. In a typical experiment, the duration of the measurement is 10 s: (1) systolic blood pressure SBP (SBP), (2) diastolic blood pressure DCP (DBP), (3) mean arterial pressure SBP (MAP), (4) heart rate (HR) and (5) activity (ACT). These parameters were measured 24 hours after application. Computer-controlled recording of the measurement results was repeated after 5 min. The original files, taken as an absolute value, were corrected in the diagram according to the actual measured barometric pressure (ambient pressure inversion monitor; APR-1, DSI).

Analysis.

After the end of the test, the source files are sorted by the analyzing software (Dataquest ™ A.R.T. 4.1 Analysis or Ponemah, DSI). The time point 2 hours before the application of the substance was taken as the zero value. Data over a predetermined time was rounded using a mean (30 min-mean).

B-11. Effects of test substances on heart rate in anesthetized dogs.

Mestizo male and female dogs (Mongrels, Marshall BioResources, USA) weighing 20-30 kg were anesthetized with pentobarbital (30 mg / kg IV, Narcoren®, Merial, Germany). Pancuronium chloride (Pansuronium-Actavis®, Actavis, Germany, 1 mg / animal intravenously) additionally serves as a muscle relaxant. The dogs are intubated and maintained breathing with an oxygen-air mixture (40/60%, approximately 5-6 L / min). Artificial lung ventilation was performed using a GE Healthcare (Avance) ventilator, which simultaneously served as an anesthesia control device (CO ₂ analyzer). Anesthesia is served vertically with a constant infusion of pentobarbital (50 μg / kg / min); the analgesic agent is fentanyl (10 μg / kg / h). An alternative to pentobarbi-158 038451 talu is the use of isoflurane (1-2 vol.%).

The following instruments were used in dogs:

a catheter in the bladder to empty the bladder or to measure the flow of urine

EKG limb lead (for ECG measurement);

insertion of a soft tube filled with NaCl Fluidmedic-PE-300 into the femoral artery. It is linked to a pressure transducer (Braun Melsungen, Melsungen, Germany) to measure systemic blood pressure;

introduction of a NaCl-filled venous catheter (Vygon, Germany) into the femoral vein for infusion of test substances or blood collection for analysis;

insertion of a Millar-type catheter (type 350 PC, Millar Instruments, Houston, USA) through the left atrium or through the amalgamations in the A. carotis gateway to measure cardiac hemodynamics;

insertion of a Swan-Ganz catheter (CCOmbo 7.5F, Edwards, Irvine, USA) through V. jugularis into A. pulmonalis to measure cardiac output, oxygen saturation, pulmonary arterial pressure and central venous pressure;

installation of an ultrasonic probe for flow measurement (Transsonic SysteMC, Ithaka, USA) in the descending aorta to measure aortic flow;

installation of an ultrasonic probe for flow measurement (Transsonic SysteMC, Ithaka, USA) in the left coronary artery to measure coronary flow;

installation of a peripheral venous catheter in Venae cephalicae for infusion of pentobarbital, fluid replacement and for taking blood for analysis (to determine the level of a substance in plasma or other clinical blood values);

placement of a peripheral venous catheter in Venae saphenae for the infusion of pentobarbital and for administration of the substance.

The primary signals are amplified as appropriate (Gould amplifier, Gould Instrument Systems, Valley View, USA or Edwards-Vigilance monitor, Edwards, Irvine, USA) and then sent for data processing to a Ponemah system (DataSciences Inc., Minneapolis, USA ). Signals are continuously recorded throughout the experiment, digitally processed by this software, and averaged over 30 s.

B-12. Effects of test substances on heart rate and heart rate instability in healthy, awake dogs.

To characterize test substances with respect to their effect on heart rate, heart rate volatility (HRV) and blood pressure, telemetry measurements were performed on healthy male beagle dogs. Under isoflurane anesthesia, the animals were first implanted with a telemetry transmitter (model L21, Data Sciences International, USA). At the same time, after left-sided thoracotomy, pressure sensors were installed in the aorta and in the left ventricle. Then electrodes were placed on the heart to record an electrocardiogram (EKG). The animals were then returned to their housing for wound healing with antibiotics (Clindamycin, Zoetis, Germany) and analgesics (Fentanyl, Janssen, Germany). Using antennas installed in the animal room, blood pressure and ECG signals were transmitted to a computer with a data collection system and presented in digital form using analysis software (Ponemah, Data Sciences International, USA). The telemetry device facilitated the continuous collection of blood pressure and ECG signals from awake animals. Technical details can be taken from the manufacturer's documents (Data Sciences International, USA).

The test substances were taken orally in healthy dogs in the form of gelatin capsules in a mixture of suitable solvents. The group of animals that are treated with the drug base is called the control group. Telemetry measurements were started prior to ingestion of the substance and were recorded over a period of several hours. The graphical presentation of the time course of the data with the calculated time value was carried out using the GraphPadPrism Software (GraphPad, USA). For HRV analysis, ECG data from frequency-domain analysis were used. For this, the R-R intervals provided by EKG's were used. Data outside the previously defined ranges of 0.2-1.5 s are excluded from the analysis. The excluded data is replaced with values that were obtained using linear interpolation. This data is converted by spline interpolation to equally spaced support points. Then, to analyze the heart rate instability, the data were divided into 30 s steps into 300 s packets. The Fourier transform was taken into account for each data packet. Then, from this, the result was calculated for three frequency ranges (vlf = 0.0033-0.04 1 / s; lf = 0.04-0.15 1 / s; hf = 0.15-0.5 1 / s). The total performance (the sum of all three frequency ranges) for HRV analysis was used to characterize the test substance.

Claims (22)

CLAIM 1. Compound of formula (I) in which X means halogen; R ¹ means hydrogen, or means -NR ⁴ R ⁵ , where R ⁴ means hydrogen, methyl, (C2-C4) αalkyl or (C3-C6) cycloalkyl, and (C2-C4) αalkyl can be substituted with hydroxyl or up to three times fluorine, R ⁵ means ( _{C 1} -C ₆ ) alkyl or (C ₃ -C ₆ ) cycloalkyl, wherein (C _{1 -C 6} ) alkyl and (C ₃ -C ₆ ) cycloalkyl can be substituted up to three times, identically or differently , methyl, difluoromethyl, trifluoromethyl, hydroxyl, hydroxycarbonyl, oxo, methoxy, difluoromethoxy, trifluoromethoxy, cyano and further up to four times with fluorine, or means a heterocycle attached to the nitrogen atom of the formula where ** denotes the place of attachment to the remainder of the molecule, R ¹⁰ is fluorine, methyl, hydroxyl, hydroxymethyl, methoxycarbonyl or acetyloxy, p is the number 0, 1 or 2, and in the case where the substituents R ¹⁰ occur repeatedly, their meanings can be the same or different, respectively; Y ¹ is —NH—, —N (CH ₃ ) - or —O—; R ² means a group of the formula where * denotes the place of attachment of the amide group to the nitrogen atom, R ^6A means hydrogen or (C ₁ -C ₄ ) alkyl, R ^6B means hydrogen, (C ₁ -C ₄ ) alkyl, cyclopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, methoxymethyl or trifluoromethoxymethyl, R ⁷ means (C ₁ -C ₆ ) alkyl or up to four times substituted by fluorine (C ₃ -C ₅ ) cycloαalkyl, and (C ₁ -C ₆ ) alkyl can be substituted by amino, hydroxyl, (C ₁ -C ₆ ) alkoxy and up to five times with fluorine, where (C ₁ -C ₆ ) alkoxy can be substituted up to five times with fluorine, R ¹¹ means hydrogen, R ¹² means methoxycarbonyl, R ¹³ means hydrogen or tert-butoxycarbonyl, L ¹ means a bond or a group of the formula -C (R ^8A R ^8B ) - (C (R ^9A R ^9B )) _m -, where m is 0 or 1, R ^8A is hydrogen or methyl, R ^8B represents hydrogen, methyl, trifluoromethyl, pentafluoroethyl or trifluoromethoxymethyl, R ^9A and R ^9B independently represent hydrogen or methyl, Ar ² means phenyl, wherein phenyl may be substituted one to three times, identically or differently, with fluorine, chlorine, (C ₁ -C ₃ ) alkyl, difluoromethoxymethyl, trifluoromethoxymethyl and / or trifluoromethyl, Ar ¹ means a group of the formula - 160 038451 where *** denotes the place of attachment to the nitrogen atom, R ^3A means fluorine, chlorine, trifluoromethyl or methyl, R ^3B means hydrogen or fluorine, R ^3C means hydrogen, fluorine, chlorine or methyl, or means a pyridine ring bonded to a carbon atom of the ring, and the pyridine ring may be substituted once or twice with fluorine, chlorine, cyano, methyl or trifluoromethyl, as well as its salts. 2. A compound of formula (I) according to claim 1, wherein X means fluorine, chlorine or bromine; R ¹ means hydrogen, or means NR4R ⁵ , where R ⁴ means hydrogen, methyl or ethyl and R ⁵ means (C ₁ -C ₃ ) α-alkyl, up to four times substituted with fluorine, and (C ₁ -C ₃ ) alkyl may be substituted hydroxyl, or means a heterocycle of the formula attached to a nitrogen atom where ** denotes the place of attachment to the remainder of the molecule, R ¹⁰ is fluorine, methyl, hydroxyl, hydroxymethyl, methoxycarbonyl or acetyloxy, p is the number 0, 1 or 2, and in the case where the substituents R ¹⁰ occur repeatedly, their meanings can be the same or different, respectively; Y ¹ is —NH—, —N (CH ₃ ) - or —O—; R ² means a group of the formula where * denotes the place of attachment of the amide group to the nitrogen atom, R ^6A means hydrogen or (C ₁ -C ₄ ) alkyl, R ^6B means methyl, ethyl, isopropyl, cyclopropyl, monofluoromethyl, difluoromethyl or trifluoromethyl, R ⁷ means up to five times substituted with fluorine (C ₁ -C ₄ ) alkyl, up to four times substituted with fluorine (C ₃ -C ₅ ) cycloalkyl, methoxymethyl or trifluoromethoxymethyl, R ¹¹ means hydrogen, R ¹² means methoxycarbonyl, R ¹³ means hydrogen or tert-butoxycarbonyl, L ¹ means a bond or a group of the formula -CR ^8A R ^8B -, where R ^8A is hydrogen, R ^8B represents hydrogen, methyl, trifluoromethyl, pentafluoroethyl or trifluoromethoxymethyl, Ar ² means phenyl, and phenyl may be substituted from one to three times, equally or differently, with fluorine or chlorine; Ar ¹ means a group of the formula where *** denotes the place of attachment to the nitrogen atom, R ^3A means fluorine, chlorine, trifluoromethyl or methyl, R ^3B means hydrogen or fluorine, R ^3C means hydrogen, fluorine, chlorine or methyl, or means a pyridine ring bonded to a carbon atom of the ring, and the pyridine ring may be substituted once or twice with fluorine, chlorine or cyano, - 161 038451 as well as its salts. 3. A compound of formula (I) according to claim 1 or 2, in which X means fluorine, chlorine or bromine; R ¹ is NR4R ⁵ , where R ⁴ is methyl or ethyl and R ⁵ is methyl, 2-hydroxyethyl, or 2-hydroxypropyl, or means a heterocycle attached to a nitrogen atom of the formula where ** denotes the place of attachment to the remainder of the molecule, R ¹⁰ is fluorine, methyl, hydroxyl, hydroxymethyl, methoxycarbonyl or acetyloxy, p is the number 0, 1 or 2, and in the case where substituents R ¹⁰ occur repeatedly, their meanings can be the same or different, respectively, Y ¹ is —NH—, —N (CH ₃ ) - or —O—; R ² means a group of the formula where * denotes the place of attachment of the amide group to the nitrogen atom, R ^6A means hydrogen, methyl or ethyl, R ^6B means methyl, ethyl, trifluoromethyl, isopropyl or cyclopropyl, R ⁷ means methyl, ethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, isopropyl, isobutyl, methoxymethyl, trifluoromethoxymethyl or cyclopropyl, R ¹¹ means hydrogen, R ¹² means methoxycarbonyl, R ¹³ means hydrogen or tert-butoxycarbonyl, L ¹ means a bond or a group of the formula -CR ^8A R ^8B -, where R ^8A is hydrogen, R ^8B is hydrogen, methyl or trifluoromethyl, Ar ² means phenyl, and phenyl may be substituted once or twice, identically or differently, with fluorine or chlorine; Ar ¹ means a group of the formula where *** denotes the place of attachment to the nitrogen atom, R ^3A means fluorine or chlorine, R ^3C means hydrogen or fluorine, as well as its salts. 4. A compound of formula (I) according to one of claims 1 to 3, in which X means fluorine; R ¹ means a heterocycle of the formula attached to a nitrogen atom where ** denotes the place of attachment to the remainder of the molecule; R ² means a group of the formula - 162 038451 where * denotes the place of attachment of the amide group to the nitrogen atom; Ar ¹ means a group of the formula where *** denotes the place of attachment to the nitrogen atom, as well as its salt. 5. A compound of formula (I) according to one of claims 1 or 2, in which X means fluorine; R ¹ means a heterocycle of the formula attached to a nitrogen atom where ** denotes the place of attachment to the remainder of the molecule; R ² means a group of the formula where * denotes the place of attachment of the amide group to the nitrogen atom; Ar ¹ means a group of the formula where *** denotes the place of attachment to the nitrogen atom, as well as its salt. 6. A compound of formula (I) according to one of claims 1 to 3, in which R ¹ is a nitrogen-linked heterocycle of the formula where ** denotes the place of attachment to the remainder of the molecule. 7. A compound of formula (I) according to claim 1, which is a compound of formula 8. A compound of formula (I) according to claim 1, which is a compound of formula - 163 038451 9. A compound of formula (I) according to claim 1, which is a compound of formula 10. A compound of formula (I) according to claim 1, which is a compound of formula 11. A compound of formula (I) according to claim 1, which is a compound of formula 12. A compound of formula (I) according to claim 1, which is a compound of formula 13. A compound of formula (I) according to claim 1, which is a compound of formula 14. A compound of formula (I) according to claim 1, which is a compound of formula 15. A compound of formula (I) according to claim 1, which is a compound of formula 16. A process for the preparation of a compound of formula (I) as defined in one of claims 1-6, characterized in that: [A] compound of formula (II) - 164 038451 in which X, R ² and Ar ¹ have the meanings indicated in one of claims 1-6 for compounds of formula (I); and Hal means fluorine, chlorine, bromine or iodine, is converted with a compound of formula (III) ^{r1 — H} (HI), in which R ¹ has the meanings indicated in one of claims 1-6 for compounds of formula (I), and R ^{1 is} not means hydrogen, in the carboxylic acid amide of formula (IA) in which X, R ¹ , R ² and Ar ¹ are specified in one of and R ¹ does not mean hydrogen; or [B] the compound of the formula (IV) of claims 1-6 for the compounds of the formula (I), the meanings in which X, R ¹ and Ar ¹ have the above-mentioned one, are converted with compounds of formula (V) ^R “ ^NH ₂ from claims 1-6 for compounds of formula (I) the value of which R ² has the meaning indicated in one of claims 1-6 for compounds of formula (I), in carboxylic acid amide of formula (I) in which R ¹ , R ² and Ar ¹ have the meanings given above in one of claims 1 to 6 for the compounds of formula (I). 17. The method according to claim 16, wherein the additionally obtained compounds of formula (I) are separated into their enantiomers and / or diastereomers and / or are converted into their salts with the corresponding (i) solvents and / or (ii) bases or acids. 18. A compound of formula (II) in which X, R ² and Ar ¹ have values of formula (I); and Hal stands for fluorine, chlorine, bromine or iodine. 19. Compounds of formula (IV) which are indicated in one of claims 1-6 for compounds in which X and R ¹ have the meanings that are indicated in one of claims 1-6 for compounds of formula (I); Ar ¹ means a group of the formula where *** denotes the place of attachment to the nitrogen atom. - 165 038451 in which X, R ² and Ar ¹ have the meanings that are indicated in one of claims 1-6 for compounds of formula (I); and Hal means fluorine, chlorine, bromine or iodine, or compounds of formula (IV) 20. Use of a compound of formula (II) in which X, R ¹ and Ar ¹ have the meanings indicated in one of claims 1-6 for compounds of formula (I), to obtain a compound of formula (I) according to one of claims 1-6. 21. The use of a compound as defined in one of claims 1 to 15 for the preparation of a medicament for the treatment and / or prevention of diseases. 22. Use of a compound of formula (I) as defined in one of claims 1 to 15 for the preparation of a medicament for the treatment and / or prevention of heart failure, coronary heart disease, atrial and ventricular arrhythmias, renal failure and nephropathy.