EA038455B1 - Novel naphthyridinone derivatives and their use in the treatment of arrhythmia - Google Patents

Abstract

The invention provides a compound of formula II or III or a pharmaceutically acceptable salt thereof; wherein R1 and R3-R6 are defined in the claims, and its therapeutic uses in the treatment of a disease or disorder responsive to the inhibition of GIRK receptor.

Description

The technical field to which the invention relates

The present invention provides naphthyridinone compounds, their use for inhibiting the GIRK 1/4 channel, and methods of treating diseases through their use.

Background of the invention

The normal cardiac cycle begins in the sinoatrial node, in which an excitatory electrical stimulus is generated, which propagates in an orderly manner through the myocardium of the atria and ventricles, inducing contraction (systole). At the cellular level, an exciting electrical impulse triggers the action potential of the heart muscle. It is characterized by an initial rapid depolarization of the membrane followed by a plateau phase and then repolarization with a return to the resting potential of the membrane. The action potential of the heart muscle regulates the propagation of the signal through the heart. For example, the amount of initial cellular depolarization determines the rate at which excitatory stimuli propagate. The duration of the repolarization phase determines the duration of the action potential (APD) and the refractory period or time during which the cardiomyocyte cannot respond to another electrical stimulus.

Disturbances in the action potential of the heart muscle are associated with arrhythmias. For example, an excessive decrease in the duration of the action potential and the associated refractory period may provide the basis for so-called reciprocal tachycardia. In this condition, instead of normal propagation, the cardiac impulse returns to its place of origin through the excited tissue with the formation of a reentry loop (Waldo and Wit, 1993. Mechanism of cardiac arrhythmias. Lancet 341, 1189-1193). Current class III antiarrhythmic drugs are believed to act by increasing APD and associated effective refractory period (ERP), thereby minimizing the risk of re-excitation and subsequent reentry loops causing fibrillation (Singh BN and Vaughan Williams, EM, 1970. A third class of anti-arrhythmic action. Effects on atrial and ventricular intracellular potentials, and other pharmacological actions on cardiac muscle, of MJ 1999 and AH3474. British Journal of pharmacology 39, 675-687).

Certain class III antiarrhythmic drugs (eg, sotalol) are used in the treatment of atrial fibrillation (AF). AF is the most common form of persistent cardiac arrhythmias in humans and is characterized by fibrillatory contractions that disrupt atrial function. AF is associated with adverse cardiovascular events. In particular, the presence of AF is an independent risk factor for thromboembolic stroke, heart failure, and mortality from any cause (Estes et al., (2008). Journal of the American College of Cardiology 51, 865-884) (Fang et al., 2008 . Comparison of risk stratification schemes to predict thromboembolism in people with nonvalvular atrial fibrillation. Journal of the American College of Cardiology 51, 810-815). AF can also reduce the quality of life in some patients, causing palpitations and less exercise tolerance (Thrall et al., 2006. Quality of life in patients with atrial fibrillation: a systematic review. The American journal of medicine 119, 448.e441419 ). The goal of antiarrhythmic therapy for AF is to avoid such undesirable effects and outcomes.

The disadvantage of existing class III antiarrhythmic drugs is that they lead to prolongation of the effective refractory period both in the atria and in the ventricles. Excessive prolongation in ventricular tissue increases the QTc interval and may have a proarrhythmic effect, and certain drugs with this mechanism of action (e.g., dofetilide) are known to cause potentially life-threatening ventricular arrhythmias such as pirouette-type ventricular tachycardia (Redfern et al., 2003. Relationships between preclinical cardiac electrophysiology, clinical QT interval prolongation and torsade de pointes for a broad range of drugs: evidence for a provisional safety margin in drug development. Cardiovascular research 58, 3245). Thus, there is a need for a new antiarrhythmic therapy for AF that selectively targets atrial tissue rather than ventricular tissue.

The configuration and duration of the action potential of the heart muscle is controlled at the cellular level by the action of several different transmembrane ion channels. For example, the initial phase of depolarization is mediated by the influx of sodium ions through the heart-specific Na _v l channel. 5. Potassium channels are responsible for the next phase of repolarization and thus contribute to the regulation of the total duration of the action potential. Indeed, class III antiarrhythmic drugs that target potassium channels (eg, dofetilide) provide prolongation of both the duration of the action potential and the effective refractory period. There are several different types of transmembrane potassium channels (Schmitt et al., 2014. Cardiac potassium channel subtypes: new roles in repolarization and arrhythmia. Physiological reviews 94, 609-653; Tamargo et al., 2004. Pharmacology of cardiac potassium channels. Cardiovascular research 62, 9-33), including voltage-gated channels (Kv1-9); calcium-activated channels (KCa1-2); double-pore channels (for example, TASK); internal rectification channels (Kir1-6).

While most potassium channels in the heart are involved in repolarization in both atrial and ventricular tissue in humans, it is believed that two channels, K _v 1.5 and GIRK1 / 4 (i.e., G-protein-coupled

- 1 038455 potassium channel of internal rectification 1/4), are expressed exclusively in the atria (Gaborit et al., 2007. Regional and tissue specific transcript signatures of ion channel genes in the non-diseased human heart. The Journal of physiology 582, 675- 693). This atrial-specific expression pattern makes them particularly attractive targets for new antiarrhythmic therapies for AF since they would not have the ventricular adverse effects of existing class III drugs such as dofetilide.

In mammals, four different GIRK channels are expressed (GIRK 1, 2, 3 and 4; encoded by KCNJ3, KCNJ6, KCNJ9 and KCNJ5, respectively). Such transmembrane proteins are arranged in the form of tetramers (either homo- or heterotetramers) with the formation of a functional potassium channel (Krapivinsky et al., 1995. The G-protein-gated atrial K + channel IKACh is a heteromultimer of two inwardly rectifying K (+) - channel proteins. Nature 374, 135-141). Such channels are ligand-gated (i.e., regulated by ligand binding to Gi-protein coupled receptors present in the same cell membrane). For example, the GIRK1 / 4 channel is a heterotetramer (two subunits, each of GIRK1 and GIRK4), expressed in the sinoatrial and atrioventricular nodes, as well as in the atrial myocardium (Wickman et al., 1999. Structure, G protein activation, and functional relevance of the cardiac G protein-gated K + channel, IKACh. Annals of the New York Academy of Sciences 868, 386-398). One function of this channel is to mediate autonomous regulation of heart rate. Acetylcholine, released during parasympathetic stimulation of efferent neurons of the vagus nerve of the heart, binds to Gi-coupled muscarinic M2 receptors in the heart. This frees the GeY subunits, which in turn opens the GIRK1 / 4 channels, ensuring the outflow of potassium from cardiomycytes and, thus, contributes to membrane repolarization. With spontaneous depolarization of the pacemaker cells of the sinoatrial node, the magnitude of this repolarization determines the time between depolarizations and, consequently, the heart rate. Since it is regulated by acetylcholine, the current mediated by the GIRK1 / 4 channel is called IKA _ch (Wickman et al., 1999).

Several datasets point to GIRK1 / 4 as a desirable antiarrhythmic target for AF. In animals, stimulation of the vagus nerve promotes the release of acetylcholine from the afferent fibers of the vagus nerve and increases I _KAch . This in turn shortens the duration of the action potential in the atria (but not the ventricles) and the effective refractory period and can induce AF via the reentry mechanism (Hashimoto et al., 2006. Tertiapin, a selective IKACh blocker, terminates atrial fibrillation with selective atrial effective refractory period prolongation. Pharmacological research: the official journal of the Italian Pharmacological Society 54, 136-141). It has been shown that in atrial tissues from people with chronic AF, as well as from animals subjected to ultrafrequent electrical atrial stimulation (a generally accepted model for providing electrical remodeling and susceptibility to AF), I _KAch regulation is impaired. In particular, the canal is usually constitutively open, even in the absence of acetylcholine (Cha et al., 2006. Kir3-based inward rectifier potassium current: potential role in atrial tachycardia remodeling effects on atrial repolarization and arrhythmias. Circulation 113, 1730- 1737; Voigt et al., 2014. Constitutive activity of the acetylcholine-activated potassium current IK, ACh in cardiomyocytes. Advances in pharmacology (San Diego, Calif) 70, 393-409). In these studies in patients and animals, the APD / ERP in the atria was observed to be short.

Thus, the development of GIRK1 / 4 blockers will be useful for the treatment of cardiac arrhythmias such as atrial fibrillation.

Brief description of the invention

There remains a need for new therapies and therapies for arrhythmias. The present invention provides compounds, their pharmaceutically acceptable salts, pharmaceutical compositions based on them, and combinations thereof, wherein the compounds are GIRK1 / 4 channel blockers. The present invention further provides methods of treating, preventing or reducing the severity of cardiac arrhythmias, atrial fibrillation, primary hyperaldosteronism, hypertension and / or sick sinus syndrome, comprising administering to a subject in need thereof an effective amount of a GIRK1 / 4 channel blocker.

Various embodiments of the present invention are described herein.

In certain aspects, provided herein is a compound of Formula II or III:

- 2 038455 where R ¹ is C _1-4 alkyl, -CN, C _1-4 alkoxyC _1-4 alkyl, halogen-C _1-4 alkyl, -CH = N-OH, hydroxy-C _1-4 alkyl, -CH2OP (O) (OH) 2 or C _3-5 cycloalkyl;

R ³ represents -OR ^a ; -NHR ^b ; -C (O) NH2;

C (O) [hydroxyC _1-4 alkyl];

4-7 membered monocyclic heterocyclyl containing at least one heteroatom selected from O, N and S, and optionally substituted with one or more substituents independently selected from OH and hydroxyC _1-4 alkyl; and 5- or 6-membered monocyclic heteroaryl containing from 1 to 4 heteroatoms independently selected from O, N and S and optionally substituted with one or more C _1-4 alkyl; or R ³ is C _1-4 alkyl substituted with one or more substituents independently selected from —C (O) [hydroxyC _1-4 alkyl] and —OR ^c ;

R ^a is —C1-6alkyl substituted with one or more substituents independently selected from —OR ^c , —NHS (O) 2C _1-4 alkyl, and 4-7 membered monocyclic heterocyclyl containing at least one heteroatom selected from Oh, N and

5, which is further optionally substituted with one or more substituents independently selected from C _1-4 alkyl and hydroxyC _1-4 alkyl; or

R ^a represents - [CH ₂ -CH ₂ -O] _p -H, - [CH ₂ -CH ₂ -O] _m -CH ₃ or 5-6 membered monocyclic heteroaryl containing from 1 to 4 heteroatoms, independently selected from O, N and S, optionally substituted with one or more C _1-4 alkyl; where n is 2-6 and m is 1-6;

R ^b is —C1-6alkyl substituted with one or more substituents independently selected from —OR ^c , —C (O) NH- (hydroxyC1-4alkyl), 5- or 6-membered monocyclic heteroaryl containing from 1 to 4 heteroatoms independently selected from O, N and S, a 4-7 membered monocyclic heterocyclyl containing at least one heteroatom selected from O, N and S, —SO2 C _1-4 alkyl and —NHS (O) ₂ C _{1- 4} alkyl; or

R ^b represents -S (O) ₂ -5-6 membered monocyclic heteroaryl containing 1 to 4 heteroatoms independently selected from O, N and S; or

R ^b is a 4-7 membered monocyclic heterocyclyl containing at least one heteroatom selected from O, N and S, optionally substituted with one or more hydroxy groups; or

R ^b represents H, -OR ^c ; - [CH ₂ -CH ₂ -O] _p -H, - [CH ₂ -CH ₂ -O] _m -CH ₃ or 5-6 membered monocyclic heteroaryl containing from 1 to 4 heteroatoms independently selected from O, N and S optionally substituted with one or more C _1-4 alkyl; where n is 2-6 and m is 1-6;

R ^c is H or hydroxyC _1-4 alkyl;

R ² is H, C _1-4 alkoxy, halogen, C _1-4 alkyl, or —NH — C _1-4 alkyl;

R ⁴ is H, halogen, C _1-4 alkyl, C _3-5 cycloalkyl;

R ⁵ is H, halogen or CN; or

R ⁵ is C2-6 alkynyl optionally substituted with NR ^g R ^h , where R ^g and R ^{h are} independently H or C1-4 alkyl; or R ^g and R ^h form, together with the nitrogen atom to which they are attached, a 4-7 membered monocyclic heterocyclyl optionally containing an additional heteroatom selected from O, S and N, the heteroatom being in its oxidized form; and wherein said monocyclic heterocyclyl is optionally substituted with C _1-4 alkyl; and

R ⁶ is halogen or CN;

or a pharmaceutically acceptable salt thereof.

In another embodiment, the present invention provides the use of a compound of Formula II or Formula III, or a pharmaceutically acceptable salt thereof, for the treatment or prevention of a disease or disorder responsive to GIRK receptor inhibition.

In another embodiment, the present invention provides a method of either preventing a disease or disorder susceptible to inhibition of a GIRK receptor in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula II or Formula III, or a pharmaceutically acceptable salt thereof.

Brief description of graphic materials

FIG. 1 illustrates the X-ray powder diffractograms of Example 1 with hydrated Form B.

FIG. 2 illustrates the differential scanning calorimetry (DSC) results for Example 1 with hydrated Form B using a perforated sample crucible.

FIG. 3 illustrates Differential Scanning Calorimetry (DSC) results for Example 1 with Hydrate Form B using a sealed sample crucible.

FIG. 4 illustrates the thermogravimetric analysis (TGA) results for Example 1 with hydrated Form B.

Detailed description

Thus, in Embodiment 1, the present invention provides a compound of Formula II or III:

- 3 038455

where R ¹ is C _1-4 alkyl, -CN, C _1-4 alkoxy C _1-4 alkyl, halogen-C _1-4 alkyl, -CH = N-OH, hydroxy-C _1-4 alkyl, -CH ₂ OP (O) (OH) ₂ or C _3-5 cycloalkyl;

R ³ represents -OR ^a ; -NHR ^b ; -C (O) NH ₂ ;

C (O) [hydroxyC _1-4 alkyl];

4-7 membered monocyclic heterocyclyl containing at least one heteroatom selected from O, N and S, and optionally substituted with one or more substituents independently selected from OH and hydroxyC _1-4 alkyl; and a 5- or 6-membered monocyclic heteroaryl containing 1 to 4 heteroatoms independently selected from O, N and S and optionally substituted with one or more C _1-4 α-alkyl; or

R ³ is C _1-4 alkyl substituted with one or more substituents independently selected from —C (O) [hydroxyC _1-4 alkyl] and —OR ^c ;

R ^a is —C1-6alkyl substituted with one or more substituents independently selected from —OR ^c , —NHS (O) 2C _1-4 αalkyl, and 4-7 membered monocyclic heterocyclyl containing at least one heteroatom selected from O, N and S, which is further optionally substituted with one or more substituents independently selected from C _1-4 alkyl and hydroxyC _1-4 alkyl; or

R ^a represents co6oy- [CH ₂ -CH ₂ -O] _p -H, - [CH ₂ -CH ₂ -O] _m -CH ₃ or 5-6 membered monocyclic heteroaryl containing from 1 to 4 heteroatoms, independently selected from O, N and S, optionally substituted with one or more C _1-4 alkyl; where n is 2-6 and m is 1-6;

R ^b is —C1-6alkyl substituted with one or more substituents independently selected from —OR ^c , —C (O) NH- (hydroxyC1-4alkyl), 5- or 6-membered monocyclic heteroaryl containing from 1 to 4 heteroatoms independently selected from O, N and S, a 4-7 membered monocyclic heterocyclyl containing at least one heteroatom selected from O, N and S, —SO ₂ C _1-4 alkyl and —NHS (O) ₂ C _{1 -4} alkyl; or

R ^b represents -S (O) ₂ -5-6 membered monocyclic heteroaryl containing 1 to 4 heteroatoms independently selected from O, N and S; or

R ^b is a 4-7 membered monocyclic heterocyclyl containing at least one heteroatom selected from O, N and S, optionally substituted with one or more hydroxy groups; or

R ^b represents H, -OR ^c ; - [CH ₂ -CH ₂ -O] _p -H, - [CH ₂ -CH ₂ -O] _m -CH ₃ or 5-6 membered monocyclic heteroaryl containing from 1 to 4 heteroatoms independently selected from O, N and S optionally substituted with one or more C _1-4 α-alkyl; where n is 2-6 and m is 1-6;

R ^c is H or hydroxyC _1-4 alkyl;

R ² is H, C _1-4 α alkoxy, halogen, C _1-4 alkyl, or —NH — C _1-4 alkyl;

R ⁴ is H, halogen, C _1-4 alkyl, C _3-5 cycloalkyl;

R ⁵ is H, halogen or CN; or

R ⁵ is C2-6 alkynyl optionally substituted with NR ^g R ^h , where R ^g and R ^{h are} independently H or C1-4αalkyl; or R ^g and R ^h form, together with the nitrogen atom to which they are attached, a 4-7 membered monocyclic heterocyclyl optionally containing an additional heteroatom selected from O, S and N, the heteroatom being in its oxidized form; and wherein said monocyclic heterocyclyl is optionally substituted with C _1-4 alkyl; and

R ⁶ is halogen or CN;

or a pharmaceutically acceptable salt thereof.

Unless otherwise indicated, the term compounds of the present invention or compounds of this invention refers to compounds of formula II or III, and their salts, as well as all stereoisomers (including diastereoisomers and enantiomers), rotamers, tautomers and isotopically labeled compounds (including substitutions deuterium), as well as initially formed fragments.

For the purposes of the interpretation of this description, the following definitions will apply, unless otherwise indicated, and where appropriate, terms used in the singular will also include the plural, and vice versa.

It should be noted that, as used herein and in the appended claims, the singular includes the plural unless the context clearly dictates otherwise. Thus, for example, a link to a connection includes a link to one or more

- 4 038455 connections, etc.

The term alkyl refers to a fully saturated branched or unbranched (or straight chain or straight) hydrocarbon moiety containing 1-6 carbon atoms. Preferably, the alkyl contains 1-4 carbon atoms. C _1-4 alkyl refers to an alkyl chain containing 1-4 carbon atoms. C _1-6 alkyl refers to an alkyl chain containing 1-6 carbon atoms.

As used herein, the term haloalkyl (i.e., halogen-C _1-4 alkyl) refers to an alkyl (i.e., C _1-4 alkyl) as defined herein that is substituted with one or more halogen groups as defined herein document. Preferably, haloalkyl can be monohaloalkyl, dihaloalkyl or polyhaloalkyl, including perhaloalkyl. Monohaloalkyl may contain one iodine, bromine, chlorine or fluorine in the alkyl group. Dihaloalkyl and polyhaloalkyl groups can contain two or more of the same halogen atoms or a combination of different halogen groups in the alkyl. Preferably, the polyhaloalkyl contains no more than 12, or 10, or 8, or 6, or 4, or 3, or 2 halogen groups. Illustrative examples of haloalkyl are fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl, and dichloropropyl. The term halo-C _1-4 alkyl refers to a hydrocarbon containing from one to four carbon atoms and substituted with one or more halogen groups.

As used herein, the term hydroxyalkyl (ie, hydroxy-C _1-4 alkyl) refers to an alkyl (ie, Cl- ₄ alkyl) as defined herein that is substituted with one or more hydroxy groups as defined herein.

As used herein, the term alkoxyalkyl (i.e., Cl _-4 alkoxyCl _-4 alkyl) refers to an alkyl (i.e., Cl _-4 alkyl) as defined herein that is substituted with one or more alkoxy groups (i.e., Cl _-4 alkoxy) as defined herein.

As used herein, the term alkoxy (i.e., refers to the radical alkyl-O-, where alkyl is as defined herein above. Illustrative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy , hexyloxy, cyclopropyloxy, cyclohexyloxy, etc. Preferably alkoxy groups contain about 1-8, more preferably about 1-4 carbon atoms.

As used herein, the term haloalkoxy (i.e., halo-C _1-4 alkoxy) refers to an alkoxy as defined herein that is substituted with one or more halo groups as defined herein.

As used herein, the term C3 _-5 cycloalkyl refers to saturated or unsaturated, but not aromatic, monocyclic hydrocarbon groups of 3-5 carbon atoms. Illustrative monocyclic hydrocarbon groups include cyclopropyl, cyclobutyl, cyclopentyl, or cyclopentenyl.

The term heteroaryl includes a monocyclic heteroaryl containing 5 or 6 ring members selected from carbon atoms and 1-4 heteroatoms, each heteroatom being independently selected from O, N, or S, where S and N can be oxidized to different oxidation states. The heteroaryl radical can be linked via a carbon atom or a heteroatom (eg, via N).

Typical monocyclic heteroaryl groups include thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxa-2,3-diazolyl, oxa-2,4-diazolyl, oxa-2,5-diazolyl, oxa3,4-diazolyl, thia -2, 3-diazolyl, thia-2,4-diazolyl, thia-2,5-diazolyl, thia-3,4-diazolyl, 3-, 4-, or 5-isothiazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or 5-isoxazolyl, 3- or 5-1,2,4-triazolyl, 4- or 5-1,2,3triazolyl, tetrazolyl, 2-, 3- or 4-pyridyl, 3- or 4 -pyridazinyl, 3-, 4- or 5-pyrazinyl, 2-pyrazinyl, 2-, 4- or 5-pyrimidinyl.

As used herein, and unless otherwise indicated, the term heterocyclyl refers to an optionally substituted saturated or unsaturated non-aromatic (partially unsaturated) ring that is 4-, 5-, 6-, or 7-membered monocyclic and contains at least one a heteroatom selected from O, S and N, where N and S can also optionally be oxidized to different oxidation states. The heterocyclyl radical can be linked via a carbon atom or a heteroatom (eg N). In one embodiment, the heterocyclyl moiety is a saturated monocyclic ring containing 4-7 ring atoms and optionally containing an additional heteroatom selected from O, S, or N. The heterocyclic group may be attached at a heteroatom or carbon atom. Examples of heterocycles include dihydrofuranyl, dioxolanyl, dioxanyl, dithianil, piperazinyl, pyrrolidine, dihydropyranyl, oxathiolanyl, dithiolane, oxathianyl, thiomorpholino, oxiranyl, aziridinyl, oxetanyl, tetanyl, tetanyl, oxepanyl, azetidroferinyl , oxapinil, oxaazepanil, oxathianil, thiepanil, azepanil, dioxepanil, and diazepanil.

Various (listed) embodiments of the present invention are described herein. It will be understood that the characteristics described in each embodiment may be combined with other described characteristics to provide additional embodiments of the present invention.

In Embodiment 2, the present invention relates to the compound of Embodiment 1 wherein R ¹ is CH ₃ , cyclopropyl, —CH ₂ OH, or CH═NH — OH; or a pharmaceutically acceptable salt thereof.

In Embodiment 3, the present invention relates to a compound according to any one of Embodiments 1 or 2, wherein R ² is H or —NH — CH3; or a pharmaceutically acceptable salt thereof.

In Embodiment 4, the present invention relates to a compound according to any of Embodiments 1-3, wherein R ⁴ is H or halogen; or a pharmaceutically acceptable salt thereof.

In Embodiment 5, the present invention relates to a compound according to any one of Embodiments 1-4, wherein R ⁵ is H, F, CN, or C _2-4 alkynyl substituted with thiomorpholine; or a pharmaceutically acceptable salt thereof.

In Embodiment 6, the present invention relates to a compound according to any of Embodiments 1-5, wherein R ⁶ is Cl or CN; or a pharmaceutically acceptable salt thereof.

In Embodiment 7, the present invention relates to a compound according to any one of Embodiments 1-6, wherein R ³ is hydroxyC _1-4 alkyl, hydroxyC _1-6 alkoxy, —O (CH2CH2 — O) nH, —O- (CH2CH2- O) _m CH3, -NH- (CH2CH2O) nH, -NH- (CH2CH2-O) _m CH3, azetidine substituted by hydroxyl, pyrrolidine substituted with one or more substituents independently selected from hydroxyl and hydroxyC _1-4 alkyl or piperazine, substituted with hydroxyC _1-4 alkyl; or its pharmaceutically acceptable salt.

In Embodiment 8, the present invention relates to a compound according to any one of Embodiments 1-6, wherein R ^{3 is} selected from the following groups:

where n is equal to 2-6;

or a pharmaceutically acceptable salt thereof.

In Embodiment 9, the present invention relates to a compound according to any one of Embodiments 1-6, wherein R ^{3 is} selected from the following groups:

or a pharmaceutically acceptable salt thereof.

- 6 038455

In embodiment 12, the present invention relates to a compound according to embodiment 1, wherein R ¹ is CH ₃ or CH 2 OH, R ² is H, R ³ is —OR ^a or —NHR ^b , R ⁴ is Cl, R ⁵ is H or F, and R ⁶ is Cl; or a pharmaceutically acceptable salt thereof.

In embodiment 11, the present invention relates to a compound selected from the group consisting of (S) -8-chloro-1- (2,6-dichlorophenyl) -5- (2,3-dihydroxypropoxy) 2- (hydroxymethyl) -1 , 6-naphthyridin-4 (1H) -one;

(R) -8-chloro-1- (2,6-dichlorophenyl) -5- (2,3-dihydroxypropoxy) 2- (hydroxymethyl) -1,6-naphthyridin-4 (1H) -one;

8-chloro-1- (2,6-dichlorophenyl) -5- (2,3-dihydroxypropoxy) -2 (hydroxymethyl) -1,6-naphthyridin-4 (1H) -one;

8-chloro-1- (2,6-dichlorophenyl) -5- (2, 3-dihydroxy-Zmethylbutoxy) -2- (hydroxymethyl) -1,6-naphthyridin-4 (1H) -one;

8-chloro-1- (2,6-dichlorophenyl) -2- (hydroxymethyl) -5 - ((3 (hydroxymethyl) oxetan-3-yl) methoxy) -1,6-naphthyridin-4 (1H) -one;

N- (2- ((8-chloro-1- (2,6-dichlorophenyl) -2- (hydroxymethyl) -4-oxo1,4-dihydro-1,6-naphthyridin-5-yl) oxy) ethyl) methanesulfonamide ;

8-chloro-1- (2,6-dichlorophenyl) -5- (2- (2- (2- (2hydroxyethoxy) ethoxy) ethoxy) ethoxy) -2- (hydroxymethyl) -1,6naphthyridine-4 (1Н) - she;

8-chloro-1- (2,6-dichlorophenyl) -5- (3-hydroxy-2 (hydroxymethyl) propoxy) -2- (hydroxymethyl) -1,6-naphthyridin-4 (1H) one;

8-chloro-1- (2,6-dichlorophenyl) -5- ((1, 3-dihydroxypropan-2yl) oxy) -2- (hydroxymethyl) -1,6-naphthyridin-4 (1H) -one;

- 7 038455

8-chloro-1- (2,6-dichlorophenyl) -2- (hydroxymethyl) -5- (oxetane-3ylmethoxy) -1,6-naphthyridin-4 (1H) -one;

8-chloro-1- (2,6-dichlorophenyl) -2- (hydroxymethyl) -5- (2- (2methoxyethoxy) ethoxy) -1,6-naphthyridin-4 (1H) -one;

8-chloro-1- (2,6-dichlorophenyl) -5- (2-hydroxyethoxy) -2 (hydroxymethyl) -1,6-naphthyridin-4 (1H) -one;

8-chloro-1- (2,6-dichlorophenyl) -5- ((2- (2- (2- (2hydroxyethoxy) ethoxy) ethoxy) ethyl) amino) -2- (hydroxymethyl) -1.6naphthyridine-4 ( 1H) -one;

8-chloro-1- (2,6-dichlorophenyl) -5 - ((14-hydroxy-3, 6,9,12 tetraoxatetradecyl) oxy) -2-methyl-1,6-naphthyridin-4 (1H) -one;

5- (2,5,8,11,14,17-hexaoxanoneadecan-19-yloxy) -8-chloro-1 (2,6-dichlorophenyl) -2-methyl-1,6-naphthyridine-4 (1H) - she;

3-chloro-2- (8-chloro-5- ((2- (2- (2- (2hydroxyethoxy) ethoxy) ethoxy) ethyl) amino) -2-methyl-4-oxo-1,6naphthyridine-1 (4H ) -yl) benzonitrile;

3 - ((8-chloro-1- (2,6-dichlorophenyl) -2-methyl-4-oxo-1,4-dihydro-

1,6-naphthyridin-5-yl) amino) -2-hydroxy-N- (2hydroxyethyl) propanamide;

3,5-dichloro-4- (5- (2,3-dihydroxypropoxy) -2-methyl-4-oxo

1,7-naphthyridin-1 (4H) -yl) benzonitrile;

8-chloro-1- (2,6-dichlorophenyl) -5 - ((17-hydroxy-3, 6,9,12,15pentaoxaheptadecyl) oxy) -2-methyl-1,6-naphthyridine-4 (1H) - she;

8-chloro-1- (2,6-dichlorophenyl) -5- (3- (2,3-dihydroxypropoxy) -2 hydroxypropoxy) -2-methyl-1,6-naphthyridin-4 (1H) -one;

3-chloro-2- (8-chloro-5- (2- (2- (2- (2hydroxyethoxy) ethoxy) ethoxy) ethoxy) -2-methyl-4-oxo-1,6naphthyridin-1 (4H) -yl ) benzonitrile;

N- (2- ((1- (2,6-dichloro-4-cyanophenyl) -2-methyl-4-oxo-1,4-dihydro-1,7-naphthyridin-5-yl) amino) ethyl) methanesulfonamide;

3-chloro-2- (8-chloro-5- (2- (2- (2- (2hydroxyethoxy) ethoxy) ethoxy) ethoxy) -2-methyl-4-oxo-1,6naphthyridin-1 (4H) -yl ) -5-fluorobenzonitrile;

8-chloro-1- (2,6-dichloro-4-fluorophenyl) -5 - ((17-hydroxy3,6,9,12,15-pentaoxaheptadecyl) oxy) -2-methyl-1,6-naphthyridine4 (1Н )-she;

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3,5-dichloro-4- (8-chloro-5- (4- (2-hydroxyethyl) piperazin-1-yl) 2-methyl-4-oxo-1,6-naphthyridin-1 (4H) -yl) benzonitrile;

8-chloro-1- (2,6-dichlorophenyl) -2-methyl-5- (2,3,4trihydroxybutoxy) -1,6-naphthyridin-4 (1H) -one;

3,5-dichloro-4- (5 - ((2-hydroxyethyl) amino) -2-methyl-4-oxo-1,7naphthyridin-1 (4H) -yl) benzonitrile;

8-chloro-1- (2,6-dichlorophenyl) -5- (3-hydroxy-2,2bis (hydroxymethyl) propoxy) -2-methyl-1,6-naphthyridin-4 (1H) -one;

3,5-dichloro-4- (5- (3-hydroxyazetidin-1-yl) -2-methyl-4-oxo1,7-naphthyridin-1 (4H) -yl) benzonitrile;

8-chloro-1- (2,6-dichlorophenyl) -5- (2- (2- (2- (2hydroxyethoxy) ethoxy) ethoxy) ethoxy) -2-methyl-1,6-naphthyridin4 (1H) -one;

8-chloro-1- (2,6-dichlorophenyl) -5 - ((2R, 4S) -4-hydroxy-2 (hydroxymethyl) pyrrolidin-1-yl) -2-methyl-1,6-naphthyridine-4 ( 1H) she;

8-chloro-1- (2,6-dichloro-4-fluorophenyl) -5- (2- (2- (2- (2hydroxyethoxy) ethoxy) ethoxy) ethoxy) -2-methyl-1,6-naphthyridine4 (1Н )-she;

8-chloro-1- (2,6-dichlorophenyl) -5 - ((3R, 4S) -3,4 dihydroxypyrrolidin-1-yl) -2-methyl-1,6-naphthyridin-4 (1H) -one;

3-chloro-2- (8-chloro-5- (2,3-dihydroxypropoxy) -2-methyl-4-oxo1,6-naphthyridin-1 (4H) -yl) benzonitrile;

5 - ((2 - (1H-imidazol-4-yl) ethyl) amino) -8-chloro-1- (2,6dichlorophenyl) -2-methyl-1,6-naphthyridin-4 (1H) -one;

N- (2- ((8-chloro-1- (2,6-dichlorophenyl) -2-methyl-4-oxo-1,4-dihydro-1,6-naphthyridin-5-yl) oxy) ethyl) methanesulfonamide;

8-chloro-1- (2,6-dichlorophenyl) -5- ((2- (2- (2- (2hydroxyethoxy) ethoxy) ethoxy) ethyl) amino) -2-methyl-1,6-naphthyridine4 (1H) -she;

8-chloro-1- (2,6-dichlorophenyl) -5- (2,3-dihydroxypropoxy) -2methyl-1,6-naphthyridin-4 (1H) -one;

(S) -8-chloro-1- (2,6-dichlorophenyl) -5 - ((2,3dihydroxypropyl) amino) -2-methyl-1,6-naphthyridin-4 (1H) -one;

8-chloro-1- (2,6-dichlorophenyl) -5- (2, 3-dihydroxy-Zmethylbutoxy) -2-methyl-1,6-naphthyridin-4 (1H) -one;

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8-chloro-1- (2,6-dichlorophenyl) -5- (3-hydroxy-2- (hydroxymethyl) 2-methylpropoxy) -2-methyl-1,6-naphthyridin-4 (1H) -one;

8-chloro-1- (2,6-dichlorophenyl) -5- (2-hydroxy-2-methylpropoxy) 2-methyl-1,6-naphthyridin-4 (1H) -one;

3,5-dichloro-4- (8-chloro-5 - (((3R, 4S) -4-hydroxytetrahydrofuran3-yl) amino) -2-methyl-4-oxo-1,6-naphthyridine-1 (4H) -yl) benzonitrile

3,5-dichloro-4- (8-chloro-5 - ((2-hydroxyethoxy) amino) -2-methyl-4oxo-1,6-naphthyridin-1 (4H) -yl) benzonitrile;

8-chloro-1- (2,6-dichlorophenyl) -2-methyl-5 - ((1-methyl-1H-tetrazol5-yl) amino) -1,6-naphthyridin-4 (1H) -one;

8-chloro-1- (2,6-dichlorophenyl) -2-methyl-5 - ((1-methyl-1H-tetrazol5-yl) oxy) -1,6-naphthyridin-4 (1H) -one;

8-chloro-1- (2,6-dichlorophenyl) -2-methyl-5 - ((2-methyl-2H-tetrazol5-yl) amino) -1,6-naphthyridin-4 (1H) -one;

8-chloro-1- (2,6-dichlorophenyl) -5- (2-hydroxyethoxy) -2-methyl1,6-naphthyridin-4 (1H) -one;

8-chloro-1- (2,6-dichlorophenyl) -5- ((2-hydroxyethoxy) amino) -2methyl-1,6-naphthyridin-4 (1H) -one;

8-chloro-1- (2,6-dichlorophenyl) -2-methyl-5- (oxetan-3-ylmethoxy) 1,6-naphthyridin-4 (1H) -one;

8-chloro-1- (2,6-dichlorophenyl) -2- (hydroxymethyl) -5 - ((2 (methylsulfonyl) ethyl) amino) -1,6-naphthyridin-4 (1H) -one;

8-cyclopropyl-1- (2,6-dichlorophenyl) -5- (2,3dihydroxypropoxy) -2-methyl-1,6-naphthyridin-4 (1H) -one;

8-chloro-1- (2,6-dichlorophenyl) -5- (3-hydroxy-2 (hydroxymethyl) propoxy) -2- (methoxymethyl) -1,6-naphthyridin-4 (1H) one;

8-chloro-1- (2,6-dichlorophenyl) -5- (2,3-dihydroxypropoxy) -2 (methoxymethyl) -1,6-naphthyridin-4 (1H) -one;

3-chloro-2- (8-chloro-2-cyclopropyl-5- (2,3-dihydroxypropoxy) 4-oxo-1,6-naphthyridin-1 (4H) -yl) benzonitrile;

4- (5- ((2- (1H-imidazol-4-yl) ethyl) amino) -2-methyl-4-oxo-1,7naphthyridin-1 (4H) -yl) -3,5-dichlorobenzonitrile;

8-chloro-1- (2,6-dichlorophenyl) -5- ((2,2-dimethyl-1, 3-dioxolan-4yl) methoxy) -2- (hydroxymethyl) -1,6-naphthyridine-4 (1Н )-she;

(R) -8-chloro-1- (2,6-dichlorophenyl) -5- (2, 3-dihydroxy-3- 10 038455 methylbutoxy) -2-methyl-1,6-naphthyridin-4 (1H) -one ;

(S) -8-chloro-1- (2,6-dichlorophenyl) -5- (2, 3-dihydroxy-Zmethylbutoxy) -2-methyl-1, b-naphthyridin-4 (1H) -one;

8-chloro-1- (2,6-dichloro-4-fluorophenyl) -5- (2,3dihydroxypropoxy) -2- (hydroxymethyl) -1,6-naphthyridin-4 (1H) -one;

8-chloro-1- (2,6-dichloro-4-fluorophenyl) -5- (2-hydroxyethoxy) -2 (hydroxymethyl) -1,6-naphthyridin-4 (1H) -one;

8-chloro-1- (2,6-dichlorophenyl) -2- (difluoromethyl) -5- (2,3dihydroxypropoxy) -1,6-naphthyridin-4 (1H) -one;

8-chloro-1- (2,6-dichlorophenyl) -5- (2,3-dihydroxypropoxy) -4oxo-1,4-dihydro-1,6-naphthyridine-2-carbonitrile;

8-chloro-1- (2,6-dichlorophenyl) -5-hydroxy-2- (hydroxymethyl) -

1,6-naphthyridin-4 (1H) -one;

1- (2,6-dichlorophenyl) -5- (2,3-dihydroxypropoxy) -2-methyl-7 (methylamino) -1,6-naphthyridin-4 (1H) -one;

1- (2,6-dichlorophenyl) -5- (2,3-dihydroxypropoxy) -7-ethyl-2methyl-1,6-naphthyridin-4 (1H) -one;

1- (2-chloro-6-ethylphenyl) -5- (2,3-dihydroxypropoxy) -7-ethyl-2 methyl-1,6-naphthyridin-4 (1H) -one;

1- (2,6-dichlorophenyl) -5- (2,3-dihydroxypropoxy) -7-methoxy-2 methyl-1,6-naphthyridin-4 (1H) -one;

1- (2,6-dichlorophenyl) -5- (2,3-dihydroxypropoxy) -8-ethyl-2methyl-1,6-naphthyridin-4 (1H) -one;

Ν- (1- (2,6-dichloro-4-cyanophenyl) -2-methyl-4-oxo-1,4-dihydro1,7-naphthyridin-5-yl) -1H-pyrazole-4-sulfonamide;

8-chloro-1- (2,6-dichlorophenyl) -2-methyl-5- (1H-1,2,4-triazol-1yl) -1,6-naphthyridin-4 (1H) -one;

3,5-dichloro-4- (2-methyl-4-oxo-5- (1H-pyrazol-3-yl) -1,7naphthyridin-1 (4H) -yl) benzonitrile;

3,5-dichloro-4- (2-methyl-5- (1-methyl-1H-pyrazol-4-yl) -4-oxo

1,7-naphthyridin-1 (4H) -yl) benzonitrile;

8-chloro-1- (2,6-dichlorophenyl) -2- (hydroxymethyl) -5- (3hydroxypropyl) -1,6-naphthyridin-4 (1H) -one;

8-chloro-1- (2,6-dichlorophenyl) -5- (3,4-dihydroxybutyl) -2 (hydroxymethyl) -1,6-naphthyridin-4 (1H) -one;

(R) -8-chloro-1- (2,6-dichlorophenyl) -5- (3,4-dihydroxybutyl) -2-11,038455 (hydroxymethyl) -1,6-naphthyridin-4 (1H) -one;

(S) -8-chloro-1- (2,6-dichlorophenyl) -5- (3,4-dihydroxybutyl) -2 (hydroxymethyl) -1,6-naphthyridin-4 (1H) -one;

8-chloro-1- (2,6-dichlorophenyl) -5- (2,3-dihydroxypropyl) -2 (hydroxymethyl) -1,6-naphthyridin-4 (1H) -one;

(R) -8-chloro-1- (2,6-dichlorophenyl) -5- (2,3-dihydroxypropyl) -2 (hydroxymethyl) -1,6-naphthyridin-4 (1H) -one;

(S) -8-chloro-1- (2,6-dichlorophenyl) -5- (2,3-dihydroxypropyl) -2 (hydroxymethyl) -1,6-naphthyridin-4 (1H) -one;

8-chloro-1- (2,6-dichlorophenyl) -5- (2,3-dihydroxypropyl) -2methyl-1,6-naphthyridin-4 (1H) -one;

8-chloro-1- (2,6-dichlorophenyl) -5- (1,2-dihydroxyethyl) -2 (hydroxymethyl) -1,6-naphthyridin-4 (1H) -one;

(R) -8-chloro-1- (2,6-dichlorophenyl) -5- (1,2-dihydroxyethyl) -2 (hydroxymethyl) -1,6-naphthyridin-4 (1H) -one;

(S) -8-chloro-1- (2,6-dichlorophenyl) -5- (1,2-dihydroxyethyl) -2 (hydroxymethyl) -1,6-naphthyridin-4 (1H) -one;

8-chloro-1- (2,6-dichlorophenyl) -5- (1,2-dihydroxyethyl) -2-methyl1,6-naphthyridin-4 (1H) -one;

8-chloro-1- (2,6-dichlorophenyl) -5- (2-hydroxyacetyl) -2-methyl1,6-naphthyridin-4 (1H) -one;

8-chloro-1- (2,6-dichlorophenyl) -5 - ((2,3dihydroxypropoxy) methyl) -2- (hydroxymethyl) -1,6-naphthyridin4 (1H) -one;

8-chloro-1- (2,6-dichlorophenyl) -5 - (((1, 3-dihydroxypropane-2yl) oxy) methyl) -2- (hydroxymethyl) -1,6-naphthyridin-4 (1Н) -one ;

8-chloro-1- (2,6-dichlorophenyl) -5- (2,4-dihydroxy-3-oxobutane-2yl) -2-methyl-1,6-naphthyridin-4 (1H) -one;

1- (4- (3-amino-3-methylbut-1-yn-1-yl) -2,6-dichlorophenyl) -8chloro-5- (2,3-dihydroxypropoxy) -2-methyl-1,6- naphthyridine-4 (1H) one;

8-chloro-1- (2,6-dichloro-4- (3-morpholinoprop-1-yn-1-yl) phenyl) -5 (2-hydroxyethoxy) -2-methyl-1,6-naphthyridine-4 ( 1H) -one;

8-chloro-1- (2,6-dichloro-4- (3- (1,1-dioxidothiomorpholino) prop-1in-1-yl) phenyl) -5- (2-hydroxyethoxy) -2-methyl-1, 6-naphthyridin4 (1H) -one;

8-chloro-1- (2,6-dichloro-4- (3- (dimethylamino) prop-1-yn-1yl) phenyl) -5- ((2,2-dimethyl-1, 3-dioxolane-4- yl) methoxy) -2-methyl1,6-naphthyridin-4 (1H) -one and (8-chloro-1- (2,6-dichlorophenyl) -5- (2,3-dihydroxypropoxy) -4oxo-1, 4 -dihydro-1,6-naphthyridin-2-yl) methyldihydrogen phosphate; or a pharmaceutically acceptable salt thereof.

12. A compound according to claim 1 selected from the group consisting of (S) -8-chloro-1- (2,6-dichlorophenyl) -5- (2,3-dihydroxypropoxy) 2- (hydroxymethyl) -1.6 -naphthyridin-4 (1H) -one;

(R) -8-chloro-1- (2,6-dichlorophenyl) -5- (2,3-dihydroxypropoxy) 2- (hydroxymethyl) -1,6-naphthyridin-4 (1H) -one;

8-chloro-1- (2,6-dichlorophenyl) -5- (2,3-dihydroxypropoxy) -2 (hydroxymethyl) -1,6-naphthyridin-4 (1H) -one;

(R) -8-chloro-1- (2,6-dichlorophenyl) -5- (3,4-dihydroxybutyl) -2 (hydroxymethyl) -1,6-naphthyridin-4 (1H) -one;

(S) -8-chloro-1- (2,6-dichlorophenyl) -5- (3,4-dihydroxybutyl) -2 (hydroxymethyl) -1,6-naphthyridin-4 (1H) -one; and

8-chloro-1- (2,6-dichlorophenyl) -5- (3,4-dihydroxybutyl) -2 (hydroxymethyl) -1,6-naphthyridin-4 (1H) -one; or a pharmaceutically acceptable salt thereof.

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In Embodiment 13, the present invention relates to a compound representing (S) -8-chloro-1- (2,6-dichlorophenyl) -5- (2,3-dihydroxypropoxy) -2- (hydroxymethyl) -1,6- naphthyridin4 (1H) -one or a pharmaceutically acceptable salt thereof.

In Embodiment 14, the present invention provides (S) -8-chloro-1- (2,6-dichlorophenyl) -5- (2,3-dihydroxypropoxy) -2- (hydroxymethyl) -1,6-naphthyridine-4 (1H ) -one characterized by an X-ray powder diffractogram (XRPD) containing one or more peaks selected from 7.0 ± 0.2 ° 2θ, 14.1 ± 0.2 ° 2θ, 18.5 ± 0.2 ° 2θ, 24.7 ± 0.2 ° 2θ, 26.0 ± 0.2 ° 2θ and 26.9 ± 0.2 ° 2θ, when measured using CuKa radiation with a wavelength of 1.5418 A and a temperature of 22 ° WITH.

The term essentially the same with reference to the positions of the X-ray diffraction peaks means that the typical variability in the position and intensity of the peak is taken into account. For example, one skilled in the art will understand that peak positions (2θ) will exhibit some variability between devices, typically up to 0.2 °. Sometimes variability can be more than 0.2 ° depending on differences in device calibration. In addition, one skilled in the art will understand that the relative peak intensity values will exhibit some variability between devices, as well as variability due to the degree of crystallinity, preferred orientation obtained by the sample surface, and other factors known to those of skill in the art and should be considered. only as a qualitative indicator.

Depending on the choice of starting materials and procedures, the compounds can be in the form of one of the possible stereoisomers or in the form of mixtures thereof, for example, in the form of pure optical isomers, or in the form of a mixture of stereoisomers, such as racemates and mixtures of diastereoisomers, depending on the number of asymmetric atoms carbon. The present invention is intended to include all such possible stereoisomers, including racemic mixtures, mixtures of diastereoisomers, and optically pure forms. Optically active (R) - and (S) -stereoisomers can be prepared using chiral synthons or chiral reagents, or isolated using conventional techniques. If the compound contains a double bond, the substituent can have the E- or Z-configuration. If the compound contains a disubstituted cycloalkyl, the cycloalkyl substituent may have the cis or trans configuration. Also intended to include all tautomeric forms.

As used herein, the terms salt or salts refer to an acid addition or base addition salt of a compound of the present invention. Salts include, in particular, pharmaceutically acceptable salts. The term pharmaceutically acceptable salts refers to salts that retain the biological effectiveness and properties of the compounds of the present invention and which are generally not biologically or otherwise undesirable. In many cases, the compounds of the present invention are capable of forming acidic and / or base salts due to the presence of amino and / or carboxyl groups or the like.

Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids.

Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.

Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, sulfosalicylic acid and the like.

In another aspect, the present invention provides compounds of formula II or III in the form of a salt of acetate, ascorbate, adipate, aspartate, benzoate, besylate, bromide / hydrobromide, bicarbonate / carbonate, bisulfate / sulfate, camphorsulfonate, caprate, chloride / hydrochloride, chlorotheophyllonate, citrate, ethanedisulfonate, fumarate, gluceptate, gluconate, glucuronate, glutamate, glutarate, glycolate, hippurate, hydroiodide / iodide, isethionate, lactate, lactobionate, lauryl sulfate, malate, methylate, malonic acid acids, naphthoic acid salt, napsylate, nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate, phosphate / hydrogen phosphate / dihydrogen phosphate, polygalacturonate, propionate, sebacate, stearate, succinate, sulfosalicylate, sulphate acetate, tartaric acid trifate ...

Any formula given in this document also implies the presence of unlabeled forms as well as isotopically labeled forms of the compounds. Isotopically labeled compounds have the structures depicted by the formulas set forth herein, except that one or more atoms are replaced by an atom having a selected atomic mass or mass number.

Isotopes that can be included in the compounds of the present invention include, for example, hydrogen isotopes.

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In addition, substitution with heavier isotopes, in particular deuterium (i.e. ² H or D), may provide certain therapeutic benefits due to higher resistance to metabolic inactivation, for example, increased in vivo half-life, or reduced dosage rates. , or improvement in therapeutic index or tolerance. It should be understood that deuterium in this context is considered as a substitute for a compound of formula II or III. The deuterium concentration can be determined by means of the isotope enrichment factor. As used herein, the term isotope enrichment factor means the ratio of the abundance of an isotope to the abundance in nature of a specified isotope. When a substituent in a compound of the present invention is indicated as deuterium, such a compound has an isotopic enrichment factor for each designated deuterium atom of at least 3500 (introduction of 52.5% deuterium for each designated deuterium atom), at least 4000 (introduction of 60% deuterium), at least 4500 (introducing 67.5% deuterium), at least 5000 (introducing 75% deuterium), at least 5500 (introducing 82.5% deuterium), at least 6000 (introducing 90% deuterium) at least 6333.3 (introduction of 95% deuterium), at least 6466.7 (introduction of 97% deuterium), at least 6600 (introduction of 99% deuterium) or at least 6633.3 (introduction of 99.5% deuterium). It should be understood that the term isotopic enrichment factor can be applied to any isotope in the same manner as described for deuterium.

Other examples of isotopes that can be included in the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, such as ³ H, C ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁸ F ³¹ P, ³² P, ³⁵ S, ³⁶ Cl, ¹²³ I, ¹²⁴ I, ¹²⁵ I, respectively. Therefore, it should be understood that the present invention includes compounds that include one or more of any of the above isotopes, including, for example, radioactive isotopes such as ³ H and ¹⁴ C, or compounds in which non-radioactive isotopes are present, such as ² H and ¹³ C. Such isotopically labeled compounds are useful in metabolic studies (using ¹⁴ C), reaction kinetic studies (using, for example, ² H or ³ H), detection or imaging techniques such as positron emission tomography ( PET) or single photon emission computed tomography (SPECT), including tissue distribution assays of a drug or substrate, or in radiation therapy of patients. In particular, an ¹⁸ F or labeled compound may be particularly suitable for PET or SPECT studies. Isotopically labeled compounds of formula (I) can generally be prepared using conventional techniques known to those skilled in the art, or by methods analogous to those described in the accompanying examples and preparation methods, using a suitable isotopically labeled reagent instead of an unlabeled reagent. used previously.

Pharmaceutically acceptable solvates according to the present invention include those wherein the crystallization solvent may be isotope substituted, eg D ₂ O, d ₆ -acetone, d ₆ DMSO.

As used herein, the term pharmaceutical composition refers to a compound of the present invention, or a pharmaceutically acceptable salt thereof, together with at least one pharmaceutically acceptable carrier in a form suitable for oral or parenteral administration.

As used herein, the term pharmaceutically acceptable carrier refers to a substance useful in the preparation or use of a pharmaceutical composition and includes, for example, suitable diluents, solvents, dispersion media, surfactants, antioxidants, preservatives, isotonic agents, buffering agents, emulsifiers, absorption delaying agents, salts, drug stabilizers, binders, auxiliaries, disintegrating agents, lubricants, wetting agents, sweetening agents, flavoring agents, colors and combinations thereof, which should be known to those skilled in the art (see, for example , Remington The Science and Practice of Pharmacy , 22 ^nd Ed. Pharmaceutical Press, 2013, pp. 1049-1070).

The term therapeutically effective amount of a compound of the present invention refers to the amount of a compound of the present invention that will elicit a biological or medical response in a subject, for example, decrease or inhibit the activity of an enzyme or protein, or reduce the severity of symptoms, alleviate conditions, slow down or restrain the progression of a disease. or to prevent disease, etc. In one non-limiting embodiment, the term therapeutically effective amount refers to an amount of a compound of the present invention that, when administered to a subject, is effective in (1) at least partially alleviating, inhibiting, preventing and / or reducing the severity of a condition or disorder or disease, (i) mediated by the GIRK1 / 4 channel, or (ii) associated with the activity of the GIRK1 / 4 channel, or (iii) characterized by activity (normal or abnormal) GIRK1 / 4 channel; or (2) decreasing or inhibiting the activity of the GIRK1 / 4 channel; or (3) decreasing or inhibiting the expression of the GIRK1 / 4 channel. In another non-limiting embodiment, a therapeutically effective amount refers to an amount of a compound of the present invention that, when introduced into a cell, tissue, or non-cellular biological material, or medium, is effective to at least partially reduce or inhibit channel activity GIRK1 / 4; or at least partially reducing or inhibiting the expression of the GIRK1 / 4 channel.

As used herein, the term “subject” refers to humans, men or women. In other embodiments, the subject is a human.

As used herein, the term inhibit, inhibit, or inhibit refers to a decrease or amelioration of a given condition, symptom, or disorder, or disease, or a significant decrease in the original activity in relation to a biological activity or process.

As used herein, the term treat, treat, or treat any disease or disorder refers to alleviating or reducing the severity of a disease or disorder (ie, slowing or stopping the development of a disease or at least one of its clinical symptoms); or facilitating or reducing at least one physical parameter or biomarker associated with the disease or disorder, including those that may not be obvious to the patient.

As used herein, the term prevent, prevent, or prevent any disease or disorder refers to the prophylactic treatment of a disease or disorder, or slowing the onset or progression of a disease or disorder.

As used herein, the singular and similar terms used in the context of the present invention (particularly in the context of the claims) are to be construed to encompass both the singular and the plural, unless otherwise indicated herein, or there is no apparent contradiction in context.

All methods described herein can be performed in any suitable order, unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples or exemplary language (eg, such as) herein is intended only to better explain the present invention and is not intended to limit the scope of the present invention otherwise claimed. Any asymmetric atom (eg, carbon or the like) of the compound (s) of the present invention may be in racemic or enantiomerically enriched form, eg, in the (R) -, (S) - or (R, S) -configuration. In certain embodiments, each asymmetric atom has an enantiomeric excess of at least 50%, an enantiomeric excess of at least 60%, an enantiomeric excess of at least 70%, an enantiomeric excess of at least 80%, an enantiomeric excess of at least 90%, an enantiomeric excess of at least 95%, or an enantiomeric excess of at least 99%, in the (I) or S-configuration. Substituents on atoms with unsaturated double bonds may, if possible, be in the cis- (2) - or trans- (E) -form.

Accordingly, the compound of the present invention used in this document may be in the form of one of the possible stereoisomers, rotamers, atropisomers, tautomers, or mixtures thereof, for example, in the form of substantially pure geometric (cis or trans) stereoisomers, diastereomers, optical isomers (antipodes ), racemates or mixtures thereof.

Any resulting mixtures of stereoisomers can be separated on the basis of physicochemical differences of the constituents into pure or substantially pure geometric or optical isomers, diastereomers, racemates, for example, by chromatography and / or fractional crystallization.

Any resulting racemates of end products or intermediates can be resolved into optical antipodes by known methods, for example, by separating their diastereomeric salts obtained with an optically active acid or base and isolating an optically active acidic or base compound. In particular, the basic moiety can thus be used to separate the compounds of the present invention into their optical antipodes, for example, by fractional crystallization of a salt formed with an optically active acid, for example tartaric acid, dibenzoyltartaric acid, diacetyl tartaric acid, di-O, O ' -p-toluene acid, mandelic acid, malic acid or camphor-10sulfonic acid. Racemic products can also be separated by chiral chromatography such as high pressure liquid chromatography (HPLC) using a chiral adsorbent.

The present invention also provides prodrugs based on the compounds of the present invention that are converted in vivo to the compounds of the present invention. A prodrug is an active or inactive compound that is chemically modified by an in vivo physiological action such as hydrolysis, metabolism, etc., into a compound of the present invention after the prodrug is administered to a subject. Suitability and techniques used

15,038455 useful for the manufacture and use of prodrugs are well known to those skilled in the art. Prodrugs can essentially be divided into two non-exclusive categories: bioprecursor prodrugs and carrier prodrugs. See The Practice of Medicinal Chemistry, Ch. 31-32 (Ed. Wermuth, Academic Press, San Diego, Calif., 2001). Typically, bioprecursor prodrugs are compounds that are inactive or have low activity compared to the corresponding active drug compound, which contain one or more protecting groups and are converted to the active form by metabolism or solvolysis. Both the active drug form and any released metabolic products should have acceptably low toxicity.

Carrier prodrugs are drug compounds that contain a transport moiety, for example, that enhances uptake and / or localized delivery to the site (s) of action. Desirably, for such a prodrug carrier, the bond between the drug moiety and the transport moiety is a covalent bond, the prodrug is inactive or less active than the drug compound, and any released transport moiety is acceptably non-toxic. For prodrugs where the transport moiety is intended to increase uptake, the release of the transport moiety should generally be rapid. In other cases, it is desirable to use a moiety that provides slow release, for example, certain polymers or other moieties such as cyclodextrins. A prodrug carrier, for example, can be used to improve one or more of the following properties: increased lipophilicity, increased duration of pharmacological effects, increased site specificity, reduced toxicity and adverse reactions, and / or improvement in drug formulation (e.g. stability, solubility in water, suppression of undesirable organoleptic or physicochemical properties). For example, lipophilicity can be increased by esterification of (a) hydroxyl groups with lipophilic carboxylic acids (e.g., carboxylic acid containing at least one lipophilic moiety) or (b) carboxylic acid groups with lipophilic alcohols (e.g., alcohol containing at least one lipophilic moiety) at least one lipophilic moiety, for example aliphatic alcohols). For example, the solubility can be increased by esterification of the hydroxy group with phosphoric acid.

Illustrative prodrugs, for example, are O-acyl or O-phosphate derivatives of alcohols or phenols, where acyl is as defined herein. Suitable acids for the formation of O-acyl prodrugs are, for example, substituted or unsubstituted alkyl, cycloalkyl or benzyl carboxylic acids. Amines have been disguised as arylcarbonyloxymethyl substituted derivatives that are cleaved by esterases in vivo to release free drug and formaldehyde (Bundgaard, J. Med. Spec. 2503 (1989)). Moreover, drugs containing an acidic NH group, such as imidazole, imide, indole, etc., have been masked with N-acyloxymethyl groups (Bundgaard, Design of Prodrugs, Elsevier (1985)). Hydroxy groups were masked as esters and ethers, vicinal diols were masked as cyclic acetals or ketals. In addition, the compounds of the present invention, including their salts, can also be obtained in the form of their hydrates, or they can include other solvents used to crystallize them. The compounds of the present invention may, by nature or by design, form solvates with pharmaceutically acceptable solvents (including water); therefore, the present invention is intended to encompass both solvated and unsolvated forms. The term solvate refers to a molecular complex of a compound of the present invention (including pharmaceutically acceptable salts thereof) with one or more solvent molecules. Such solvent molecules are those widely used in the pharmaceutical field that are known to be non-toxic to the recipient, for example water, ethanol, and the like. The term hydrate refers to a complex in which the solvent molecule is water.

In one embodiment, the compound of formula II or III is in the form of a hydrate.

Typically, compounds of Formula II or III can be prepared according to Schemes B, C, D below. The required intermediates J are prepared as described below in Scheme A.

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Scheme A

In Scheme A, aromatic starting material A is deprotonated with a strong base (eg, LDA or n-BuLi) and reacted with, for example, an alkyl formate or DMF to provide an aromatic aldehyde. Aldehyde B can be reacted with a deprotonated alkyne (eg, Grignard reagent or lithiated material) to provide benzyl alcohols C, which are oxidized to a ketone under suitable oxidizing conditions, for example with a Dess-Martin periodine reagent. Alternatively, ketones D can be obtained from aromatic acids E, which are coupled with an amine to form amides F, which are a substrate for reaction with suitable Grignard reagents. The reaction of aniline under Lewis acid catalysis conditions (for example, AlCl ₃ , BF ₃ * Et2O, Sc (OTf) ₃ ) provides intermediates H, which can be cyclized to give annelated 4pyridones under basic conditions (for example, using potassium carbonate) ...

X ² , X ^{3 are} defined in the Summary of the Invention section, and R ¹ *, R ⁴ *, R ⁵ * and R ⁶ * include definitions for R ¹ , R ⁴ , R ⁵ and R ⁶ as defined in the Summary of the Invention section. but can also represent substituents that can be converted to R ¹ , R ⁴ , R ⁵ and R ⁶ .

Scheme B describes the synthesis of a compound of formulas II or III, where R ¹ is CH2OH, CHF2, CHO, CN, CH3, R ³ is —OR ^a or —NHR ^b , and / or R ² is C1-4α alkoxy, haloC _1-4 alkoxy; and —NH — C _1-4 alkyl.

Scheme B

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Intermediates J can be directly converted to compounds 1a by nucleophilic aromatic substitution with amines and alcohols and, if necessary, subsequent manipulation of the protecting group. For intermediates K, the substituent R4 can be introduced, for example, by reaction with zinc-containing reagents or by Suzuki coupling with boronic acids. For intermediates L, the methyl group can be oxidized with selenium dioxide to an aldehyde, which can be converted to a primary alcohol, for example, by reduction with NaBH ₄ . The aldehyde functional group can also be converted to a difluoromethyl group by fluorination with a suitable fluorinating agent. Additionally, the aldehyde group can be converted to nitrile by a sequence of reactions involving oxidation to acid, amide formation and dehydration. For intermediates N with X ² = CC1, a second nucleophilic aromatic substitution with alcohols, amines, Grignard reagents or zinc-containing reagents can provide compounds of general formula Ib.

Scheme C describes the introduction of various R ³ groups other than that described in Scheme B.

Scheme C

In accordance with Scheme C, Intermediates J can be coupled via Pd-catalyzed Suzuki coupling with boronic acids to give examples of general formula Ic where R is attached to the ring system via a C-C bond. Alternatively, intermediates J can also be reacted with Grignard reagents to give compounds P, which can be converted to examples of formula Id and Ie using the conditions outlined in the scheme. The reaction of intermediates J with stannanes provides, for example, intermediates O and Q, which can be converted by a number of conditions into additional examples of the general formula If and Ig.

Scheme D describes the synthesis of a compound of Formula I wherein R ⁵ is C _2-6 alkynyl.

Scheme D

R is selected such that RW is part of R ³ defined in formula I

R is selected such that —CC — R is part of R ⁵ as defined in formula I

Intermediates J can be converted to R compounds via nucleophilic aromatic substitution. Reaction with terminal alkynes by Pd / Cu catalysis (Sonogashira coupling) and, if necessary, subsequent manipulations with the protecting group provide examples of general formula Ih.

The present invention further includes any variant of the methods of the present invention, in which the intermediate product obtained in any of its steps is used as a starting material and the remaining steps are carried out, or in which the starting materials are obtained in situ under the reaction conditions, or in which the components of the reaction mixture used in the form of their salts or optically pure substances.

The compounds of the present invention and intermediates can also be converted into each other according to methods well known to those skilled in the art.

Method of the present invention

Compounds of any of formulas II or III, in free form or in pharmaceutically acceptable salt form, exhibit valuable pharmacological properties, for example, modulating properties on the GIRK1 / 4 channel, for example, as shown by the in vitro and in vivo tests set forth in the following sections, and are therefore intended for therapy or for use as research chemicals, for example as pharmacologically active compounds.

As previously described, GIRK1 / 4 has been identified as a desirable antiarrhythmic target in atrial fibrillation.

In addition, GIRK1 / 4 blockers have been described as potentially useful in dysregulation of the sinoatrial / atrioventricular nodes: GIRK1 / 4 channels mediate the repolarization of spontaneously depolarized cells of the sinoatrial (SAN) and atrioventricular (AVN) nodes. Acetylcholine, released from efferent neurons of the vagus nerve, binds to muscarinic M2 receptors present in these tissues, which in turn act on the GIRK1 / 4 channels, leading to their opening, and ensure the outflow of potassium ions from the cell. This repolarization (or hyperpolarization, depending on the amount of outflow) determines the time between spontaneous depolarizations and, therefore, the heart rate and the magnitude of the AV nodal conduction. Blockade of GIRK1 / 4 channels is expected to counteract the negative chronotropic effects of acetylcholine, and this has been observed with the selective peptide, tertiapine, which is a GIRK1 / 4 blocker (Drici et al., 2000. The bee venom peptide tertiapin underlines the role of I (KACh) in acetylcholineinduced atrioventricular blocks.British journal of pharmacology 131, 569-577). In human diseases associated with pacemakers (for example, sick sinus syndrome), regulation in the sinoatrial or atrioventricular nodes is impaired, which can cause various types of arrhythmias, including bradycardia and types of asystole. It is expected that GIRK1 / 4 blockade may reduce the severity of these types of arrhythmias. For example, recent studies have shown that genetic deletion of GIRK4 helps to avoid the cessation of cardiac impulse generation and conduction induced by heart-specific silencing of the so-called amuse current, which mediates spontaneous depolarization in sinoatrial and atrioventicular tissues (Mesirca et al., 2014. Cardiac arrhythmia induced by genetic silencing of 'funny' (f) channels is rescued by GIRK4 inactivation. Nature communications 5, 4664).

In addition, GIRK1 / 4 blockers have been described as potentially useful in primary hyperaldosteronism: somatic and germinal gain-of-function mutations in KCNJ5 (encoding GIRK4) have recently been shown to be involved in primary aldosteronism, a condition that causes hypertension. These mutations alter the selective filter of the GIRK4 channel and allow the influx of sodium ions into certain adrenal cells. The resulting cellular depolarization provides calcium influx, which in turn enhances the production and secretion of aldosterone and can also induce cell proliferation with the formation of aldosterone-secreting adenomas (Scholl and Lifton, 2013. New insights into aldosterone-producing adenomas and hereditary aldosteronism: mutations in the K + channel KCNJ5. Current opinion in nephrology and hypertension 22, 141-147). Therefore, it is possible that the selective GIRK4 blocker can prevent the influx of sodium ions and the concomitant stimulation of aldosterone secretion in these patients.

Therefore, the compounds of the present invention may be useful in the treatment of an indication selected from cardiac arrhythmias, atrial fibrillation, primary hyperaldosteronism, hypertension, and sick sinus syndrome.

Thus, as a further embodiment, the present invention provides for the use of a compound of either formula II or III in therapy. In a further embodiment, the therapy is directed to a disease selected from diseases that can be treated by inhibiting the GIRK1 / 4 channel. In another embodiment, the disease is selected from cardiac arrhythmia, atrial fibrillation, primary hyperaldosteronism, hypertension, and sick sinus syndrome, preferably atrial fibrillation.

Thus, as a further embodiment, the present invention provides a compound of any of formulas II or III for use in therapy. In a further embodiment, the therapy is directed to a disease selected from diseases that can be treated by inhibiting the GIRK1 / 4 channel. In another embodiment, the disease is selected from cardiac arrhythmia, atrial fibrillation, primary hyperaldosteum, hypertension, and sick sinus syndrome, preferably atrial fibrillation.

In another embodiment, the present invention provides a method of treating a disease, the treatment of which is achieved by inhibiting the GIRK1 / 4 channel, comprising administering a therapeutically acceptable amount of a compound of either formula II or III. In a further embodiment, the disease is selected from cardiac arrhythmia, atrial fibrillation, primary hyperaldosteronism, hypertension, and sick sinus syndrome, preferably atrial fibrillation.

In yet another embodiment, the present invention relates to the use of a compound according to any of the preceding embodiments 1-14, or a pharmaceutically acceptable salt thereof, for the treatment of cardiac arrhythmia, atrial fibrillation, primary hyperaldosteronism, hypertension and / or sick sinus syndrome.

The activity of a compound of the present invention can be assessed by the following in vitro method.

1. Buffers.

a. External buffer: 10 mM NaCl, 50 mM Na gluconate, 80 mM K gluconate, 1.8 mM CaCl2, 1 mM MgCl2, 10 mM HEPES, 10 mM glucose, pH 7.4; osmolality 300-310 osmol / l.

b. Internal buffer: 30 mM KCl, 100 mM K gluconate, 1 mM MgCl2, 10 mM HEPES, 1 mM EGTA, 10 mM NaCl, pH 7.2; osmolality 284-292 osmol / l.

2. Connections.

a. A series of seven-fold dilutions of compound (10 mM to 20 μM) in 100% DMSO are prepared in 384-well polypropylene plates.

b. Propafenone (Sigma Aldrich cat # P4670) was used as positive control and DMSO as neutral control.

with. Resuspend 1 μl of compounds in DMSO in 65.7 μl of external buffer in a 384-well polypropylene plate and load onto Quattro plate portion 1 from Molecular Devices.

3. Quattro tincture.

a. Load a 384-well cell population clamp plate (Molecular Devices # 9000-0902) in Quattro.

b. Fill the F Quattro wash with 20% DMSO and 50% EtOH.

c. Fill the Quattro buffer tank with an external buffer.

d. Attach the inner buffer vial to the Quattro inner buffer tube.

e. Attach a bottle of PBS (phosphate buffered saline, Ca and Mg free. PH 7.4) to the F-head and E-head wash station on the Quattro.

4. Antibiotic.

a. Resuspend 5.6 mg of amphotericin B (Sigma Aldrich, cat # A2411) in 175 μl DMSO.

b. Add the resulting solution to 50 ml of internal buffer, mix and attach to the antibiotic tubing port on the Quattro.

5. Cells.

a. Use HEK293 cells stably expressing GIRK 1/4 (obtained from ChanTest, 14 656 Neo Parkway, Cleveland, OH 44128) grown to ~ 80% confluence in the following cell culture medium: DMEM containing 10% (v / v .) fetal bovine serum, penicillin / streptomycin (at 1X concentration of 100X stock solution), 0.5 mg / ml G418 and 0.1 mg / ml zeocin.

b. Wash cells with PBS (no Ca and Mg). Provide detachment of cells using Detachin (Genlantis, 11011 Torreyana, San Diego, CA 92121) and resuspend in external buffer (final volume 5 ml with 2.0-2.1x106 cells / ml).

c. Load into a Quattro cell container.

6. Analysis protocol.

The Quattro is controlled using IonWorks version 2 software with the following steps.

a. Add 3.5 μl of cells plus 3.5 μl of external buffer to the wells of the Quattro fixation plate.

b. Amphotericin B and internal buffer are circulated in the cells.

c. The following voltage application protocol is applied: pulse 1 of 15 mV for 300 milliseconds (ms), then pulse 2 of -120 mV for 400 ms, then pulse 3 of -15 mV for 400 ms, and finally pulse 4 of -120 mV for 40 mV for 500 ms (this is a voltage ramp).

d. The value of the incoming potassium current is measured at a time of 1200-1220 ms from the beginning of pulse 1 (i.e., during the voltage ramp phase).

e. Add 3.5 μl of diluted compounds (or DMSO) to the wells and repeat steps c-d (final compound concentrations range from 50 μM to 0.1 μM, for highly active compounds from

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0.5 μM to 0.01 μM, and each concentration is tested in four replicates, i.e. in 4 separate holes).

f. The difference between the amount of current before the addition of the compound and thereafter allows the measurement of the inhibition of GIRK1 / 4.

7. Data analysis.

_{IC 50} values are calculated by plotting percent current reduction (normalized to DMSO only control) versus compound concentration using standard data analysis software.

Using test assay No. 1 (described in this application), the compounds of the present invention exhibit inhibition efficacy in accordance with table. 1 below.

Table 1. Inhibition activity of the compounds

Approx. IC ₅₀ GIRK1 / 4 (μM) Approx. IC ₅₀ GIRK1 / 4 (μM) 1 0.1044 51 0.041 2 0.159 52 0.073 3 0.131 53 0, 028 4 0.141 54 0.029 5 0.235 55 0.054 6 0.099 56 0, 197 7 0.431 57 0.032 eight 0.351 58 0.017 nine 0.257 59 0.014 ten 0, 120 60 0.261 eleven 0.073 61 0.068 12 0.036 62 0.013 13 0.071 63 0.016 fourteen 0.052 64 0.97 15 0.025 65 0.39 16 0, 176 66 0.034 17 0.060 67 0, 168 eighteen 1,855 68 0.234 19 0.098 69 0, 115 twenty 0.173 70 3, 052 21 0.154 71 0, 176 22 0, 148 72 0.28 23 0.344 73 0.329 24 0.253 74 0.069 25 0.146 75 0.214 26 0.031 76 0.355 27 0, 150 77 0.366 28 0.039 78 0.352 29 0.505 79 0.299 thirty 0.025 80 0.365 31 0, 1 81 0.023 32 0.033 82 0.147 33 0, 1 83 0.278 34 0.240 84 0.16 35 0.035 85 0.019 36 0, 009 86 0.037 37 0, 006 87 2,265 38 0, 008 88 1.227 39 0.015 89 0.024 40 0.013 90 0.327 41 0, 028 91 0.04 42 0.015 92 0.047 43 0.026 93 0.046 44 0.056 45 0.149 46 0, 128 47 0.059 48 0, 009 49 0.042 50 0.011

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Illustrative examples of the invention

The following examples are intended to illustrate the present invention and should not be construed as limiting it. Temperature values are given in degrees Celsius. Unless otherwise indicated, all evaporation operations are carried out under reduced pressure, typically from about 15 to 100 mm Hg. (= 20-133 mbar). The structure of the final products, intermediates and starting materials is confirmed by standard analytical methods, for example, microanalysis and spectroscopic characteristics, for example, MS, NMR. Abbreviations used are standard abbreviations in the art.

All starting materials, building blocks, reagents, acids, bases, dehydrogenating agents, solvents and catalysts used to synthesize the compounds of the present invention are commercially available or can be obtained by organic synthesis methods known to those of ordinary skill in the art (Houben -Weyl 4th Ed. 1952, Methods of Organic Synthesis, Thieme, Volume 21).

Also, the compounds of the present invention can be prepared by organic synthesis methods known to a person skilled in the art, as shown in the following examples.

The compounds of the examples below were found to have an IC ₅₀ value ranging from about 0.01 nM to about 50,000 nM in a GIRK1 / 4 ratio, more preferably from 1 nM to 10,000 nM.

List of abbreviations

ACN - acetonitrile;

aq. - water;

BOC - tert-butyloxycarbonyl;

br - wide;

bs - wide singlet;

° С - degrees Celsius;

conc. - concentrated;

δ — chemical shift of NMR in ppm towards the weak field from tetramethylsilane;

d - doublet;

DCE - 1,2-dichloroethane;

DCM for dichloromethane;

DEA - diethylamine;

DIPEA - N, N-diisopropylethylamine;

DMA for dimethylacetamide;

DMAP - 4- (dimethylamino) pyridine;

DME for dimethoxyethane;

DMEM - Dulbecco's modified Eagle's medium;

DMF is N, N-dimethylformamide;

DMSO - dimethyl sulfoxide;

DPPF - 1,1'-bis (diphenylphosphino) ferrocene;

Et is ethyl;

EtOAc - ethyl acetate;

g - gram;

h - hour;

HEPES - (4- (2-hydroxyethyl) -1-piperazineethanesulfonic acid;

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

HRMS - High Resolution Mass Spectrometry;

i-Pr is isopropyl;

l - liter;

LDA - lithium diisopropylamide;

LC-MS - liquid chromatography with mass spectrometry;

M - molarity;

m - multiplet;

Me is methyl;

mg - milligram;

MHz - megahertz;

min - minute;

ml - milliliter;

μl - microliter;

mmol - millimol;

n. - normal;

NBS - N-bromosuccinimide;

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NCS - N-chlorosuccinimide;

n-Bu is normal butyl;

n-BuLi - n-butyllithium;

NMM - N-methylmorpholine;

NMR - nuclear magnetic resonance;

NMP is N-methyl-2-pyrrolidone;

NMO is N-methylmorpholine-N-oxide;

o / n - during the night;

Ph is phenyl;

pH - concentration -log ₁₀ H ⁺ ;

ppm - parts per million;

q - quartet;

Rt is the retention time;

RP-HPLC - Reverse Phase High Performance Liquid Chromatography; s - singlet;

SFC - supercritical fluid chromatography;

saturate - saturated;

t is a triplet;

t-Bu is tert-butyl;

TBAF - tert-butylammonium fluoride;

Tf is trifluoromethanesulfonyl;

TFA, trifluoroacetic acid;

TFAA - trifluoroacetic anhydride;

TBDMS, tert-butyldimethylsilyl;

TEA - triethylamine;

pace. - temperature;

THF - tetrahydrofuran;

TLC - Thin Layer Chromatography.

Liquid Chromatography (LC) Methods

LC Method 1 Retention times in minutes (Rt) were obtained on an Agilent 1100 system with an XBridge C18 3.5 μm column, 3.0x30 mm column. A gradient of H ₂ O (+ 0.05% ammonium hydroxide) / CH3CN (+ 0.05% ammonium hydroxide) was applied from 98/2 to 2/98 for 1.7 min, then held for 0.3 min (flow rate solvent 2.0 ml / min) at an oven temperature of 40 ° C.

LC Method 2 Retention times in minutes (Rt) were obtained on an Agilent 1100 system with a Sunfire C18 3.5 μm column, 3.0x30 mm column. _{A H 2} O (+ 0.05% trifluoroacetic acid) / CH3CN (+ 0.05% trifluoroacetic acid) gradient was applied from 95/5 to 5/95 for 1.7 min, then held for 0.3 min (flow rate solvent 2.0 ml / min) at an oven temperature of 40 ° C.

LC Method 3 Retention times in minutes (Rt) were obtained on an Agilent 1100 system with an XBridge C18 3.5 μm column, 3.0x30 mm column. A gradient of H ₂ O (+ 0.05% ammonium hydroxide) / CH3CN (+ 0.05% ammonium hydroxide) was applied from 98/2 to 2/98 for 1.7 min, then held for 0.3 min (flow rate solvent 2.0 ml / min) at an oven temperature of 40 ° C.

LC Method 4 Retention times in minutes (Rt) were obtained on a Waters AcQuity UPLC system with an AcQuity UPLC VEN C18 1.7 μm 2.1x30 mm column. A gradient of H ₂ O (+ 0.05% ammonium hydroxide) / CH3CN (+ 0.05% ammonium hydroxide) was applied from 98/2 to 2/98 for 1.7 min, then held for 0.3 min (flow rate solvent 1.0 ml / min) at an oven temperature of 50 ° C.

Synthesis of Intermediates 1-13

5,8-Dichloro-1- (2,6-dichlorophenyl) -2-methyl-1,6-naphthyridin-4 (1H) -one (intermediate 1) ci o

Stage 1. 2,4,5-Trichloronicotinic aldehyde

CI

LDA (2M in heptane,

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20.56 ml, 41.1 mmol) at -78 ° C. The mixture was stirred at -78 ° C for 1 h. Then methyl formate (8.23 g, 137 mmol) in THF (20 mL) was added to the reaction mixture, followed by stirring at -78 ° C for 1 h. The reaction mixture was quenched saturated aqueous NH4Cl and extracted three times with EtOAc. The combined organic layers were dried over anhydrous Na ₂ SO ₄ and the volatiles were removed under reduced pressure. The residue was purified by silica gel chromatography (10% to 100% EtOAc in heptane) to give the title compound as a solid (4.2 g, 73% yield). ESI-MS mass / charge: 211.8 [M + H] + (Rt = 0.86 min, LC method 1).

1H NMR (400 MHz, DCM-d ₂ ) δ ppm = 10.43 (s, 1H), 8.61 (s, 1H).

Stage 2.1- (2,4,5-Trichloropyridin-3-yl) but-2-in-1-ol

Cl

II Τ

CI he

To a solution of 2,4,5-trichloronicotinic aldehyde (2.11 g, 10.03 mmol) in THF (30 ml) was added prop-1-yn-1-yl magnesium bromide (0.5 M in THF, 26.1 ml , 13.03 mmol) at 0 ° C. The reaction mixture was stirred at 0 ° C for 1 h. An aqueous saturated NH4Cl solution was added to the mixture, followed by extraction with EtOAc. The combined organic layers were washed with water and brine, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The crude material was purified by silica gel chromatography (10 to 100% EtOAc in heptane) to afford the title compound (1.95 g, 78% yield). ESI-MS mass / charge: 250.0 [M + H] + (Rt = 0.94 min, LC method 1).

Ή NMR (400 MHz, DCM-d ₂ ) δ ppm = 8.42 (s, 1H), 6.13 (s, 1H), 3.11 (bs, 1H), 1.90 (s, 3H).

Stage 3.1- (2,4,5-Trichloropyridin-3-yl) but-2-in-1-one

Cl ίΐ Ί

Cl o

Cooled 1- (2,4,5-trichloropyridin-3-yl) but-2-yn-1-ol (3.4 g, 13.57 mmol) in DCM (60 mL) to 0 ° C. Dess-Martin reagent (6.91 g, 16.29 mmol) was then added. The resulting solution was stirred at room temperature for 1 hour. The resulting solution was then carefully quenched with saturated aqueous NaHCO ₃ followed by dilution with DCM. The organic layer was washed with brine, dried over anhydrous MgSO ₄ , filtered, and concentrated under reduced pressure. The crude material was purified by silica gel chromatography (10 to 100% EtOAc in heptane) to afford the title compound (2.6 g, 77% yield). ESI-MS mass / charge: 248.0 [M + H] + (Rt = 1.15 min, LC method 1).

¹ H NMR (400 MHz, DCM-d2) δ ppm = 8.51 (s, 1H), 2.16 (s, 3H).

Step 4. (E) -3 - ((2,6-Dichlorophenyl) amino) -1- (2,4,5-trichloropyridin-3-yl) but-2-en-1-one

Into a solution of 1- (2,4,5-trichloropyridin-3-yl) but-2-yn-1-one (2.36 g, 9.50 mmol) and 2,6-dichloroaniline (1.69 g, 10 , 45 mmol) in 50 ml of DCM was added AlCl ₃ (1.52 g, 11.40 mmol) at 0 ° C. The reaction mixture was stirred at room temperature overnight. The reaction mixture was added 2N. NaOH solution and it was extracted three times with DCM. The combined organic layers were dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The crude material was purified by silica gel chromatography (10 to 100% EtOAc in heptane) to afford the title compound (2.99 g, 77%).

ESI-MS mass / charge: 410.9 [M + H] + (Rt = 1.39 min, LC method 1).

Step 5. 5,8-Dichloro-1- (2,6-dichlorophenyl) -2-methyl-1,6-naphthyridin-4 (1H) -one

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Into a solution of 3 - ((2,6-dichlorophenyl) amino) -1- (2,4,5-trichloropyridin-3-yl) but-2-en-1-one (2.99 g, 7.28 mmol) K2CO3 (3.02 g, 21.85 mmol) was added in 45 ml DMF at room temperature. The resulting solution was stirred overnight. The reaction mixture was diluted with water and extracted three times with EtOAc. The combined organic layers were washed with brine and dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (10 to 100% EtOAc in heptane) to afford the title compound (1.8 g, 66% yield). ESI-MS mass / charge: 375.0 [M + H] + (Rt = 1.06 min, LC method 1).

1H NMR (400 MHz, DMSO-d6) δ ppm = 8.51 (s, 1H), 7.83-7.72 (m, 3H), 6.63 (d, J = 0.7 Hz, 1H) , 1.94 (s, 3H).

5,8-Dichloro-1- (2,6-dichloro-4-fluorophenyl) -2-methyl-1,6-naphthyridin-4 (1H) -one (intermediate 2)

Intermediate 2 was prepared analogously to intermediate 1, but using 2,6-dichloro-4-fluoroaniline in step 4 of the synthesis procedure to give a white powder of the title compound.

2: Ή NMR (400 MHz, DMSO-d6) δ ppm = 8.32-8.76 (m, 1H), 7.92 (d, J = 8.31 Hz, 2 H), 6.63 (d , J = 0.73 Hz, 1H), 1.96 (s, 3H).

3,5-Dichloro-4- (5,8-dichloro-2-methyl-4-oxo-1,6-naphthyridin-1 (4H) -yl) benzonitrile (intermediate 3)

Intermediate 3 was prepared analogously to intermediate 1, but using 2,6-dichloro-4-cyanoaniline and BF ₃ * OEt ₂ in step 4 of the synthesis procedure to obtain a yellow powder.

3: ¹ H NMR (400 MHz, chloroform-d3) δ ppm = 8.33 (s, 1H), 7.80 (s, 2H), 6.49 (d, J = 0.7 Hz, 1H), 1.95 (d, J = 0.6 Hz, 3H).

1- (4-Bromo-2,6-dichlorophenyl) -5,8-dichloro-2-methyl-1,6-naphthyridin-4 (1H) -one (intermediate 4)

Intermediate 4 was prepared analogously to intermediate 1 but using 4-bromo-2,6-dichloroaniline in step 4 of the synthesis procedure to give a white powder representing the title compound.

4: ¹ H NMR (400 MHz, DMSO-d6) δ ppm = 8.53 (s, 1H), 8.16 (s, 2H), 6.62 (d, J = 0.7 Hz, 1H), 1.96 (s, 3H).

3-Chloro-2- (5,8-dichloro-2-methyl-4-oxo-1,6-naphthyridin-1 (4H) -yl) benzonitrile (intermediate 5)

Intermediate 5 was prepared analogously to intermediate 1, but using 2-cyano-6-chloroaniline and scandium triflate in step 4 of the synthesis procedure, as described below.

Stage 4.3-Chloro-2 - ((4-oxo-4- (2,4,5-trichloropyridin-3-yl) but-2-en-2-yl) amino) benzonitrile

In a mixture of a solution of 1- (2,4,5-trichloropyridin-3-yl) but-2-yn-1-one (600 mg, 2.415 mmol) and 2-amino-3chlorobenzonitrile (0.368 g, 2.415 mmol) in DCM ( 15 ml) scandium trifluoromethanesulfonate (1.12 g, 2.415 mmol) was carefully added at rt. After stirring at rt overnight, the mixture was quenched with 1N. aqueous NaOH solution, the product was extracted with DCM. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude residue was purified by column chromatography on silica gel eluting with EtOAc in heptane 0 to 50% to afford the following products: 3-chloro-2 - ((4-oxo4- (2,4,5-trichloropyridin-3-yl ) but-2-en-2-yl) amino) benzonitrile (0.166 g, 17.2%), ESI-MS mass / charge: 400.2 [M + H] +, and 3-chloro-2- (5 , 8-dichloro-2-methyl-4-oxo-1,6-naphthyridin-1 (4H) -yl) benzonitrile (0.143 g, 16.2% yield) ESI-MS mass / charge: 364.2 [M + H] ⁺ .

1H NMR (400 MHz, MeCN-d3) δ ppm = 8.36 (s, 1 H) 7.87-8.06 (m, 2 H) 7.62-7.85 (m, 1 H) 6, 47 (d, J = 0.63 Hz, 1 H) 1.98 (s, 3 H).

Step 5. 3-Chloro-2- (5,8-dichloro-2-methyl-4-oxo-1,6-naphthyridin-1 (4H) -yl) benzonitrile

A mixture of 3-chloro-2 - ((4-oxo-4- (2,4,5-trichloropyridin-3-yl) but-2-en-2-yl) amino) benzonitrile (0.49 g, 1, 22 mmol) and potassium carbonate (0.422 g, 3.05 mmol) in DMF (10 ml) at 95 ° C for 1 h. After cooling to rt. the mixture was diluted with water and the product was extracted with EtOAc. The organic layer was washed with water, brine, dried over anhydrous sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using EtOAc / heptane 0 to 100% as eluent to afford the title compound (0.31 g, 70%).

5: ESI-MS mass / charge: 364.2 [M + H] ⁺ . 1H NMR (400 MHz, MeCN-d ₃ ) δ ppm = 8.36 (s, 1 H) 7.87-8.06 (m, 2 H) 7.62-7.85 (m, 1 H) 6 , 47 (d, J = 0.63 Hz, 1 H) 1.98 (s, 3 H).

3-Chloro-2- (5,8-dichloro-2-methyl-4-oxo-1,6-naphthyridine-1 (4H) -yl) -5-fluorobenzonitrile (intermediate 6)

- 26 038455

Intermediate 6 was prepared analogously to intermediate 5, but using 2-amino-3-chloro-5-fluorobenzonitrile, which was synthesized by the following procedure to give a white powder.

6: ESI-MS mass / charge: 382.2 [M + H] +.

Obtaining 2-amino-3-chloro-5-fluorobenzonitrile

NCS (4.75 g, 35.6 mmol) was added to a solution of 2-amino-5-fluorobenzonitrile (4.4 g, 32.3 mmol) in MeCN (92 ml). The resulting mixture was stirred at 80 ° C overnight. After reducing the volume under vacuum to half the volume, the residue was poured into water, the precipitate was collected by filtration, washed with water, and dried to obtain the required aniline (4 g, 73%). ¹ H NMR (400 MHz, DMSOd6) δ ppm = 7.64 (dd, J = 8.40, 2.97 Hz, 1 H) 7.50 (dd, J = 8.40, 2.97 Hz, 1 H) 6.08 (br s, 2 H).

2 - (((tert-Butyldimethylsilyl) oxy) methyl) -5,8-dichloro-1- (2,6-dichlorophenyl) -1,6-naphthyridin-4 (1H) one (intermediate 7)

Stage 1. 2,4,5-Trichloronicotinic aldehyde

To a solution of 2,4,5-trichloropyridine (5 g, 27.4 mmol) in 150 ml THF was added LDA (2 M in heptane, 20.56 ml, 41.1 mmol) at -78 ° C. The mixture was stirred at -78 ° C for 1 h. Then methyl formate (8.23 g, 137 mmol) in THF (20 mL) was added to the reaction mixture, followed by stirring at -78 ° C for 1 h. The reaction mixture was quenched saturated aqueous NH ₄ Cl and extracted three times with EtOAc. The combined organic layers were dried over anhydrous Na ₂ SO ₄ and the volatiles were removed under reduced pressure. The residue was purified by silica gel chromatography (10 to 10 0% EtOAc in heptane) to give the title compound as a solid (4.2 g, 73%). ESI-MS mass / charge: 211.8 [M + H] + (Rt = 0.86 min, LC method 1).

¹ H NMR (400 MHz, DCM-d ₂ ) δ ppm = 10.43 (s, 1H), 8.61 (s, 1H).

Stage 2.4 - ((tert-Butyldimethylsilyl) oxy) -1- (2,4,5-trichloropyridin-3-yl) but-2-in-1-ol

Cool tert-butyldimethyl (prop-2-yn-1-yloxy) silane (11.14 g, 65.4 mmol) in 20 mL THF to -78 ° C and add n-BuLi (1.6 M, 24 , 52 ml, 39.2 mmol). The mixture was stirred at -78 ° C for 45 min and then treated with a solution of 2,4,5-trichloronicotinaldehyde (6.88 g, 32.7 mmol)

- 27 038455 in 40 ml THF. The mixture was allowed to stir at -78 ° C for 2 hours. The progress of the reaction was monitored by LC-MS, which showed complete consumption of the aldehyde starting material. The mixture was quenched with saturated NH ₄ Cl solution and extracted with EtOAc. The organic layer was washed with water and brine, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the crude compound as a yellow liquid, which was used further without any purification. ESI-MS mass / charge: 382 [M + H] + (Rt = 1.47 min, LC method 1).

¹ H NMR (400 MHz, DC'M-dj δ ppm = 8.32 (s, 1H), 6.27-5.96 (m, 1H), 4.40-4.15 (m, 2H), 0.93 (s, 9H), 0.02 (s, 6H).

Stage 3.4 - ((tert-butyldimethylsilyl) oxy) -1 - (2,4,5-trichloropyridin-3-yl) but-2-yn-1-one

Into a stirred solution of 4 - ((tert-butyldimethylsilyl) oxy) -1- (2,4,5-trichloropyridin-3-yl) but2-yn-1-ol (12.45 g, 32.7 mmol) in DCM ( 131 ml) Dess-Martin periodinane (16.64 g, 39.2 mmol) was added at 0 ° C. The resulting solution was stirred at room temperature for 30 minutes. The progress of the reaction was monitored by LC-MS, which showed complete consumption of the starting material. The reaction mixture was carefully quenched with saturated aqueous NaHCO ₃ followed by dilution with DCM. The precipitate was filtered off. The organic layer was washed with saturated NaHCO ₃ solution and washed with brine, dried over anhydrous Na ₂ SO ₄ . The organic layer was concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography (10 to 100% EtOAc in heptane) to give the desired compound (7.5 g, 61%). ESI-MS mass / charge: 380 [M + H] + (Rt = 1.66 min, LC method 1).

1H NMR (400 MHz, DCM-d ₇ ) δ ppm = 8.38 (s, 1H), 4.44 (s, 2H), 0.82 (s, 9H), 0.01 (s, 6H).

Step 4. (E) -4 - ((tert-butyldimethylsilyl) oxy) -3 - ((2,6-dichlorophenyl) amino) -1 - (2,4,5-trichloropyridin-3-yl) but-2- en-1 -on

Into a stirred solution of 4 - ((tert-butyldimethylsilyl) oxy) -1- (2,4,5-trichloropyridin-3-yl) but2-in-1-one (7.41 g, 19.56 mmol) in DCM ( 185 ml), 2,6-dichloroaniline (3.49 g, 21.52 mmol) was added, followed by the addition of AlCl ₃ (2.87 g, 21.52 mmol) in one portion at 0 ° C and the reaction mixture was stirred for 2 h at room temperature. The progress of the reaction was monitored using LCMS, which showed complete consumption of the starting material. 2N HCl was added to the reaction mixture. NaOH (20 ml) and the mixture was stirred for 30 min at room temperature. The reaction mixture was extracted with DCM and the combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ . The organic layer was concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography (10 to 100% EtOAc in heptane) to afford the title compound (6.4 g, 61% yield). ESI-MS mass / charge: 540.9 [M + H] + (Rt = 2.01 min, LC method 1).

Step 5.2 - (((tert-Butyldimethylsilyl) oxy) methyl) -5,8-dichloro-1- (2,6-dichlorophenyl) -1,6-naphthyridin-4 (1H) -one

Into a stirred solution (E) -4 - ((tert-butyldimethylsilyl) oxy) -3 - ((2,6-dichlorophenyl) amino) -1 (2,4,5-trichloropyridin-3-yl) but-2-ene -1-one (6.37 g, 11.78 mmol) in DMF (47 ml) was added potassium carbonate (8.14 g, 58.9 mmol) and the reaction mixture was stirred at 80 ° C for 3 h. The reaction mixture poured into ice water and extracted with EtOAc. The organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ and evaporated under reduced pressure. The crude compound was purified by silica gel column chromatography (10 to 100% EtOAc in Hep

- 28 038455 tane) to obtain the desired compound (4.6 g, 77% yield).

7: ESI-MS mass / charge: 504.9 [M + H] + (Rt = 1.62, LC-method 1) 1H NMR (400 MHz, DCM-d ₂ ) δ ppm = 8.26 (s, 1H), 7.48 (d, J = 2.0Hz, 3H), 6.73 (s, 1H), 4.05-3.90 (m, 2H), 0.85 (s, 9H) , 0.01 (s, 6H).

5,8-Dichloro-1- (2,6-dichlorophenyl) -2- (methoxymethyl) -1,6-naphthyridin-4 (1H) -one (interm. 8)

Cl Cl

Intermediate 8 was prepared analogously to intermediate 7, but using 3-methoxyprop-1-yne in step 2 of the synthesis procedure to give a white powder.

8: ESI-MS mass / charge: 405.2 [M + H] ⁺ (Rt = 1.08 min, LC method 1); ¹ H NMR (400 MHz, DCM-d ₂ ) δ ppm = 8.33 (s, 1H), 7.63-7.49 (m, 3H), 6.71 (s, 1H), 3.88 ( s, 2H), 3.32 (s, 3H).

3-Chloro-2- (5,8-dichloro-2-cyclopropyl-4-oxo-1,6-naphthyridine-1 (4H) -yl) benzonitrile (intermediate 9)

SG Cl

Intermediate 9 was prepared analogously to intermediate 7, but using ethynylcyclopropane in step 2 and 2-amino-3-chlorobenzonitrile in step 4 of the synthesis procedure to give a white powder.

9: ESI-MS mass / charge: 392.0 [M + H] ⁺ (Rt = 1.01 min, LC method 1).

8-Bromo-5-chloro-1- (2,6-dichlorophenyl) -2-methyl-1,6-naphthyridin-4 (1H) -one (intermediate

ten)

SG Bg

Intermediate 10 was prepared in a similar manner to Intermediate 1 using 5-bromo-2,4-dichloropyridine as starting material to give a white powder.

10: ¹ H NMR (400 MHz, chloroform-d3) δ ppm = 8.50 (s, 1H), 7.50 (s, 3H), 6.51 (d, J = 0.7 Hz, 1H), 1.96 (dd, J = 2.5, 0.7 Hz, 3H).

5,7-Dichloro-1- (2,6-dichlorophenyl) -2-methyl-1,6-naphthyridin-4 (1H) -one (interm. 11)

Cl O

Stage 1. 2,4,6-Trichloronicotinic aldehyde

Cooled 2,4,6-trichloropyridine (5 g, 27.4 mmol) in anhydrous THF (100 ml) to -78 ° C. Slowly

- 29 038455 was added a solution of n-butyllithium (22.27 ml, 28.8 mmol) (1.6 M in hexane) at -78 ° C. The solution was stirred at -78 ° C for 30 min, then treated with a solution of ethyl formate (10.15 g, 137 mmol) while maintaining the internal temperature below -74 ° C. The resulting solution was stirred at -78 ° C until all the starting material was consumed (monitored by TLC, heptane / EtOAC, 9: 1), then it was quenched at -78 ° C with saturated ammonium chloride solution and with 50 ml 0.5n. aq. HCl with vigorous stirring. Then provided heating obtained to rt. The quenched mixture was extracted with EtOAc, the organic phase was washed with brine, dried over MgSO ₄ and concentrated. The crude residue (light yellow solid) was purified by flash chromatography on silica gel with EtOAc / heptane 0 to 20% to give 5.1 g (88% yield) of the desired 2,4,6-trichloronicotinic aldehyde in the form of a white solid.

1H NMR (400 MHz, chloroform-d3) δ ppm = 10.42 (s, 1H), 7.45 (s, 1H).

The remaining steps were carried out analogously to those described for intermediate 1. Intermediate 11 was obtained as a white powder.

11: 1H NMR (400 MHz, chloroform-d3) δ ppm = 7.75-7.53 (m, 3H), 6.42 (d, J = 0.8 Hz, 1H), 6.29 (s, 1H), 1.97 (d, J = 0.8 Hz, 3H).

3,5-Dichloro-4- (5-fluoro-2-methyl-4-oxo-1,7-naphthyridin-1 (4H) -yl) benzonitrile (intermediate 12)

Suspended 3, 5-difluoroisonicotinic acid (18.78 g, 118 mmol), N, O-dimethylhydroxylamine hydrochloride (12.09 g, 124 mmol), HATU (47.1 g, 124 mmol) and DIPEA (61.9 ml, 354 mmol) in DCM (236 ml). The mixture was allowed to stir at room temperature for 24 hours. The mixture was concentrated under reduced pressure. The residue was extracted with EtOAc washing with saturated aqueous NH4Cl (2x), water, saturated NaHCO ₃ and brine. The organic layer was dried over sodium sulfate and concentrated. The crude material was purified by silica gel chromatography using 0 to 75% EtOAc in heptanes as eluent to give the title compound (18.9 g, 79% yield). ESI-MS mass / charge: 203.1 [M + H] + (Rt = 0.81 min, LC method 2).

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm = 9.16 (s, 2H), 4.03 (s, 3H), 3.82 (s, 3H).

Stage 2. 3,5-Difluoro-N-methoxy-N-methylisonicotinamide

F O

Dissolve 3,5-difluoro-N-methoxy-N-methyl-isonicotinamide (10.25 g, 50.7 mmol) in THF (127 ml) and cool the reaction mixture to 0 ° C. Then prop-1-yn-1-yl magnesium bromide (0.5 M in THF, 304 ml, 152 mmol) was slowly added (~ 30 min) using a dropping funnel and the mixture was allowed to warm to room temperature overnight. The next day, the resulting product was quenched by adding 0.5N hydrochloric acid to a stirred solution. HCl at 0 ° C and it was extracted with DCM (3X). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0 to 50% EtOAc in heptane) to give the title compound as a solid (7.22 g, 79% yield).

ESI-MS mass / charge: 182.0 [M + H] ⁺ (Rt = 1.11 min, LC method 2); 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm = 8.74 (s, 2H), 2.22 (s, 3H).

Stage 3.3- (2,6-Dichloro-4-cyanophenyl) -6- (3,5-difluoropyridin-4-yl) -2,2-difluoro-4-methyl-2,3-dihydro-1,3 , 2-oxazaborinin-1-u-2-uid

- 30 038455

1- (3,5-difluoropyridin-4-yl) but-2-yn-1-one (7.86 g, 43.4 mmol) and 4-amino-3,5-dichlorobenzonitrile (9.74 g, 52.1 mmol) in DCM (174 ml) and the mixture was treated with BF ₃ * OEt ₂ (16.50 ml, 130 mmol). The reaction mixture was stirred at 50 ° C overnight. The next day, the result was quenched by slow addition to a saturated solution of NaHCO ₃ . Some MeOH was used to completely dissolve and transfer to the reaction mixture. The mixture was extracted with DCM (3x). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (10 to 100% EtOAc in heptane) to afford the title compound (10.05 g, 55.7% yield).

ESI-MS mass / charge: 68.0 [M + H] + (Rt = 1.43 min, LC method 2).

Stage 4. 3,5-Dichloro-4- (5-fluoro-2-methyl-4-oxo-1,7-naphthyridin-1 (4H) -yl) benzonitrile

Heated a mixture of 3- (2,6-dichloro-4-cyanophenyl) -6- (3,5-difluoropyridin-4-yl) -2,2-difluoro-4-methyl-2,3-dihydro-1,3,2- oxazaborinin-1-i-2-uide (17.16 g, 41.3 mmol) and K ₂ CO ₃ (28.5 g, 206 mmol) in THF (110 ml) and MeOH (55 ml) at 50 ° С over 1.5 h. EtAOc was added to the reaction mixture. The solution was washed with water and brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (0 to 100% EtOAc in heptane) to afford the title compound (8.26 g, 57%).

12: HRMS calc. 348.0095 [M + H] +; found 348.0102; Ή NMR (400 MHz, DMSO-d6) δ ppm = 9.06 (s, 2H), 8.99 (d, J = 2.3 Hz, 1H), 8.61 (s, 1H), 6.92 (s, 1H).

3,5-Dichloro-4- (5-bromo-2-methyl-4-oxo-1,7-naphthyridin-1 (4H) -yl) benzonitrile (interm. 13)

Stage 1.3-Bromo-5-fluoroisonicotinic aldehyde

To a LDA solution (1M in hexanes / THF, 12.55 ml, 12.55 mmol) was added dropwise a solution of 3-bromo-5fluoropyridine (1.84 g, 10.46 mmol) in THF (20 ml) at -78 ° WITH. The mixture was stirred at -78 ° C for 1 hour. Then DMF (1.62 ml, 1.53 g, 20.91 mmol) was added to the reaction mixture. After stirring at 78 ° C for 30 min, the reaction mixture was quenched with sat. aq. _{NaHCO 3} solution, followed by extraction three times with EtOAC and twice with DCM. All organic layers were combined and dried over anhydrous Na ₂ SO ₄ . The solid was filtered off. The volatiles were removed under reduced pressure and the residue was purified by silica gel chromatography (DCM) to give the title compound (0.478 g, 22%). ¹ H NMR (400 MHz, chloroform-d3) δ ppm = 10.36 (s, 1H), 8.75 (s, 1H), 8.63-8.57 (m, 1H).

Stage 2.1- (3-Bromo-5-fluoropyridin-4-yl) but-2-in-1-ol

- 31 038455

A solution of prop-1-yn-1-yl magnesium bromide (0.5 M in THF, 8.36 ml, 4.18 mmol) at 0 ° C. After stirring at 0 ° C for 2 h, sat. aq. NaHCO ₃ solution with quenching of the reaction mixture, followed by extraction twice with EtOAc and twice with DCM. All organic layers were combined and dried over anhydrous Na ₂ SO ₄ . The solid was filtered off. The volatiles were removed under reduced pressure to give the title compound (0.78 g, 99%). It was used directly in the next step without further purification. ESIMS mass / charge: 245.9 [M + H] + (Rt = 0.92 min, LC-method 3)

Stage 3.1- (3-Bromo-5-fluoropyridin-4-yl) but-2-in-1-one

Dess-Martin reagent (1 , 63 g, 3.84 mmol) at 0 ° C. The reaction mixture was stirred at room temperature for 30 min, followed by quenching with excess sat. aq. NaHCO ₃ solution. The mixture was extracted three times with DCM. All DCM layers were combined, concentrated and then purified by silica gel chromatography (10% EtOAc / heptane) to provide the title compound. ESI-MS mass / charge: 244.2 [M + H] + (Rt = 1.17 min, LC method 3).

Stage 4.4 - ((4- (3-bromo-5-fluoropyridin-4-yl) -4-oxobut-2-en-2-yl) amino) -3,5-dichlorobenzonitrile

and 6- (3-bromo-5-fluoropyridin-4-yl) -3- (2,6-dichloro-4-cyanophenyl) -2,2-difluoro-4-methyl-2H-1,3,2-oxazaborinine -3-n-2-uid

A mixture of 1- (3-bromo-5-fluoropyridin-4-yl) but-2-in-1-one (2.50 g, 10.33 mmol), 4-amino3,5-dichlorobenzonitrile (2.22 g , 11.88 mmol) and BF ₃ * OEt ₂ (8.80 g, 62.0 mmol) in DCE (120 ml) at 80 ° C overnight. The reaction mixture was quenched with 1N. aq. NaOH solution, followed by extraction three times with DCM. All layers based on DCM were combined and dried over anhydrous Na ₂ SO ₄ . The solid was filtered off. The volatiles were removed under reduced pressure and the residue was purified by silica gel chromatography (10 to 50% EtOAc / heptane) to give a mixture of 4 ((4- (3-bromo-5-fluoropyridin-4-yl) -4-oxobut- 2-en-2-yl) amino) -3,5-dichlorobenzonitrile (ESI-MS mass / charge: 429.7 [M + H] + (Rt = 1.22 min, LC method 3)) and its complex with BF2,6- (3-bromo-5-fluoropyridine-4yl) -3- (2,6-dichloro-4-cyanophenyl) -2,2-difluoro-4-methyl-2H-1,3,2-oxazaborinine- 3-2-uide (ES - MS mass / charge: 475.9 [M-H] ^- (Rt = 1.37 min, LC method 3)) (total 3.84 g). The mixture was used directly in the next step.

Step 5.4- (5-Bromo-2-methyl-4-oxo-1,7-naphthyridine-1 (4H) -yl) -3,5-dichlorobenzonitrile

- 32 038455

K2CO3 (3.22 g, 23.31 mmol) was added to a solution of the mixture (2.50 g) obtained in step 4 in DMF (15 ml). The reaction mixture was stirred at 100 ° C for 25 min. The solid was filtered off. The volatiles were removed under reduced pressure and the residue was purified by silica gel chromatography (EtOAc / heptane, 20 to 50%) to give a brown solid as the title compound (1.2 g).

13: ESI-MS mass / charge: 410.0 [M + H] +; ¹ H NMR (400 MHz, DMSO-d6) δ ppm = 8.69 (s, 1 H), 8.58 (s, 2 H), 8.24 (s, 1 H), 6.50 (s, 1 H), 2.00 (s, 3 H).

Synthesis of examples

Synthesis of Examples 1-57

The following examples of formulas Ia, Ib were prepared from intermediates 1-13 by nucleophilic aromatic substitution with alcohols and amines. If necessary, the removal of protective groups from additional functional alcohol groups in the molecules was carried out as a final step.

General way

Intermediates 1-13 (typically 0.1-0.25 mmol, 1 eq.), Alcohol (5-10 eq.) Or amine (1.2 eq.), K2CO3 (5-10 eq.) and DMAP (0.1-0.5 eq.) in MeCN (1-3 ml). Other solvents that have been used in the case of poor solubility are THF or NMP or DMF.

The resulting reaction mixture was heated for 1-16 h at 80 ° C. The reaction mixture was diluted with EtOAc and washed with water. The organic phase was dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by silica gel chromatography or, in the case of very polar products, by reverse phase HPLC (0.1% ammonia in MeCN / water) to give the desired products Ia, Ib (40-80% yield) as white or an off-white solid. In cases where an alcohol or an amine has several reactive nucleophilic centers, reagents were used where additional (additional) functional (functional) group (s) were protected using TBDMS, Boc group, or as a ketal. In this case, the protecting group was removed by treatment with TFA in DCM at room temperature, TBAF in THF at 0 ° C, or an AcOH / water mixture (~ 2/1) at room temperature. After the aqueous work-up described above, the crude product was purified by silica gel chromatography or, in the case of very polar products, by reverse phase HPLC (0.1% ammonia in MeCN / water) to give the desired products Ia, Ib as a white or off-white solid.

Example 1 (S) -8-Chloro-1- (2,6-dichlorophenyl) -5- (2,3-dihydroxypropoxy) -2- (hydroxymethyl) -1,6naphthyridin-4 (1H) -one

Stage 1. (R) -2 - (((tert-Butyldimethylsilyl) oxy) methyl) -8-chloro-1- (2,6-dichlorophenyl) -5 - ((2,2-dimethyl-1,3-dioxolane -4-yl) methoxy) -1,6-naphthyridin-4 (1H) -one.

Dissolved 2 - (((tert-butyldimethylsilyl) oxy) methyl) -5,8-dichloro-1- (2,6-dichlorophenyl) -1,6-naphthyridin-4 (1H) -one (intermediate 7, 1, 3 g, 2.58 mmol) in MeCN (15 ml).

This solution was treated with potassium carbonate (1.069 g, 7.73 mmol), DMAP (0.157 g, 1.289 mmol) and (R) - (2,2-dimethyl-1,3-dioxolan-4-yl) methanol (1.022 g, 7.73 mmol). The resulting mixture was heated at 80 ° C overnight. The next day, the reaction mixture was filtered and rinsed with ACN. The organic layer was concentrated in vacuo. The residue was purified by silica gel column chromatography (10% to 50% EtOAc in heptane) to afford the title compound (0.8 g, 52% yield). ESI-MS mass / charge: 601.0 [M + H] + (Rt = 3.53 min, LC method 1); 1H NMR (400

MHz, DCM-d2) δ ppm = 8.03 (s, 1H), 7.47 (s, 3H), 6.67 (s, 1H), 4.60-4.39 (m, 3H), 4 , 24-4.10 (m, 1H), 4.10-3.93 (m, 3H), 1.40 (s, 3H), 1.36 (s, 3H), 0.85 (s, 9H ), 0.0 (s, 6H).

Stage 2j. (S) -8-chloro-1- (2,6-dichlorophenyl) -5- (2,3-dihydroxypropoxy) -2- (hydroxymethyl) -1,6naphthyridin-4 (1H) -one.

Pre-mixed water (2 ml) and acetic acid (3 ml) and added to a flask containing (R) -2 - (((t-butyldimethylsilyl) oxy) methyl) -8-chloro-1- (2,6-dichlorophenyl ) -5 - ((2,2-dimethyl-1,3-dioxolan-4-yl) methoxy) -1,6-naphthyridin-4 (1H) -one (0.280 g, 0.467 mmol). To aid dissolution, the starting material flask was sonicated for 5-10 minutes. The reaction mixture was stirred at room temperature overnight and then LC / MS was performed. The obtained was concentrated in vacuo at a bath temperature of 26 ° C and a vacuum of 20 mbar. Most of the acetic acid was removed and the remaining aqueous solution was cooled in an ice bath and diluted with EtOAc. 10% aqueous sodium carbonate solution was added slowly until pH 7. The layers were separated and the organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (0-10% MeOH in DCM) to afford the title compound at 97% ee (0.15 g, 72% yield) (about 3% formation of the regioisomer of Example 9 observed).

1: ESI-MS mass / charge: 446.9 [M + H] ⁺ (Rt = 0.74 min, LC method 4).

¹ H NMR (400 MHz, DCM-d2) δ ppm = 8.13 (s, 1H), 7.58-7.43 (m, 3H), 6.94 (s, 1H), 4.70 (dd , J = 11.2, 1.7 Hz, 1H), 4.39 (dd, J = 11.2, 3.8 Hz, 1H), 4.07 (s, 2H), 4.04-3, 97 (m, 1H), 3.91 (dd, J = 11.7, 2.1 Hz, 1H), 3.78 (dd, J = 11.6, 5.2 Hz, 1H).

Alternatively, example 1 can be obtained through the following procedures.

HPLC method.

Column: Waters Acquity VEN C18, length 100 mm, inner diameter 2.1 mm, particle size: 1.7 μm.

Mobile phase: A: 0.05% TFA in water, B: 0.05% TFA in methanol.

Gradient:

Time [min.] Phase B [%] buo uo

10,095.0

13,095.0

13,15,0

16.05.0

Consumption 0.4 ml / min.

UV detection 220nm

Column temperature: 30 ° C.

Sample solvent: acetonitrile.

Chiral chromatography method.

Column: Daicel Chiralpak IE-3.

Length 150 mm, inner diameter 4.6 mm, particle size: 3.0 μm.

Mobile phase: A: 0.1% TFA in heptane, B: ethanol, (isocratic mode: A / B = 70/30; run time: 25 min) Flow rate 1.0 ml / min.

Detection of UV 265 nm.

Column temperature: 40 ° C.

Stage 1.2 - {[(ret-Butyldimethylsilyl) oxy] methyl} -8-chloro-1- (2,6-dichlorophenyl) -5 - {[(4R) -2,2-dimethyl-1,3-dioxolane -4-yl] methoxy} -1,4-dihydro-1,6-naphthyridin-4-one.

To a solution of ((R) -2,2-dimethyl- [1,3] dioxolan-4-yl) -methanol (6.3 g, 47.59 mmol) in THF (140 ml) was added lithium diisopropylamide (2M in THF, 24 ml, 47.59 mmol) at a temperature from -10 to -5 ° C. The reaction mixture was stirred at -5 to 0 ° C for 1 h. Then a solution of 2 - {[(tert-butyldimethylsilyl) oxy] methyl} -5,8-dichloro-1- (2,6-dichlorophenyl ) -1,4 dihydro-1,6-naphthyridin-4-one (intermediate 7: 20 g, 39.658 mmol) in THF (60 ml) at -10 to -5 ° C. The reaction mixture was slowly warmed to room temperature over 30 minutes and stirred for 2 hours. The progress of the reaction was monitored by HPLC. If the starting material was <0.5%, work-up was started, otherwise the reaction mixture was stirred for a further 4-16 hours while monitoring by HPLC. THF / H ₂ O = 20 ml / 2 ml with an internal temperature of 20-25 ° C was added to the _{reaction mixture, then 20% NH 4} Cl solution (100 ml) with an internal temperature of 20-25 ° C was added. The layers were separated and the aqueous layer was extracted with ethyl acetate (2x100 ml). The combined organic layers were washed with water (100 ml) followed by

- 34 038455 rinsing with 20% saline (100 ml).

Crystallization.

The organic layer was concentrated under reduced pressure to obtain a residue weighing about 40 g, then n-heptane (2x400 ml) was used, carrying out azeotropic distillation to obtain 50 g of a residue. To the residue was added n-heptane (400 ml) and the mixture was heated to an internal temperature of 60 ° C for 30 minutes, held for 1-2 hours, and then the hot mixture was filtered. The filtrate was cooled to 0 ° C over 10 hours and stirred for 6 hours. The formed precipitate was separated by filtration. This wet cake was suspended in ethyl acetate (20 ml) and n-heptane (200 ml) and heated to 55 ° C for 30 minutes. The resulting solution was stirred for 30 min at 55 ° C. The solution was slowly cooled to 0 ° C over 6 hours and held for at least 3 hours. The precipitate was filtered and dried to give an off-white solid of the title compound (13.8 g, 57% yield).

ESI-MS mass / charge: 601.0 [M + H] +; HPLC purity: 98.9% ee: 99.1%; Ή NMR (400 MHz, DMSO-d6) δ ppm = 8.26 (s, 1 H), 7.82-7.68 (m, 3H), 6.53 (s, 1H), 4.53-4 , 38 (m, 3H), 4.174.08 (m, 1H), 4.06-3.98 (m, 3H), 1.37 (s, 3H), 1.33 (s, 3H), 0, 85 (s, 9H), 0.02-0.05 (m, 6H); ¹³ C NMR (101 MHz, DMSO-d6) δ ppm = -5.22, 18.37, 26.05, 26.20, 27.02, 60.72, 66.30, 67.09, 73.85 , 109.20, 110.04, 111.18, 114.93, 129.48, 133.07, 133.90, 136.12, 145.07, 150.45, 151.56, 162.57, 175 ,16.

Stage 2. (R) -8-Chloro-1- (2,6-dichlorophenyl) -5 - ((2,2-dimethyl-1,3-dioxolan-4-yl) methoxy) -2- (hydroxymethyl) - 1,6-naphthyridin-4 (1H) -one.

In a solution of 2- {[(tert-butyldimethylsilyl) oxy] methyl} -8-chloro-1- (2,6-dichlorophenyl) -5- {[(4R) -2,2dimethyl-1,3-dioxolane-4- yl] methoxy} -1,4-dihydro-1,6-naphthyridin-4-one (15 g, 25 mmol) in THF (50 ml), a solution of tetrabutylammonium fluoride trihydrate (9.5 g, 30 mmol) in THF (25 ml) with an internal temperature of 20-25 ° C. The reaction mixture was allowed to stir for 2 hours. The progress of the reaction was monitored by HPLC. HPLC results showed 96.8% product with complete consumption of starting material. The reaction mixture was cooled to an internal temperature of 0-5 ° C, and then ice water (75 ml) with an internal temperature of 0-5 ° C was added dropwise, followed by the addition of isopropyl acetate (75 ml).

The layers were separated and the aqueous layer was extracted with isopropyl acetate (75 ml).

The combined organic layer was washed with water (1x75 ml) followed by 20% brine (1x75 ml).

Crystallization.

The organic layer was concentrated in vacuo to obtain 40 g of a residue and then isopropyl acetate (5x150 ml) was added with azeotropic distillation to obtain 50 g of a residue. The mixture was cooled to 20-25 ° C. and product seeded (6 mg) was added. The mixture was incubated for 2 h at an internal temperature of 20-25 ° C, then the mixture was heated to an internal temperature of 35 ± 3 ° C for 30 min, incubated for 30 min, and n-heptane (150 ml) was added over 6 h. The mixture was cooled to an internal temperature of 0 ± 3 ° C over 5 h and held for at least 3 h. The desired product was obtained by filtration and the wet cake was washed with n-heptane (15 ml) and then dried under vacuum at 40 ° C. obtaining the title compound as a light yellow solid (10.5 g, 86.5% yield).

ESI-MS mass / charge: 486.9 [M + H] +; HPLC purity: 98.3% ee: 99.6%; Ή NMR (400 MHz, DMSO-d6) δ ppm = 8.23 (s, 1 H), 7.78-7.68 (m, 3H), 6.54 (s, 1H), 5.85 (t , J = 6.0 Hz, 1H), 4.49-4.37 (m, 3H), 4.14-4.08 (m, 1H), 4.04-3.97 (m, 1H), 3.78 (d, J = 5.26 Hz, 2H), 1.36 (s, 3H), 1.31 (s, 3H). ¹³ C NMR (101 MHz, DMSO-d6) δ ppm = 26.20, 27.00, 58.86, 66.33, 67.11, 73.86, 109.21, 110.00, 111.16, 114.06, 129.48, 133.15, 133.80, 135.98, 136.01, 145.00, 150.25, 153.49, 162.58, 175.10.

Step 3. (S) -8-Chloro-1- (2,6-dichlorophenyl) -5- (2,3-dihydroxynropoxy) -2- (hydroxymethyl) -1.6naphthyridin-4 (1H) -one.

Acetonitrile (67.9 g) and (R) -8-chloro-1- (2,6-dichlorophenyl) -5 ((2,2-dimethyl-1,3-dioxolan-4-yl ) methoxy) -2- (hydroxymethyl) -1,6-naphthyridin-4 (1H) -one (13.1 g, 1.0 eq.). Acetonitrile (29.1 g), water (1.96 g) and Bi (OTf) ₃ (4.42 g, 0.25 eq.) Were added to another 100 ml flask. The corresponding Bi (OTf) ₃ solution was added to the FlexyCube at 20 ± 3 ° C over 15 min. The reaction mixture was cooled to 10 ± 3 ° C over 40 min and kept at 10 ± 3 ° C for 45 min. Thereafter, the reaction mixture was cooled to 0 ± 3 ° C over 30 min and held at 0 ± 3 ° C for 30 min when the reaction was complete according to UPLC analysis. The reaction mixture was slowly added 5 wt. % aq. NaHCO ₃ solution (67 g) keeping the temperature below 10 ° C. Ethyl acetate (120 g) was added and the mixture was warmed to room temperature. The phases were separated and the aqueous solution was extracted with ethyl acetate (59 g) and isopropyl alcohol (5.1 g). The combined organic phase was washed with 20 wt% brine (75 g). The organic solvent was replaced with isopropyl alcohol and concentrated at 50-100 mbar at 50 ° C. to give 32.6 g of a residue. Methyl tert-butyl ether (20 g) was added to the residue at 50 ± 3 ° C over 30 min. The mixture was stirred for another 30 min until the

- 35 038455 for additional solids. Methyl tert-butyl ether (80 g) was added over 1 h. The temperature was lowered to 23 ± 3 ° C over 2 h, methyl tert-butyl ether (60 g) was added over 1 h and held for 2 h. The solid was filtered; the wet filter cake was washed twice with a mixed solvent of isopropyl alcohol (3.9 g) and methyl tert-butyl ether (37 g). Then the crude material was dissolved in acetonitrile (27.2 g) and water (103 g) at 25 ± 3 ° C until a clear solution was formed. A seed (48 mg) was added and stirred for 30 min, followed by the addition of water (137.5 g) over 2 h.The mixture was kept at 25 ± 3 ° C for 1 h and then cooled to 0 ± 3 ° C for 7 h. It was filtered and the wet cake was washed with water. The wet precipitate was dried under vacuum at 60 ° C for 16 h to obtain (S) -8-chloro1- (2,6-dichlorophenyl) -5- (2,3-dihydroxypropoxy) -2- (hydroxymethyl) -1.6 -naphthyridin-4 (1H) -one as a light yellow solid (7.95 g, 66% yield).

ESI-MS mass / charge: 445.011 [M + H] +; HPLC purity: 99.34% ee: 99.3%; Ή NMR (400 MHz, DMSO-d6) δ ppm = 8.28 (s, 1 H), 7.91-7.70 (m, 3H), 6.62 (s, 1H), 5.91 (s , 1H), 5.24 (t, J = 5.38 Hz, 1H), 4.85 (t, J = 5.75 Hz, 2H), 3.85 (br d, J = 5.38 Hz, 2H), 3.75 (t, J = 5.56 Hz, 4H); ¹³ C NMR (101 MHz, DMSO-d6) δ ppm = 8.27, 63.36, 68.90, 69.03, 109.24, 110.52, 113.35, 128.93, 132.48, 133.29, 135.35, 144.26, 149.95, 153.26, 162.20, 174.94.

Example 1A (hydrated form B).

Recrystallization.

To 200 mg of the amorphous substance of Example 1, 1 ml of acetonitrile / water (9: 1, v / v) was added to obtain a clear solution at 50 ° C. with stirring. After stirring for 1 hour at this temperature, the solution was slowly cooled to 5 ° C. and a white precipitate formed. The precipitate was separated by centrifugation and dried at 40 ° C for 12 hours. A white crystalline powder (modified hydrated form B) of the compound was obtained.

Alternatively, hydrate B can be prepared by subjecting (S) -8-chloro-1- (2,6-dichlorophenyl) -5- (2,3-dihydroxypropoxy) -2- (hydroxymethyl) -1,6-naphthyridine-4 ( 1H) -one (any form from example 1) exposed to 92% RH for more than 72 hours at 25 ° C or by suspending (S) -8chloro-1 - (2,6-dichlorophenyl) -5- (2,3- dihydroxypropoxy) -2- (hydroxymethyl) -1,6-naphthyridin-4 (1H) -one (any form from example 1) in pure water at 25 ° C for at least 72 hours.

a) Description of the X-ray powder diffraction (XRPD) method.

An X-ray powder diffractogram was recorded on a Bruker ™ D8 Advance diffractometer with a CuKa anode (CuKa radiation (λ = 1.5418 A)). A sample weighing about 75-100 mg is placed on a Si-backed sample holder with a zero background and centered in the X-ray beam. The X-ray diffraction pattern thus determined is shown in FIG. 1 and is presented in table. 2 below by means of reflection lines from the most important lines.

table 2

Injection D value % intensity 2-Theta, ° Angstrem 6, 7 13,149 16, 1 7.0 12,578 100 11.9 7.423 37.4 12.3 7.162 15, 8 14.1 6, 257 54, 6 18.5 4.787 50, 0 22.2 4,008 37.2 24.7 3.597 92.3 26, 0 3.424 70.3 26, 9 3.307 95, 9 34.2 2, 619 39, 3 39, 1 2.302 30.7

b) Differential Scanning Calorimetry (DSC) and Thermogravimetric Analysis (TGA).

Differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) results for a small amount of Form B were obtained using Q2000 (DSC) and Q5000 (TGA) from TA Instruments using the heating range indicated in FIG. 2-3.

Description of the DSC method.

Accurately weigh 0.5-1.5 mg of each test substance into a perforated sample crucible and a closed (sealed) sample crucible. Empty sample crucibles are used as this

- 36 038455 bosom. The DSC thermogram is recorded as follows. The temperature in the still is adjusted to about -40 ° C and heated to 300 ° C at a heating rate of 10 ° C / min, with a nitrogen flow rate of 50 ml / min. The instrument is calibrated for temperature and enthalpy with indium at least 99.9999% pure, up to 300 ° C at a heating rate of 10 ° C / min, at a nitrogen flow rate of 50 ml / min. The accuracy of the measured sample temperature using this method is approximately ± 1 ° C, and the specific heat of fusion can be measured with a relative error of approximately ± 5%.

In the case of a crucible for a sample with holes (Fig. 2), the beginning of the glass transition temperature: T _onset = 38.77 ° C, the beginning of the melting endotherm: T _onset = 113.69 ° C;

In the case of a sealed crucible for the sample (Fig. 3), the beginning of the melting endotherm: T _onset = 82.30 ° C. Description of the TGA method

Accurately weigh 10-20 mg of the test substance into an A1 sample crucible. The TGA thermogram is recorded as follows. To avoid weight loss, the sample crucible contains a hermetically sealed lid, which is automatically pushed through only a few moments before loading the sample into the oven. The temperature was equilibrated to 30 ° C and increased to 200 ° C at a heating rate of 10 ° C / min at a nitrogen flow rate of 25 ml / min.

The instrument was temperature calibrated with nickel and aluminum and calibrated for weight with 5 and 10 mg standards (FIG. 4).

The following examples in table. 3 was obtained using method A.

- 37 038455

Table 3. Examples 2-58

Approx. Structure Chemical name Analytical data 2 Cl-'d ^ CI I ¹ । ChG '.o o (ΌΗ OH (R) -8-Chloro-1- (2, 6dichlorophenyl) -5- (2,3- dihydroxypropoxy) -2- (hydroxymethyl) - 1,6-naphthyridine- 4 (1H) -one ESI-MS mass / charge: 445 [M + H] ⁺ (Rt = 0.80 minutes, LC-method 1). ² H NMR (400 MHz, DMSO-d6) δ ppm = 8.24 (s, 1H), 7.85-7.57 (m, 3H), 6.56 (s, 1H), 5.85 ( t, J = 5.9 Hz, 1H), 4.88 (d, J = 5.2 Hz, 1H), 4.76 (t, J = 6.0 Hz, 1H), 4.38 (dd, J = 10.7, 5.5 Hz, 1H), 4.30 (dd, J = 10.7, 5.8 Hz, 1H), 3.86 (p, J = 5.4 Hz, 1H), 3.79 (d, J = 5.2 Hz, 2H), 3.65-3.48 (m, 2H). 3 about I 8-Chloro-1- (2.6- dichlorophenyl) -5- (2,3- dihydroxypropoxy) -2- (hydroxymethyl) - 1,6-naphthyridine- 4 (1H) -one ESI-MS mass / charge: 445 [M + H] ⁺ (Rt = 0.79 minutes, LC-method 1). ² H NMR (4 00 MHz, DCM-d2) δ ppm = 8.02 (d, J = 3.8 Hz, 1H), 7.42 (d, J = 2.6 Hz, 3H), 6.74 (d, J = 4.4 Hz, 1H), 4.61 (ddd,

- 38 038455

but

he

J = ll, 2, 2.2, 1,2 Hz, 1H), 4.25 (dd, J = ll, 2, 3.6 Hz, 1H), 3.97 (s, 2H), 3.91-3.80 (t, 2H), 3.73-3.66 (t, 1H).

H RMS calc.

474,7386 found

474.7356

[M + H] ⁺ ;

^d H NMR

8-Chloro-1- (2,6dichlorophenyl) -2 (hydroxymethyl) -5 (hydroxymethyl) ocetan-3yl) methoxy) -1.6naphthyridine-4 (1H) one (400 MHz

MeCN-d3)

8-Chloro-1- (2.6- δ ppm = 8.18 (s, 1 dichlorophenyl) -5- Η) 7.40-7.83 (m, 3 (2, 3-dihydroxy-3- Η) 6, 42-6, 90 (m, 1 methylbutoxy) -2- Η) 4.87 (s, 1 Η) (hydroxymethyl) - 4.66 (d, J = 3.03 1,6-naphthyridine- Hz, 1 Η) 4.27-4.51 4 (1H) -one (m, 1 Η) 3.90-4.07 (m, 2 Η) 3.85 (m, 1 Η) 3.67 (m, 2 Η) 1.96 (s, 3 Η) 1.28 (d, J = 19.96 Hz, 6 Η)

ESI-MS mass / charge: 471 [M + H] ⁺ (Rt = Ό, 89 minutes, LC-way eleven IMP (400 MHz, DMSO-d6) ι δ ppm = 8.26 (s, 1H), 7.82-7.58 (m, 3H), 6.54 (s, 1H), 5, 85 (t, J = 5, 9 HZ, 1H), 5.03 (t, J = 5.8 HZ, 1H), 4.57 (s, 2H),

- 39 038455

4.52-4.28 (m, 4H), 3.82 (dd, J = 26.8, 5.5 Hz, 4H). 6 _ о Cr ² Y ° / = ² ? ζ-ω— τ II Ο Ν- (2- ((8-Chloro-1 (2,6-dichlorophenyl) 2- (hydroxymethyl) 4-okco-I, 4-dihydro-1,6naphthyridine-5yl) oxy) ethyl) methane sulfonamide HRMS calc. 466,0507 [M + H] ⁺ ; found value 466, 0506,! H NMR (4 00 MHz, DCM-d2) δ ppm = 9.78 (s, 1H), 7.97 (s, 3H), 7.11 (s, 1H), 6, 37-6.17 (m, 1H), 4.74 (s, 1H), 3.58 (q, J = 5.8 Hz, 2H), 3.48 (q, J = 5.6 Hz, 2H ), 3.02 (s, 3H), 2.10 (s, 3H). 7 υυ _ΗΟ ~ ^Ο ^ _Ο ^ ° ° 8-Chloro-1- (2,6dichlorophenyl) -5- (2 (2- (2- (2- hydroxyethoxy) is xi) ethoxy) ethoxy) -2- (hydroxymethyl) - 1,6-naphthyridine- 4 (1H) -one HRMS calc. 547.0806 [M + H] ⁺ ; found value 547.0796,! H NMR (4 00 MHz MeCN-d3) δ ppm = 8.03-8.22 (t, 1 H) 7.41-7.73 (t, 3 H) 6.60 ( t, 1 H) 4.51-4.70 (t, 2 H) 3.93 (t, 2 H) 3.84-3.89 (t, 2 H) 3.72-3.78 (t, 2 H) 3.57-3.65 (t, 9 H) 3.48-3.53 (t, 2 H) 2.94 (br s, 1 H)

- 40 038455

eight % U ^CI Ά X OH he 8-Chloro-1- (2,6dichlorophenyl) -5- (3hydroxy-2- (hydroxymethyl) pro poxy) -2- (hydroxymethyl) - 1,6-naphthyridine- 4 (1H) -one ESI-MS mass / charge 445.1 [M + H] ⁺ (Rt = 0.84 minutes, LC method 1),! H NMR (4 00 MHz, MeCN-d3) δ ppm = 8.07 (s, 1H), 7.50 (d, J = 2.9 Hz, 3H), 6.56 (s, 1H), 4.41 (d, J = 5.8 Hz, 2H), 3.89-3.77 (m, 3H) , 3.70-3.54 (m, 4H). nine about I 8-Chloro-1- (2,6dichlorophenyl) -5- ((1,3- dihydroxypropan2-yl) oxy) -2- (hydroxymethyl) 1,6-naphthyridine- 4 (1H) -one ESI-MS mass / charge 445 [M + H] ⁺ (Rt = 0.78 minutes, LC-method 1), NMR (40 0 MHz, DCM-d2) δ ppm = 8.01 (s, 1H), 7.42 (d, J = 2.6 Hz, 3H), 6.72 (s, 1H), 4.88 (dt, J = 7.6, 4.2 Hz, 1H), 3.97 (s, 2H), 3, 68 (qd, J = 12.2, 5.4Hz, 4H). ten ° E> - h Z = \ ° A ^ -L ^{o =} \ _ / ~ \ ^ / - o m 8-Chloro-1- (2,6dichlorophenyl) -2 (hydroxymethyl) -5 (oxetane-3- ylmethoxy) -1,6 naphthyridin-4 (1H) one ESI-MS mass / charge 443 [M + H] ⁺ (Rt = 0.93 minutes, LC-method 1), NMR (40 0 MHz, MeCN-d3) δ ppm = 8.13 (s, 1H), 7, 68-7, 56 (m, 3H),

- 41 038455

, ο

6.60 (t, J = l, l Hz, 1H), 4.76 (dd, J = 8.0, 6.0 Hz, 2H), 4.70-4.53 (t, ZN), 3, 98-3, 86 (t, 2H), 3.77 (q, J = 6.4, 5.5 Hz, 1H), 3.50 (dtd, J = 14.3, 6.4, 1.5 Hz, 1H). 8-Chloro-1- (2.6- dichlorophenyl) -2- (hydroxymethyl) -5- (2- (2- methoxyethoxy) ethoxy) -1.6- naphthyridine-4 (1H) - he ESI-MS mass / charge: 475 [M + H] ⁺ (Rt = 0.96 minutes, LC-method 1),% NMR (400 MHz, DCM-d2) δ ppm = 7.96 (s, 1H) , 7.39 (d, J = l, 3 Hz, ZN), 6.61 (t, J = l, 0 Hz, 1H), 4.48 (dd, J = 5.5, 4.3 Hz, 2H), 3.92 (d, J = 1, 0 Hz, 2H), 3.79 (dd, J = 5.5, 4.3 Hz, 2H), 3.693.57 (m, 2H), 3, 48-3.38 (m, 2H), 3.25 (s, 3H). 8-Chloro-1- (2,6dichlorophenyl) -5- (2hydroxyethoxy) -2 (hydroxymethyl) 1,6-naphthyridine4 (1H) -one HRMS: calc. 415.0019 [M + H] ⁺ , value found 415.0008; NMR (400 MHz, DMSO-d6) δ ppm = 8.22 (s, 1H), 7.78-7.63 (m,

- 42 038455

ZN), 6, 53 (s, 1H), 5, 83 (s, 1H), 4.77 (t, J = 5, 6 Hz, 1H), 4.42 (t, J = 5, 5 Hz, 2H), 3, 76 (dd, J = ll , 0, 5.5 Hz, 4H)

HRMS calc.

546,0966 [M + H] ⁺ ; found value

546, 0653,! H NMR

8-Chloro-1- (2.6- (400 MHz, MeCN-d3) dichlorophenyl) -5-

13 but ^ · ^ ύΨ ) // \ .NH О Г V ^x ci ((2- (2- (2- (2hydroxyethoxy) is xi) ethoxy) ethyl) am ino) -2- (hydroxymethyl) - 1,6-naphthyridine- 4 (1H) -one δ ppm = 10.1 Η) 7.98 7.45-7.72 6.41-6.88 3.86-3.94 3.65-3.72 3.54-3.63 Η) 3, 46-3 73 (br (s, 1 (m, 3 (m, 1 (m, 2 (m, 4 (m,, 52 (m s, H) H) H) H) H) eleven 2 Η) 2.86 ( t, J = 5 , 87 Hz, 1 Η) 2.13 (s, 3Η) 1.97 (s, 3 H)

HRMS calculated 575,1119 [M + H] ⁺ ; 8-Chloro-1- (2.6- found meaning dichlorophenyl) -5- 575.1125, ^d H NMR ((14-hydroxy- (400 MHz, MeCN-d3) 3,6,9,12- δ ppm = 8.06-8.29 tetraoxatetradecy (m, 1 Η) 7.49-7.71 l) hydroxy) -2-methyl- (m, 3 Η) 6.38 (d, 1,6-naphthyridine- J = 0.76 Hz, 1 Η) 4 (1H) -one 4.44-4.74 (m, 2 Η) 3.82-3.96 (m, 2 Η) 3.70-3.77 (m, 2 Η)

- 43 038455

3.54-3.65 (t, 12 H) 3.45-3.50 (t, 2 H) 2.97-3.13 (t, 1 Η) 1.97 (s, 3 H) 15 ^{C |} <Л Cl <* / <° ° / ° CT V / o- ¹ 5- (2,5,8,11,14,17Hexaoxanoneadecan-19-yloxy) -8chloro-1- (2,6dichlorophenyl) -2methyl-1,6naphthyridin-4 (1H) one ESI-MS mass / charge: 635 [M + H] ⁺ (Rt = 1, 08 minutes, LC-method 1), ^d H NMR (400 MHz DCM-d2) δ ppm = 8.09 (s, 1H), 7.61-7.33 (t, 3H), 6.38 (d, J = 0.8 Hz, 1H), 4.72-4.46 (t, 2H), 4.01-3.90 ( t, 2H), 3.84-3.75 (t, 2H), 3.71-3.56 (t, 16H), 3.57-3.47 (t, 2H), 3.37 (s, 3N), 1.94 (d, J = 0.7 Hz, 3N). 16 ciOL Cl τ Cl τ। <1 / _Ho ^ O ^ _o j ^ NH O 3-Chloro-2- (8-chloro5- ((2- (2- (2- (2hydroxyethoxy) is xy) ethoxy) ethyl) am ino) -2-methyl-4oxo-1,6naphthyridin-1 (4Н) yl ) benzonitrile HRMS calc. 521.1359 [M + H] ⁺ ; found value 521.1365, ^d H NMR (400 MHz, MeCN-d3) δ ppm = 10.67 (br s, 1 Η) 8.00 (s, 1 Η) 7.83-7.94 (m, 2 Η) 7.74 (d, J = 8.08 Hz, 1 Η) 6.39 (d, J = 0.76 Hz, 1 Η) 3.67 (t, 4 Η) 3.59 (t, 10 Η) 3.49 (t, 2 Η) 2.77-2.90 (t,

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1 H) 1.96 (s, 3 H) 17 CI ^ Y ^ CI i ¹ 1 NH О ΗΟ ^ γ ^^^ ΟΗ О 3- ((8-Chloro-1- (2,6dichlorophenyl) -2methyl-4-oxo-1,4dihydro-l, 6naphthyridine-5yl) amino) -2hydroxy-N- (2hydroxyethyl) propanamide HRMS calc. 485.0551 [M + H] ⁺ ; found value 485, 0576,! H NMR (400 MHz, MeCN-d3) δ ppm = 10.72 (br s, 1 H) 7.89 (s, 1 H) 7.38-7.61 (m, 3 H) 7.11-7.30 (m, 1 H) 6.31 (d, J = 0.76 Hz, 1 H) 4.06-4.30 (m, 1 H) 3.74-3, 95 (m, 1 H) 3.62 (d, J = 14.02 Hz, 1 H) 3.37-3.46 (m, 2 H) 3.33 (t, J = 5.49 Hz, 1 H) 3.05-3.27 (m, 2 H) 2.56 (t, J = 5.56 Hz, 1 H) 1.82 (d, J = 0.63 Hz, 3 H) eighteen CN CI ^^^ CI vA. Oh oh but ^ ^he 3,5-Dichloro-4- (5 (2,3 - dihydroxypropoxy) -2-methyl-4-oxo1,7-naphthyridine- 1 (4H) - sludge) benzonitrile HRMS calc. 420.0518 [M + H] ⁺ ; found 420, 0505, NMR (400 MHz, DMSO-d6) δ ppm = 8.57 (s, 2H), 8.32 (s, 1H), 7.78 (s, 1H), 6.35 (s , 1H), 5.75 (s, 1H), 5.06 (dd, J = 8.5, 5.6 Hz, 1H), 4.80 (t, J = 6.0 Hz, 1H),

- 45 038455

4.20 (d, J = 5.3 Hz, 2H), 3.57 (tt, J = 12.7, 6.1 Hz, 2H), 1.98 (d, J = 9.1 Hz, ZN). 19 ί? ' Uh but ^ o ^ o ^ o 0 8-Chloro-1- (2,6dichlorophenyl) -5 ((17-hydroxy3,6,9,12,15- pentaoxaheptadecyl) oxy) -2-methyl1,6-naphthyridin4 (1H) -one HRMS calc. 619.1381 [M + H] ⁺ ; found value 619.1394,! H NMR (400 MHz, MeCN-d3) δ ppm = 8.13 (s, 1 Η) 7.47-7.72 (m, 3 Η) 6.37 (d, J = 0.76 Hz, 1 Η) 4.52-4.73 (m, 2 Η) 3.84-3.98 (m, 2 Η) 3.67-3.80 (m, 2 Η) 3.55 -3.65 (m, 17 Η) 3.45- 3.53 (m, 2 Η) 1.93 (s, 3 Η) twenty about t 8-Chloro-1- (2,6dichlorophenyl) -5- (3 (2,3- dihydroxypropoxy) -2- hydroxypropoxy) 2-methyl-1,6naphthyridin-4 (1H) one HRMS calc. 503.0543 [M + H] ⁺ ; found value 503.0533,! H NMR (400 MHz, methanol ci 4) δ ppm = 8.18 (s, 1Η), 7.64 (d, J = 2.0 Hz, ZN), 6.52 (d, J = 9.0 Hz, 1H), 4, 64-4.43 (m, 2H), 4.29-4.15 (m, 1H), 3.91-3.45 (m, 7H), 2 , 00 (d, J = 2.5 Hz, 3N).

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21 i O ί τ 3-Chloro-2- (8-chloro5- (2- (2- (2- (2hydroxyethoxy) is xi) ethoxy) ethoxy) -2-methyl-4-oxo1,6-naphthyridine1 (4H) yl) benzonitrile HRMS calc. 522.1199 [M + H] ⁺ ; found value 522.1204,! H NMR (400 MHz, MeCN-d3) δ ppm = 8.15 (s, 1 Η) 7.92 (d, J = 2.15 Hz, 2 Η) 7.77 (s , 1 Η) 6.38 (d, J = 0.76 Hz, 1 Η) 4.52-4.81 (m, 2 Η) 3.84-3.98 (m, 2 Η) 3.70- 3.79 (m, 2 Η) 3.57-3.65 (m, 8 Η) 3.51 (d, J = 5.31 Hz, 2 Η) 1.97 (s, 3 Η) 22 CN CI ^^^ CI y / HN 0 ^ NH o = s = o 1 N- (2- ((1- (2,6Dichloro-4cyanophenyl) -2methyl-4-oxo-1,4dihydro-1,7naphthyridine-5yl) amino) ethyl) meta nsulfonamide HRMS calc. 466,0507 [M + H] ⁺ ; found value 466, 0506,! H NMR (4 00 MHz, DCM-d2) δ 9.78 (s, 1H), 7.97 (s, 3H), 7.11 (s, 1H), 6.37- 6.17 (m, 1H), 4.74 (s, 1H), 3.58 (q, J = 5.8 Hz, 2H), 3.48 (q, J = 5.6 Hz, 2H), 3.02 (s, 3H), 2.10 (s, 3H).

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23 CI '^ Y'CN ι ¹ । 3-Chloro-2- (8-chloro5- (2- (2- (2- (2hydroxyethoxy) is xi) ethoxy) ethoxy) -2-methyl-4-oxo1,6-naphthyridine 1 (4H) -yl) -5fluorobenzonitrile HRMS calc. 540, 1105 [M + H] ⁺ ; found 540, 1110,! H NMR (400 MHz, MeCN-d3) δ ppm = 8.11-8.35 (m, 1 Η) 7.78 (ddd, J = 15.38, 7.86, 2 , 78 Hz, 2 Η) 6.39 (d, J = 0.76 Hz, 1 Η) 4.40-4.84 (m, 2 Η) 3.83-4.01 (m, 2 Η) 3 , 71-3.78 (m, 2) 3.57-3.65 (m, 8 Η) 3.46-3.54 (m, 2 Η) 2.92 (br s, 1 H) 1, 97 (s, 3 H) 24 О V ¢ 5 ^ - (7-9 \ = Z Y i I r 8-Chloro-1- (2.6— dichloro-4- fluorophenyl) -5 - ((17hydroxy- 3,6,9,12,15- pentaoxaheptadecyl) oxy) -2-methyl1,6-naphthyridine- 4 (1H) -one HRMS: calc. 637.1287 [M + H] ⁺ , 637.1303 found,! H NMR (400 MHz, DMSO-d ₆ ) δ ppm = 8.23 (s, 1H), 7.89 (d, J = 8, 3 Hz, 2H), 6.44 (d, J = 0.8 Hz, 1H), 4.55 (t, J = 5.4 Hz, 1H), 4.48 (dd, J = 5.5, 4.2 Hz, 2H), 3.833.76 (m, 2H), 3.66 (dd, J = 5.7, 3.9 Hz, 2H), 3.57-3.44 (m, 16H), 3.43-

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3.36 (m, 2H), 1.90 (s, 3H). 25 CN YY N O Ν HE 3,5-Dichloro-4- (8chlor-5- (4- (2- hydroxyethyl) piperazin-1-yl) -2methyl-4-oxo-1, 6naphthyridin-1 (4H) yl) benzonitrile HRMS calc. 492.0751 [M + H] ⁺ ; found value 492.0746; NMR (400 MHz, chloropoφopm-d3) δ ppm = 8.01 (s, 1H), 7.76 (s, 2H), b.sg3 (s, 1H), 3.75-3.49 (t, 6H ), 2.67 (dt, J = 30.9, 4.8 Hz, 6H), 1.90 (s, 3H). 26 ci ^^ y ^ ci I ¹ 1 A. o o but ^ ^he ΌΗ 8-Chloro-1- (2,6dichlorophenyl) -2methyl-5- (2,3,4trihydroxybutoxy) -1,6-naphthyridine4 (1H) -one HRMS calc. 459, 0281 [M + H] ⁺ ; found value 459.0278, ² H NMR (400 MHz, methanol d4) δ ppm = 8.19 (d, J = 3.5 Hz, 1H), 7.65 (d, J = 2.2 Hz, ZN), 6, 60-6, 48 (m, 1H), 4.70 (dd, J = ll, 3, 3.7 Hz, 1H), 4.56 (dd, J = ll, 3, 5.4 Hz, 1H), 4.04-3.93 (m, 1H), 3.85-3.74 (m, 2H), 3.75-3.62 (m, 1H), 2.05-1.98 ( m, 3H).

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27 CN C1 ' ^X ^^ ^X C1 HN 0 ΌΗ 3,5-Dichloro-4- (5- ((2- hydroxyethyl) amino ) -2-methyl-4-oxo 1,7-naphthyridine- 1 (4H) - sludge) benzonitrile HRMS calc. 389.0572 [M + H] ⁺ ; found 389.0569, NMR (400 MHz, DMSO-d6) δ ppm = 9.54 (t, J = 5.5 Hz, 1H), 8.55 (s, 2H), 7.88 (s, 1H ), 7.07 (s, 1H), 6.29 (s, 1H), 4.87 (t, J = 5.1 Hz, 1H), 3.65 (q, J = 5.4 Hz, 2H ), 3.41-3.30 (q, J = 5.4 Hz, 2H), 1.95 (s, 3H). 28 ci η // Μ he he 8-Chloro-1- (2,6dichlorophenyl) -5- (3- hydroxy-2,2bis (hydroxymethyl) propoxy) -2-methyl- 1,6-naphthyridine- 4 (1H) -one ESI-MS mass / charge: 475 [M + H] ⁺ (Rt = l, 80 minutes, LC-method 1), NMR (40 0 MHz, DCM-d2) δ ppm = 8.02 (s, 1H) , 7.53-7.12 (m, 3H), 6.36 (d, J = 0.7 Hz, 1H), 4.31 (s, 2H), 3.68 (s, 6H), 1, 87 (d, J = 0.7 Hz, 4H). 29 CN C | N 0 OH 3,5-Dichloro-4- (5 (3- hydroxyazetidin1-yl) -2-methyl-4- oxo-1,7- naphthyridine-1 (4H) yl) benzonitrile HRMS calc. 401.0572 [M + H] ⁺ ; the found value is 401.0576. NMR (400 MHz, chloroform-dS) δ ppm = 7.90 (s, 2H),

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7.71 (s, 1H), 7.16 (s, 1H), 6.24 (s, 1H), 4.77 (ddd, J = 10.9, 6.5, 4.4 Hz, 1H), 4.52 (dd, J = 10, l, 6.9 Hz, 2H), 4.02 (dd, J = 10.6, 4.3 Hz, 2H), 1.96 (s, ZN).

8-Chloro-1- (2.6- dichlorophenyl) -5- (2- HRMS 531.0856 found 531.0881, (400 MHz, δ ppm = 8,: calculated [M + H] ⁺ ; value ² Η NMR MeCN-d3) 2 (s, 1 thirty 5 (2- (2- (2- hydroxyethoxy) is xi) ethoxy) ethoxy) -2-methyl-1, 6- Η) 7.61 6, 30-6, 44 4.52-4.64 3.82-3.92 (m, 3 Η) (m, 1 Η) (m, 2 Η) (m, 2 Η) '/ 2 naphthyridine-4 (1H) he 3.70-3.76 3.56-3.64 3.47-3.53 2.86 (t, Hz, 1 Η) 3 Η) (m, 2 Η) (m, 8 Η) (m, 2 Η) J = 5.87 1.93 (s,

8-Chloro-1- (2,6dichlorophenyl) -5 ((2R, 4S) -4hydroxy-2 (hydroxymethyl) pyrrolidin-1-yl) -2methyl-1,6naphthyridin-4 (1H) one

HRMS calc.

454,0492 [M + H] ⁺ ; found value 454.0483, ² H NMR (400 MHz, chloroform-FZ) δ ppm = 7.94 (s, 1H),

7.54-7.37 (m, 3H), 6, 38-6, 24 (m, 1H), 4.90 (td, J = 7.0,

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ZN).

Hz, 1H), 4.44 1H) , 4.25 (s, 4, 10-3.95 (T, 3.59 (dd, , 7, 3.7 Hz, 2.72 (dd, , 7, 2.1 Hz, 2, 52-1.95 (T, 1, 95-1.87 (T,

8-Chloro-1- (2,6-dichloro-4fluorophenyl) -5- (2 (2- (2- (2hydroxyethoxy) is xi) ethoxy) ethoxy)

-2-methyl-1, 6naphthyridin-4 (1H) one

HRMS calculated 549.0762 [M + H] ⁺ , found meaning 549.0756, % NMR (400 MHz, methanol d ₄ ) δ ppm = = 8.19 (s, 1H), 7, 59 (d, 2 = 8.1 P B 2H), 6.50 (s 1H), 4.68-4.61 (T, 2H), 3.97-3.90 (T, 2H), 3.80-3.74 (T, 2H), 3.69-3.58 (T, 9H), 3.58-3.51 (T, 2H), 2.03-1.99 (T, ZN).

8-Chloro-1- (2,6dichlorophenyl) -5- ((3R, 4S) -3.4- dihydroxypyrrolid in-1-yl) -2-methyl1,6-naphthyridine- 4 (1H) -one HRMS calc. 440.0335 [M + H] ⁺ , found 440.0324; NMR (400 MHz, methanol24) δ ppm = 7.99 (s, 1H), 7.69-7.52 (m, 3H), 6.42 (s, 1Η), 4.25 (t, J = 4 , 0 Hz, 2H), 3.71 (dd,

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J = ll, 6, 4.9 Hz, 2H), 3.42 (dd, J = ll, l, 4.2 Hz, 2H), 1.97 (s, 3H). 34 _C | UU \ _CN i ¹ । OH 3-Chloro-2- (8-chloro- 5- (2,3- dihydroxypropoxy) -2-methyl-4-oxo1,6-naphthyridine- 1 (4H) - sludge) benzonitrile HRMS calc. 420.0518 [M + H] ⁺ , found 420.0530; 1H NMR (400 MHz, chloroform-FZ) δ 8.11 (d, J = 0.7 Hz, 1H), 7.87-7.72 (m, 2H), 7.65 (t, J = 8, 0 Hz, 1H), 6.46 (s, 1H), 5.16-4.83 (m, 1H), 4.77 (t, J = 12.2 Hz, 1H), 4.37 (ddd, J = ll, 3, 9.9, 3.5 Hz, 1H), 4.10-3.72 (m, 4H), 1.97 (s, 3H). 35 Cl y ^ CI% NH О HN ^/ ^ 7 \ iN 5 - ((2- (1Nimidazole-4- yl) ethyl) amino) -8chloro-1- (2,6dichlorophenyl) -2- methyl-1,6naphthyridin-4 (1H) one ESI-MS mass / charge: 448.1 [M + H] ⁺ (Rt = 2.08 minutes, LC-method 1), NMR (40 0 MHz, DCM-d2) δ ppm = l0.73 (s, 1H), 8.02 (s, 1H), 7.64 (s, 1H), 7.59-7.38 (m, 3H), 6.94 (s, 1H), 6.36 (s, 1H ), 3.92-3.71 (m, 2H), 3.01 (t, J = 6.7 Hz,

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2H), 1.94 (s, 3H).

36 ^ci O Cl Y ^ CI .о о ньг Ο = Ξ = Ο 1 Ν- (2- ((8-Chloro-1- (2,6-dichlorophenyl) - 2-methyl-4-oxo 1,4-dihydro-1,6- n and f thyridine-5- yl) oxy) ethyl) methane sulfonamide HRMS calc. 476,0019 [M + H] ⁺ ; found value 476.0002,! H NMR (4 00 MHz, DCM-d2) δ 8.13 ppm = (s, 1H), 7.55 (t, J = 7.4 Hz, 3H), 6.82 ( bs, 1H), 6.47 (s, 1H), 4, 64-4.56 (m, 2H), 3.56 (q, J = 5.1 Hz, 2H), 3.03 (s, 3H ), 2.01 (s, 3H). 37 A % but - oh 8-Chloro-1- (2,6dichlorophenyl) -5- ((2- (2- (2- (2hydroxyethoxy) is xi) ethoxy) ethyl) am ino) -2-methyl-1,6naphthyridin-4 (1H) one HRMS calc. 530,1016 [M + H] ⁺ ; found 530, 1026, ^g H NMR (400 MHz, MeCN-d3) δ ppm = 10.58-10.87 (m, 1 H) 7.99 (s, 1 H) 7.50-7.70 ( m, 3 H) 6.39 (d, J = 0.76 Hz, 1 H) 3.56-3.76 (m, 14

8-Chloro-1- (2,6-dichlorophenyl) -5 (2,3dihydroxypropoxy) -2-methyl-1, 6naphthyridine-4 (1H) H) 3.45-3.54 (t, 2

H) 2.16-2.51 (t, 1

H) 1.91 (s, 3 H)

HRMS calc.

429,0176 [M + H] ⁺ ;

found value 429, 0169, NMR (400 MHz, chloroform-FZ) δ

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he ppm = 8.09 (s, 1H), 7.48 (s, 3H), 6.45 (s, 1H), 5.14 (dd, J = 10.4, 3.9 Hz, 1H), 4.77 (dd, J = ll, 2, 2.0 Hz, 1H), 4.35 (dd, J = ll, 2, 3.5 Hz, 1H), 4.09-3.70 (t, 4H), 1.94 (s, 3H). 39 i ¹ 1 νΦΓ 0 (S) -8-Chloro-1- (2,6dichlorophenyl) -5- ((2,3- dihydroxypropyl) a mino) -2-methyl-1,6naphthyridin-4 (1H) one HRMS calc. 428.0335 [M + H] ⁺ ; found value 428.0332; ^d H NMR (400 MHz, chloroform-d) δ ppm = 10.8 8 (s, 1H), 7.92 (s, 1H), 7.54-7.37 (t, 3H), 6, 54- 6.26 (t, 1H), 4.29-3.40 (t, 7H), 1.92 (s, 3H). 40 vV about. oh ^but bn 8-Chloro-1- (2,6dichlorophenyl) -5 (2, 3-dihydroxy-3- methylbutoxy) -2methyl-1,6- naphthyridine-4 (1H) he HRMS calc. 457.0489 [M + H] ⁺ ; found value 457.0499 [M + H] ⁺ , 1H NMR (4 00 MHz, MeCN-d3) δ ppm 8.20 (s, 1 Η) 7.64 (m, 3 Η) 6.53 (s, 1 Η) 4.79-4.97 (m, 1 H) 4.65 (m, 1 Η) 4.45 (m, 1 Η) 3.81-3.95 (m, 1 Η) 3, 60- 3,732 (m, 1 Η)

- 55 038455

2.01 (s, 3 H) 1.29 (d, J = 14.91 Hz, 6 H) 41 O 8-Chloro-1- (2,6dichlorophenyl) -5- (3 - hydroxy-2- (hydroxymethyl) -2methylpropoxy) -2methyl-1,6naphthyridin-4 (1H) one ESI-MS mass / charge: 459.1 [M + H] ⁺ (Rt = 2.07 minutes, LC-method 1),! H NMR (400 MHz, DCM-d2) δ ppm = 8.01 (s, 1H), 7.51-7.27 (m, 3H), 6.34 (s, 1H), 4.22 (s, 2H), 3.74 (d, J = ll, 5 Hz, 2H), 3.52 (d, J = ll, 5 Hz, 2H), 3.44 (s, 3H), 1.86 (s, 3H). 42 o ° CZ ^ E \ Q 8-Chloro-1- (2,6dichlorophenyl) -5- (2hydroxy-2methylpropoxy) -2methyl-1,6naphthyridin-4 (1H) one HRMS calc. 427.0383 [M + H] ⁺ ; found 427.0383,! H NMR (4 00 MHz, DCM-d2) δ ppm = 7.98 (s, 1H), 7.46-7.34 (m, 3H), 6.29 (s, 1H ), 4.16 (s, 2H), 1.84 (s, 3H), 1.22 (s, 6H).

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43 CN Cl ^ d ^ CI ϊ ¹ 1 ^> ^NH О M 'OH 3,5-Dichloro-4- (8chlor-5- (((3R, 4S) 4- hydroxytetrahydro furan-3-yl) amino) 2-methyl-4-oxo 1,6-naphthyridine- 1 (4H) - sludge) benzonitrile HRMS calc. 465, 0288 [M + H] ⁺ ; the found value is 465.0289. 1H NMR (400 MHz, Chloroform-d) δ 10.77 (d, J = 3.6 Hz, 1H), 8.01 (s, 1Η), 7.78 (d, J = 0.7 Hz, 2H ), 6, 48-6, 25 (m, 1Η), 4.55 (br, s, 1H), 4.39-4.21 (m, 3H), 4.12 (dd, J = 9.6 , 5.9 Hz, 1H), 3.82 (ddd, J = 12.7, 9.0, 5.1 Hz, 2H), 1.92 (s, 3H)., 44 CN α ^ζ γ ⁴ θ ^ι ? । _o SHN O OH 3,5-Dichloro-4- (8chlor-5 - ((2hydroxyethoxy) amino) -2-methyl-4oxo-1,6naphthyridin-1 (4H) yl) benzonitrile HRMS calc. 439,0131 [M + H] ⁺ ; found value 439, 0126,! H NMR (400 MHz, chloroform-dS) δ ppm = 12.2 6 (s, 1Η), 8.12 (s, 1Η), 7.78 (s, 2H), 6, 44 (d, J = 0.8 Hz, 1H), 5.56 (s, 1H), 4.21-3.97 (m, 2H), 3.87-3, 60 (m, 2H), 1 , 94 (d, J = 0.6 Hz, 3N).

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45 CT ^^ CI Yr n ^ nh o ν '7 8-Chloro-1- (2,6dichlorophenyl) -2methyl-5 - ((1-methyl- 1Н-tetrazol-5yl) amino) -1,6 naphthyridin-4 (1Н) one HRMS calc. 436,0247 [M + H] ⁺ ; found value 43 6.024 0,! H NMR (400 MHz, chloroform-dS) δ ppm = 13.45 (s, 1H), 8.20 (s, 1H), 7.50 (s, 3H), 6 , 53 (s, 1H), 4.01 (s, 3H), 2.01 (s, 3H). 46 YY Ν ^ Ο Ο Ν '7 Ν '\ 8-Chloro-1- (2,6dichlorophenyl) -2methyl-5 - ((1-methyl- 1H-tetrazole-5- yl) oxy) -1,6 naphthyridin-4 (1H) one HRMS calc. 437.0087 [M + H] ⁺ ; found 437.0085, ² H NMR (400 MHz, chloroform-dS) δ ppm = 8.57 (s, 1H), 7.52 (d, J = 2.4 Hz, 3H), 6.42 (d , J = 0.7 Hz, 1H), 3.74 (s, 3H), 1.98 (s, 3H). 47 _S | G-G _S | ι ¹ 1 W ν ^ νη ο —ν '7 ν = ν 8-Chloro-1- (2,6dichlorophenyl) -2methyl-5 - ((2-methyl2H-tetrazol-5yl) amino) -1.6naphthyridin-4 (1H) one HRMS calc. 436,0247 [M + H] ⁺ ; found value 436.0257; NMR (400 MHz, chloroform-dS) δ ppm = 13.68 (s, 1H), 8.29 (s, 1H), 7.49 (d, J = 3.4 Hz, 3H), 6.52 ( s, 1H), 4.35 (s, 3H), 1.98 (s, 3H).

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48 about t 8-Chloro-1- (2,6dichlorophenyl) -5- (2- hydroxyethoxy) -2methyl-1,6- naphthyridine-4 (1H) - he HRMS calc. 399,0070 [M + H] ⁺ ; found value 399, 0056, ² H NMR (400 MHz, chloroform-FZ) δ ppm = 8.08 (s, 1H), 7.52-7.44 (m, 3H), 6.42 (d, J = 0.7 Hz, 1H), 4, 64-4.53 (m, 2H), 4.15 (br, s, 1H), 4.01-3.87 (m, 2H), 1.94 (s , 3H). 49 YY O ' ^NH ° he 8-Chloro-1- (2,6dichlorophenyl) -5- ((2- hydroxyethoxy) amino) -2-methyl-1,6naphthyridin-4 (1H) one HRMS calc. 414.0179 [M + H] ⁺ ; found value 414.0171; ² H NMR (400 MHz, chloroform-dS) δ ppm = 12.32 (s, 1H), 8.10 (s, 1H), 7.61-7.32 (m, 3H), 6.51-6 , 34 (m, 1H), 5.73 (s, 1H), 4.09 (dd, J = 5, l, 3.7Hz, 2H), 3.76 (s, 2H), 2.07- 1.80 (m, 3H).

- 59 038455

50 _ο λ— \ ^{Z =} \ ^V ο — ά o Q 'ό. 8-Chloro-1- (2,6dichlorophenyl) -2methyl-5- (oxetan3-ylmethoxy) -1, 6naphthyridin-4 (1H) one HRMS calc. 425,0227 [M + H] ⁺ ; found value 425.0211,! H NMR (4 00 MHz, DCM-d ₂ ) δ ppm = 8.09 (s, 1H), 7.59-7.45 (m, 3H), 6.35 (s, 1H), 4.85 (dd, J = 7.9, 6.1 Hz, 2H), 4.734.59 (m, 4H), 3.64-3.49 (m, 1H), 1.94 (s , 3H). 51 T О О / С / Г \ ¥ ° 7 * <M. ^{4 = 2} Y, ρ ω О ⁴ 8-Chloro-1- (2,6dichlorophenyl) -2 (hydroxymethyl) -5 ((2- (methylsulfonyl) et yl) amino) -1,6 naphthyridin-4 (1H) one ESI-MS mass / charge: 477.8 [M + H] ⁺ (Rt = 0.84 minutes, LC-method 4),! H NMR (40 0 MHz, DCM-d2) δ ppm = 0.62 ( t, 7 = 5.6 Hz, 1H), 7.94 (s, 1H), 7.47-7.35 (m, 3H), 6.74 (s, 1H), 3.93 (q, 7 = 6.2 Hz, 4H), 3.31 (t, 7 = 6.6 Hz, 2H), 2.87 (s, 3H). 52 □: O ¹ \ 2 = \ ° Ά \ f! o ^ο λΖ7-O 8-Cyclopropyl-1 (2,6-dichlorophenyl) 5- (2,3- dihydroxypropoxy) -2-methyl-1, 6naphthyridin-4 (1H) one HRMS calc. 435.0878 [M + H] ⁺ ; found value 435.0903,! H NMR (400 MHz, chloroform-73) δ ppm = 7, 69-7.46 (m, ZN), 6, 35-6, 24 (m,

- 60 038455

8-Chloro-1- (2,6dichlorophenyl) -5- (353 but

ОМе hydroxy-2 (hydroxymethyl) propoxy) -2 (methoxymethyl) 1,6-naphthyridine4 (1Н) -one

1H), 5.82 (s, 1H), 5.49 (s, 1H), 4.73 (d, J = ll, 4 Hz, 1H), 4.27 (dd, J = ll , 4, 2.5 Hz, 1H), 4.16-3.72 (T, 4H), 2.04-1.87 (T, ZN), 1, 69 (dd, J = 8, 0, 4, 6 Hz, 1H), 1.13-1.01 (T, 2H), 2H). 0.98-0.82 (T,

HRMS calc.

473.0438 [M + H] ⁺ ;

found value 473.0451, ^T H NMR (4 00 MHz, DCM-d2) δ ppm = 8.02 (s,

1H), 7.44-7.41 (m, 3H), 7.41 (s, 3H), 6.55 (s, 1H), 4.48 (d, J = 4.8 Hz, 2H), 3.96-3.71 (m, 8H), 3.19 (s, 3H), 2.11 (d, J = 4.5Hz, 1H).

8-Chloro-1- (2.6- HRMS calc. 459, 0281 [M + H] ⁺ ; dichlorophenyl) -5- found value ΟΐγΌΙ (2,3- 459, 0286,! H NMR fl | i ОМе dihydroxypropoxy (4 00 MHz, DCM-d2) ) ^- 2- δ ppm = 8.03 (s, oh oh (methoxymethyl) - 1H), 7.50-7.36 (m, but ^ - ^he 1,6-naphthyridine- 4 (1H) -one 3H), 6.56 (s, 1H), 4.88 (td, J = ll, 0, 9.4, 5.6 Hz, 1H),

- 61 038455

4.62 (ddd, J = ll, 2, 2.2, 1.2 Hz, 1H), 4.25 (dd, J = ll, 2, 3.6 Hz, 1H), 3.85 (d, J = 12.2 Hz, 2H), 3.76 (s, 2H), 3.75-3.64 (m, 2H), 3.19 (s, 3H). 55 § V k - ζ Vo _χ Ζ ^/ Yy ° ο τ 3-Chloro-2- (8-chloro2-cyclopropyl-5 (2,3- dihydroxypropoxy) -4-OXO-1,6 naphthyridin-1 (4Η) yl) benzonitrile ESI-MS mass / charge: 446.1 [M + H] ⁺ (Rt = 1, 67 minutes, LC-method 1), ^g H NMR (400 MHz DCM-22) δ ppm = 8.17 (s, 1H ), 7.83 (ddt, 2 = 8.8, 6.4, 1.4 Hz, 2H), 7.75-7.62 (m, 1H), 6.34 (s, 1H), 4, 73 (ddd, 2 = 10.2, 8.5, 1.7 Hz, 1H), 4.38 (ddd, 2 = 11.2, 6.0, 3, 6 Hz, 1H), 4.073, 91 (m, 2H), 3.87-3.73 (m, 2H), 1.38-1.19 (m, 1H), 0.88 (dtt, 2 = 11.3, 7.7, 4 , 1 Hz, 2H), 0.82-0.68 (m, 2H).

- 62 038455

56 CN HN O NH # = / 4- (5- ((2- (1Nimidazole-4- yl) ethyl) amino) -2methyl-4-oxo-1,7 naphthyridin-1 (4H) yl) -3,5- dichlorobenzonitrile HRMS calc. 439, 0841 [M + H] ⁺ ; found value 439.0828, ^d H NMR (400 MHz, DMSO-J6) δ ppm = 9.4 8 (dt, J = 20, l, 5.4 Hz, 1H), 8.54 (s, 3H), 7.91 (d, J = 24.6 Hz, 1H), 7.54 (d, J = 8.7 Hz, 1H), 7.09 (d, J = 12.5 Hz, 1H), 6, 32-6.18 (m, 1H), 5.75 (s, 1H), 3.00-2.87 (m, 2H), 2.83 (t, J = 6.8 Hz, 2H). 57 ΞΕ 0 o / - ^z \ / ^ ° \ = Z \ / 1 / o 8-Chloro-1- (2.6- dichlorophenyl) -5- ((2,2-dimethyl-1,3- dioxolan-4- yl) methoxy) -2- (hydroxymethyl) - 1,6-naphthyridine- 4 (1H) -one ESI-MS mass / charge: 487 [M + H] ⁺ (Rt = 1, 05 minutes, LC-method 1), ^d H NMR (40 0 MHz, DCM-d2) δ ppm = 8.14 (s, 1H), 7.54 (d, J = 1, 9 Hz, 3H), 6.99 (s, 1H), 4, 66-4.46 (m, 3H), 4.28-4.17 (m , 1H), 4.15-3.96 (m, 3H), 1.47 (s, 3H), 1.41 (s, 3H).

Chiral resolution of the racemic compound of Example 40

Examples 58 and 59 One of Examples 58 and 59 is (R) -8-chloro-1- (2,6-dichlorophenyl) -5 (2,3-dihydroxy-3-methylbutoxy) -2-methyl-1, 6-naphthyridin-4 (1H) -one, and the other is (S) -8chloro-1- (2,6-dichlorophenyl) -5- (2,3-dihydroxy-3-methylbutoxy) -2-methyl-1 , 6-naphthyridin-4 (1H) -one.

8-chloro-1- (2,6-dichlorophenyl) -5- (2,3-dihydroxy-3-methylbutoxy) -2-methyl-1,6-naphthyridin-4 (1H) -one was dissolved in methanol and subjected to several injection operations, 1.6 ml each, to perform chiral preparative SFC (ChiralPak AD-H column, 250x330 mm ID, 5 μm, flow rate 80 ml / min at 38 ° C) using 35% 2-propanol in carbon dioxide as mobile phase. After chiral separation, the fractions were dried by rotary evaporation to give Example 58 corresponding to the first elution peak (ee> 99%) and Example 59 corresponding to the second elution peak (ee> 99%) as white solids. Retention times were obtained on a ChiralPak AD-H, 4.6x100 mm, 5 μm column, using a gradient of 5 to 55% 2-propanol in carbon dioxide as mobile phase over 5.5 min, then held for 0.1 min (solvent consumption 5.0 ml / min) at an oven temperature of 38 ° C (example 58: Rt = 4.23 min; example 59: Rt = 4.68 min).

The following examples were prepared as described in Scheme B.

Example 60 8-Chloro-1- (2,6-dichloro-4-fluorophenyl) -5- (2,3-dihydroxypropoxy) -2- (hydroxymethyl) 1,6-naphthyridin-4 (1H) -one

- 63 038455

Stage 1. 8-Chloro-1- (2,6-dichloro-4-fluorophenyl) -5 - ((2,2-dimethyl-1,3-dioxolan-4-yl) methoxy) -2-methyl-1, 6-naphthyridin-4 (1 H) -one

A mixture of 5,8-dichloro-1- (2,6-dichloro-4-fluorophenyl) -2-methyl-1,6-naphthyridin-4 (1H) -one (intermediate 2, 0.4 g, 1, 02 mmol), (2,2-dimethyl-1,3-dioxolan-4-yl) methanol (0.674 g, 5.10 mmol), K ₂ CO ₃ (0.423 g, 3.06 mmol) and DMAP (0.037 g , 0.306 mmol) in acetonitrile (10 ml) at 80 ° C for 2 days. The solid was filtered off and then the reaction mixture was purified by silica gel chromatography (EtOAc / heptane, 10 to 50%) to give a white solid as the title compound (0.436 g, 88%). ESI-MS mass / charge: 489.1 [M + H] + (Rt = 1.42 min, LC-method 3)

Step 2. 8-Chloro-1- (2,6-dichloro-4-fluorophenyl) -5- (2,3-dihydroxypropoxy) -4-oxo-1,4-dihydro-1,6naphthyridine-2-carbaldehyde

A mixture of 8-chloro-1- (2,6-dichloro-4-fluorophenyl) -5 - ((2,2-dimethyl-1,3-dioxolan-4yl) methoxy) -2-methyl-1,6-naphthyridine was stirred -4 (1H) -one (0.104 g, 0.213 mmol) and SeO ₂ (0.036 g, 0.32 mmol) in 1,4 dioxane (2 ml) at 90 ° C overnight. Another batch of SeO ₂ (0.030 g, 0.27 mmol) was added to the reaction mixture, followed by stirring at 100 ° C. overnight. The solid was filtered off. The volatiles were removed under reduced pressure to give the crude product. LC-MS results indicate that the title compound is the major component of the crude product. ESI-MS mass / charge: 463.1 [M + H] ⁺ (Rt = 1.02 min, LC-method 3)

Stage 3.8-Chloro-1- (2,6-dichloro-4-fluorophenyl) -5- (2,3-dihydroxypropoxy) -2- (hydroxymethyl) -1,6naphthyridin-4 (1H) -one

Into a solution of crude 8-chloro-1- (2,6-dichloro-4-fluorophenyl) -5- (2,3-dihydroxypropoxy) -4-oxo1,4-dihydro-1,6-naphthyridine-2-carbaldehyde (0.098 g, 0.213 mmol) in EtOH (5 ml), NaBH4 (0.04 g, 1.07 mmol) was added. The reaction mixture was stirred at 60 ° C for 5 min. The solid was filtered off followed by purification by reverse phase HPLC (X-bridge column, 30x50 mm, 5 μm, ACN / H2O with 10 mM NH4OH, 75 ml / min, injection 1.5 ml, gradient: 15 to 40 % ACN over 3.5 min) to give a white solid representing the title compound (0.027 g, 26%).

60: HRMS: calc. 463.0031 [M + H] ⁺ , found 463.0036; 1H NMR (400 MHz, DMSO-d6) δ

- 64 038455 ppm = 8.26 (s, 1H), 7.88 (d, J = 8.3 Hz, 2H), 6.55 (s, 1H), 5.85 (bs, 1H), 4, 88 (bs, 1H), 4.75 (bs, 1H), 4.38 (dd,

J = 10.7, 5.5 Hz, 1H), 4.30 (dd, J = 10.7, 5.8 Hz, 1H), 3.78-3.91 (m, 3H), 3.58 (m, 2H).

The following example was prepared in a manner similar to that described for the above example using ethane-1,2-diol in step 1.

Example 61 8-Chloro-1 - (2,6-dichloro-4-fluorophenyl) -5- (2-hydroxyethoxy) -2- (hydroxymethyl) -1,6-naphthyridin-4 (1H) -one

61: HRMS: calc. 432.9925 [M + H] +, found 432.9919; 1H NMR (400 MHz, DMSO-d6) δ ppm = 8.23 (s, 1H), 7.88 (d, J = 8.3 Hz, 2H), 6.52 (s, 1H), 5.82 (bs, 1H), 4.77 (bs, 1H), 4.42 (t, J = 5.5 Hz, 2H), 3.81 (s, 2H), 3.76 (q, J = 4, 4 Hz, 2H).

Example 62 8-Chloro-1- (2,6-dichlorophenyl) -2- (difluoromethyl) -5- (2,3-dihydroxypropoxy) -1,6-naphthyridin-4 (1H) -one

Stage 1. 8-Chloro-1- (2,6-dichlorophenyl) -5 - ((2,2-dimethyl-1,3-dioxolan-4-yl) methoxy) -2-methyl-1,6naphthyridine-4 ( 1H) -one.

(2 , 2-dimethyl-1,3-dioxolan-4-yl) methanol (0.883 g, 6.68 mmol), K ₂ CO ₃ (0.277 g, 2.005 mmol) and DMAP (0.008 g, 0.067 mmol). The resulting solution was heated at 75 ° C for 1 h. The reaction mixture was taken up in EtOAc / water. The aqueous layer was extracted with EtOAc. The combined organic layers were dried over anhydrous Na ₂ SO ₄ , filtered and evaporated. The crude material was purified by silica gel chromatography (10 to 100% EtOAc in heptane) to afford the title compound (0.277 g, 79%).

ESI-MS mass / charge: 471.1 [M + H] + (Rt = 1.17 min, LC-method I), Ή NMR (400 MHz, DCM-d2) δ ppm = 8.09 (s, 1H ), 7.61-7.41 (m, 3H), 6.40 (d, J = 0.7 Hz, 1H), 4.62-4.45 (m, 3H), 4.20 (dd, J = 8.5, 6.1 Hz, 1H), 4.04 (dd, J = 8.4, 6.2 Hz, 1H), 1.95 (s, 3H), 1.47 (s, 3H ), 1.41 (s, 3H).

Stage 2. 8-Chloro-1- (2,6-dichlorophenyl) -5 - ((2,2-dimethyl-1,3-dioxolan-4-yl) methoxy) -4-oxo-1,4-dihydro- 1,6-naphthyridine-2-carbaldehyde.

The mixture of 8-chloro-1- (2,6-dichlorophenyl) -5- (3-hydroxy-2- (hydroxymethyl) propoxy) -2-methyl-1,6-naphthyridin-4 (1Н) -one was heated under reflux (0.123 g, 0.262 mmol) and selenium dioxide (0.035 g, 0.314 mmol) in 1,4-dioxane (5 ml) overnight. Insoluble materials were filtered off and washed with EtOAc. The organic layer was concentrated under reduced pressure. EtOAc and water were added to the residue. The organic layer was separated and aq. the layer was extracted with EtOAc. The combined organic layer was dried over anhydrous Na ₂ SO ₄ , filtered and evaporated. The crude material was purified by silica gel chromatography (10% to 100% EtOAc in heptane) to afford the title compound (0.057 g, 45%).

Stage 3. 8-Chloro-1- (2,6-dichlorophenyl) -2- (difluoromethyl) -5 - ((2,2-dimethyl-1,3-dioxolan-4-yl) methoxy) -1,6- naphthyridin-4 (1H) -one.

Into a solution of 8-chloro-1- (2,6-dichlorophenyl) -5 - ((2,2-dimethyl-1,3-dioxolan-4-yl) methoxy) -4-oxo-1,4-dihydro-1,6 α-naphthyridine-2-carbaldehyde (0.056 g, 0.116 mmol) in 2 ml DCM was added DeoxoFluor (0.320 ml, 1.737 mmol). The resulting mixture was stirred at room temperature over the weekend. The resulting product was quenched with 10% NaHCO ₃ solution at 0 ° C, then extracted with CH ₂ Cl ₂ . The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to dryness. The residue was purified by silica gel chromatography (10% to 100% EtOAc in heptane) to afford the title compound (0.025 g, 43% yield). ESI-MS mass / charge: 505.1 [M + H] + (Rt = 1.23 min, LC method 1).

- 65 038455

Step 4. 8-Chloro-1- (2,6-dichlorophenyl) -2- (difluoromethyl) -5- (2,3-dihydroxypropoxy) -1,6-naphthyridin-4 (1H) -one.

To a solution of 8-chloro-1- (2,6-dichlorophenyl) -2- (difluoromethyl) -5 - ((2,2-dimethyl-1,3-dioxolan-4-yl) methoxy) -1,6-naphthyridine -4 (1H) -one (0.025 g, 0.049 mmol) in 0.5 ml DCM was added 0.5 ml TFA. The reaction mixture was stirred for 1.5 hours. Then the resulting mixture was concentrated. The residue was diluted with ACN and filtered through LP-HCO ₃ resin to neutralize the TFA salt. The filtrate was concentrated to give the title compound (0.020 g, 7-8% yield).

62: ESI-MS mass / charge: 467.1 [M + H] + (Rt = 1.91 min, LC method 1); ¹ H NMR (400 MHz, DCM-d2) δ ppm = 8.09 (s, 1H), 7.56-7.36 (m, 3H), 6.78 (s, 1H), 5.99 (t , J = 53.0 Hz, 1H), 4.64 (ddd, J = 11.2, 2.4, 1.2 Hz, 1H), 4.27 (dd, J = 11.2, 3.7 Hz, 1H), 3.98-3.79 (m, 2H), 3.77-3.61 (m, 1H).

Example 63 8-Chloro-1- (2,6-dichlorophenyl) -5- (2,3-dihydroxypropoxy) -4-oxo-l, 4-dihydro-1,6-naphthyridine-2-carbonitrile

N..CN

8-chloro-1- (2,6-dichlorophenyl) -5 - ((2,2-dimethyl-1,3-dioxolan-4-yl) methoxy) -4-oxo-1,4-dihydro-1, 6-naphthyridine-2-carbaldehyde as described for example 63 in steps 1 and 2.

Step 3.8-Chloro-1- (2,6-dichlorophenyl) -5- (2,3-dihydroxypropoxy) -4-oxo-1,4-dihydro-1,6-naphthyridine-2-carboxylic acid

Into a solution of 8-chloro-1- (2,6-dichlorophenyl) -5 - ((2,2-dimethyl-1,3-dioxolan-4-yl) methoxy) -4-oxo-1,4-dihydro-1,6 -naphthyridine-2-carbaldehyde (0.358 g, 0.740 mmol) in a mixture of acetone (1 ml) and water (1 ml) sodium chlorite (0.134 g, 1.48 mmol) and sulfamic acid (0.216 g, 2.22 mmol) were added ... The mixture was stirred at room temperature overnight. The solvent was removed. The residue was washed with water, filtered and dried under vacuum. This was used as such in the next step. ESI-MS mass / charge: 460.9 [M + H] + (Rt = 0.46 min, LC method 4), 1H NMR (400 MHz, DMSO-d6) δ ppm = 8.19 (s, 1H ), 7.48 (d, J = 4.2 Hz, 3H), 6.14 (s, 1H), 4.97-4.79 (m, 2H), 4.38 (dd, J = 10, 6, 5.5 Hz, 1H), 4.26 (dd, J = 10.6, 6.0 Hz, 1H), 3.92-3.79 (m, 1H), 3.57 (dq, J = 10.8, 5.5 Hz, 2H).

Step 4. 8-Chloro-1- (2,6-dichlorophenyl) -5- (2,3-dihydroxypropoxy) -4-oxo-1,4-dihydro-1,6-naphthyridine-2-carboxamide

Into a solution of 8-chloro-1- (2,6-dichlorophenyl) -5- (2,3-dihydroxypropoxy) -4-oxo-1,4-dihydro-1,6-naphthyridine-2-carboxylic acid (0.160 g, 0.348 mmol), HATU (0.397 g, 1.044 mmol) and DIEA (0.304 ml, 1.74 mmol) in DMF (4 ml) was added ammonium chloride (0.056 g, 1.044 mmol). The mixture was stirred at room temperature overnight. The reaction mixture was diluted with EtOAc and washed with water. Aq. the layer was extracted with EtOAc. The combined organic layer was dried over

- 66 038455 anhydrous Na ₂ SO ₄ . filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0 to 10% MeOH in DCM) to afford the title compound (0.132 g, 83%). ESI-MS mass / charge: 458.0 [M + H] + (Rt = 0.68 min, LC method 4), ¹ H NMR (400 MHz, DMSO-d6) δ ppm = 8.38 (s, 1H), 8.29 (s, 1H), 7.79 (s, 1H), 7.66-7.50 (m, 3H), 6.42 (s, 1H), 4.88 (d,

J = 5.2 Hz, 1H), 4.71 (t, J = 5.9 Hz, 1H), 4.44-4.21 (m, 2H), 3.87 (q, J = 5.3 Hz, 1H), 3.66-3.48 (m, 2H).

Step 5. 8-Chloro-1- (2,6-dichlorophenyl) -5- (2,3-dihydroxypropoxy) -4-oxo-1,4-dihydro-1,6-naphthyridine-2-carbonitrile

Into a solution of 8-chloro-1- (2,6-dichlorophenyl) -5- (2,3-dihydroxypropoxy) -4-oxo-1,4-dihydro-1,6-naphthyridine-2-carboxamide (0.130 g, 0.283 mmol) in THF (3 ml) and TEA (0.099 ml, 0.709 mmol) was added dropwise TFAA (0.140 ml, 0.992 mmol) at 0 ° C (internal temperature did not exceed 15 ° C as monitored using an internal thermometer).

The reaction mixture was stirred at 0 ° C for 2 hours. The resulting mixture was then poured into water and the product was extracted with EtOAc (3X). The combined organic layers were washed with saturated aqueous NaHCO ₃ solution, brine and dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The crude material was purified by silica gel chromatography (0 to 10% MeOH in DCM) to afford the title compound (0.09 g, 72%).

63: ESI-MS mass / charge: 442.0 [M + H] + (Rt = 0.68 min, LC-method 4), Ή NMR (400 MHz, DCM-d2) δ ppm = 8.25 (s , 1H), 7.61 (d, J = 4.5 Hz, 3H), 6.99 (s, 1H), 4.70-4.59 (m, 4H), 4.52 (dd, J = 10.9, 5.6 Hz, 1H), 4.39 (dt, J = 11.1, 5.6 Hz, 2H).

Example 64 8-Chloro-1- (2,6-dichlorophenyl) -5-hydroxy-2- (hydroxymethyl) -1,6-naphthyridin-4 (1H) -one

To a solution of 2 - (((tert-butyldimethylsilyl) oxy) methyl) -5,8-dichloro-1- (2,6-dichlorophenyl) -1,6-naphthyridin-4 (1H) -one (intermediate 7, 0 , 1 g, 0.198 mmol) in water (5 ml) was added 1 N. HCl (5 ml). The resulting mixture was stirred at 80 ° C overnight. The resulting product was neutralized with saturated aqueous NaHCO ₃ and the desired product was extracted with EtOAc. The combined organic layers were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The residue was triturated with a mixture of MeCN and heptane to give the title compound (0.043 g, 55% yield).

64: ESI-MS mass / charge: 372.8 [M + H] + (Rt = 0.88 min, LC method 1), ¹ H NMR (400 MHz, DCM-d2) δ ppm = 8.19 ( s, 1H), 7.57 (d, J = 2.8 Hz, 3H), 7.01 (s, 1H), 4.23-4.08 (m, 2H).

Example 65 1- (2,6-Dichlorophenyl) -5- (2,3-dihydroxypropoxy) -2-methyl-7- (methylamino) -1,6-naphthyridin-4 (1H) -one

- 67 038455

Stage 1. 7-Chloro-1- (2,6-dichlorophenyl) -5 - ((2,2-dimethyl-1,3-dioxolan-4-yl) methoxy) -2-methyl-1,6naphthyridine-4 (1H) -one

To a solution of intermediate 11 (1 g, 2.67 mmol) in NMP (8 ml) was added DMAP (0.163 g, 1.337 mmol), K ₂ CO ₃ (1.108 g, 8.02 mmol) and (2,2-dimethyl -1,3-dioxolan-4-yl) methanol (1.060 g, 8.02 mmol) at rt. The resulting solution was stirred at 75 ° C for 1 h. The reaction mixture was cooled to rt, quenched with brine, extracted with EtOAC. The organic phase was washed with water, brine, dried over MgSO ₄ and concentrated in vacuo. The crude residue was purified by silica gel column chromatography eluting with EtOAc / heptane 0 to 100% followed by MeOH / EtOAc 5% to afford the title compound as a white solid (0.51 g, yield 40.6%). LC / MS (mass / charge, [M + H] +): 471.1.

Step 2. 1- (2,6-Dichlorophenyl) -5- (2,3-dihydroxypropoxy) -2-methyl-7- (methylamino) -1,6-naphthyridin-4 (1H) -one.

Into a solution of 7-chloro-1- (2,6-dichlorophenyl) -5 - ((2,2-dimethyl-1,3-dioxolan-4-yl) methoxy) -2-methyl-1,6naphthyridine-4 (1Н ) -one (20 mg, 0.043 mmol) in Hünig's base (0.074 ml, 0.426 mmol) and NMP (0.5 ml) methylamine hydrochloride was added and the reaction mixture was heated at 90 ° C overnight. The reaction mixture was filtered and purified by basic preparative HPLC (Waters Xbridge, 5 μm 30x100 mm, water / acetonitrile with 10 mM NH4OH, 75 ml / min, 1.5 ml injection, 30 to 45% ACN over 11.5 min. ) to obtain the desired product in the form of a white powder. This white powder was dissolved in DCM (1 ml) and TFA (1 ml) was added. The resulting solution was stirred at rt. during the night. The reaction mixture was concentrated, neutralized with conc. ammonia and then purified by basic preparative HPLC (Waters Xbridge, 5 μm 30x100 mm, water / acetonitrile with 10 mM NH4OH, 75 ml / min, 1.5 ml injection, 20 to 35% ACN in 11.5 min) with obtaining the title compound as an off-white powder (8.9 mg, 0.021 mmol).

65: HRMS: calc. 424.0844 [M + H] +, found 424.0830; Ή NMR (400 MHz, chloroform d3) δ ppm = 7.56-7.46 (m, 2H), 7.40 (dd, J = 8.6, 7.5 Hz, 1H), 6.09-5 , 99 (m, 1H), 5.67 (s, 1H), 4.72-4.51 (m, 3H), 4.18 (d, J = 9.8 Hz, 1H), 4.02- 3.70 (m, 4H), 2.64 (d, J = 5.1 Hz, 3H), 1.88-1.76 (m, 3H).

Example 66 1- (2,6-Dichlorophenyl) -5- (2,3-dihydroxypropoxy) -7-ethyl-2-methyl-1,6-naphthyridin4 (1H) -one and Example 67: 1- (2- chloro-6-ethylphenyl) -5- (2,3-dihydroxypropoxy) -7-ethyl-2-methyl-1,6-naphthyridin-4 (1H) -one

Stage 1. 1- (2,6-dichlorophenyl) -5 - ((2,2-dimethyl-1,3-dioxolan-4-yl) methoxy) -7-ethyl-2-methyl-1,6naphthyridine-4 ( 1H) -one and 1- (2-chloro-6-ethylphenyl) -5 - ((2,2-dimethyl-1,3-dioxolan-4-yl) methoxy) -7-ethyl-2methyl-1,6- naphthyridin-4 (1H) -one.

A solution of diethylzinc (3.55 ml, 3.55 mmol) (1M in heptane) was added dropwise to a mixture of 7-chloro-1 (2,6-dichlorophenyl) -5 - ((2,2-dimethyl-1,3- dioxolan-4-yl) methoxy) -2-methyl-1,6-naphthyridin-4 (1H) -one (0.833 g, 1.774 mmol), DPPF (0.197 g, 0.355 mmol) and Pd (OAc) ₂ (0.040 g , 0.177 mmol) in toluene (10 ml) at -78 ° C under nitrogen atmosphere. After the addition, the reaction mixture was heated at 90 ° C for 1 h. The reaction mixture was cooled to rt. and extinguished sat. aq. NH ₄ Cl solution, diluted with EtOAc and filtered through celite. The organic phase was washed with brine, dried over anhydrous MgSO ₄ and concentrated in vacuo. The crude residue was purified using a column

68 038455 chromatography, eluting with EtOAc / heptane 0 to 100% to give 1- (2,6dichlorophenyl) -5- (2,3-dihydroxypropoxy) -7-ethyl-2-methyl-1,6 -naphthyridin-4 (1H) -one, (0.7 g yellow solid, 1.44 mmol) and 1- (2-chloro-6-ethylphenyl) -5- (2,3-dihydroxypropoxy) -7-ethyl -2-methyl1,6-naphthyridin-4 (1H) -one (0.012 g of a white solid, 0.025 mmol).

Stage 2. The compound, which is 1- (2,6-dichlorophenyl) -5- (2,3-dihydroxypropoxy) -7ethyl-2-methyl-1,6-naphthyridin-4 (1H) -one, and 1- ( 2-chloro-6-ethylphenyl) -5- (2,3-dihydroxypropoxy) -7-ethyl-2methyl-1,6-naphthyridin-4 (1H) -one.

The above two compounds were separately dissolved in a 1: 1 mixture of DCM and TFA and stirred at rt. for 1 hour. After removal of volatiles and purification by basic preparative HPLC, fractions containing examples 66 and 67 were obtained as white powders.

66: HRMS: calc. 423.0878 [M + H] +, found 423.0897; Ή NMR (400 MHz, chloroform d3) δ ppm = 7.67-7.46 (m, 3H), 6.34 (s, 1H), 5.74 (s, 1H), 4.84 (d, J = 11.5 Hz, 1H), 4.38 (dd, J = 11.4, 3.3 Hz, 1H), 4.07-3.94 (m, 2H), 3.87 (dd, J = 11 , 7, 5.4 Hz, 1H), 2.56 (q, J = 7.5 Hz, 2H), 1.95 (s, 3H), 1.16 (t, J = 7.5 Hz, 3H ).

67: HRMS: calc. 417.1581 [M + H] +, found 417.1626; ¹ H NMR (400 MHz, chloroform-d3) δ ppm = 7.59-7.32 (m, 3H), 6.37 (d, J = 15.1 Hz, 1H), 5.83 (d, J = 41.9 Hz, 1H), 4.97-4.74 (m, 1H), 4.37 (ddd, J = 10.9, 7.1, 3.1 Hz, 1H), 4.11- 3.69 (m, 3H), 2.56 (dq, J = 15.1, 7.6 Hz, 2H), 2.29 (dddd, J = 30.2, 22.7, 15.0, 7 , 3 Hz, 2H), 1.93 (d, J = 9.4 Hz, 3H), 1.12 (dt, J = 11.1, 7.6 Hz, 6H).

Example 68/1 - (2,6-Dichlorophenyl) -5- (2,3-dihydroxypropoxy) -7-methoxy-2-methyl-1,6-naphthyridin4 (1H) -one

A mixture of 7-chloro-1 - (2,6-dichlorophenyl) -5 - ((2,2-dimethyl-1,3-dioxolan-4-yl) methoxy) -2-methyl-1,6-naphthyridine-4 ( 1H) -one (29 mg, 0.062 mmol), Na ₂ CO ₃ (19.63 mg, 0.185 mmol), X-Phos (5.75 mg, 0.012 mmol) and Pd (OAc) ₂ (1.386 mg, 6, 17 μmol) in toluene (0.5 ml) and MeOH (0.050 ml, 1.235 mmol) were purged with nitrogen and heated at 80 ° C overnight. After cooling, the mixture was concentrated, taken up in ethyl acetate and filtered through a pad of silica gel.

The solvent was removed and then the crude residue was dissolved in HOAc (1 ml). Water (1 ml) was added. The resulting solution was stirred at rt. during the night. The reaction mixture was concentrated, neutralized with conc. ammonia and purified by basic preparative HPLC (Waters Xbridge, 5 μm, 30x100 mm, water / acetonitrile with 10 mM NH4OH, 75 ml / min, 1.5 ml injection, 15 to 30% ACN in 11.5 min) with obtaining the title compound as an off-white powder (11.8 mg, 0.027 mmol).

68: HRMS: calc. 425.0671 [M + H] +, found 425.0685; 1H NMR (400 MHz, chloroform d3) δ ppm = 7.64-7.43 (m, 3H), 6.27-6.18 (m, 1H), 5.28 (s, 1H), 4.84 ( dd, J = 11.2, 1.5 Hz, 1H), 4.35 (dd, J = 11.2, 3.3 Hz, 1H), 4.10-3.96 (m, 3H), 3 , 96-3.82 (m, 5H), 1.93 (s, 3H).

Example 69 1 - (2,6-Dichlorophenyl) -5 - (2,3-dihydroxypropoxy) -8-ethyl-2-methyl-1,6-naphthyridin4 (1H) -one

Example 69 was prepared analogously to Example 66 using intermediate 10 as starting material to give a white powder.

- 69 038455

69: HRMS: calc. 423.0878 [M + H] +, found 423.0888; 1H NMR (400 MHz, chloroform d3) δ ppm = 7.96 (s, 1H), 7.59-7.44 (m, 3H), 6.42 (s, 1H), 5.23 (s, 1H) , 4.77 (d, J = 10.8 Hz, 1H), 4.37 (dd, J = 11.1,

3.4 Hz, 1H), 3.93 (dd, J = 55.4, 11.9 Hz, 4H), 1.97-1.79 (m, 5H), 0.95 (t, J = 7 , 4 Hz, 3H).

Example 70 K- (1- (2,6-dichloro-4-cyanophenyl) -2-methyl-4-oxo-1,4-dihydro-1,7-naphthyridin-5-yl) -1Hpyrazole-4-sulfonamide

Stage 1. 4- (5-amino-2-methyl-4-oxo-1,7-naphthyridine-1 (4H) -yl) -3,5-dichlorobenzonitrile

Heated a mixture of intermediate 12 (0.028 g, 0.080 mmol), concentrated aq. ammonia solution (0.035 ml, 0.402 mmol) in THF (0.5 ml) at 80 ° C in a closed tube for 1 h. The reaction mixture was concentrated in vacuo and the residue was purified by basic preparative HPLC (Waters X-bridge column, 30x50 mm, 5 μm, ACN / H2O with 10 mM NH4OH, 75 ml / min, injection of 1.5 ml, gradient: 25 to 50% ACN over 4.5 min) to give the title compound (0.015 g, yield 54 %) in the form of a white powder.

Stage 2. K- (1- (2,6-dichloro-4-cyanophenyl) -2-methyl-4-oxo-1,4-dihydro-1,7-naphthyridin-5-yl) -1Hpyrazole-4-sulfonamide ...

A mixture of 4- (5-amino-2-methyl-4-oxo-1,7-naphthyridin-1 (4H) -yl) -3,5-dichlorobenzonitrile (0.015 g, 0.043 mmol) and 1H-pyrazole-4- sulfonyl chloride (0.015 g, 0.087 mmol) in pyridine (0.5 ml) at 80 ° C overnight. The reaction mixture was concentrated in vacuo. The residue was purified by basic preparative HPLC (Waters X-bridge column, 30x50 mm, 5 μm, ACN / H2O with 10 mM NH4OH, 75 ml / min, 1.5 ml injection, gradient: 25 to 50% ACN in 4.5 min) to give the title compound (4.8 mg) as an off-white powder.

70: HRMS: calc. 475.0147 [M + H] +, found 475.0142; 1H NMR (400 MHz, chloroform d3) δ ppm = 13.01 (s, 1H), 8.78 (s, 1H), 8.05 (s, 2H), 7.94 (s, 2H), 7.58 (s, 1H), 6.40 (s, 1H), 2.05 (s, 3H).

Example 71 8-Chloro-1- (2,6-dichlorophenyl) -2-methyl-5- (1H-1,2,4-triazol-1-yl) -1,6-naphthyridin-4 (1H) one

Heat a mixture of intermediate 1 (20 mg, 0.053 mmol) and sodium 1,2,4-triazol-1-idide (7.30 mg, 0.080 mmol) in THF (1 ml) at 70 ° C for 2 h. the mixture was concentrated. The crude residue was purified by basic preparative HPLC (Waters X-bridge column, 30x50 mm, 5 μm, ACN / H2O with 10 mM NH4OH, 75 ml / min, 1.5 ml injection, gradient: 25 to 50% ACN in 4 , 5 min) to give the title compound as an off-white powder (17 mg).

71: HRMS: calc. 406.0029 [M + H] +, found 406.0036; 1H NMR (400 MHz, chloroform d3) δ ppm = 8.54 (s, 1H), 8.49 (s, 1H), 8.16 (s, 1H), 7.53 (d, J = 2.4 Hz , 3H), 6.43 (s, 1H), 1.99 (s, 3H).

The following compounds were prepared as described in Scheme C.

- 70 038455

Example 72. 3,5-Dichloro-4- (2-methyl-4-oxo-5- (1H-pyrazol-3-yl) -1,7-naphthyridin-1 (4H) -yl) benzonitrile

Stirred a mixture of 4- (5-bromo-2-methyl-4-oxo-1,7-naphthyridin-1 (4H) -yl) -3,5-dichlorobenzonitrile (intermediate compound 13, 0.040 g, 0.098 mmol), (1H -pyrazol-3-yl) boronic acid (0.044 g, 0.391 mmol), Pd (PPh ₃ ) ₄ (0.011 g, 9.78 _{mmol) and Cs 2} CO ₃ (0.096 g, 0.293 mmol) in dioxane (2 ml) in a microwave oven at 140 ° C for 10 hours. The solid was filtered off. The volatiles were removed under reduced pressure and the residue was purified by silica gel chromatography (MeOH / DCM, 0 to 5%) to give the crude product, which was further purified by reverse phase HPLC (X-bridge 30x50 mm column, 5 μm, ACN / H2O with 5 mM NH ₄ OH, 75 ml / min, injection 1.5 ml, gradient: 15 to 40% ACN in 3.5 min) to give a white powder of the title compound (10 mg, yield 25%).

72: HRMS: calc. 396.0419 [M + H] +, found 396.0422; 1H NMR (400 MHz, DMSO-d6) δ ppm = 12.77 (bs, 1H), 8.60 (s, 2 H), 8.47 (s, 1 H), 8.25 (s, 1H) , 7.65 (bs., 1H), 6.45 (d, J = 2.02 Hz, 1 H), 6.40 (s, 1H), 2.01 (s, 3H).

The following compound was prepared using methods similar to those described for the above compound.

Example 73. 3,5-Dichloro-4- (2-methyl-5- (1-methyl-1H-pyrazol-4-yl) -4-oxo-1,7-naphthyridin-1 (4H) yl) benzonitrile

73: HRMS: calc. 410.0575 [M + H] +, value found 410.0564, Ή NMR (400 MHz, DMSO-d6) δ ppm = 8.59 (s, 2H), 8.41 (s, 1H), 8.10 (s, 1H), 7.99 (s, 1H), 7.65 (s, 1H), 6.38 (s, 1H), 3.89 (s, 3H), 2.00 (s, 3H) ...

Example 74 8-Chloro-1- (2,6-dichlorophenyl) -2- (hydroxymethyl) -5- (3-hydroxypropyl) -1,6-naphthyridin4 (1H) -one

Stage 1.5- (2- (1,3-Dioxan-2-yl) ethyl) -2 - (((tert-butyldimethylsilyl) oxy) methyl) -8-chloro-1- (2,6-dichlorophenyl) - 1,6-naphthyridin-4 (1 H) -one

- 71 038455 hi ίΐ H ^OTBS

ΝχΑ /

J o o ^ o

To a solution of 2 - (((tert-butyldimethylsilyl) oxy) methyl) -5,8-dichloro-1- (2,6-dichlorophenyl) -1,6-naphthyridin-4 (1H) -one (intermediate 7, 0 , 2 g, 0.397 mmol) in THF (4 ml) was added (2- (1,3 dioxan-2-yl) ethyl) magnesium bromide (0.5 M in THF, 1.03 ml, 0.516 mmol). The mixture was stirred at room temperature for 1 hour followed by the addition of another batch of (2- (1,3-dioxane-2yl) ethyl) magnesium bromide (0.5 M in THF, 1.0 mL, 0.50 mmol). The reaction mixture was stirred at room temperature for another 1 hour. Water was then added to quench the reaction mixture. The THF was removed under reduced pressure and the residue was purified by silica gel chromatography (EtOAc / heptane, 10 to 40%) to give the title compound (0.083 g, 36% yield). ESIMS mass / charge: 585.2 [M + H] + (Rt = 1.84 min, LC method 3).

Stage 2.3- (8-Chloro-1 - (2,6-dichlorophenyl) -2- (hydroxymethyl) -4-okco-1,4-dihydro-1,6-naphthyridin-5 yl) propanal

CI ^ Y ^ CI

Ar And ^he

J o n ^ o

A mixture of 5- (2- (1,3-dioxan-2-yl) ethyl) -2 - (((tert-butyldimethylsilyl) oxy) methyl) -8chloro-1- (2,6-dichlorophenyl) -1.6 was stirred -naphthyridin-4 (1H) -one (0.044 g, 0.075 mmol) and aq. HCl (1N, 0.678 ml, 0.678 mmol) in THF (1 ml) at 60 ° C for 3 h. Then the reaction mixture was quenched with sat. aq. NaHCO ₃ solution until bubbles stop (CO ₂ ). This reaction mixture was used directly in the next step. LC-MS results indicate that the title compound is the only product at this stage. ESI-MS mass / charge: 412.8 [M + H] + (Rt = 1.12 min, LC method 3).

Stage 3. 8-Chloro-1- (2,6-dichlorophenyl) -2- (hydroxymethyl) -5- (3-hydroxypropyl) -1,6-naphthyridine 4 (1H) -one

_{EtOH (1 ml) and then NaBH 4} (0.023 g, 0.60 mmol) were added to the reaction mixture from step 2. The resulting mixture was stirred at room temperature for 20 minutes. The solid was filtered off. The THF was removed under reduced pressure and the residue was purified by reverse phase HPLC (Waters X-bridge column, 30x50 mm, 5 μm, ACN / H2O with 10 mM NH4OH, 75 ml / min, injection of 1.5 ml, gradient: from 35 to 60% ACN in 4.5 minutes) to give a white solid of the title compound (0.025 g, 77% overall yield over steps 2 and 3).

74: HRMS: calc. 413.0227 [M + H] +, found 413.0213; Ή NMR (400 MHz, DMSO-d6) δ ppm = 8.53 (s, 1H), 7.79-7.66 (m, 3H), 6.63 (s, 1H), 5.88 (s, 1H), 4.44 (t, J = 4.9 Hz, 1H), 3.85-3.78 (m, 2H), 3.543.46 (m, 2H), 3.46-3.37 (m , 2H), 1.83 (dq, J = 9.7, 6.7 Hz, 2H).

Example 75 8-Chloro-1- (2,6-dichlorophenyl) -5- (3,4-dihydroxybutyl) -2- (hydroxymethyl) -1,6-naphthyridin-4 (1H) -one

- 72 038455

Stage 1.5- (But-3-en-1-yl) -2 - (((tert-butyldimethylsilyl) oxy) methyl) -8-chloro-1- (2,6-dichlorophenyl) 1,6-naphthyridine- 4 (1H) -one

In a solution of 2 - (((tert-butyldimethylsilyl) oxy) methyl) -5,8-dichloro-1- (2,6-dichlorophenyl) -1.6naphthyridin-4 (1H) -one (0.3 g, 0.595 mmol ) in THF (6 ml) was added but-3-en-1-yl magnesium bromide (0.5 M in THF, 1.78 ml, 0.892 mmol). The resulting solution was stirred at room temperature for 3 hours. The reaction mixture was quenched with a few drops of water and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0 to 50% EtOAc in heptane) to afford the title compound (0.151 g, 48% yield). ESI-MS mass / charge: 525.1 [M + H] + (Rt = 1.99 min, LC-method 1), ¹ H NMR (400 MHz, DCM-d2) δ ppm = 8.38 (s, 1H), 7.47 (s, 3H), 6.68 (t, J = 1.1 Hz, 1H), 6.04-5.87 (m, 1H), 5.14-4.87 (m , 2H), 4.00 (d, J = 1.2 Hz, 2H), 3.54 (dd, J = 8.5, 7.0 Hz, 2H), 2.54-2.40 (m, 2H), 0.86 (s, 9H), 0.0 (s, 6H).

Stage 2.2 - (((tert-Butyldimethylsilyl) oxy) methyl) -8-chloro-1- (2,6-dichlorophenyl) -5- (3,4-dihydroxybutyl) -1,6-naphthyridine-4 (1H )-he

Osmium tetroxide (2.5 wt% solution in tert-butanol, 0.133 ml, 10.59 mmol) was added to a solution of 5 (but-3-en-1-yl) -2 - (((tert-butyldimethylsilyl) oxy) methyl) -8-chloro-1- (2,6-dichlorophenyl) -1,6-naphthyridin4 (1H) -one (0.111 g, 0.212 mmol) and N-methylmorpholine-N-oxide (0.027 g, 0.233 mmol) in mixtures of tert-butanol / water (2 ml / 2 ml). The resulting mixture was stirred at room temperature for 4 hours. The product was partitioned between EtOAc and brine and the combined organic extracts were dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0 to 100% EtOAc in heptane) to afford the title compound (0.077 g, 65% yield). ESI-MS mass / charge: 558.9 [M + H] + (Rt = 1.55 min, LC method 1), 1H NMR (400 MHz, DCM-d2) δ ppm = 8.40 (s, 1H) , 7.52-7.45 (m, 3H), 6.74 (t, J = 1.1 Hz, 1H), 4.043.95 (m, 2H), 3.68-3.43 (m, 5H ), 1.97-1.75 (m, 2H), 0.85 (s, 9H), 0.0 (s, 6H).

Step 3. 8-Chloro-1- (2,6-dichlorophenyl) -5- (3,4-dihydroxybutyl) -2- (hydroxymethyl) -1,6-naphthyridin-4 (1H) -one.

K 2 - (((tert-butyldimethylsilyl) oxy) methyl) -8-chloro-1- (2,6-dichlorophenyl) -5- (3,4-dihydroxybutyl) 1,6-naphthyridin-4 (1Н) -one (0.077 g, 0.138 mmol) in THF (2 ml) was added a 1 M solution of TBAF in THF (0.207 ml, 0.207 mmol) at 0 ° C. The reaction mixture was stirred at 0 ° C for 1 h. The resulting product was quenched with water and diluted in EtOAc. The aqueous layer was extracted with EtOAc. The combined organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0 to 5% MeOH in DCM) to afford the title compound (0.031 g, 46% yield).

75: ESI-MS mass / charge: 443.2 [M + H] + (Rt = 0.75, LC-method 1), 1H NMR (400 MHz, DCM-d2) δ ppm = 8.47 (s, 1H), 7.55 (d, J = 1.9 Hz, 3H), 6.87 (t, J = 1.1 Hz, 1H), 4.11 (s, 2H), 3.78-3, 45 (m, 5H), 2.08-1.84 (m, 2H).

- 73 038455

Chiral resolution of the above racemate

Examples 76 and 77 One of Examples 76 and 77 is (R) -8-chloro-1- (2,6-dichlorophenyl) -5 (3,4-dihydroxybutyl) -2- (hydroxymethyl) -1,6- naphthyridin-4 (1H) -one and the other is (S) -8chloro-1- (2,6-dichlorophenyl) -5- (3,4-dihydroxybutyl) -2- (hydroxymethyl) -1,6-naphthyridine -4 (1H) -one.

218 mg of 8-chloro-1- (2,6-dichlorophenyl) -5- (3,4-dihydroxybutyl) -2- (hydroxymethyl) -1.6naphthyridin-4 (1H) -one (example 75) in 20 ml methanol and subjected to several injections, 1.6 ml each, to perform chiral preparative SFC (ChiralPak AD column, 250x330 mm ID, 5 μm, flow rate 50 ml / min, at 38 ° C) using 40% ethanol in carbon dioxide with 0.1% aq. ammonia solution as a mobile phase. After chiral separation, the fractions were dried by rotary evaporation at a bath temperature of 40 ° C to give Example 76, corresponding to the first elution peak (82 mg, ee 100%), and Example 77, corresponding to the second elution peak (40 mg, ee 98.8%). , as white solids. Retention times were obtained on a ChiralPak IA column, 4.6x100 mm, 5 μm column. A gradient was applied from 5 to 55% MeOH / 2-propanol, 1: 1, in carbon dioxide with 10 mM NH ₄ OH as mobile phase for 5.5 min, then held for 0.1 min (5.0 ml / min, as solvent consumption) at an oven temperature of 38 ° C. (example 76: Rt = 3.63 min; example 77: Rt = 4.24 min).

Example 78 8-Chloro-1- (2,6-dichlorophenyl) -5- (2,3-dihydroxypropyl) -2- (hydroxymethyl) -1,6-naphthyridin-4 (1H) -one

BUT

Stage 1.5-Allyl-2 - (((tert-butyldimethylsilyl) oxy) methyl) -8-chloro-1 - (2,6-dichlorophenyl) -1,6-naphthyridin-4 (1H) -one

SG CI

To a solution of intermediate 7 (0.65 g, 1.289 mmol) in toluene (10 ml) were added allyltri-n-butyltin (0.799 ml, 2.58 mmol) and the adduct PdCl ₂ (dppf) * CH ₂ Cl ₂ (0.105 g , 0.129 mmol) at room temperature under nitrogen atmosphere. The resulting solution was purged with nitrogen and heated at 80 ° C for 1 h. Purification by column chromatography (solid addition, 0 to 30% ethyl acetate in heptane) gave 5-allyl-2 - (((tert-butyldimethylsilyl) oxy) methyl) -8-chloro-1 (2,6-dichlorophenyl) -1,6-naphthyridin-4 (1H) -one (0.6 g 1.18 mmol) as a pale yellow oil. ESI-MS mass / charge: 511.0 [M + H] +.

Stage 2.2 - (((tert-Butyldimethylsilyl) oxy) methyl) -8-chloro-1- (2,6-dichlorophenyl) -5- (2,3-dihydroxypropyl) -1,6-naphthyridine-4 (1H )-he

A solution of 5-allyl-2 - (((tert-butyldimethylsilyl) oxy) methyl) -8-chloro-1- (2,6-dichlorophenyl) -1,6-naphthyridin-4 (1Н) -one (0.6 g, 1.177 mmol) in 1,4-dioxane (8 ml) and water (1.6 ml) with osmium tetroxide (2.991 g, 0.235 mmol) and NMO (0.414 g, 3.53 mmol). The reaction mixture was stirred at room temperature for 2 hours. Saturated sodium metabisulfite solution was added and the mixture was stirred for an additional 30 minutes. Water was added and the mixture was extracted with ethyl acetate. The combined organic extracts were dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. Purification by column chromatography (0 to 100% ethyl acetate in heptane) gave 2 - (((tert-butyldimethylsilyl) oxy) methyl) -8-chloro-1- (2,6-dichlorophenyl) -5- (2,3 -dihydroxypropyl) -1,6-naphthyridin4 (1H) -one (0.5 g, 0.92 mmol) as a white foamy solid. ESI-MS mass / charge: 544.8 [M + H] +.

Stage 3. 8-Chloro-1- (2,6-dichlorophenyl) -5- (2,3-dihydroxypropyl) -2- (hydroxymethyl) -1,6-naphthyridin-4 (1H) -one

To a solution of the above compound (0.5 g, 0.919 mmol) in acetic acid (5 ml) was added water (5 ml) at room temperature. The resulting solution was stirred at room temperature overnight. The reaction mixture was concentrated, neutralized with conc. NH ₃ and purified by basic preparative RP-HPLC (Waters X-bridge column, 30x50 mm, 5 μm, ACN / H2O with 10 mM NH4OH, 75 ml / min, 1.5 ml injection, gradient: 25 to 50% ACN 4.5 min) to afford the title compound (0.3 g, 0.66 mmol) as a white powder.

78: HRMS: calc. 429.0176 [M + H] +, value found 429.0169, Ή NMR (400 MHz, chloroformd3) δ ppm = 8.45 (s, 1H), 7.49 (s, 3H), 6.94 (s , 1H), 4.92 (s, 1H), 4.26 (s, 1H), 4.05 (s, 2H), 3.66 (qd, J = 15.8, 14.3, 6.0 Hz, 5H), 2.91 (s, 1H).

Chiral resolution of the above racemate

Examples 79 and 80 One of Examples 79 and 80 is ^) - 8-chloro-1- (2,6-dichlorophenyl) -5 (2,3-dihydroxypropyl) -2- (hydroxymethyl) -1,6-naphthyridine -4 (1H) -one, and the other is (S) -8chloro-1- (2,6-dichlorophenyl) -5- (2,3-dihydroxypropyl) -2- (hydroxymethyl) -1,6-naphthyridine- 4 (1H) -one.

Racemate 78 was subjected to multiple injections, 1.6 ml each, to perform chiral preparative SFC (Cellulose-2 column, 250x330 mm i.d. 5 μm, flow rate 50 ml / min, at 38 ° C) using 40% ethanol in carbon dioxide with 0.1% aq. ammonia solution as a mobile phase. After chiral separation, the fractions were dried by rotary evaporation at a bath temperature of 40 ° C to give Example 79, corresponding to the first elution peak (ee> 98%), and Example 80, corresponding to the second elution peak (ee> 98%), as white solids. ... Retention times were obtained on a Cellulose-2 column, 4.6x150 mm, 5 μm column. A mobile phase of 40% MeOH (with 0.05% DEA) in carbon dioxide (solvent flow rate 2.4 ml / min) was used at an oven temperature of 35 ° C (example 79: Rt = 6.93 min; example 80: Rt = 7.68 minutes).

79: HRMS: calc. 429.0176 [M + H] +, found 429.0171; 1H NMR (400 MHz, chloroform d3) δ ppm = 8.46 (s, 1H), 7.49 (d, J = 4.8 Hz, 3H), 6.94 (s, 1H), 4.15 (m , 4H), 3.84-3.56 (m, 6H).

80: HRMS: calc. 429.0176 [M + H] +, found 429.0169; Ή NMR (400 MHz, chloroform d3) δ ppm = 8.45 (s, 1H), 7.49 (d, J = 4.6 Hz, 3H), 6.94 (s, 1H), 4.92 (s , 1H), 4.26 (s, 1H), 4.05 (s, 2H), 3.66 (qd, J = 15.8, 14.3, 6.0 Hz, 5H), 2.91 ( s, 1H).

The following compound was prepared using methods analogous to those described for the above compound from intermediate 1.

Example 81 8-Chloro-1- (2,6-dichlorophenyl) -5- (2,3-dihydroxypropyl) -2-methyl-1,6-naphthyridin-4 (1H) one

Cl ^z Cl

81: HRMS: calc. 413.0227 [M + H] +, found 413.0230; Ή NMR (400 MHz, chloroform d3) δ ppm = 8.45 (s, 1H), 7.49 (s, 3H), 4.98-4.81 (m, 1H), 4.27 (s, 1H) , 3.82-3.53 (m, 4H), 2.96 (s, 1H), 1.98 (s, 3H).

- 75 038455

Example 82. ridin-4 (1H) -one

8-Chloro-1 - (2,6-dichlorophenyl) -5- (1,2-dihydroxyethyl) -2- (hydroxymethyl) -1,6-naphthy-

HE

Stage 1. 'naphthyridin-4 (1H) -one

2 - (((tert-Butyldimethylsilyl) oxy) methyl) -8-chloro-1- (2,6-dichlorophenyl) -5-vinyl-1,6-

To a solution of intermediate 7 (0.47 g, 0.932 mmol) in acetonitrile (5 ml) and water (1 ml) was added a complex of vinyl boronic acid anhydride and pyridine (0.317 g, 1.864 mmol), Na ₂ CO ₃ (0.198 g, 1.864 mmol) and the adduct PdCl ₂ (dppf) * CH ₂ Cl ₂ (0.076 g, 0.093 mmol) at room temperature under nitrogen atmosphere. The resulting reaction mixture was purged with nitrogen and heated at 80 ° C in a sealed tube for 1 h. Purification by column chromatography (solid addition, 0 to 40% ethyl acetate in heptane) gave 2 - (((tert-butyldimethylsilyl) oxy) methyl) -8-chloro-1- (2,6-dichlorophenyl) -5-vinyl-1,6-naphthyridin-4 (1H) -one (0.4 g, 0.81 mmol) as pale yellow oil. ESI-MS mass / charge: 497.0.0 [M + H] +).

Steps 2 and 3 were performed in the same manner as described for the previous example to give 8-chloro-1- (2,6-dichlorophenyl) -5- (1,2-dihydroxyethyl) -2- (hydroxymethyl) -1.6 -naphthyridin-4 (1H) -one as a white solid.

82: HRMS: calc. 415.0019 [M + H] +, found 415.0016; ¹ H NMR (400 MHz, chloroform d3) δ ppm = 8.50 (s, 1H), 7.50 (s, 3H), 6.93 (s, 1H), 5.80 (d, J = 4.3 Hz, 1H), 5.30 (d, J = 6.0 Hz, 1H), 4.17-3.82 (m, 5H), 3.40 (s, 1H), 2.97 (s, 1H ).

Chiral resolution of the racemate

Examples 83 and 84 One of Examples 83 and 84 is ^) - 8-chloro-1- (2,6-dichlorophenyl) -5 (1,2-dihydroxyethyl) -2- (hydroxymethyl) -1,6-naphthyridine -4 (1H) -one, and the other is (S) -8chloro-1- (2,6-dichlorophenyl) -5- (1,2-dihydroxyethyl) -2- (hydroxymethyl) -1,6-naphthyridine- 4 (1H) -one.

Racemate 82 was dissolved in methanol and subjected to several injections, 1.6 ml each, to perform chiral preparative SFC (Cellulose-2 column, 250x330 mm i.d. 5 μm, flow rate 50 ml / min, at 38 ° C) using 40% ethanol in carbon dioxide with 0.1% aq. ammonia as a mobile phase. After chiral separation, the fractions were dried by rotary evaporation at a bath temperature of 40 ° C to give Example 83, corresponding to the first elution peak (ee> 98%) and Example 84, corresponding to the second elution peak (ee> 98%), as white solids. ... Retention times were obtained on a ChiralPak AY column, 4.6x150 mm, 3 μm column. A mobile phase of 50% 2-propanol (with 0.05% DEA) in carbon dioxide (solvent flow rate 2 ml / min) was used at an oven temperature of 35 ° C (example 83: Rt = 3.13 min; example 84: Rt = 4.32 minutes).

Example 85 8-Chloro-1- (2,6-dichlorophenyl) -5- (1,2-dihydroxyethyl) -2-methyl-1,6-naphthyridin-4 (1H) -one

- 76 038455

Stage 1. 8-Chloro-1- (2,6-dichlorophenyl) -2-methyl-5-vinyl-1,6-naphthyridin-4 (1H) -one

To a solution of intermediate 1 (1 g, 2.67 mmol) in acetonitrile (10 ml) was added a complex of vinyl boronic acid anhydride and pyridine (0.772 g, 3.21 mmol), 2.0 M aq. K ₃ PO ₄ solution (2.67 ml, 5.35 mmol). The reaction mixture was degassed and placed under a nitrogen atmosphere, after which the adduct PdCl ₂ (dppf) -CH ₂ Cl ₂ (0.218 g, 0.267 mmol) was added. The mixture was purged with nitrogen again, heated under reflux at 80 ° C in an oil bath for 1.5 h. The mixture was cooled to rt, the solvent was removed. The residue was taken up with EtOAC. The organic phase was washed with brine, dried over anhydrous MgSO ₄ , filtered and concentrated in vacuo. The crude residue was purified by column chromatography eluting with EtOAC / heptane 0 to 50% to give 8-chloro-1- (2,6-dichlorophenyl) -2-methyl-5-vinyl-1,6-naphthyridine- 4 (1H) -one (0.85 g, 8.32 mmol) as a yellow solid.

Step 2. 8-Chloro-1- (2,6-dichlorophenyl) -5- (1,2-dihydroxyethyl) -2-methyl-1,6-naphthyridin-4 (1H) -one

A solution of the product from step 1 (0.8 g, 2.188 mmol) in acetone (10 ml) and water (2 ml) was treated with NMO (0.769 g, 6.56 mmol) and osmium tetroxide (0.278 g, 0.044 mmol) at Ph.D. The reaction mixture was stirred under nitrogen atmosphere at room temperature for 16 hours to give two products. At the end of this time, a saturated Na ₂ S ₂ O ₃ solution was added and stirring was continued for 30 minutes. Water was added and the mixture was extracted with ethyl acetate (2x). The combined organic extracts were washed with brine, dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. The crude residue was purified by column chromatography eluting with EtOAC / heptane 0 to 100% to give two products, the title compound (0.6 g, 1.43 mmol) and 8-chloro-1- ( 2,6-dichlorophenyl) -5- (2-hydroxyacetyl) -2-methyl1,6-naphthyridin-4 (1H) -one (0.05 g, 0.13 mmol).

85: HRMS: calc. 399.0070 [M + H] +, found 399.0089; Ή NMR (400 MHz, chloroform d3) δ ppm = 8.50 (s, 1H), 7.50 (m, 3H), 6.60-6.40 (s, 1H), 5.82 (t, J = 5.2 Hz, 1H), 4.14-3.92 (m, 2H), 2.01-1.91 (s, 3H).

Example 86 8-Chloro-1- (2,6-dichlorophenyl) -5- (2-hydroxyacetyl) -2-methyl-1,6-naphthyridin-4 (1H) -one

This compound was obtained as a by-product during the synthesis of example 85 described above.

86: HRMS: calc. 396.9915 [M + H] +, found 396.9914; Ή NMR (400 MHz, chloroform d3) δ ppm = 8.58 (s, 1H), 7.53 (s, 3H), 6.49 (s, 1H), 4.68 (s, 2H), 2.04 (s, 3H).

Example 87 8-Chloro-1- (2,6-dichlorophenyl) -5 - ((2,3-dihydroxypropoxy) methyl) -2- (hydroxymethyl) 1,6-naphthyridin-4 (1H) -one

- 77 038455

Obtaining the stannane required in stage 1: tributyl - (((2,2-dimethyl-1,3-dioxolane-4yl) methoxy) methyl) stannane

NaH (0.046 g, 1.149 mmol) was added to a solution of (2,2-dimethyl-1,3-dioxolan-4-yl) methanol (0.207 g, 1.566 mmol) in THF (2 ml) and DMSO (2 ml) at 0 ° C in a nitrogen atmosphere. The resulting solution was stirred at room temperature for 30 min and tributyl (iodomethyl) stannane (0.45 g, 1.044 mmol) was added. The resulting solution was stirred at rt. during the night. The mixture was concentrated, taken up in heptane / EtOAC (7: 1).

The organic phase was washed with brine, dried over anhydrous MgSO ₄ , filtered and concentrated in vacuo. The crude residue (colorless oil) was used in the next step without further purification.

Stille coupling between the aforementioned stannane and intermediate 7 and subsequent deprotection steps were performed in a similar manner to Example 78 to provide the title compound.

87: HRMS: calc. 459.0281 [M + H] +, found 459.0277; ¹ H NMR (400 MHz, chloroform d3) δ ppm = 8.48 (s, 1H), 7.60-7.40 (m, 3H), 6.93 (s, 1H), 5.37-5.18 (m, 2H), 4.80 (s, 1H), 4.42 (s, 1H), 4.04 (d, J = 5.5 Hz, 2H), 3.93 (s, 1H), 3 , 77 (ddd, J = 38.5, 9.8, 4.8 Hz, 4H), 3.54 (s, 1H).

Example 88 8-Chloro-1- (2,6-dichlorophenyl) -5 - (((1,3-dihydroxypropan-2-yl) oxy) methyl) -2- (hydroxymethyl) -1,6-naphthyridine-4 (1H) -one

This compound was prepared analogously to the above example using 2,2-dimethyl1,3-dioxan-5-ol to obtain the desired stannane.

88: HRMS: calc. M + H] ⁺ 459.0281 found, 459.0280; 1H NMR (400 MHz, chloroform-d3) δ ppm = 8.47 (s, 1H), 7.48 (d, J = 1.3 Hz, 3H), 6.92 (s, 1H), 5.42 (s, 2H), 4.04 (s, 2H), 3.81-3.57 (m, 5H).

Example 89.8-Chloro-1- (2,6-dichlorophenyl) -5- (2,4-dihydroxy-3-oxobutan-2-yl) -2-methyl-1,6-naphthyridine-4 (1H) - he

- 78 038455

A mixture of intermediate 1 (0.5 g, 1.337 mmol), tributyl- (1-ethoxyvinyl) tin (0.628 g, 1.738 mmol) and PdCl ₂ (dppf) -CH ₂ Cl ₂ adduct (0.109 g, 0.134 mmol) in toluene (2 ml) was purged with nitrogen and heated at 80 ° C overnight. After cooling to rt. the mixture was concentrated under reduced pressure. The residue was taken up with EtOAc and filtered through a pad of silica gel. The solvent was removed and then the crude ethoxyvinyl intermediate (500 mg) was dissolved in a solution of tetrahydrofuran (50 ml) and 1N hydrochloric acid. acid HCl (20 ml). After the mixture was stirred at room temperature for 2 h, the tetrahydrofuran was removed in vacuo and the white solid (desired ketone product 0.3 g) was collected by filtration. The remaining aqueous phase was extracted with ethyl acetate. The organic layers were combined, dried (MgSO ₄ ) and concentrated. Purification by column chromatography (0 to 100% ethyl acetate in heptane) provided additional ketone product (yellow solid, 0.08 g). HRMS: calc. 380.0064 [M + H] +, found 380.9960; Ή NMR (400 MHz, chloroform-d3) δ ppm = 8.53 (s, 1H), 7.52 (d, J = 2.7 Hz, 3H), 6.46 (d, J = 0.7 Hz , 1H), 2.64 (s, 3H).

Stage 2. 8-Chloro-1- (2,6-dichlorophenyl) -5- (2-hydroxybut-3-en-2-yl) -2-methyl-1,6-naphthyridin-4 (1H) one

To an ice-cold solution of the ketone intermediate from Step 1 (0.2 g, 0.524 mmol) in THF (1 ml) was added 1M vinyl magnesium bromide (0.681 ml, 0.681 mmol) in THF (3 ml) dropwise under nitrogen atmosphere ... The reaction mixture was stirred at 0 ° C for 5 h, then quenched with sat. NH4Cl solution at 0 ° C and extracted with EtOAC. The organic phase was washed with brine, dried over MgSO ₄ and concentrated. The crude product was purified by column chromatography, eluting with EtOAC / heptane, 0 to 100%, to afford the desired product (0.048 g, 0.11 mmol) as a yellow solid, ESI-MS w / w: 411.1 [ M + H] +.

Step 3.8-Chloro-1- (2,6-dichlorophenyl) -5- (2,4-dihydroxy-3-oxobutan-2-yl) -2-methyl-1,6-naphthyridine-4 (1H) - he

- 79 038455

Osmium tetroxide (7.66 μl, 0.024 mmol) and NMO (42.9 mg, 0.366 mmol) were added to a solution of the product from step 2 (50 mg, 0.122 mmol) in dioxane (3 ml) and water (0.2 ml) at c.t. The resulting solution was stirred at rt. during the night. The reaction mixture was concentrated and taken up with EtOAC. The organic phase was washed with water, brine, dried (over MgSO ₄ ), filtered and concentrated in vacuo. The crude residue was purified by basic preparative HPLC (Waters X-bridge column, 30x50 mm, 5 μm, ACN / H ₂ O with 10 mM NH4OH, 75 ml / min, 1.5 ml injection, gradient: 25 to 50% ACN for 4.5 min) to give 8-chloro-1- (2,6-dichlorophenyl) -5- (2,4-dihydroxy-3oxobutan-2-yl) -2-methyl-1,6-naphthyridine-4 ( 1H) -one (4.6 mg, 9.37 μmol).

89: HRMS: calc. 441.0175 [M + H] +, found 441.0191; ¹ H NMR (400 MHz, chloroform d3) δ ppm = 8.08 (s, 1H), 7.56-7.41 (m, 3H), 6.42 (s, 1H), 5.13 (s, 1H ), 4.76 (dd, J = 10.7, 4.1 Hz, 1H), 4.63 (dd, J = 10.7, 4.6 Hz, 1H), 4.42 (s, 1H) , 2.49 (s, 3H), 1.94 (s, 3H).

The examples below were prepared as described in Scheme D.

Example 90 1- (4- (3-Amino-3-methylbut-1-yn-1-yl) -2,6-dichlorophenyl) -8-chloro-5- (2,3-dihydroxypropoxy) -2-methyl -1,6-naphthyridin-4 (1H) -one

Stage 1. 1- (4-Bromo-2,6-dichlorophenyl) -8-chloro-5 - ((2,2-dimethyl-1,3-dioxolan-4-yl) methoxy) -2methyl-1,6- naphthyridin-4 (1H) -one

A mixture of 1- (4-bromo-2,6-dichlorophenyl) -5,8-dichloro-2-methyl-1,6-naphthyridin-4 (1H) -one (intermediate compound 4, 0.2 g, 0.442 mmol ), (2,2-dimethyl-1,3-dioxolan-4-yl) methanol (0.875 g, 6.62 mmol), K ₂ CO ₃ (0.366 g, 2.65 mmol) and DMAP (11 mg, 0.088 mmol) in acetonitrile (24 ml) at 75 ° C overnight. The solid was filtered off. The volatiles were removed under reduced pressure and the residue was purified by silica gel chromatography (EtOAc / heptane, 20 to 50%) to give the title compound (0.212 g, 88%). ESI-MS mass / charge: 548.9 [M + H] ⁺ (Rt = 1.50 min, LC method 3).

Stage 2.1 - (4- (3-Amino-3-methylbut-1-in-1-yl) -2,6-dichlorophenyl) -8-chloro-5 - ((2,2-dimethyl-1,3 -dioxolan-4-yl) methoxy) -2-methyl-1,6-naphthyridin-4 (1H) -one

- 80 038455

Into a mixture of 1- (4-bromo-2,6-dichlorophenyl) -8-chloro-5 - ((2,2-dimethyl-1,3-dioxolan-4-yl) methoxy) -2-methyl1,6-naphthyridine -4 (1H) -one (46 mg, 0.084 mmol), 2-methylbut-3-yn-2-amine (21 mg, 0.252 mmol), Pd (PPh ₃ ) ₄ (19 mg, 0.017 mmol) and CuI ( 6.4 mg, 0.034 mmol) in DMF (pre-purged with N ₂ for 30 min) was added TEA (42 mg, 0.419 mmol). The reaction mixture was stirred at 70 ° C. under N2 for 1 h. The volatiles were removed under reduced pressure and the residue was purified by silica gel chromatography (MeOH / DCM, 1% to 5%) to afford the title compound. ESI-MS mass / charge: 552.0 [M + H] + (Rt = 1.37 min, LC method 3).

Stage 3.1- (4- (3-amino-3-methylbut-1-yn-1-yl) -2,6-dichlorophenyl) -8-chloro-5- (2,3-dihydroxypropoxy) -2-methyl -1,6-naphthyridin-4 (1H) -one

A mixture of 1- (4- (3-amino-3-methylbut-1-yn-1-yl) -2,6-dichlorophenyl) -8-chloro-5 - ((2,2-dimethyl-1,3- dioxolan-4-yl) methoxy) -2-methyl-1,6-naphthyridin-4 (1H) -one (46 mg, 0.084 mmol) and aq. a solution of HCl (1 N, 1.0 ml, 1.0 mmol) in THF (2 ml) at room temperature overnight. Then the reaction mixture was quenched with aq. NaOH solution (1 N, 1 ml, 1.0 mmol). THF was then removed under reduced pressure and the residue was purified by reverse phase HPLC (Waters X-bridge column, 30x50 mm, 5 μm, ACN / H2O with 10 mM NH4OH, 75 ml / min, injection of 1.5 ml, gradient: from 25 to 50% ACN in 4.5 min) to give a white solid of the title compound (26 mg, 58% yield).

90: HRMS: calc. 510.0749 [M + H] ⁺ , found 510.0752; Ή NMR (400 MHz, DMSO-d6) δ ppm = 8.25 (s, 1H), 7.75 (s, 2H), 6.47 (d, J = 0.7 Hz, 1H), 4.87 (d, J = 5.2 Hz, 1H), 4.76 (t, J = 6.0 Hz, 1H), 4.37 (dd, J = 10.7, 5.5 Hz, 1H), 4 , 28 (dd, J = 10.7, 5.8 Hz, 1H), 3.86 (q, J = 5.3 Hz, 1H), 3.64-3.49 (m, 2H), 1, 90 (s, 3H), 1.40 (s, 6H)

Example 91 8-Chloro-1- (2,6-dichloro-4- (3-morpholinoprop-1-yn-1-yl) phenyl) -5- (2-hydroxyethoxy) -2methyl-1,6-naphthyridine- 4 (1H) -one

- 81 038455

This compound was prepared analogously to the above example using unprotected ethane-1,2-diol in step 1 and skipping the optional deprotection step.

91: HRMS: calc. 522.0754 [M + H] +, found 522.0751; ¹ H-NMR (400 MHz, DMSO-d6) δ ppm = 8.23 (s, 1H), 7.88 (s, 2H), 6.45 (d, J = 0.8 Hz, 1H), 4 , 76 (t, J = 5.6 Hz, 1H), 4.41 (t, J = 5.5 Hz, 2H), 3.75 (q, J = 5.5 Hz, 2H), 3.65 -3.60 (m, 4H), 3.59 (s, 2H), 2.58-2.53 (m, 4H), 1.95-1.82 (m, 3H).

Example 92 8-Chloro-1- (2,6-dichloro-4- (3- (1,1-dioxidothiomorpholino) prop-1-yn-1-yl) phenyl) -5- (2hydroxyethoxy) -2-methyl -1,6-naphthyridin-4 (1H) -one

This compound was prepared analogously to the above example using unprotected ethane-1,2-diol in step 1 and skipping the optional deprotection step.

92: HRMS: calc. 570.0424 [M + H] +, found 570.0422; Ή NMR (400 MHz, DMSO-d6) δ ppm = 8.23 (s, 1H), 7.87 (s, 2H), 6.45 (d, J = 0.7 Hz, 1H), 4.76 (t, J = 5.4 Hz, 1H), 4.41 (t, J = 5.5 Hz, 2H), 3.76 (d, J = 10.0 Hz, 4H), 3.23-3 , 13 (m, 4H), 3.05 (dd, J = 6.6, 3.5Hz, 4H), 1.90 (s, 3H).

Example 93 8-Chloro-1- (2,6-dichloro-4- (3- (dimethylamino) prop-1-yn-1-yl) phenyl) -5 - ((2,2-dimethyl-1,3-dioxolane -4-yl) methoxy) -2-methyl-1,6-naphthyridin-4 (1H) -one

This compound was prepared analogously to the above example, using N, N-82 038455 dimethylprop-2-yn-1-amine in step 2 and skipping the optional step 3 of deprotection.

93: HRMS: calc. 550.1067 [M + H] +, found 550.1076; 1H NMR (400 MHz, DMSO-d6) δ ppm = 8.23 (s, 1H), 7.86 (s, 2H), 6.50-6.39 (m, 1H), 4.51-4, 32 (m, 3H), 4.10 (td, J = 6.0, 3.2 Hz, 1H), 4.03-3.94 (m, 1H), 3.53 (s, 2H), 2 , 27 (s, 6H), 1.90 (s, 3H), 1.35 (s, 3H), 1.31 (s, 3H).

Obtaining phosphate prodrugs

Examples with a free hydroxy group can be converted to phosphate prodrugs as shown by way of example 3.

Prodrug based on example 3. (8-Chloro-1- (2,6-dichlorophenyl) -5- (2,3-dihydroxypropoxy) -4oxo-1,4-dihydro-1,6-naphthyridin-2-yl) methyldihydrogen phosphate

Stage 1.2 - (((tert-Butyldimethylsilyl) oxy) methyl) -8-chloro-1- (2,6-dichlorophenyl) -5 - ((2,2-dimethyl1,3-dioxolan-4-yl) methoxy ) -1,6-naphthyridin-4 (1H) -one.

Heated a mixture of 2 - (((tert-butyldimethylsilyl) oxy) methyl) -5,8-dichloro-1- (2,6-dichlorophenyl) -1,6naphthyridin-4 (1H) -one (3.5 g, 6, 94 mmol), (2,2-dimethyl-1,3-dioxolan-4-yl) methanol (4.59 g, 34.7 mmol), K ₂ CO ₃ (2.88 g, 20.82 mmol) and DMAP (0.848 g, 6.94 mmol) in ACN (40 ml) at 80 ° C overnight. The reaction mixture was filtered and washed with ACN. The filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography (10% to 50% EtOAc in heptane) to afford the title compound (2.99 g, 72% yield). ESI-MS mass / charge: 601.1 [M + H] + (Rt = 1.62 min, LC-method 1), Ή NMR (400 MHz, DCM-d2) δ ppm = 8.03 (s, 1H ), 7.47 (s, 3H), 6.67 (t, J = 1.1 Hz, 1H), 4.60-4.40 (m, 3H), 4.22-3.92 (m, 4H), 1.40 (s, 3H), 1.36 (s, 3H), 0.85 (s, 9H), 0.0 (s, 6H).

Step 2. 8-Chloro-1- (2,6-dichlorophenyl) -5 - ((2,2-dimethyl-1,3-dioxolan-4-yl) methoxy) -2- (hydroxymethyl) -1.6 - naphthyridin-4 (1H) -one.

To a solution of 2 - (((tert-butyldimethylsilyl) oxy) methyl) -8-chloro-1- (2,6-dichlorophenyl) -5 - ((2,2-dimethyl1,3-dioxolan-4-yl) methoxy) -1,6-naphthyridin-4 (1H) -one (2.9 g, 4.83 mmol) in THF (20 ml) was added a 1 M solution of TBAF in THF (7.25 ml, 7.25 mmol) at 0 ° C. The reaction mixture was stirred at 0 ° C for 1 h. The resulting product was quenched with water and diluted in EtOAc. The aqueous layer was extracted with EtOAc. The combined organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (10% to 100% EtOAc in heptane) to afford the title compound (1.74 g, 74% yield). ESI-MS mass / charge: 487 [M + H] + (Rt = 1.06 min, LC-method 1), Ή NMR (400 MHz, DCM-d2) δ ppm = 8.14 (s, 1H), 7.54 (d, J = 1.9 Hz, 3H), 6.99 (s, 1H), 4.66-4.46 (m, 3H), 4.28-4.17 (m, 1H) , 4.15-3.96 (m, 3H), 1.47 (s, 3H), 1.41 (s, 3H).

Stage 3. Dibenzyl - ((8-chloro-1- (2,6-dichlorophenyl) -5 - ((2,2-dimethyl-1,3-dioxolan-4-yl) methoxy) -4oxo-1,4- dihydro-1,6-naphthyridin-2-yl) methyl) phosphate.

Hünig's base (0.027 ml, 0.154 mmol) and tetrabenzyl pyrophosphate (0.078 g, 0.144 mmol) were added to a solution of 8-chloro-1 - (2,6-dichlorophenyl) -5 - ((2,2-dimethyl-1,3-dioxolane -4-yl) methoxy) -2- (hydroxymethyl) -1,6-naphthyridin-4 (1H) -one (0.05 g, 0.103 mmol) in DCM (0.5 ml) at RT. followed by the addition of MgCl ₂ (9.80 mg, 0.103 mmol). The resulting mixture was stirred at room temperature overnight. The mixture was filtered through a plug of silica / MgSO ₄ , 20: 1, and washed with EtOAc / ether. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (0 to 100% EtOAc in heptane) to give the title compound (0.061 g, 79% yield). ESI-MS mass / charge: 747.0 [M + H] + (Rt = 1.43 min, LC-method 1), ¹ H NMR (400 MHz, DCM-d2) δ ppm = 8.10 (s, 1H), 7.52-7.28 (m, 13H), 6.61-6.48 (m, 1H), 5.03 (d, J = 8.6 Hz, 4H), 4.66-4 , 48 (m, 3H), 4.37 (dd, J = 6.7, 0.8 Hz, 2H), 4.22 (dd, J = 8.5, 6.1 Hz, 1H), 4, 06 (dd, J = 8.4, 6.2Hz, 1H), 1.49 (s, 3H), 1.43 (s, 3H).

Steps 4 and 5. (8-Chloro-1- (2,6-dichlorophenyl) -5- (2,3-dihydroxypropoxy) -4-oxo-1,4-dihydro-1,6naphthyridin-2-yl) methyldihydrogen phosphate.

In solution dibenzyl - ((8-chloro-1- (2,6-dichlorophenyl) -5 - ((2,2-dimethyl-1,3-dioxolan-4-yl) methoxy) -4oxo-1,4-dihydro -1,6-naphthyridin-2-yl) methyl) phosphate (40 mg, 0.054 mmol) and 1,4-cyclohexadiene (0.228 g, 2.84 mmol) in MeOH (5 ml) under a nitrogen atmosphere was added 10% palladium on activated carbon (quantitatively) and the mixture was stirred at room temperature under nitrogen atmosphere for 4 hours. The resultant was filtered through a filter (nylon, 0.45 µm) and the filtrate was concentrated to dryness under reduced pressure. Diethyl ether was added to the solid, the mixture was stirred, and the organic layer was decanted. The residue was dried under vacuum to give a mixture of the two products. This mixture was dissolved in 0.5 ml of MeOH and TFA (0.044 ml, 0.566 mmol) was added at room temperature. The resulting solution was stirred for 2 hours and concentrated under reduced pressure. The residue was lyophilized from ACN and water to give the title product as a white solid (0.026 g, 87% yield). The title compound also contained some 3 - ((8-chloro-1- (2,6-dichlorophenyl) -4-oxo-2 - ((phosphonooxy) methyl) -1,4 dihydro-1,6-naphthyridine-5 -yl) oxy) -2-hydroxypropyl-2,2,2-trifluoroacetate as observed by LC-Mass under acidic conditions.

Stage 6. Salt, which is (8-chloro-1- (2,6-dichlorophenyl) -5- (2,3-dihydroxypropoxy) -4oxo-1,4-dihydro-1,6-naphthyridin-2-yl) monosodium methyldihydrogen phosphate.

The mixture (0.026 g) from the previous step was dissolved in MeOH (1 ml). A solution of NaHCO ₃ (0.015 g, 0.183 mmol) in H ₂ O (1 ml) was added to the flask. The resulting solution was stirred at room temperature for 5 minutes and concentrated under reduced pressure. The residue was lyophilized from ACN and water to give the title compound (0.026 g, 99% yield). ESI-MS mass / charge: 524.9 [M + H] + (Rt = 0.66 min, LC method 2), Ή NMR (400 MHz, methanol-d4) δ ppm = 8.16 (s, 1H) , 7.60 (s, 3H), 7.14 (t, J = 1.2 Hz, 1H), 4.61-4.47 (m, 2H), 4.35 (dd, J = 4.4 , 1.2 Hz, 2H), 4.06 (p, J = 5.2 Hz, 1H), 3.81-3.66 (m, 2H).

Claims (20)

CLAIM 1. Compound of formula II or III SG R ² where R ¹ is C _1-4 αalkyl, -CN, C _1-4 alkoxyC _1-4 alkyl, halogen-C _1-4 alkyl, -CH = N-OH, hydroxy-C _1-4 alkyl, - CH ₂ OP (O) (OH) ₂ or C _3-5 cycloalkyl; R ³ represents -OR ^a ; -NHR ^b ; -C (O) NH2; -C (O) [hydroxyC1-4alkyl]; 4-7 membered monocyclic heterocyclyl containing at least one heteroatom selected from O, N and S, and optionally substituted with one or more substituents independently selected from OH and hydroxyC1-4alkyl; and 5- or 6-membered monocyclic heteroaryl containing 1 to 4 heteroatoms independently selected from O, N and S, and optionally substituted with one or more C1-4αalkyl; or R ³ is C1-4αalkyl substituted with one or more substituents independently selected from —C (O) [hydroxyC _1-4 alkyl] and —OR ^c ; Ra is —C _1-6 alkyl substituted with one or more substituents independently selected from —OR ^c , —NHS (O) ₂ C _1-4 alkyl and 4-7 membered monocyclic heterocyclyl containing at least one heteroatom, selected from O, N and S, which is further optionally substituted with one or more substituents independently selected from C _1-4 alkyl and hydroxyC _1-4 alkyl; or Ra is - [CH ₂ -CH ₂ -O] nH, - [CH ₂ -CH ₂ -O] _m -CH ₃ or 5-6 membered monocyclic heteroaryl containing 1 to 4 heteroatoms independently selected from O, N and S optionally substituted with one or more C _1-4 alkyl; where n is 2-6 and m is 1-6; R ^b is —C1-6αalkyl substituted with one or more substituents independently selected from —OR ^c , —C (O) NH- (hydroxyC1-4alkyl), 5- or 6-membered monocyclic heteroaryl containing from 1 to 4 heteroatoms independently selected from O, N and S, a 4-7 membered monocyclic heterocyclyl containing at least one heteroatom selected from O, N and S, —SO ₂ C _1-4 alkyl and —NHS (O) ₂ C _{1 -4} alkyl; or R ^b represents -S (O) ₂ -5-6 membered monocyclic heteroaryl containing 1 to 4 heteroatoms independently selected from O, N and S; or R ^b is a 4-7 membered monocyclic heterocyclyl containing at least one heteroatom selected from O, N and S, optionally substituted with one or more hydroxy groups; or R ^b represents H, -OR ^c ; - [CH ₂ -CH ₂ -O] _p -H, - [CH ₂ -CH ₂ -O] _m -CH ₃ or 5-6 membered monocyclic heteroaryl containing from 1 to 4 heteroatoms independently selected from O, N and S, optional - 84 038455 but substituted with one or more C _1-4 alkyl; where n is 2-6 and m is 1-6; R ^c is H or hydroxyC _1-4 alkyl; R ² is H, C _1-4 alkoxy, halogen, C _1-4 alkyl, or —NH — C _1-4 alkyl; R ⁴ is H, halogen, C _1-4 alkyl, C _3-5 cycloalkyl; R ⁵ is H, halogen or CN; or R ⁵ is C2-6 alkynyl optionally substituted with NR ^g R ^h , where R ^g and R ^{h are} independently H or C1-4 alkyl; or R ^g and R ^h form, together with the nitrogen atom to which they are attached, a 4-7 membered monocyclic heterocyclyl optionally containing an additional heteroatom selected from O, S and N, the heteroatom being in its oxidized form; and wherein said monocyclic heterocyclyl is optionally substituted with C _1-4 alkyl; and R ⁶ is halogen or CN; or a pharmaceutically acceptable salt thereof. 2. The compound according to claim 1, where R ¹ represents CH3, cyclopropyl, -CH ₂ OH or CH = NH-OH; or a pharmaceutically acceptable salt thereof. 3. A compound according to any one of claims 1 or 2, where R ² is H or —NH — CH3; or a pharmaceutically acceptable salt thereof. 4. The compound according to any one of claims 1 to 3, where R ⁴ represents H or halogen; or a pharmaceutically acceptable salt thereof. 5. The compound according to any one of claims 1-4, where R ⁵ represents H, F, CN or C _2-4 alkynyl substituted with thiomorpholine; or a pharmaceutically acceptable salt thereof. 6. The compound according to any one of claims 1 to 5, where R ⁶ represents Cl or CN; or a pharmaceutically acceptable salt thereof. 7. A compound according to any one of claims 1-6, wherein R ³ is hydroxyC _1-4 alkyl, hydroxyC _1-6 alkoxy, -O- (CH2CH2-O) nH, -O- (CH2CH2-O) _m CH3, -NH- (CH2CH2O) nH, -NH- (CH2CH2-O) tCH3, azetidine substituted with hydroxyl, pyrrolidine substituted with one or more substituents independently selected from hydroxyl and hydroxyC _1-4 alkyl or piperazine substituted with hydroxyC _1-4 alkyl ; or a pharmaceutically acceptable salt thereof. 8. A compound according to any one of claims 1-6, wherein R ^{3 is} selected from the following groups: where n is equal to 2-6; or a pharmaceutically acceptable salt thereof. 9. A compound according to any one of claims 1-6, wherein R ^{3 is} selected from - 85 038455 or a pharmaceutically acceptable salt thereof. 10. A compound according to claim 1, wherein R ¹ is CH3 or CH2OH, R2 is H, R ³ is —OR ^a or —NHR ^b , R ⁴ is Cl, R ⁵ is H or F and R ⁶ represents Cl; or a pharmaceutically acceptable salt thereof. 11. A compound according to claim 1 selected from the group consisting of (S) -8-chloro-1- (2,6-dichlorophenyl) -5- (2,3-dihydroxypropoxy) -2- (hydroxymethyl) -1, 6-naphthyridin4 (1H) -one; (R) -8-chloro-1- (2,6-dichlorophenyl) -5- (2,3-dihydroxypropoxy) -2- (hydroxymethyl) -1,6-naphthyridin4 (1H) -one; 8-chloro-1- (2,6-dichlorophenyl) -5- (2,3-dihydroxypropoxy) -2- (hydroxymethyl) -1,6-naphthyridine-4 (1H) one; 8-chloro-1- (2,6-dichlorophenyl) -5- (2,3-dihydroxy-3-methylbutoxy) -2- (hydroxymethyl) -1,6naphthyridin-4 (1H) -one; 8-chloro-1- (2,6-dichlorophenyl) -2- (hydroxymethyl) -5 - ((3- (hydroxymethyl) oxetan-3-yl) methoxy) -1,6naphthyridin-4 (1H) -one; Ν- (2 - ((8-χλορ- 1 - (2,6-dichlorophenyl) -2- (hydroxymethyl) -4-oxo-1,4-dihydro-1,6-naphthyridin-5 yl) oxy) ethyl) methanesulfonamide; 8-chloro-1- (2,6-dichlorophenyl) -5- (2- (2- (2- (2-hydroxyethoxy) ethoxy) ethoxy) ethoxy) -2- (hydroxymethyl) 1,6-naphthyridine-4 ( 1H) -one; 8-chloro-1- (2,6-dichlorophenyl) -5- (3-hydroxy-2- (hydroxymethyl) propoxy) -2- (hydroxymethyl) -1,6naphthyridin-4 (1H) -one; 8-chloro-1- (2,6-dichlorophenyl) -5 - ((1,3-dihydroxypropan-2-yl) oxy) -2- (hydroxymethyl) -1,6naphthyridin-4 (1H) -one; 8-chloro-1 - (2,6-dichlorophenyl) -2- (hydroxymethyl) -5 - (oxetane-3-ylmethoxy) -1,6-naphthyridin-4 (1H) -one; 8-chloro-1 - (2,6-dichlorophenyl) -2- (hydroxymethyl) -5 - (2- (2-methoxyethoxy) ethoxy) -1,6-naphthyridin4 (1H) -one; 8-chloro-1 - (2,6-dichlorophenyl) -5- (2-hydroxyethoxy) -2- (hydroxymethyl) -1,6-naphthyridin-4 (1H) -one; 8-chloro-1- (2,6-dichlorophenyl) -5 - ((2- (2- (2- (2-hydroxyethoxy) ethoxy) ethoxy) ethyl) amino) -2 (hydroxymethyl) -1,6-naphthyridine -4 (1H) -one; 8-chloro-1- (2,6-dichlorophenyl) -5 - ((14-hydroxy-3,6,9,12-tetraoxatetradecyl) oxy) -2-methyl-1,6naphthyridin-4 (1H) -one; 5- (2,5,8,11,14,17-hexaoxanoneadecan-19-yloxy) -8-chloro-1 - (2,6-dichlorophenyl) -2-methyl-1,6naphthyridin-4 (1H) -one ; 3-chloro-2- (8-chloro-5 - ((2- (2- (2- (2-hydroxyethoxy) ethoxy) ethoxy) ethyl) amino) -2-methyl-4-oxo-1,6naphthyridine-1 (4H) -yl) benzonitrile; 3 - ((8-chloro-1- (2,6-dichlorophenyl) -2-methyl-4-oxo-1,4-dihydro-1,6-naphthyridin-5-yl) amino) -2-hydroxy-N- ( 2-hydroxyethyl) propanamide; 3,5-dichloro-4- (5- (2,3-dihydroxypropoxy) -2-methyl-4-oxo-1,7-naphthyridin-1 (4H) -yl) benzonitrile; 8-chloro-1- (2,6-dichlorophenyl) -5 - ((17-hydroxy-3,6,9,12,15-pentaoxaheptadecyl) oxy) -2-methyl-1,6naphthyridine-4 (1H) - she; 8-chloro-1- (2,6-dichlorophenyl) -5- (3- (2,3-dihydroxypropoxy) -2-hydroxypropoxy) -2-methyl-1,6naphthyridin-4 (1H) -one; 3-chloro-2- (8-chloro-5- (2- (2- (2- (2-hydroxyethoxy) ethoxy) ethoxy) ethoxy) -2-methyl-4-oxo-1,6naphthyridine-1 (4H) -yl) benzonitrile; N- (2 - ((1- (2,6-dichloro-4-cyanophenyl) -2-methyl-4-oxo-1,4-dihydro-1,7-naphthyridine-5yl) amino) ethyl) methanesulfonamide; 3-chloro-2- (8-chloro-5- (2- (2- (2- (2-hydroxyethoxy) ethoxy) ethoxy) ethoxy) -2-methyl-4-oxo-1,6naphthyridine-1 (4H) -yl) -5-fluorobenzonitrile; 8-chloro-1- (2,6-dichloro-4-fluorophenyl) -5 - ((17-hydroxy-3,6,9,12,15-pentaoxaheptadecyl) oxy) -2methyl-1,6-naphthyridine-4 (1H) -one; 3,5-dichloro-4- (8-chloro-5- (4- (2-hydroxyethyl) piperazin-1-yl) -2-methyl-4-oxo-1,6-naphthyridin-1 (4H) yl) benzonitrile; 8-chloro-1- (2,6-dichlorophenyl) -2-methyl-5- (2,3,4-trihydroxybutoxy) -1,6-naphthyridin-4 (1H) -one; 3,5-dichloro-4- (5 - ((2-hydroxyethyl) amino) -2-methyl-4-oxo-1,7-naphthyridin-1 (4H) -yl) benzonitrile; 8-chloro-1- (2,6-dichlorophenyl) -5- (3-hydroxy-2,2-bis (hydroxymethyl) propoxy) -2-methyl-1,6- 86 038455 naphthyridin-4 (1H) -one ; 3,5-dichloro-4- (5- (3-hydroxyazetidin-1-yl) -2-methyl-4-oxo-1,7-naphthyridin-1 (4H) -yl) benzonitrile; 8-chloro-1- (2,6-dichlorophenyl) -5- (2- (2- (2- (2-hydroxyethoxy) ethoxy) ethoxy) ethoxy) -2-methyl-1,6naphthyridine-4 (1H) - she; 8-chloro-1- (2,6-dichlorophenyl) -5 - ((2R, 4S) -4-hydroxy-2- (hydroxymethyl) pyrrolidin-1-yl) -2-methyl1,6-naphthyridine-4 (1H )-she; 8-chloro-1- (2,6-dichloro-4-fluorophenyl) -5- (2- (2- (2- (2-hydroxyethoxy) ethoxy) ethoxy) ethoxy) -2-methyl1,6-naphthyridine-4 (1H) -one; 8-chloro-1- (2,6-dichlorophenyl) -5 - ((3R, 4S) -3,4-dihydroxypyrrolidin-1-yl) -2-methyl-1,6-naphthyridin4 (1H) -one; 3-chloro-2- (8-chloro-5- (2,3-dihydroxypropoxy) -2-methyl-4-oxo-1,6-naphthyridin-1 (4H) yl) benzonitrile; 5 - ((2- (1H-imidazol-4-yl) ethyl) amino) -8-chloro-1- (2,6-dichlorophenyl) -2-methyl-1,6-naphthyridin-4 (1H) one; N- (2 - ((8-chloro-1- (2,6-dichlorophenyl) -2-methyl-4-oxo-1,4-dihydro-1,6-naphthyridine-5yl) oxy) ethyl) methanesulfonamide; 8-chloro-1- (2,6-dichlorophenyl) -5 - ((2- (2- (2- (2-hydroxyethoxy) ethoxy) ethoxy) ethyl) amino) -2-methyl-1,6naphthyridine-4 ( 1H) -one; 8-chloro-1- (2,6-dichlorophenyl) -5- (2,3-dihydroxypropoxy) -2-methyl-1,6-naphthyridin-4 (1H) -one; (S) -8-chloro-1- (2,6-dichlorophenyl) -5 - ((2,3-dihydroxypropyl) amino) -2-methyl-1,6-naphthyridin-4 (1H) one; 8-chloro-1- (2,6-dichlorophenyl) -5- (2,3-dihydroxy-3-methylbutoxy) -2-methyl-1,6-naphthyridin-4 (1H) one; 8-chloro-1- (2,6-dichlorophenyl) -5- (3-hydroxy-2- (hydroxymethyl) -2-methylpropoxy) -2-methyl-1,6naphthyridin-4 (1H) -one; 8-chloro-1- (2,6-dichlorophenyl) -5- (2-hydroxy-2-methylpropoxy) -2-methyl-1,6-naphthyridin-4 (1H) -one; 3,5-dichloro-4- (8-chloro-5 - (((3R, 4S) -4-hydroxytetrahydrofuran-3-yl) amino) -2-methyl-4-oxo-1,6naphthyridine-1 (4H) -yl) benzonitrile; 3,5-dichloro-4- (8-chloro-5 - ((2-hydroxyethoxy) amino) -2-methyl-4-oxo-1,6-naphthyridin-1 (4H) yl) benzonitrile; 8-chloro-1- (2,6-dichlorophenyl) -2-methyl-5 - ((1-methyl-1H-tetrazol-5-yl) amino) -1,6-naphthyridin-4 (1H) one; 8-chloro-1- (2,6-dichlorophenyl) -2-methyl-5 - ((1-methyl-1H-tetrazol-5-yl) oxy) -1,6-naphthyridin-4 (1H) one; 8-chloro-1- (2,6-dichlorophenyl) -2-methyl-5 - ((2-methyl-2H-tetrazol-5-yl) amino) -1,6-naphthyridin-4 (1H) one; 8-chloro-1- (2,6-dichlorophenyl) -5- (2-hydroxyethoxy) -2-methyl-1,6-naphthyridin-4 (1H) -one; 8-chloro-1- (2,6-dichlorophenyl) -5 - ((2-hydroxyethoxy) amino) -2-methyl-1,6-naphthyridin-4 (1H) -one; 8-chloro-1- (2,6-dichlorophenyl) -2-methyl-5- (oxetan-3-ylmethoxy) -1,6-naphthyridin-4 (1H) -one; 8-chloro-1- (2,6-dichlorophenyl) -2- (hydroxymethyl) -5 - ((2- (methylsulfonyl) ethyl) amino) -1.6naphthyridin-4 (1H) -one; 8-cyclopropyl-1- (2,6-dichlorophenyl) -5- (2,3-dihydroxypropoxy) -2-methyl-1,6-naphthyridine-4 (1H) one; 8-chloro-1- (2,6-dichlorophenyl) -5- (3-hydroxy-2- (hydroxymethyl) propoxy) -2- (methoxymethyl) -1,6naphthyridin-4 (1H) -one; 8-chloro-1- (2,6-dichlorophenyl) -5- (2,3-dihydroxypropoxy) -2- (methoxymethyl) -1,6-naphthyridine-4 (1H) one; 3-chloro-2- (8-chloro-2-cyclopropyl-5- (2,3-dihydroxypropoxy) -4-oxo-1,6-naphthyridin-1 (4H) yl) benzonitrile; 4- (5 - ((2- (1H-imidazol-4-yl) ethyl) amino) -2-methyl-4-oxo-1,7-naphthyridin-1 (4H) -yl) -3,5-dichlorobenzonitrile; 8-chloro-1- (2,6-dichlorophenyl) -5 - ((2,2-dimethyl-1,3-dioxolan-4-yl) methoxy) -2- (hydroxymethyl) -1,6 naphthyridine-4 (1Н )-she; (R) -8-chloro-1 - (2,6-dichlorophenyl) -5- (2,3-dihydroxy-3-methylbutoxy) -2-methyl-1,6-naphthyridin-4 (1H) one; (S) -8-chloro-1- (2,6-dichlorophenyl) -5- (2,3-dihydroxy-3-methylbutoxy) -2-methyl-1,6-naphthuridin-4 (1H) one; 8-chloro-1- (2,6-dichloro-4-fluorophenyl) -5 - (2,3-dihydroxypropoxy) -2- (hydroxymethyl) -1,6naphthyridin-4 (1H) -one; 8-chloro-1- (2,6-dichloro-4-fluorophenyl) -5- (2-hydroxyethoxy) -2- (hydroxymethyl) -1,6-naphthyridin4 (1H) -one; 8-chloro-1- (2,6-dichlorophenyl) -2- (difluoromethyl) -5- (2,3-dihydroxypropoxy) -1,6-naphthyridine-4 (1H) - 87 038455 one; 8-chloro-1- (2,6-dichlorophenyl) -5- (2,3-dihydroxypropoxy) -4-oxo-1,4-dihydro-1,6-naphthyridine-2carbonitrile; 8-chloro-1- (2,6-dichlorophenyl) -5-hydroxy-2- (hydroxymethyl) -1,6-naphthyridin-4 (1H) -one; 1- (2,6-dichlorophenyl) -5- (2,3-dihydroxypropoxy) -2-methyl-7- (methylamino) -1,6-naphthyridin-4 (1H) one; 1- (2,6-dichlorophenyl) -5- (2,3-dihydroxypropoxy) -7-ethyl-2-methyl-1,6-naphthyridin-4 (1H) -one; 1- (2-chloro-6-ethylphenyl) -5- (2,3-dihydroxypropoxy) -7-ethyl-2-methyl-1,6-naphthyridin-4 (1H) -one; 1- (2,6-dichlorophenyl) -5- (2,3-dihydroxypropoxy) -7-methoxy-2-methyl-1,6-naphthyridin-4 (1H) -one; 1- (2,6-dichlorophenyl) -5- (2,3-dihydroxypropoxy) -8-ethyl-2-methyl-1,6-naphthyridin-4 (1H) -one; N- (1- (2,6-dichloro-4-cyanophenyl) -2-methyl-4-oxo-1,4-dihydro-1,7-naphthyridin-5-yl) -1H-pyrazole-4sulfonamide; 8-chloro-1- (2,6-dichlorophenyl) -2-methyl-5- (1H-1,2,4-triazol-1-yl) -1,6-naphthyridin-4 (1H) -one; 3,5-dichloro-4- (2-methyl-4-oxo-5- (1H-pyrazol-3-yl) -1,7-naphthyridin-1 (4H) -yl) benzonitrile; 3,5-dichloro-4- (2-methyl-5- (1-methyl-1H-pyrazol-4-yl) -4-oxo-1,7-naphthyridin-1 (4H) -yl) benzonitrile; 8-chloro-1- (2,6-dichlorophenyl) -2- (hydroxymethyl) -5- (3-hydroxypropyl) -1,6-naphthyridin-4 (1H) -one; 8-chloro-1- (2,6-dichlorophenyl) -5- (3,4-dihydroxybutyl) -2- (hydroxymethyl) -1,6-naphthyridin-4 (1H) -one; (R) -8-chloro-1 - (2,6-dichlorophenyl) -5- (3,4-dihydroxybutyl) -2- (hydroxymethyl) -1,6-naphthyridin-4 (1H) one; (S) -8-chloro-1- (2,6-dichlorophenyl) -5- (3,4-dihydroxybutyl) -2- (hydroxymethyl) -1,6-naphthyridin-4 (1H) one; 8-chloro-1- (2,6-dichlorophenyl) -5- (2,3-dihydroxypropyl) -2- (hydroxymethyl) -1,6-naphthyridine-4 (1H) one; (R) -8-chloro-1- (2,6-dichlorophenyl) -5- (2,3-dihydroxypropyl) -2- (hydroxymethyl) -1,6-naphthuridin4 (1H) -one; (S) -8-chloro-1- (2,6-dichlorophenyl) -5- (2,3-dihydroxypropyl) -2- (hydroxymethyl) -1,6-naphthuridin4 (1H) -one; 8-chloro-1- (2,6-dichlorophenyl) -5- (2,3-dihydroxypropyl) -2-methyl-1,6-naphthyridin-4 (1H) -one; 8-chloro-1- (2,6-dichlorophenyl) -5- (1,2-dihydroxyethyl) -2- (hydroxymethyl) -1,6-naphthyridin-4 (1H) -one; (R) -8-chloro-1- (2,6-dichlorophenyl) -5- (1,2-dihydroxyethyl) -2- (hydroxymethyl) -1,6-naphthyridin-4 (1H) one; (S) -8-chloro-1- (2,6-dichlorophenyl) -5- (1,2-dihydroxyethyl) -2- (hydroxymethyl) -1,6-naphthyridin-4 (1H) one; 8-chloro-1- (2,6-dichlorophenyl) -5- (1,2-dihydroxyethyl) -2-methyl-1,6-naphthyridin-4 (1H) -one; 8-chloro-1- (2,6-dichlorophenyl) -5- (2-hydroxyacetyl) -2-methyl-1,6-naphthyridin-4 (1H) -one; 8-chloro-1- (2,6-dichlorophenyl) -5 - ((2,3-dihydroxypropoxy) methyl) -2- (hydroxymethyl) -1.6naphthyridin-4 (1H) -one; 8-chloro-1- (2,6-dichlorophenyl) -5 - (((1,3-dihydroxypropan-2-yl) oxy) methyl) -2- (hydroxymethyl) -1,6naphthyridin-4 (1H) -one ; 8-chloro-1- (2,6-dichlorophenyl) -5- (2,4-dihydroxy-3-oxobutan-2-yl) -2-methyl-1,6-naphthyridin-4 (1H) one; 1 - (4- (3-amino-3-methylbut-1-yn-1-yl) -2,6-dichlorophenyl) -8-chloro-5- (2,3-dihydroxypropoxy) -2methyl-1,6- naphthyridin-4 (1H) -one; 8-chloro-1- (2,6-dichloro-4- (3-morpholinoprop-1-yn-1-yl) phenyl) -5 - (2-hydroxyethoxy) -2-methyl-1,6naphthyridine-4 (1Н )-she; 8-chloro-1- (2,6-dichloro-4- (3 - (1,1-dioxidothiomorpholino) prop-1-yn-1-yl) phenyl) -5- (2hydroxyethoxy) -2-methyl-1, 6-naphthyridin-4 (1H) -one; 8-chloro-1- (2,6-dichloro-4- (3- (dimethylamino) prop-1-yn-1-yl) phenyl) -5 - ((2,2-dimethyl-1,3-dioxolane- 4yl) methoxy) -2-methyl-1,6-naphthyridin-4 (1H) -one and (8-chloro-1- (2,6-dichlorophenyl) -5- (2,3-dihydroxypropoxy) -4-oxo -1,4-dihydro-1,6-naphthyridine-2yl) methyldihydrogen phosphate; or a pharmaceutically acceptable salt thereof. 12. A compound according to claim 1 selected from the group consisting of (S) -8-chloro-1- (2,6-dichlorophenyl) -5- (2,3-dihydroxypropoxy) -2- (hydroxymethyl) -1, 6-naphthuridin4 (1H) -one; (R) -8-chloro-1- (2,6-dichlorophenyl) -5- (2,3-dihydroxypropoxy) -2- (hydroxymethyl) -1,6-naphthyridin4 (1H) -one; 8-chloro-1- (2,6-dichlorophenyl) -5- (2,3-dihydroxypropoxy) -2- (hydroxymethyl) -1,6-naphthyridine-4 (1H) one; (R) -8-chloro-1 - (2,6-dichlorophenyl) -5- (3,4-dihydroxybutyl) -2- (hydroxymethyl) -1,6-naphthyridin-4 (1H) one; (S) -8-chloro-1- (2,6-dichlorophenyl) -5- (3,4-dihydroxybutyl) -2- (hydroxymethyl) -1,6-naphthuridin-4 (1H) - 88 038455 she and 8-chloro-1- (2,6-dichlorophenyl) -5- (3,4-dihydroxybutyl) -2- (hydroxymethyl) -1,6-naphthyridin-4 (1H) -one; or a pharmaceutically acceptable salt thereof. 13. Compound representing (S) -8-chloro-1- (2,6-dichlorophenyl) -5- (2,3-dihydroxypropoxy) -2- (hydroxymethyl) -1,6-naphthyridine-4 (1H) -one or a pharmaceutically acceptable salt thereof. 14. Crystalline form of (S) -8-chloro-1- (2,6-dichlorophenyl) -5- (2,3-dihydroxypropoxy) -2 (hydroxymethyl) -1,6-naphthyridin-4 (1H) -one hydrate characterized by an X-ray powder diffractogram (XRPD) containing one or more peaks selected from 7.0 ± 0.2 ° 2θ, 14.1 ± 0.2 ° 2θ, 18.5 ± 0.2 ° 2θ, 24.7 ± 0.2 ° 2θ, 26.0 ± 0.2 ° 2θ and 26.9 ± 0.2 ° 2θ, when measured using CuKa radiation with a wavelength of 1.5418 A and a temperature of 22 ° C. 15. A method of treating or preventing a disease or disorder susceptible to inhibition of a GIRK receptor in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of formula II or formula III according to any one of claims 1-14, or a pharmaceutically acceptable salt thereof. 16. The method of claim 15, wherein the disease or disorder is selected from cardiac arrhythmia, atrial fibrillation, primary hyperaldosteronism, hypertension, and sick sinus syndrome. 17. The method of claim 15, wherein the disease or disorder is atrial fibrillation. 18. Use of a compound of formula II or formula III according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, for the treatment or prevention of a disease or disorder susceptible to inhibition of a GIRK receptor. 19. Use of a compound of formula II or formula III according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof for the treatment of cardiac arrhythmias, atrial fibrillation, primary hyperaldosteronism, hypertension or sick sinus syndrome. 20. Use of a compound of formula II or formula III according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, for the treatment of atrial fibrillation.