RU2802512C2 - Method for producing 2-[(3r)-3-methylmorpholin-4-yl]-4-(1-methyl-1h-pyrazol-5-yl)-8-(1h-pyrazol-5-yl)-1,7-nafthyridine - Google Patents

Abstract

FIELD: chemical industry.

SUBSTANCE: invention relates to a method for obtaining 2-[(3R)-3-methylmorpholin-4-yl]-4-(1-methyl-1H-pyrazol-5-yl)-8-(1H-pyrazol-5-yl)-1 ,7-naphthyridine ("compound of formula (I)", as well as intermediate compounds suitable for obtaining compounds of formula (I).

EFFECT: new effective method for obtaining a compound of formula (I) has been developed, which makes it possible to obtain a product with a high yield and purity.

20 cl, 6 dwg, 1 tbl, 7 ex

Description

The present invention covers a process for the preparation of 2-[(3R)-3-methylmorpholin-4-yl]-4-(1-methyl-1H-pyrazol-5-yl)-8-(1H-pyrazol-5-yl)-1 ,7-naphthyridine ("compound of formula (I)" hereinafter), as well as intermediate compounds suitable for the preparation of the compound of formula (I). The present invention also covers polymorph Form B of the compound of formula (I) in very high purity.

PREREQUISITES FOR CREATION OF THE INVENTION

Example 111 of WO 2016020320 A1 describes a method for the synthesis of 2-[(3R)-3-methylmorpholin-4-yl]-4-(1-methyl-1H-pyrazol-5-yl)-8-(1H-pyrazol-5- yl)-1,7-naphthyridine of formula (I) using the following synthesis route:

The synthesis of compound (IIa) (=8-chloro-2-((R)-3-methylmorpholin-4-yl)-[1,7]naphthyridin-4-ol) is described in WO 2016020320 A1 in Example "Intermediate- 7", stage c.

According to WO 2016020320 A1 "Intermediate-9", which corresponds to compound (IV) (=2-[((R)-3-methylmorpholin-4-yl)-8-[2-(tetrahydropyran-2-yl) -2H-pyrazol-3-yl]-[1,7]naphthyridin-4-ol), was prepared by the Suzuki coupling reaction from the compound of formula (IIa) and the tetrahydropyranyl-protected boronic ester compound (IIIc) (=1- (tetrahydropyran-2-yl)-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole) under argon using the complex [1,1' -bis(diphenylphosphino)ferrocene]dichloropalladium(II) with dichloromethane (1:1) as a catalyst and cesium carbonate in absolute 1,4-dioxane. The reaction mixture was stirred at 90°C for 16 hours. The brown reaction solution was purified using column chromatography [silica gel 60; ethyl acetate)]. 506 mg (yield 72% of theoretical) 2-[(R)-3-methylmorpholin-4-yl)-8-[2-(tetrahydropyran-2-yl)-2H-pyrazol-3-yl]-[1, 7]naphthyridin-4-ol was separated as a yellow oil.

For the following reasons, given by way of example, the laboratory scale production process for the compound of formula (IV) which is described in WO 2016020320 A1 is not suitable for use as a large scale production process:

• The use of an absolute solvent (eg 1,4-dioxane) is difficult to handle on a large scale.

• Cesium carbonate is a relatively expensive inorganic base.

• Long reaction time required (16 hours at 90°C).

• The compound of formula (IV) is an oil and therefore cannot be purified by the low-effort crystallization step that is the preferred method for large-scale production.

• Purification using column chromatography is time-consuming and expensive.

According to WO 2016020320 A1 "Intermediate 9", the oily compound of formula (IV) is then converted into "Intermediate 10", which corresponds to the compound of formula (V) (=2-[(3R)-3-methylmorpholine-4- yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridin-4-yl trifluoromethanesulfonate) by treatment with N-phenylbis-(trifluoromethanesulfonimide) and N,N-diisopropylethylamine in an argon atmosphere in absolute dichloromethane. The reaction time at room temperature was three days. The solvent was distilled off under reduced pressure and the residue was chromatographed twice [silica gel 60 (400 g); dichloromethane: methanol, 98:21 ethyl acetate]. After evaporation to dryness, the compound of formula (V) was obtained in a yield of 2.6 g (42% of theory) as a yellow solid.

The disadvantages of this technique are, for example:

• Use of an absolute solvent (requires high costs).

• Very long reaction time (three days at room temperature), which is costly.

• Two stages of chromatographic purification which are very time consuming and costly.

• Very low yield (42%) for this step.

• Isolation by evaporation of chromatographic fractions. This operation is not feasible for scale-up because it is very energy-intensive and expensive.

The compound of formula (V) was converted to the compound of formula (VIIc/VIId) by the Suzuki reaction using 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H -pyrazole (VIb), aq. potassium carbonate solution (1.4 ml, 2 M) and bis(triphenylphosphine) palladium(II) dichloride (67 mg, 0.094 mmol), which were dissolved in dimethoxyethane (60 ml). The reaction mixture was stirred for 20 minutes at 130°C under microwave irradiation. After cooling to room temperature, the reaction mixture was filtered through a silicone filter and concentrated under reduced pressure. The crude material was purified by flash column chromatography (using hexane/ethyl acetate/ethanol). The target fractions were concentrated under reduced pressure and dissolved in conc. sulfuric acid (5 ml). The mixture was stirred for 3 hours at room temperature. The mixture was then poured onto ice and made alkaline using solid sodium bicarbonate. The suspension was filtered and the solid was stirred with ethanol at 40°C, filtered and dried under reduced pressure. The compound of formula (I) was obtained in 78% yield (0.28 g).

At least the following points are critical for upscaling:

• Using a microwave reactor for scale-up is not possible. Conducting a large-scale reaction at 130°C in just 20 minutes is complex and cannot be achieved on a multi-kilogram scale.

• Performing chromatography for isolation and purification is time-consuming and expensive when scaled up.

• Evaporation of compound-containing chromatographic fractions on a large scale is not possible because it is a very energy-intensive and expensive operation.

• The purity of the compound of formula (I) does not meet GMP (Good Manufacturing Practice) requirements.

To summarize, it should be noted that the described method for obtaining the target compound (I) starting from the compound of formula (IIa) (=8-chloro-2-((R)-3-methylmorpholin-4-yl)-[1,7]naphthyridine -4-ol) is very inefficient, time consuming and expensive since it involves three chromatographic steps and results in long reaction times and very low overall yield (from compound of formula (II) to compound (I): theoretical yield 23.6% ).

Therefore, the object of the present invention was to provide a process for the preparation of 2-[(3R)-3-methylmorpholin-4-yl]-4-(1-methyl-1H-pyrazol-5-yl)-8-(1H-pyrazol- 5-yl)-1,7-naphthyridine of formula (I), which does not have one or more of the above-mentioned disadvantages.

DEFINITIONS

The term "substituted" means that one or more hydrogen atoms on the designated atom or group are replaced by substituent(s) selected from the designated group, provided that the normal valency of the designated atom at existing circumstances is not exceeded. Combinations of substituents and/or variables are acceptable.

The term "optionally substituted" means that the number of substituents may be zero or non-zero. Unless otherwise indicated, optionally substituted groups may be replaced by as many optional substituents as can be accommodated by replacing each hydrogen atom with a non-hydrogen substituent on any available carbon or nitrogen atom. Typically, the number of optional substituents, if present, may be 1, 2, 3, 4 or 5, in particular 1, 2 or 3.

As used herein, the term "one or more", for example in the definition of substituents of the compounds of general formula (I) of the present invention, means 1, 2, 3, 4 or 5, in particular 1, 2, 3 or 4, more particularly , 1, 2 or 3, even more specifically, 1 or 2.

The term "comprising" as used herein includes "consisting of".

If in this text any element is referred to as "as mentioned in this application", this means that it can be mentioned anywhere in this text.

The terms mentioned in this text have the following meanings:

The term "C ₁ -C ₆ -alkyl" means a linear or branched, saturated, monovalent hydrocarbon group containing 1, 2, 3, 4, 5 or 6 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, butyl, sec. butyl, isobutyl, tert-butyl, pentyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neo-pentyl, 1,1-dimethylpropyl, hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1-ethylbutyl, 2-ethylbutyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2,3-dimethylbutyl, 1,2-dimethylbutyl or 1,3- dimethylbutyl group, or its isomer. In particular, the group contains 1, 2, 3 or 4 carbon atoms ("C ₁ -C ₄ -alkyl"), for example, represents methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl or tert-butyl a group, more particularly 1, 2 or 3 carbon atoms (“C ₁ -C ₃ -alkyl”), for example, is a methyl, ethyl, n-propyl or isopropyl group.

As used herein, the term "C ₁ -C ₆ ", for example in the context of the definition of "C ₁ -C ₆ -alkyl", means an alkyl group having a finite number of carbon atoms from 1 to 6, i.e. 1, 2, 3, 4, 5 or 6 carbon atoms.

In cases where a range of values is specified, the specified range covers every value and subrange within the specified range.

For example: "C ₁ -C ₆ " covers C ₁ , C ₂ , C ₃ , C ₄ , C ₅ , C ₆ , C ₁ -C ₆ , C ₁ -C ₅ , C ₁ -C ₄ , C ₁ -C ₃ , C ₁ -C ₂ , C ₂ -C ₆ , C ₂ -C ₅ , C ₂ -C ₄ , C ₂ -C ₃ , C 3 -C ₆ , C ₃ -C ₅ , C _{3 -C 4} , C ₄ -C ₆ , C ₄ -C ₅ and C ₅ -C ₆ .

The compound of formula (I) may exist as a tautomer of formula (Ia)

One skilled in the art will also know that compounds of formula (I) and (Ia) can exist as mixtures of both tautomers (I) and (Ia).

The compounds of the present invention of formula (VIIIa) or (IXa) optionally contain more than one, in particular two, asymmetric centers, depending on the location and nature of the various substituents required. However, one or more asymmetric carbon atoms may be present in the (R) or (S) configuration, which can lead to racemic mixtures in the case of a single asymmetric center, and diastereomeric mixtures in the case of several asymmetric centers.

Separated, pure or partially purified isomers and stereoisomers or racemic or diastereomeric mixtures of the compounds of the present invention are also included within the scope of the present invention. Purification and separation of such substances can be accomplished using standard techniques known in the art. Such separated, pure or partially purified isomers or racemic mixtures of the compounds of this invention are also included within the scope of the present invention. Purification and separation of such substances can be accomplished using standard techniques known in the art.

Optical isomers can be prepared by resolving racemic mixtures according to conventional methods, for example by forming diastereomeric salts using an optically active acid or base, or by forming covalent diastereomers. Examples of suitable acids are tartaric, diacetyltartaric, ditoluoyltartaric and camphorsulfonic acid. Mixtures of diastereoisomers can be separated into their individual diastereoisomers based on their physical and/or chemical differences using methods known in the art, such as chromatography or fractional crystallization. The optically active bases or acids are then released from the separated diastereomeric salts. Another method for separating optical isomers involves the use of chiral chromatography (eg, chiral phase HPLC columns), with or without conventional derivatization optimally selected to maximize enantiomer separation. Suitable chiral phase HPLC columns are commercially available, in particular such columns are manufactured by Daicel, for example Chiracel OD and Chiracel OJ, for example, among many others commonly selected. Enzymatic separation methods, with or without derivatization, are also suitable. The optically active compounds of the present invention can also be prepared by chiral synthesis using optically active starting materials.

In order to distinguish between the different types of isomers, reference is made to the IUPAC rules, section E (Pure Appl Chem 45, 11-30, 1976).

The present invention includes all possible stereoisomers of the compounds of the present invention of formula (VIIIa) or (IXa) in the form of individual stereoisomers, or in the form of any mixture of these stereoisomers, for example, (R) - or (S) - isomers, in any ratio. Isolation of a single stereoisomer, for example a single enantiomer or a single diastereomer, of a compound of the present invention is achieved using any suitable prior art method, such as, for example, chromatography, in particular chiral chromatography.

Moreover, the compounds of the present invention may exist as N-oxides, which are defined by the fact that at least one nitrogen atom of the compounds of the present invention is oxidized. The present invention includes all such possible N-oxides.

The present invention also covers suitable forms of the compounds of the present invention of formula (VIIIa) or (IXa), such as hydrates, solvates, salts, in particular pharmaceutically acceptable salts, and/or co-precipitation products.

Moreover, the compounds of the present invention of formula (VIIIa) or (IXa) may exist in free form, for example, as a free base, or as a free acid, or as a zwitterion, or may exist in the form of a salt. Said salt may be any salt, either organic or inorganic addition salt, in particular any pharmaceutically acceptable organic or inorganic addition salt which is commonly used in pharmaceuticals, or which is used, for example, for isolating or purifying the compounds of the present invention.

The term "pharmaceutically acceptable salt" refers to the addition salt of an inorganic or organic acid to a compound of the present invention of formula (VIIIa) or (IXa). For example, see S.M. Berge et al. "Pharmaceutical Salts," J. Pharm. Sci. 1977, 66, 1-19.

A suitable pharmaceutically acceptable salt of a compound of the present invention of formula (VIIIa) or (IXa) may be, for example, an acid addition salt of a compound of the present invention bearing a nitrogen atom in a chain or ring, for example, which is sufficiently basic, such as an addition salt inorganic acid, or "mineral acid", such as, for example, hydrochloric, hydrobromic, hydroiodic, sulfuric, sulfamic, beading, phosphoric or nitric acid, or organic acids, such as, for example, formic, acetic, acetoacetic, pyruvic, trifluoroacetic, propionic, butyric, hexane, heptane, undecane, lauric, benzoic, salicylic, 2-(4-hydroxybenzoyl)-benzoic, camphoric, cinnamic, cyclopentanepropionic, digluconic, 3-hydroxy-2-naphthoic, nicotinic, pamoic, pectic, 3- phenylpropionic, pivalic, 2-hydroxyethanesulfonic, itaconic, trifluoromethanesulfonic, dodecyl sulfuric, ethanesulfonic, benzenesulfonic, para-toluenesulfonic, methanesulfonic, 2-naphthalene sulfonic, naphthalene disulfonic, camphorsulfonic acid, citric, tartaric, stearic, lactic, oxalic, malonic, amber, apple, adipine , alginic, maleic, fumaric, D-gluconic, mandelic, ascorbic, glucoheptanic, glycerophosphoric, aspartic, sulfosalicylic or thiocyanic acid.

Moreover, another suitable pharmaceutically acceptable salt of the compound of the present invention of formula (VIIIa) or (IXa) which is sufficiently acidic is an alkali metal salt, for example a sodium or potassium salt, an alkaline earth metal salt, for example a calcium, magnesium or strontium salt , or an aluminum or zinc salt, or an ammonium salt obtained from ammonia or from an organic primary, secondary or tertiary amine containing from 1 to 20 carbon atoms, such as ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, diethylaminoethanol, tris(hydroxymethyl)aminomethane, procaine, dibenzylamine, N-methylmorpholine, arginine, lysine, 1,2-ethylenediamine, N-methylpiperidine, N-methylglucamine, N,N-dimethylglucamine, N-ethylglucamine, 1,6- hexanediamine, glucosamine, sarcosine, serinol, 2-amino-1,3-propanediol, 3-amino-1,2-propanediol, 4-amino-1,2,3-butanetriol, or a salt with a quaternary ammonium ion containing 1 up to 20 carbon atoms, such as tetramethylammonium, tetraethylammonium, tetra(n-propyl)ammonium, tetra(n-butyl)ammonium, N-benzyl-N,N,N-trimethylammonium, choline or benzalkonium.

Those skilled in the art will also understand that acid addition salts of the claimed compounds of formula (VIIIa) or (IXa) can be prepared by reacting the compounds with a suitable inorganic or organic acid using any of a number of known methods. Alternatively, alkali and alkaline earth metal salts of the acidic compounds of the present invention of formula (VIIIa) or (IXa) are prepared by reacting the compounds of the present invention with a suitable base using a variety of known methods.

The present invention includes all possible salts of the compounds of the present invention of formula (VIIIa) or (IXa) in the form of individual salts, or in the form of any mixture of these salts, in any ratio.

Unless otherwise noted, additions to chemical names or structural formulas referring to salts, such as "hydrochloride", "trifluoroacetate", "sodium salt" or "xHCl", " _xCF3COOH ", "xNa ⁺ ", for example, means a salt form, the stoichiometry of which is not precisely determined.

Moreover, the present invention includes all possible crystalline forms, or polymorphs, of the compounds of the present invention of formula (VIIIa) or (IXa), either as individual polymorphs or as a mixture of more than one polymorph, in any ratio.

Compounds of formula (VIIIa) or (IXa) may exist as isotopic variants. Thus, the invention includes one or more isotopic variants of compounds of formula (VIIIa) or (IXa), in particular deuterium-containing variants of compounds of formula (VIIIa) or (IXa).

The term "isotopic variant" of a compound or reagent is defined as a compound that exhibits a non-naturally occurring relative abundance of one or more of the isotopes that make up the compound.

The term "isotopic variant of a compound of formula (VIIIa) or (IXa)" is defined as a compound of formula (VIIIa) or formula (IXa) exhibiting a non-naturally occurring relative abundance of one or more isotopes that constitute such compound.

The expression "non-natural relative abundance" means a relative abundance of an isotope that is higher than its occurrence in nature. Information regarding the natural abundances of isotopes mentioned in this context is described in the document "Isotopic Compositions of the Elements 1997", Pure Appl. Chem., 70(1), 217-235, 1998.

Examples of such isotopes include stable and radioactive isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine and iodine, such as ^2H (deuterium), ^3H (tritium), ^11C , ^13C , ^14C , ¹⁵ N, ¹⁷ O, ¹⁸ O ^{, 32} P, 33 P, ³³ S, ³⁴ S, 35 S, ³⁶ S, ¹⁸ F ^{, 36} Cl, ⁸² Br, ¹²³ I, ¹²⁴ I, ¹²⁵ I, ¹²⁹ I and ¹³¹ I, respectively.

With respect to the present invention, isotopic variants of compounds of general formula (VIIIa) or (IXa) preferably contain deuterium (“deuterium-containing compounds of formula (VIIIa) or (IXa)”).

Isotopic variants of compounds of formula (VIIIa) or (IXa) can generally be prepared by methods known to one skilled in the art, such as those described in the diagrams and/or examples in this application, by replacing the reagent with an isotopic variant of said reagent, preferably one containing deuterium reagent. Depending on the desired deuteration sites, in some cases the deuterium from D ₂ O can be introduced either directly into the compounds or into reagents that are useful for the synthesis of such compounds. Deuterium gas is also a useful reagent for introducing deuterium into molecules. A quick way to introduce deuterium is through catalytic deuteration of olefin bonds and acetylene bonds. Metal catalysts (ie Pd, Pt and Rh) in the presence of deuterium gas can be used to directly exchange hydrogen for deuterium in functional groups containing hydrocarbon groups. A variety of deuterated reagents and building blocks for synthesis are commercially available from companies such as C/D/N Isotopes, Quebec, Canada; Cambridge Isotope Laboratories Inc., Andover, MA, USA; and CombiPhos Catalysts, Inc., Princeton, NJ, USA.

The term "deuterium-containing compound of formula (VIIIa) or (IXa)" is defined as a compound of formula (VIIIa) or formula (IXa) in which one or more hydrogen atom(s) is replaced by one or more atom(s) c) deuterium and wherein the relative abundance of deuterium at each deuterated position of such compound of formula (VIIIa) or (IXa) is higher than the abundance of deuterium in nature, which is approximately 0.015%. Particularly, in a deuterium-containing compound of formula (VIIIa) or (IXa), the relative content of deuterium at each deuterated position of the compound of general formula (I) is greater than 10%, 20%, 30%, 40%, 50%, 60%, 70% or 80%, preferably greater than 90%, 95%, 96% or 97%, even more preferably at said position(s) the deuterium content is greater than 98% or 99%. It should be understood that the relative content of deuterium at each deuterated position is independent of the relative content of deuterium at the other deuterated position(s).

DESCRIPTION OF THE INVENTION

The process for preparing the compound of formula (I) according to the invention is characterized by various advantageous preparation steps as well as intermediate compounds, which can be illustrated by the following diagram:

The new synthesis route from intermediate (II) to the compound of formula (I) has several advantages over the route described in WO 2016020320 A1. The new route provides at least one or more of the following advantages over the previously described method:

• There is no need for a chromatographic purification step, neither for intermediates of formula (VIIIa) or (IXa), nor for intermediates of formula (VIIa) or (VIIb).

• A microwave reactor is not used.

• The two new intermediates (VIIIa)/(VIIIb) and (IXa)/(IXb) are crystalline and can be easily isolated and purified by crystallization, in particular by using environmentally friendly solvents such as, for example, isopropanol and n-butanol.

• Shorter reaction time.

• Overall yield is significantly increased. If the best yields from each step are taken into account, the overall yield increases by approximately a factor of 2, resulting in approximately 49.0% theoretical yield for the new synthesis route, compared to 23.6% theoretical yield for the method described in WO 2016020320 A1.

• The purity of the compound of formula (I) is significantly increased, for example:

Residual palladium content is very low (< 10 ppm)

Residual boron content is very low (< 10 ppm)

• Residual solvents comply with regulatory requirements.

• The new process allows large-scale production of the polymorphic form B of the compound of formula (I).

The method according to the invention for producing a compound of formula (I)/(Ia) is characterized by at least one of the following steps:

1. Synthesis of a compound of formula (I) or (Ia) via an intermediate of formula (VIIa) or (VIIb) starting from an intermediate of formula (IXa) or (IXb).

2. Synthesis of an intermediate of formula (IXa) or (IXb) by reacting an intermediate of formula (VIIIa) or (VIIIb) with a compound of formula (VIa) or (VIb).

3. Synthesis of an intermediate of formula (VIIIa) or (VIIIb) starting from a compound of formula (II) or (IIa).

The method according to the invention for preparing a compound of formula (I) and the corresponding individual process steps are further characterized by new intermediates (IXa)/(IXb) (see section 4) and (VIIIa)/(VIIIb) (see section 5), and provide the compound of formula (I) with high purity (see section 6).

1. Synthesis of a compound of formula (I) or (Ia) via an intermediate of formula (VIIa) or (VIIb) starting from an intermediate of formula (IXa) or (IXb)

In accordance with one aspect, the present invention relates to a process for preparing a compound of formula (I)

or its tautomer of formula (Ia)

or mixtures thereof,

wherein said method comprises the following sequential steps: (a) reacting the intermediate of formula (IXa)

Where

R ¹ represents a chlorine, bromine or iodine atom or represents a group selected from [(trifluoromethyl)sulfonyl]oxy, [(nonafluorobutyl)sulfonyl]oxy, (methylsulfonyl)oxy, (p-toluenesulfonyl)oxy, (phenylsulfonyl)oxy, [(4-bromophenyl)sulfonyl]oxy, [(4-nitrophenyl)sulfonyl]oxy, [(2-nitrophenyl)sulfonyl]oxy, [(4-isopropylphenyl)sulfonyl]oxy, [(2,4,6-triisopropylphenyl) sulfonyl]oxy, [(2,4,6-trimethylphenyl)sulfonyl]oxy, [(4-tert-butylphenyl)sulfonyl]oxy and [(4-methoxyphenyl)sulfonyl]oxy;

with a compound of formula (IIIa) or (IIIb)

or a mixture thereof,

Where

R ² and R ³ represent, independently of each other, a hydrogen atom or a C ₁ -C ₆ alkyl group;

or

R ² and R ³ together represent a -CH ₂ -CH ₂ - group or -CH ₂ -CH ₂ -CH ₂ - group, wherein said -CH ₂ -CH ₂ - group or -CH ₂ -CH ₂ -CH ₂ - the group is optionally substituted one, two, three or four times with a group selected from methyl and ethyl;

or

R ² and R ³ together represent the group

where "*" represents the site of attachment to the rest of the molecule; And

R ⁴ represents a group selected from tetrahydro-2H-pyran-2-yl, 1-methyl-1-methoxyethyl, 1-methyl-1-phenoxyethyl, 1-methyl-1-benzyloxyethyl;

to obtain an intermediate of formula (VIIa) or (VIIb)

or mixtures thereof,

Where

R ⁴ represents a group selected from tetrahydro-2H-pyran-2-yl, 1-methyl-1-methoxyethyl, 1-methyl-1-phenoxyethyl, 1-methyl-1-benzyloxyethyl; And

(b) removing the R ⁴ group from the intermediate of formula (VIIa) or (VIIb), thereby providing a compound of formula (I), or a tautomer of formula (Ia), or a mixture thereof.

In another embodiment of the method according to the present invention, R ¹ of the compound of formula (IXa) is a chlorine or bromine atom, preferably a chlorine atom.

A compound of formula (IXa) wherein R ¹ is a chlorine atom is a preferred compound of formula (IXb):

In another embodiment of the method according to the present invention, R ¹ of the compound of formula (IXa) is a group selected from [(trifluoromethyl)sulfonyl]oxy, [(nonafluorobutyl)sulfonyl]oxy, (methylsulfonyl)oxy, (p-toluenesulfonyl)oxy , (phenylsulfonyl)oxy, [(4-bromophenyl)sulfonyl]oxy, [(4-nitrophenyl)sulfonyl]oxy, [(2-nitrophenyl)sulfonyl]oxy, [(4-isopropylphenyl)sulfonyl]oxy, [(2, 4,6-triisopropylphenyl)sulfonyl]oxy, [(2,4,6-trimethylphenyl)sulfonyl]oxy, [(4-tert-butylphenyl)sulfonyl]oxy and [(4-methoxyphenyl)sulfonyl]oxy.

In another embodiment of the method according to the present invention, R ¹ of the compound of formula (IXa) is a group selected from [(trifluoromethyl)sulfonyl]oxy, [(nonafluorobutyl)sulfonyl]oxy, (methylsulfonyl)oxy and (p-toluenesulfonyl)oxy .

In another embodiment of the present invention, R ² and R ³ of the compounds of formula (IIIa) or (IIIb) represent, independently of each other, a hydrogen atom or a C ₁ -C ₃ alkyl group, in particular a methyl or ethyl group.

In another embodiment of the present invention, R ² and R ³ compounds of formula (IIIa) or (IIIb) together represent a -CH ₂ -CH ₂ - group or -CH ₂ -CH ₂ -CH ₂ - group, wherein said -CH ₂ - The CH ₂ - group or -CH ₂ -CH ₂ -CH ₂ - group is optionally substituted one, two, three or four times with a group selected from methyl and ethyl.

If R ² and R ³ of the compounds of formula (IIIa) or (IIIb) together represent a -CH ₂ -CH ₂ - group or -CH ₂ -CH ₂ -CH ₂ - group specified -CH ₂ -CH ₂ - group or specified -CH ₂ -CH ₂ -CH ₂ - group, together with the boron atom and oxygen atoms to which the specified group is attached, forms a 5- or 6-membered ring.

In another embodiment of the present invention, R ² and R ³ compounds of formula (IIIa) or (IIIb) together represent the group

where "*" represents the site of attachment to the rest of the molecule.

In another embodiment of the present invention, R ² and R ³ of the compounds of formula (IIIa) or (IIIb) together are -C(CH ₃ ) ₂ -C(CH ₃ ) ₂ - or -CH ₂ -C(CH ₃ ) ₂ - CH ₂ - group.

In a preferred embodiment of the present invention, R ² and R ³ of the compounds of formula (IIIa) or (IIIb) together represent a -C(CH ₃ ) ₂ -C(CH ₃ ) ₂ group.

In a preferred embodiment of the present invention, the compound of formula (IIIa) is 1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-5-boronic acid pinacol ester (formula IIIc):

Compounds of formula (IIIa), (IIIb) or (IIIc) are commercially available or can be synthesized by methods known to one skilled in the art.

In another embodiment of the present invention, R ⁴ of the compound of formula (IIIa), (IIIb), (VIIa) or (VIIb) is a group selected from tetrahydro-2H-pyran-2-yl, 1-methyl-1-methoxyethyl, 1 -methyl-1-phenoxyethyl, 1-methyl-1-benzyloxyethyl.

In a preferred embodiment of the present invention, R ⁴ of the compound of formula (IIIa), (IIIb), (VIIa) or (VIIb) is a tetrahydro-2H-pyran-2-yl group.

In another preferred embodiment of the present invention, the intermediate of formula (VIIa) is a compound of formula (VIIc)

In another preferred embodiment of the present invention, the intermediate of formula (VIIa) is a compound of formula (VIId)

In another preferred embodiment of the present invention, the intermediate of formula (VIIa) is a mixture, in particular a 1:1 mixture, of compounds of formula (VIIc) and (VIId). Said 1:1 mixture is (3R)-3-methyl-4-(4-(1-methyl-1H-pyrazol-5-yl)-8-(1-(tetrahydro-2H-pyran-2-yl) -1H-pyrazol-5-yl)-1,7-naphthyridin-2-yl)morpholine, which is also referred to as the compound of formula (VIIc/VIId) hereinafter:

In another embodiment of the method according to the present invention, an intermediate of formula (IXa) is reacted with a compound of formula (IIIa).

In a preferred embodiment of the method according to the present invention, (R)-4-(8-chloro-4-(1-methyl-1H-pyrazol-5-yl)-1,7-naphthyridin-2-yl)-3- methylmorpholine (IXb) is reacted with 1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-5-boronic acid pinacol ester (IIIc).

In a preferred embodiment of the method according to the present invention, the compound of formula (IXa) is (R)-4-(8-chloro-4-(1-methyl-1H-pyrazol-5-yl)-1,7-naphthyridin- 2-yl)-3-methylmorpholine; and/or the compound of formula (IIIa) is 1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-5-boronic acid pinacol ester; and/or the compound of formula (VIIa) is (3R)-3-methyl-4-(4-(1-methyl-1H-pyrazol-5-yl)-8-(1-(tetrahydro-2H-pyran-2 -yl)-1H-pyrazol-5-yl)-1,7-naphthyridin-2-yl)morpholine.

In another embodiment of the method according to the present invention, the intermediate of formula (IXa) is reacted with 0.95-2.0 molar equivalents of a compound of formula (IIIa) or (IIIb), preferably with 1.0-1.7 molar equivalents of a compound of formula (IIIa) or (IIIb) , most preferably with 1.2-1.5 molar equivalents of a compound of formula (IIIa) or (IIIb).

In another embodiment of the method according to the present invention, the intermediate of formula (IXa) is reacted with 0.95-2.0 molar equivalents of 1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-boronic acid pinacol ester ( IIIc), preferably with 1.0-1.7 molar equivalents of 1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-boronic acid pinacol ester (IIIc), most preferably with 1.2-1.5 molar equivalents of pinacol ester 1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-5-boronic acid (IIIc).

In another embodiment of the method according to the present invention, (R)-4-(8-chloro-4-(1-methyl-1H-pyrazol-5-yl)-1,7-naphthyridin-2-yl)-3- methylmorpholine (IXb) is reacted with 0.95-2.0 molar equivalents of 1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-boronic acid ester (IIIc), preferably with 1.0-1.7 molar equivalents of pinacol ester 1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-boronic acid ester (IIIc), most preferably with 1.2-1.5 molar equivalents of 1-(tetrahydro-2H-pyran-2-yl) pinacol ester )-1H-pyrazole-5-boronic acid (IIIc).

In another embodiment of the method according to the present invention, a compound of formula (IIIa) or (IIIb), in particular 1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-5-boronic acid pinacol ester (IIIc ), dissolved in a solvent, e.g. isopropylacetate, ethyl acetate, 1,2-dimethoxyethane, dioxane, N,N-dimethylformamide (=DMF), 1,2-dimethoxyethane (=DME), tetrahydrofuran (=THF), 2-methyltetrahydrofuran (=2-Me-THF) or isopropanol.

In a preferred embodiment of the method according to the present invention, a compound of formula (IIIa) or (IIIb), in particular 1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-5-boronic acid pinacol ester (IIIc ), dissolved in isopropylacetate or ethyl acetate, most preferably ethyl acetate.

In another embodiment of the method according to the present invention, a compound of formula (IXa) or (IXb) is dissolved in a solvent, for example isopropyl acetate, ethyl acetate, 1,2-dimethoxyethane, dioxane, N,N-dimethylformamide (=DMF), 1, 2-dimethoxyethane (=DME), tetrahydrofuran (=THF), 2-methyltetrahydrofuran (=2-Me-THF) or isopropanol.

In a preferred embodiment of the method according to the present invention, a compound of formula (IXa) or (IXb), in particular (IXb), is dissolved in isopropyl acetate or ethyl acetate, most preferably ethyl acetate.

In another embodiment of the method according to the present invention, the reaction of an intermediate of formula (IXa), in particular (R)-4-(8-chloro-4-(1-methyl-1H-pyrazol-5-yl)-1, 7-naphthyridin-2-yl)-3-methylmorpholine, with a compound of formula (IIIa) or (IIIb), in particular with the pinacol ester 1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5 -boronic acid is carried out within 1-36 hours, in particular within 1.5-5 hours, preferably within 1.5-3 hours, most preferably within 100-140 minutes.

In another embodiment of the method according to the present invention, the reaction of an intermediate of formula (IXa), in particular (R)-4-(8-chloro-4-(1-methyl-1H-pyrazol-5-yl)-1, 7-naphthyridin-2-yl)-3-methylmorpholine, with a compound of formula (IIIa) or (IIIb), in particular with the pinacol ester 1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5 -boronic acid is carried out in the presence of a suitable catalyst system, such as, for example, a palladium catalyst.

In another embodiment of the method according to the present invention, the palladium catalyst is selected from the group consisting of [1,1'-bis(diphenylphosphino)ferrocene]palladium(II)dichloro, palladium(II) acetate, bis(triphenylphosphine)palladium(II) dichloride ), dichlorobis(tricyclohexylphosphine)palladium(II), (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2-aminoethyl)phenyl)]palladium(II) chloride , chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II), tetrakis(triphenylphosphine )palladium(0), bis(tri-tert-butylphosphine)palladium(0), bis[tris(2-methylphenyl)phosphine]palladium(0), tris(dibenzylideneacetone)dipalladium(0).

In a preferred embodiment of the process according to the present invention, the palladium catalyst is [1,1'-bis(diphenylphosphino)ferrocene]dichloro palladium(II).

In another embodiment of the method according to the present invention, the reaction of an intermediate of formula (IXa), in particular (R)-4-(8-chloro-4-(1-methyl-1H-pyrazol-5-yl)-1, 7-naphthyridin-2-yl)-3-methylmorpholine, with a compound of formula (IIIa) or (IIIb), in particular with the pinacol ester 1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5 -boronic acid is carried out in the presence of 0.001-0.1 molar equivalents, preferably 0.005-0.05 molar equivalents, most preferably 0.01-0.03 molar equivalents of palladium catalyst, preferably [1,1'-bis(diphenylphosphino)ferrocene]dichloro palladium(II).

In another embodiment of the method according to the present invention, the reaction of an intermediate of formula (IXa), in particular (R)-4-(8-chloro-4-(1-methyl-1H-pyrazol-5-yl)-1, 7-naphthyridin-2-yl)-3-methylmorpholine (IXb), with a compound of formula (IIIa) or (IIIb), in particular with the pinacol ester 1-(tetrahydro-2H-pyran-2-yl)-1H- pyrazole-5-boronic acid (IIIc) is carried out in an organic solvent, where the solvent includes isopropylacetate, ethyl acetate, 1,2-dimethoxyethane, 1,4-dioxane, dimethylformamide, tetrahydrofuran, 2-methyltetrahydrofuran, methanol, ethanol, 1-propanol, isopropanol, 1-butanol or 2-butanol; or wherein said reaction is carried out in a solvent mixture comprising one or more of said solvents and water.

In another embodiment of the method according to the present invention, the reaction of an intermediate of formula (IXa), in particular (R)-4-(8-chloro-4-(1-methyl-1H-pyrazol-5-yl)-1,7 -naphthyridin-2-yl)-3-methylmorpholine, with a compound of formula (IIIa) or (IIIb), in particular with pinacol ester 1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5- boronic acid is carried out in an organic solvent, where the solvent includes isopropyl acetate and ethyl acetate; or wherein said reaction is carried out in a solvent mixture comprising isopropyl acetate and water, or comprising ethyl acetate and water. Preferably the solvent mixture includes ethyl acetate and water.

In another embodiment of the method according to the present invention, in the case of the reaction of an intermediate compound of formula (IXa), in particular (R)-4-(8-chloro-4-(1-methyl-1H-pyrazol-5-yl)- 1,7-naphthyridin-2-yl)-3-methylmorpholine, with a compound of formula (IIIa) or (IIIb), in particular with the pinacol ester 1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole -5-boronic acid, per kg of compound of formula (IXa) 5-20 kg of organic solvent is used, preferably 6-15 kg of organic solvent, most preferably 7-11 kg of organic solvent. A preferred organic solvent includes isopropyl acetate or ethyl acetate, a preferred solvent mixture includes isopropyl acetate and water, or it includes ethyl acetate and water.

In another embodiment of the method according to the present invention, in the case of the reaction of an intermediate compound of formula (IXa), in particular (R)-4-(8-chloro-4-(1-methyl-1H-pyrazol-5-yl)- 1,7-naphthyridin-2-yl)-3-methylmorpholine (IXb), with a compound of formula (IIIa) or (IIIb), in particular with pinacol ester 1-(tetrahydro-2H-pyran-2-yl)- 1H-pyrazole-5-boronic acid (IIIc), per kg of compound of formula (IXa) or (IXb) use 5-20 kg of organic solvent and 1-5 kg of water, preferably 6-15 kg of organic solvent and 1-4 kg of water , most preferably 7-11 kg of organic solvent and 1.5-2.5 kg of water.

In another embodiment of the method according to the present invention, the reaction of an intermediate of formula (IXa), in particular (R)-4-(8-chloro-4-(1-methyl-1H-pyrazol-5-yl)-1,7 -naphthyridin-2-yl)-3-methylmorpholine (IXb), with a compound of formula (IIIa) or (IIIb), in particular with the pinacol ester 1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole -5-boronic acid (IIIc) is carried out in the presence of a base. Bases such as potassium phosphate, potassium carbonate, potassium bicarbonate, sodium phosphate, sodium carbonate, sodium bicarbonate, barium hydroxide, barium carbonate, cesium carbonate or lithium carbonate can be used. Potassium phosphate or sodium phosphate are preferred, with potassium phosphate being the most preferred.

In another embodiment of the method according to the present invention, the reaction of an intermediate of formula (IXa), in particular (R)-4-(8-chloro-4-(1-methyl-1H-pyrazol-5-yl)-1, 7-naphthyridin-2-yl)-3-methylmorpholine (IXb), with a compound of formula (IIIa) or (IIIb), in particular with the pinacol ester 1-(tetrahydro-2H-pyran-2-yl)-1H- pyrazole-5-boronic acid (IIIc) is carried out in the presence of 1-15 molar equivalents, preferably 2-11 molar equivalents, most preferably 3-10 molar equivalents of base.

In another embodiment of the method according to the present invention, the reaction of an intermediate of formula (IXa), in particular (R)-4-(8-chloro-4-(1-methyl-1H-pyrazol-5-yl)-1, 7-naphthyridin-2-yl)-3-methylmorpholine (IXb), with a compound of formula (IIIa) or (IIIb) is carried out in the presence of a palladium catalyst and/or base.

In another embodiment of the method according to the present invention, the reaction of an intermediate of formula (IXa), in particular (R)-4-(8-chloro-4-(1-methyl-1H-pyrazol-5-yl)-1, 7-naphthyridin-2-yl)-3-methylmorpholine (IXb), with a compound of formula (IIIa) or (IIIb), in particular with the pinacol ester 1-(tetrahydro-2H-pyran-2-yl)-1H- pyrazole-5-boronic acid (IIIc) is carried out at temperatures ranging from room temperature to the boiling point of the solvent.

In another embodiment of the method according to the present invention, the reaction of an intermediate of formula (IXa), in particular (R)-4-(8-chloro-4-(1-methyl-1H-pyrazol-5-yl)-1, 7-naphthyridin-2-yl)-3-methylmorpholine (IXb), with a compound of formula (IIIa) or (IIIb), in particular with the pinacol ester 1-(tetrahydro-2H-pyran-2-yl)-1H- pyrazole-5-boronic acid (IIIc) is carried out under pressure at temperatures above the boiling point.

In another embodiment of the method according to the present invention, the reaction of an intermediate of formula (IXa), in particular (R)-4-(8-chloro-4-(1-methyl-1H-pyrazol-5-yl)-1, 7-naphthyridin-2-yl)-3-methylmorpholine, with a compound of formula (IIIa) or (IIIb), in particular with the pinacol ester 1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5 -boronic acid, is carried out in isopropyl acetate or in isopropyl acetate and water at a temperature of 55-75°C, preferably at 60-70°C, most preferably at 65°C.

In another embodiment of the method according to the present invention, the reaction of an intermediate of formula (IXa), in particular (R)-4-(8-chloro-4-(1-methyl-1H-pyrazol-5-yl)-1, 7-naphthyridin-2-yl)-3-methylmorpholine, with a compound of formula (IIIa) or (IIIb), in particular with the pinacol ester 1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5 -boronic acid is carried out in ethyl acetate or in ethyl acetate and water at a temperature of 45-65°C, preferably at 50-60°C, most preferably at 55°C.

In particular, if the reaction of an intermediate of formula (IXa) is preferably (R)-4-(8-chloro-4-(1-methyl-1H-pyrazol-5-yl)-1,7-naphthyridin-2-yl) -3-methylmorpholine, with a compound of formula (IIIa) or (IIIb), preferably 1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-boronic acid pinacol ester, is carried out in a mixture of ethyl acetate and water , said ethyl acetate and said water are stirred, in particular stirred vigorously. Preferably, ethyl acetate and water are mixed under conditions that ensure sufficient mixing of the ethyl acetate and aqueous phases.

In a preferred embodiment of the method according to the present invention, the reaction of an intermediate of formula (IXa), in particular (R)-4-(8-chloro-4-(1-methyl-1H-pyrazol-5-yl)-1, 7-naphthyridin-2-yl)-3-methylmorpholine (IXb), with a compound of formula (IIIa) or (IIIb), in particular with the pinacol ester 1-(tetrahydro-2H-pyran-2-yl)-1H- pyrazole-5-boronic acid (IIIc) is carried out under an inert gas atmosphere, where the inert gas is nitrogen or argon, preferably nitrogen.

1.1 Further processing of the crude intermediate of formula (VIIa), (VIIb), (VIIc), (VIId) or (VIIc/VIId)

In another embodiment of the process according to the present invention, the intermediate of formula (VIIa) or (VIIb), which is obtained by reacting an intermediate of formula (IXa) with an intermediate of formula (IIIa) or (IIIb), is not isolated after said reaction (" the crude intermediate of formula (VIIa) or (VIIb)"hereinafter) and/or the intermediate of formula (VIIa) or (VIIb) is not purified.

In a preferred embodiment of the process according to the present invention, the intermediate of formula (VIIc/VIId), which is obtained by reacting an intermediate of formula (IXb) with an intermediate of formula (IIIc), is not isolated after said reaction (the "crude intermediate of formula (VIIc) /VIId)" hereinafter) and/or the intermediate of formula (VIIc/VIId) are not purified.

In another embodiment of the method according to the present invention, the intermediate of formula (VIIa) or (VIIb) is not isolated and/or purified before removing the R ⁴ group from the intermediate of formula (VIIa) or formula (VIIb). The crude intermediate of formula (VIIa) or (VIIb) is converted directly to the compound of formula (I) or its tautomer of formula (Ia) by removing the R ⁴ group from the compound of formula (VIIa) or (VIIb).

In a preferred embodiment of the process according to the present invention, the intermediate of formula (VIIc), (VIId) or (VIIc/VIId) is not isolated and/or purified before removing the R ⁴ group from the intermediate of formula (VIIc), (VIId) or (VIIc/VIId). The crude intermediate of formula (VIIc), (VIId) or (VIIc/VIId) is converted directly to the compound of formula (I) or its tautomer of formula (Ia) by removing the R ⁴ group from the compound of formula (VIIc), (VIId) or (VIIc/VIId).

In another embodiment of the method according to the present invention, the intermediate of formula (VIIa), (VIIb), (VIIc), (VIId) or (VIIc/VIId) is not isolated and/or purified before removing the R ⁴ group from the intermediate of formula (VIIa), (VIIb), (VIIc), (VIId) or (VIIc/VIId), and after reacting an intermediate of formula (IXa) or (IXb) with a compound of formula (IIIa), (IIIb) or (IIIc) and before removing the R ⁴ group from an intermediate of formula (VIIa), (VIIb), (VIIc), (VIId) or (VIIc/VIId), the solvent or solvent mixture of the said reaction is replaced by another solvent ("solvent X" hereinafter), wherein solvent X includes a solvent selected from dichloromethane, ethyl acetate, isopropyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran, toluene, chloroform or mixtures thereof; and, optionally,

a) solvent X is washed with an aqueous solution of a base selected from potassium hydroxide, potassium carbonate, potassium bicarbonate, potassium hydroxide, potassium tert-butoxide, sodium hydroxide, sodium phosphate, sodium carbonate, sodium hydroxide, sodium tert-butoxide, barium hydroxide, cesium carbonate , triethylamine; preferably solvent X is washed with potassium hydroxide; and, optionally,

b) solvent X is treated with an adsorbent; preferably the adsorbent is activated carbon; and optional

c) the adsorbent, in particular activated carbon, is filtered off;

to obtain a solution of a compound of formula (VIIa), (VIIb), (VIIc), (VIId) or (VIIc/VIId) in solvent X.

Suitable adsorbents such as, for example, activated carbon (= activated carbon), oxides such as Al, Mg, Th, Ti, Zr and B oxides and mixtures thereof, silicic acid, boric acid, silicates such as diatomaceous earth, kieselguhr and silica gel; Fuller's earth, phloridin, and clays such as bentonites, montmorillonites and acid-treated clays, resins, activated alumina or zeolites are known to one skilled in the art.

In another embodiment of the method according to the present invention, the intermediate of formula (VIIa), (VIIb), (VIIc), (VIId) or (VIIc/VIId) is not isolated and/or purified before removing the R ⁴ group from the intermediate of formula (VIIa), (VIIb), (VIIc), (VIId) or (VIIc/VIId), and after reacting an intermediate of formula (IXa) or (IXb) with a compound of formula (IIIa), (IIIb) or (IIIc) and before removing the R ⁴ group from an intermediate of formula (VIIa), (VIIb), (VIIc), (VIId) or (VIIc/VIId), a solvent or mixture of solvents of the said reaction, in particular ethyl acetate with/without water, or isopropyl acetate with/without water, replaced with another solvent, including dichloromethane; and, optionally,

a) the resulting dichloromethane solution is washed with an aqueous solution of a base selected from potassium hydroxide, potassium carbonate, potassium bicarbonate, potassium hydroxide, potassium tert-butoxide, sodium hydroxide, sodium phosphate, sodium carbonate, sodium hydroxide, sodium tert-butoxide, barium hydroxide , cesium carbonate, triethylamine; preferably the dichloromethane is washed with potassium hydroxide; and, optionally,

b) the resulting dichloromethane solution is treated with an adsorbent; preferably the adsorbent is activated carbon; and optional

c) the adsorbent, in particular activated carbon, is filtered off;

to obtain a solution of a compound of formula (VIIa), (VIIb), (VIIc), (VIId) or (VIIc/VIId) in dichloromethane.

In another embodiment of the process according to the present invention, the intermediate of formula (VIIc/VIId) is not isolated and/or purified before removing the R ⁴ group from the intermediate of formula (VIIc/VIId), and after the reaction of (R)-4-( 8-chloro-4-(1-methyl-1H-pyrazol-5-yl)-1,7-naphthyridin-2-yl)-3-methylmorpholine (IXb) with pinacol ester 1-(tetrahydro-2H-pyran- 2-yl)-1H-pyrazole-5-boronic acid (IIIc) and before removing the R ⁴ group from the intermediate compound of formula (VIIc/VIId), a solvent or mixture of solvents of the said reaction, in particular isopropyl acetate with/without water or ethyl acetate with/without water, replaced with another solvent, including dichloromethane; And,

a) the resulting dichloromethane solution is washed with an aqueous solution of a base selected from potassium hydroxide, potassium carbonate, potassium bicarbonate, potassium hydroxide, potassium tert-butoxide, sodium hydroxide, sodium phosphate, sodium carbonate, sodium hydroxide, sodium tert-butoxide, barium hydroxide , cesium carbonate, trimethylamine, preferably dichloromethane is washed with potassium hydroxide; and/or

b) the resulting dichloromethane solution is treated with an adsorbent; preferably the adsorbent is activated carbon; and the adsorbent is filtered;

to obtain a purified solution of the intermediate of formula (VIIc/VIId) in dichloromethane ("purified solution of the intermediate of formula (VIIc/VIId) in dichloromethane" hereinafter).

In another embodiment of the method according to the present invention, the intermediate of formula (VIIa), (VIIb), (VIIc), (VIId) or (VIIc/VIId) is not isolated and/or purified before removing the R ⁴ group from the intermediate of formula (VIIa), (VIIb), (VIIc), (VIId) or (VIIc/VIId), and after reacting an intermediate of formula (IXa) or (IXb) with a compound of formula (IIIa), (IIIb) or (IIIc) and before removing the R ⁴ group from an intermediate of formula (VIIa), (VIIb), (VIIc), (VIId) or (VIIc/VIId), a solvent for said reaction, in particular ethyl acetate with/without water or isopropyl acetate with/without water water, preferably ethyl acetate and water, is washed with water and/or treated with an adsorbent as defined above, in particular activated carbon, to obtain a purified solution of the intermediate of formula (VIIa), (VIIb), (VIIc), (VIId) or (VIIc/ VIId), in particular a purified solution in ethyl acetate or isopropyl acetate ("a purified solution of an intermediate of formula (VIIa), (VIIb), (VIIc), (VIId) or (VIIc/VIId) in ethyl acetate or isopropyl acetate" hereinafter).

In another embodiment of the process according to the present invention, the intermediate of formula (VIIc/VIId) is not isolated and/or purified before removing the R ⁴ group from the intermediate of formula (VIIc/VIId), and after reacting the intermediate of formula (IXb) with compound of formula (IIIc) and before removing the R ⁴ group from the intermediate compound of formula (VIIc/VIId), the solvent of said reaction, in particular ethyl acetate with/without water or isopropyl acetate with/without water, preferably ethyl acetate and water, is washed with water and /or treated with an adsorbent as defined above, in particular activated carbon, to obtain a purified solution of an intermediate of formula (VIIc/VIId) (“purified solution of an intermediate of formula (VIIc/VIId)”), in particular a solution of (VIIc/VIId) in ethyl acetate or isopropyl acetate ("a purified solution of the intermediate of formula (VIIc/VIId) in ethyl acetate or isopropyl acetate" hereinafter), preferably a solution of the intermediate of formula (VIIc/VIId) in ethyl acetate ("a purified solution of the intermediate of formula (VIIc/VIId)" in ethyl acetate" hereinafter).

1.2 Removal of the R ⁴ group from an intermediate of formula (VIIa), (VIIb), (VIIc), (VIId) or (VIIc/VIId) to obtain the crude compound of formula (I)

In another embodiment of the method according to the present invention, the R ⁴ group is removed from an intermediate of formula (VIIa) or formula (VIIb) by reacting the intermediate of formula (VIIa) or formula (VIIb) with an acid, such as, for example, an aqueous solution hydrochloric acid, aqueous solution of hydrochloric acid with methanol, hydrochloric acid with methanol, aqueous solution of hydrochloric acid with ethanol, hydrochloric acid with ethanol, aqueous solution of hydrochloric acid with 1-propanol, hydrochloric acid with 1-propanol, aqueous solution of hydrochloric acid with isopropanol, hydrochloric acid with isopropanol, aqueous hydrochloric acid with 1-butanol, hydrochloric acid with 1-butanol, aqueous hydrochloric acid with 2-butanol, hydrochloric acid with 2-butanol, aqueous sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid, trifluoroacetic acid or phosphoric acid, or mixtures of one or more of these acids (hydrochloric acid, aqueous sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid, trifluoroacetic acid and/or phosphoric acid) with one or more alcohols such as methanol, ethanol, 1-propanol, isopropanol, 1-butanol, 2-butanol. Preferably the acid comprises an aqueous solution of hydrochloric acid and methanol.

In another embodiment of the process according to the present invention, the R ⁴ group is removed from an intermediate of formula (VIIc), (VIId) or (VIIc/VIId) by reacting an intermediate of formula (VIIc), (VIId) or (VIIc/VIId) ), with acid as defined above.

0.7-10 molar equivalents of acid may be used, preferably 1-7.5 molar equivalents, most preferably 1.5-5 molar equivalents. An aqueous hydrochloric acid solution is preferred, in particular an aqueous hydrochloric acid-methanol solution or an aqueous hydrochloric acid-methanol solution with ethyl acetate.

In particular, when the R ⁴ group is removed according to the method of the present invention, the pH is less than 3 (pH<3), preferably less than 2 (pH<2), most preferably less than 1.5 (pH<1.5).

In another embodiment of the method according to the present invention, when removing an R ⁴ group from an intermediate of formula (VIIa), (VIIb), (VIIc), (VIId) or (VIIc/VIId) with an acid in a solvent, the solvent is protic or an aprotic solvent such as, for example, methanol, ethanol, propanol, butanol, dichloromethane, tetrahydrofuran (=THF), 2-methyltetrahydrofuran (=2-Me-THF), 1,4-dioxane, 1,2-dimethoxyethane, ethyl acetate, isopropyl acetate; or the solvent is a mixture of solvents, including the specified solvent(s) and optionally further including water. A preferred solvent includes dichloromethane, a preferred solvent mixture includes dichloromethane with methanol, or methanol with ethyl acetate, or methanol with ethyl acetate and water, or methanol with isopropyl acetate, or methanol with isopropyl acetate and water.

In another embodiment of the method according to the present invention, when removing an R ⁴ group from an intermediate of formula (VIIa), (VIIb), (VIIc), (VIId) or (VIIc/VIId), the acid is selected from the group consisting of hydrochloric acid, an aqueous solution of hydrochloric acid, an aqueous solution of hydrochloric acid with methanol, an aqueous solution of hydrochloric acid with isopropanol, an aqueous solution of hydrochloric acid with methanol and dichloromethane, and an aqueous solution of hydrochloric acid with methanol and ethyl acetate.

In a preferred embodiment of the process according to the present invention, when removing the R ⁴ group from an intermediate of formula (VIIc/VIId), the acid is an aqueous solution of hydrochloric acid and the solvent mixture comprises dichloromethane and methanol, in particular dichloromethane, methanol and water.

In a preferred embodiment of the process according to the present invention, when removing the R ⁴ group from an intermediate of formula (VIIc/VIId) in a purified solution in dichloromethane as defined above, the acid is an aqueous solution of hydrochloric acid and the solvent mixture includes dichloromethane, methanol and water .

When using an aqueous solution of hydrochloric acid with methanol and dichloromethane, 1-20 kg of 1 N is used per kg of compound of formula (VIIa), (VIIb), (VIIc), (VIId) or (VIIc/VIId). an aqueous solution of hydrochloric acid in 1-20 kg of methanol and 1-20 kg of dichloromethane. Preferably use 5-15 kg 1 N. an aqueous solution of hydrochloric acid in 2-15 kg of methanol and 2-15 kg of dichloromethane.

In a preferred embodiment of the process according to the present invention, when removing the R ⁴ group from an intermediate of formula (VIIc/VIId), the acid is an aqueous solution of hydrochloric acid and the solvent mixture includes methanol with ethyl acetate, or methanol with isopropyl acetate, preferably the solvent mixture includes methanol with ethyl acetate and water.

In a preferred embodiment of the process according to the present invention, when removing the R ⁴ group from an intermediate of formula (VIIc/VIId) in purified solution in ethyl acetate or isopropyl acetate as defined above, the acid is an aqueous solution of hydrochloric acid, in particular 1 N. an aqueous solution of hydrochloric acid, and the solvent mixture includes methanol with ethyl acetate with/without water, or methanol with isopropyl acetate with/without water, preferably the solvent mixture includes methanol with ethyl acetate and water.

The use of solvent mixtures including methanol is particularly preferred in order to prevent the formation of by-products such as, for example,

When using an aqueous solution of hydrochloric acid with methanol and ethyl acetate, 1-20 kg of 1 N is used per kg of compound of formula (VIIa), (VIIb), (VIIc), (VIId) or (VIIc/VIId). an aqueous solution of hydrochloric acid with 1-20 kg of methanol and 1-20 kg of ethyl acetate. Preferably use 5-15 kg 1 N. an aqueous solution of hydrochloric acid with 2-15 kg of methanol and 2-15 kg of ethyl acetate.

In another embodiment of the method according to the present invention, the reaction of an intermediate of formula (VIIa) or formula (VIIb), preferably a compound of formula (VIIc) or (VIId) or a mixture of compounds of formula (VIIc) and (VIId), with an acid is carried out at a temperature -10-40°C, preferably at 0-30°C, most preferably at 10-25°C. The reaction time is 2-60 minutes, preferably 2-30 minutes, most preferably 5-20 minutes.

In another embodiment of the method according to the present invention, the reaction of removing the R ⁴ group from an intermediate compound of formula (VIIa), (VIIb), (VIIc), (VIId) or (VIIc/VIId) with an acid is carried out under an inert gas atmosphere, where the inert gas is nitrogen or argon, preferably nitrogen.

Immediately after completion of the reaction of the intermediate of formula (VIIa), (VIIb), (VIIc), (VIId) or (VIIc/VIId) with an acid, the crude compound of formula (I) is obtained ("crude compound of formula (I)" hereinafter).

After removing the R ⁴ group from the intermediate compound of formula (VIIc/VIId) using an aqueous solution of hydrochloric acid in a solvent mixture comprising dichloromethane, methanol and water, the crude compound of formula (I) is dissolved in an acidified aqueous phase (hereinafter "acidified aqueous solution of crude compounds of formula (I)"), wherein the pH of the resulting acidified aqueous solution is less than 3 (pH<3), preferably less than 2 (pH<2), most preferably less than 1.5 (pH<1.5).

The crude compound of formula (I) can be further processed (section 1.3) and/or crystallized (section 1.4).

1.3 Further processing of the crude compound of formula (I)

In another embodiment of the method according to the present invention for preparing a compound of formula (I),

a) an acidified aqueous solution of the crude compound of formula (I) described above is extracted one or more times with solvent A defined below and/or treated one or more times with a Pd scavenger defined below;

b) the acidified aqueous solution of the crude compound of formula (I) obtained in the previous step a) is treated with solvent A and an aqueous solution of the base defined below to obtain a two-phase system, wherein the aqueous phase of said two-phase system has a pH>12;

c) the aqueous phase is separated from said two-phase system to obtain a solution of the crude compound of formula (I) in solvent A; and, optionally,

d) replacing solvent A of the solution of the crude compound of formula (I) in solvent A with solvent B, as defined below, to obtain a solution of the crude compound of formula (I) in solvent B.

In a preferred embodiment of the process according to the present invention for preparing a compound of formula (I),

a) an acidified aqueous solution of the crude compound of formula (I) described above is extracted one or more times with dichloromethane and/or treated one or more times with a Pd scavenger defined below;

b) the acidified aqueous solution of the crude compound of formula (I) obtained in the previous step a) is treated with dichloromethane and an aqueous solution of potassium hydroxide, in particular 5 N. an aqueous solution of potassium hydroxide to obtain a two-phase system, wherein the aqueous phase of said two-phase system has a pH>12;

c) the aqueous phase is separated from said two-phase system to obtain a solution of the crude compound of formula (I) in dichloromethane; and, optionally,

d) replacing the dichloromethane solution of the crude compound of formula (I) in dichloromethane with n-butanol to obtain a solution of the crude compound of formula (I) in n-butanol.

In another embodiment of the method according to the present invention for preparing a compound of formula (I), the crude compound of formula (I) is dissolved in a solvent ("solvent A" hereinafter), wherein solvent A includes a solvent selected from dichloromethane, ethyl acetate, isopropyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran, toluene, chloroform; or in a solvent mixture comprising one or more of said solvents A (“solvent mixture A”); the preferred solvent A is dichloromethane.

Preferably, solvent A comprises the same solvent or the same mixture of solvents as the solvent/mixture of solvents that was used to remove the R ⁴ group from the intermediate of formula (VIIa), (VIIb), (VIIc), (VIId) or (VIIc/VIId).

In another embodiment of the method according to the present invention for preparing a compound of formula (I), the crude compound of formula (I) is dissolved in dichloromethane.

In another embodiment of the method according to the present invention for preparing a compound of formula (I), the crude compound of formula (I), dissolved in solvent A, is treated with an aqueous solution of a base selected from potassium hydroxide, potassium carbonate, potassium hydrogen carbonate, potassium hydroxide, tert-butoxide potassium, sodium hydroxide, sodium phosphate, sodium carbonate, sodium hydroxide, sodium tert-butoxide, barium hydroxide, cesium carbonate, triethylamine; preferably the dichloromethane is washed with potassium hydroxide. Preferably, the crude compound of formula (I), dissolved in solvent A, in particular dichloromethane, is treated with potassium hydroxide.

In particular, when treating the crude compound of formula (I) dissolved in solvent A, in particular dichloromethane, with an aqueous solution of the base defined above, the pH is greater than 11 (pH>11), preferably greater than 12 (pH>12) , most preferably pH=12-14, in particular pH=12.5-13.5.

In another embodiment of the method according to the present invention for preparing a compound of formula (I), the crude compound of formula (I), dissolved in solvent A, preferably dissolved in dichloromethane, is treated with a palladium scavenger defined below.

In another embodiment of the method according to the present invention for preparing a compound of formula (I), the crude compound of formula (I), dissolved in solvent A, preferably dissolved in dichloromethane, is treated with an aqueous solution of the base defined above, and then treated with a palladium scavenger defined below.

In another embodiment of the method according to the present invention for preparing a compound of formula (I), the crude compound of formula (I), dissolved in solvent A, preferably dissolved in dichloromethane, is treated with a palladium scavenger defined below, and then treated with an aqueous solution of a base defined above.

A palladium scavenger is a reagent that can be used to separate palladium from a palladium catalyst from the crude compound of formula (I). Various palladium scavengers, for example, are further described by Garret and Prasad (Advanced Synthesis & Catalysis (2004), 346 (8), 889-900CODEN: ASCAF7; ISSN: 1615-4150, Wiley-VCH Verlag GmbH & Co. KGaA). These include, for example, trimercaptotriazine (TMT), polystyrene-linked TMT, MP-TMT (highly cross-linked macroporous polystyrene-linked trimercaptotriazine resin), polystyrene-linked ethylenediamine, activated carbon, glass bead sponges, smopex (= fiber-based polyethylene or cellulose containing grafted side chains with appropriate functional groups to form a complex with metals), polymer-linked ligands and silica gel-linked ligands.

In one embodiment of the present invention, the palladium scavenger is selected from the group consisting of N-acetylcysteine, quadrasyl mercaptopropyl (CAS number 1225327-73-0) and Si-TMT isolute (Pd scavenger from Biotage AB, Sweden, catalog no. 9538- 1000) - a silica gel-bound equivalent of 2,4,6-trimercaptotriazine, or a mixture thereof.

In another embodiment of the present invention, the palladium scavenger comprises a mixture of N-acetylcysteine with quadrasyl-mercaptopropyl, N-acetylcysteine with Si-TMT isolute, or Si-TMT isolute with quadrasyl-mercaptopropyl.

The most preferred palladium scavenger includes a mixture of N-acetylcysteine, quadrasyl mercaptopropyl and Si-TMT isolute.

In another embodiment of the method according to the present invention for producing a compound of formula (I), solvent A as defined above is replaced by a solvent ("solvent B" hereinafter) selected from ethanol, n-propanol, n-butanol, 2-butanol, isopropanol, preferably solvent A is replaced with n-butanol.

In another embodiment of the method according to the present invention for producing a compound of formula (I), dichloromethane (solvent A) is replaced by n-butanol (solvent B).

In another embodiment of the method according to the present invention for producing a compound of formula (I), solvent A is replaced by solvent B after treating solvent A with a Pd scavenger, and/or after treating solvent A with an aqueous base solution.

In another embodiment of the method according to the present invention for producing a compound of formula (I), dichloromethane is replaced by n-butanol after treating the dichloromethane with a Pd scavenger and/or after treating the dichloromethane with an aqueous base solution.

In another embodiment of the method according to the present invention for producing a compound of formula (I), solvent A is replaced by solvent B after treating solvent A with a Pd scavenger and/or after treating solvent A with an aqueous base solution; and solvent B is then treated with a Pd scavenger.

In another embodiment of the method according to the present invention for preparing a compound of formula (I), dichloromethane is replaced by n-butanol after treating the dichloromethane with a Pd scavenger and/or after treating the dichloromethane with an aqueous base solution; and n-butanol is then treated with a Pd scavenger.

In another embodiment of the method according to the present invention for producing a compound of formula (I), solvent A is replaced by solvent B before treating solvent A with a Pd scavenger, and solvent B is then treated with a Pd scavenger.

In another embodiment of the method according to the present invention for producing a compound of formula (I), dichloromethane is replaced by n-butanol before treating the dichloromethane with a Pd scavenger, and the n-butanol is then treated with a Pd scavenger.

1.4 Crystallization of the crude compound of formula (I) to obtain its polymorphic form B

The crystallization step provides the polymorphic form B of the compound of formula (I) (=Mod B) by a reproducible and reliable method, which can be characterized, firstly, by the replacement of a solvent, namely solvent A with solvent B, and, secondly, a subsequent crystallization step .

1.4.1 Replacing solvent

In another embodiment of the method according to the present invention for preparing a compound of formula (I), the crude compound of formula (I), dissolved in solvent A, preferably dichloromethane, is crystallized in solvent B to obtain polymorphic form B of the compound of formula (I).

In order to crystallize a compound of formula (I) into its polymorph form B, solvent A must first be replaced by solvent B ("solvent exchange"). Therefore, in another embodiment of the process according to the present invention for preparing a compound of formula (I), solvent A, preferably dichloromethane, is replaced by solvent B, preferably n-butanol.

In another embodiment of the method according to the present invention for preparing a compound of formula (I), solvent A, preferably dichloromethane, is replaced by solvent B, preferably n-butanol, by firstly mixing solvent A and solvent B; and secondly, distilling off solvent A under normal pressure or under reduced pressure.

In another embodiment of the method according to the present invention for producing a compound of formula (I), solvent A is replaced by solvent B by firstly mixing solvent A and solvent B to form an azeotrope; and secondly, separating solvent A from solvent B by conventional methods known to one skilled in the art to obtain “a compound of formula (I) dissolved in solvent B.”

In another embodiment, a "compound of formula (I) dissolved in solvent B" is heated to produce a "compound of formula (I) dissolved in heated solvent B". In particular, solvent B is heated to a temperature of at least 40°C, preferably to a temperature of 60-120°C, preferably to a temperature of 90-110°C to obtain a “compound of formula (I) dissolved in heated solvent B”.

In another embodiment of the method according to the present invention for preparing a compound of formula (I), dichloromethane (solvent A) is replaced by n-butanol (solvent B) by first mixing dichloromethane and n-butanol; and, secondly, distilling off solvent A.

In order to distill off dichloromethane, a mixture of dichloromethane and n-butanol is heated to a temperature of at least 60°C, in particular to a temperature of 60-120°C, preferably to a temperature of 90-110°C to obtain the “compound of formula (I) , dissolved in heated n-butanol."

1.4.2 Crystallization of polymorphic form B of the compound of formula (I)

To obtain polymorph Form B of the compound of formula (I), the compound of formula (I), dissolved in solvent B, in particular heated solvent B, preferably heated n-butanol, is cooled.

The X-ray powder diffraction pattern of the Form B polymorph of compound (I) is shown in Figure 1.

In another embodiment of the present invention, after heating a mixture of solvent A and solvent B, and after replacing solvent A, preferably dichloromethane, with heated solvent B, preferably heated n-butanol, heated solvent B, preferably heated n-butanol, is cooled to 0-30 °C.

In particular, the expression "after replacing solvent A, preferably dichloromethane, with solvent B, preferably n-butanol" means that no solvent A, preferably dichloromethane, remains when solvent B, preferably n-butanol, is cooled.

In another embodiment of the present invention, after replacing solvent A, preferably dichloromethane, with solvent B, preferably n-butanol, solvent B is heated to a temperature of at least 60°C, in particular to a temperature of 60-120°C, preferably to a temperature 90-110°C, and then cooled to 0-30°C.

Preferably, solvent B is cooled to 15-30°C, preferably 20-30°C in a first step, and then further cooled to 0-5°C, preferably 2-4°C, in a second step.

In another embodiment of the method according to the present invention for preparing a compound of formula (I), solvent B is cooled to 0-30°C, preferably 20-30°C, over 2-36 hours, in particular within 3-24 hours , preferably within 4-12 hours, most preferably within 6-10 hours.

Preferably, solvent B is firstly cooled from a temperature of 60-120°C within 2-36 hours, in particular within 3-24 hours, preferably within 4-12 hours, most preferably within 6-10 hours , preferably from a temperature of 90-110°C, to a temperature of 15-30°C, preferably to a temperature of 20-30°C, and secondly, solvent B is then further cooled to a temperature of 0-5°C, preferably to a temperature of 2 -4°C, and the temperature is kept constant for at least 0.5 hours, in particular for 0.5-12 hours, preferably for 1-8 hours.

Preferably solvent B,

a) firstly, within 2-36 hours, in particular within 3-24 hours, preferably within 4-12 hours, most preferably within 6-10 hours, cool to a temperature of 15-30°C, preferably up to a temperature of 20-30°C; And

b) secondly, the temperature of solvent B is maintained constant for at least 0.5 hours, in particular for 1-12 hours, preferably for 1-8 hours, most preferably for 1-2 hours; And

c) thirdly, solvent B for 2-36 hours, in particular for 3-24 hours, preferably for 4-12 hours, most preferably for 6-10 hours, then cooled to a temperature of 0-5° C, preferably up to a temperature of 2-4 ° C; And

d) fourthly, the temperature of solvent B is kept constant for at least 0.5 hours, in particular for 0.5-12 hours, preferably for 0.5-8 hours, most preferably for 0.5-2 hours.

In another embodiment, for example, to improve the filtration properties of the suspension, after cooling solvent B, in particular cooling to the temperatures defined above, solvent B is heated again to a temperature of at least 40°C, preferably to a temperature of 60-120°C, preferably to a temperature of 90-110°C, for example to a temperature of 60-100°C, in particular over a period of 0.5-10 hours, preferably within 1-4 hours, and then cooled again to a temperature of 0-30°C, preferably to a temperature of 20-30°C, within 2-36 hours, in particular within 3-24 hours, preferably within 4-12 hours, most preferably within 6-10 hours.

Crystallization of the compound of formula (I) in solvent B, preferably n-butanol, is carried out using 2-10 kg, preferably 3-6 kg, most preferably 3.5-5 kg of solvent B, preferably n-butanol, per kg of compound of formula (I). .

After cooling solvent B, in particular in accordance with the cooling procedure described above, polymorphic form B of the compound of formula (I) is obtained in crystalline form.

In another embodiment of the method according to the present invention, crystals of the polymorphic form B of the compound of formula (I) are isolated, in particular they are isolated by filtration.

In another embodiment of the method according to the present invention, the isolated crystals of polymorph B of the compound of formula (I) can be further purified by dissolving the isolated crystals of polymorph B of the compound of formula (I) in solvent A, preferably dichloromethane, and repeating one or more times in particular once, by replacing the solvent described in section 1.4.1, and/or by repeating one or more times, in particular once, the crystallization of polymorphic form B of the compound of formula (I) described in section 1.4.2.

The isolated polymorph form B of the compound of formula (I) can be further purified, in particular it can be washed with 1-10 kg, in particular 1-7 kg, preferably 1-3 kg, n-butanol, based on kg polymorphic form In the compounds of formula (I), preferably with chilled n-butanol having a temperature of -5-10°C, preferably -3°-5°C.

Polymorph Form B of the compound of formula (I) can be dried at a temperature of 35-75°C, preferably at a temperature of 50-75°C, most preferably at a temperature of 40-60°C.

Polymorph Form B of the compound of formula (I) can be dried in vacuum at 20-100 mbar, preferably at 30-50 mbar, and in vacuum at 20-100 mbar, preferably at 30-50 mbar, and at temperatures of 35-75°C, preferably in vacuum at 20-100 mbar, preferably at 30-50 mbar, and at temperatures of 50-75°C, most preferably in vacuum at 20-100 mbar, preferably at 30-50 mbar, and at temperatures 40-60°C .

The crystallization process for obtaining polymorph Form B of the compound of formula (I) is very effective in ensuring the purity of the compound of formula (I).

2. Synthesis of an intermediate of formula (IXa) or (IXb) by reacting an intermediate of formula (VIIIa) or (VIIIb) with a compound of formula (VIa) or (VIb)

According to another aspect, the present invention provides a process for preparing a compound of formula (IXa) or (IXb), comprising the step of reacting an intermediate of formula (VIIIa)

Where

R ¹ represents a chlorine, bromine or iodine atom or represents a group selected from [(trifluoromethyl)sulfonyl]oxy, [(nonafluorobutyl)sulfonyl]oxy, (methylsulfonyl)oxy, (p-toluenesulfonyl)oxy, (phenylsulfonyl)oxy, [(4-bromophenyl)sulfonyl]oxy, [(4-nitrophenyl)sulfonyl]oxy, [(2-nitrophenyl)sulfonyl]oxy, [(4-isopropylphenyl)sulfonyl]oxy, [(2,4,6-triisopropylphenyl) sulfonyl]oxy, [(2,4,6-trimethylphenyl)sulfonyl]oxy, [(4-tert-butylphenyl)sulfonyl]oxy and [(4-methoxyphenyl)sulfonyl]oxy; And

R ⁵ represents a chlorine, bromine or iodine atom or represents a group selected from [(trifluoromethyl)sulfonyl]oxy, [(nonafluorobutyl)sulfonyl]oxy, (methylsulfonyl)oxy, (p-toluenesulfonyl)oxy, (phenylsulfonyl)oxy, [(4-bromophenyl)sulfonyl]oxy, [(4-nitrophenyl)sulfonyl]oxy, [(2-nitrophenyl)sulfonyl]oxy, [(4-isopropylphenyl)sulfonyl]oxy, [(2,4,6-triisopropylphenyl) sulfonyl]oxy, [(2,4,6-trimethylphenyl)sulfonyl]oxy, [(4-tert-butylphenyl)sulfonyl]oxy and [(4-methoxyphenyl)sulfonyl]oxy;

with a compound of formula (VIa)

Where

R ² and R ³ represent, independently of each other, a hydrogen atom or a C ₁ -C ₆ alkyl group;

or

R ² and R ³ together represent a -CH ₂ -CH ₂ - group or -CH ₂ -CH ₂ -CH _{2 -} group, wherein said -CH ₂ -CH ₂ - group or -CH ₂ -CH ₂ -CH ₂ - the group is optionally substituted one, two, three or four times with a group selected from methyl and ethyl;

or

R ² and R ³ together represent the group

where "*" represents the site of attachment to the rest of the molecule;

to obtain intermediate compound of formula (IXa)

where R ¹ represents a chlorine, bromine or iodine atom or represents a group selected from [(trifluoromethyl)sulfonyl]oxy, [(nonafluorobutyl)sulfonyl]oxy, (methylsulfonyl)oxy, (p-toluenesulfonyl)oxy, (phenylsulfonyl)oxy , [(4-bromophenyl)sulfonyl]oxy, [(4-nitrophenyl)sulfonyl]oxy, [(2-nitrophenyl)sulfonyl]oxy, [(4-isopropylphenyl)sulfonyl]oxy, [(2,4,6-triisopropylphenyl )sulfonyl]oxy, [(2,4,6-trimethylphenyl)sulfonyl]oxy, [(4-tert-butylphenyl)sulfonyl]oxy and [(4-methoxyphenyl)sulfonyl]oxy.

In another embodiment of the method according to the present invention for producing a compound of formula (I), the method further comprises (before reacting an intermediate of formula (IXa) or (IXb) with a compound of formula (IIIa), (IIIb) or (IIIc)) the following step:

(a) carrying out the reaction of the intermediate compound of formula (VIIIa)

Where

R ¹ represents a chlorine, bromine or iodine atom or represents a group selected from [(trifluoromethyl)sulfonyl]oxy, [(nonafluorobutyl)sulfonyl]oxy, (methylsulfonyl)oxy, (p-toluenesulfonyl)oxy, (phenylsulfonyl)oxy, [(4-bromophenyl)sulfonyl]oxy, [(4-nitrophenyl)sulfonyl]oxy, [(2-nitrophenyl)sulfonyl]oxy, [(4-isopropylphenyl)sulfonyl]oxy, [(2,4,6-triisopropylphenyl) sulfonyl]oxy, [(2,4,6-trimethylphenyl)sulfonyl]oxy, [(4-tert-butylphenyl)sulfonyl]oxy and [(4-methoxyphenyl)sulfonyl]oxy; And

R ⁵ represents a chlorine, bromine or iodine atom or represents a group selected from [(trifluoromethyl)sulfonyl]oxy, [(nonafluorobutyl)sulfonyl]oxy, (methylsulfonyl)oxy, (p-toluenesulfonyl)oxy, (phenylsulfonyl)oxy, [(4-bromophenyl)sulfonyl]oxy, [(4-nitrophenyl)sulfonyl]oxy, [(2-nitrophenyl)sulfonyl]oxy, [(4-isopropylphenyl)sulfonyl]oxy, [(2,4,6-triisopropylphenyl) sulfonyl]oxy, [(2,4,6-trimethylphenyl)sulfonyl]oxy, [(4-tert-butylphenyl)sulfonyl]oxy and [(4-methoxyphenyl)sulfonyl]oxy;

with a compound of formula (VIa)

Where

R ² and R ³ represent, independently of each other, a hydrogen atom or a C ₁ -C ₆ alkyl group;

or

R ² and R ³ together represent a -CH ₂ -CH ₂ - group or -CH ₂ -CH ₂ -CH _{2 -} group, wherein said -CH ₂ -CH ₂ - group or -CH ₂ -CH ₂ -CH ₂ - the group is optionally substituted one, two, three or four times with a group selected from methyl and ethyl;

or

R ² and R ³ together represent the group

where "*" represents the site of attachment to the rest of the molecule;

to obtain intermediate compound of formula (IXa)

where R ¹ represents a chlorine, bromine or iodine atom or represents a group selected from [(trifluoromethyl)sulfonyl]oxy, [(nonafluorobutyl)sulfonyl]oxy, (methylsulfonyl)oxy, (p-toluenesulfonyl)oxy, (phenylsulfonyl)oxy , [(4-bromophenyl)sulfonyl]oxy, [(4-nitrophenyl)sulfonyl]oxy, [(2-nitrophenyl)sulfonyl]oxy, [(4-isopropylphenyl)sulfonyl]oxy, [(2,4,6-triisopropylphenyl )sulfonyl]oxy, [(2,4,6-trimethylphenyl)sulfonyl]oxy, [(4-tert-butylphenyl)sulfonyl]oxy and [(4-methoxyphenyl)sulfonyl]oxy.

In another embodiment of the method according to the present invention, R ¹ of the compound of formula (VIIIa) is a chlorine or bromine atom, preferably a chlorine atom.

In another embodiment of the method according to the present invention, R ¹ of the compound of formula (IXa) is a group selected from [(trifluoromethyl)sulfonyl]oxy, [(nonafluorobutyl)sulfonyl]oxy, (methylsulfonyl)oxy, (p-toluenesulfonyl)oxy , (phenylsulfonyl)oxy, [(4-bromophenyl)sulfonyl]oxy, [(4-nitrophenyl)sulfonyl]oxy, [(2-nitrophenyl)sulfonyl]oxy, [(4-isopropylphenyl)sulfonyl]oxy, [(2, 4,6-triisopropylphenyl)sulfonyl]oxy, [(2,4,6-trimethylphenyl)sulfonyl]oxy, [(4-tert-butylphenyl)sulfonyl]oxy and [(4-methoxyphenyl)sulfonyl]oxy.

In another embodiment of the method according to the present invention, R ¹ of the compound of formula (VIIIa) is a group selected from [(trifluoromethyl)sulfonyl]oxy, [(nonafluorobutyl)sulfonyl]oxy, (methylsulfonyl)oxy and (p-toluenesulfonyl)oxy .

In another embodiment of the method according to the present invention, R ⁵ of the compound of formula (VIIIa) represents a chlorine, bromine or iodine atom.

In another embodiment of the method according to the present invention, R ⁵ of the compound of formula (IXa) is a group selected from [(trifluoromethyl)sulfonyl]oxy, [(nonafluorobutyl)sulfonyl]oxy, (methylsulfonyl)oxy, (p-toluenesulfonyl)oxy , (phenylsulfonyl)oxy, [(4-bromophenyl)sulfonyl]oxy, [(4-nitrophenyl)sulfonyl]oxy, [(2-nitrophenyl)sulfonyl]oxy, [(4-isopropylphenyl)sulfonyl]oxy, [(2, 4,6-triisopropylphenyl)sulfonyl]oxy, [(2,4,6-trimethylphenyl)sulfonyl]oxy, [(4-tert-butylphenyl)sulfonyl]oxy and [(4-methoxyphenyl)sulfonyl]oxy.

In a preferred embodiment of the method according to the present invention, R ⁵ of the compound of formula (VIIIa) is a [(trifluoromethyl)sulfonyl]oxy group.

In another embodiment of the method according to the present invention, R ¹ of the compound of formula (VIIIa) is a chlorine or bromine atom, preferably a chlorine atom, and R ⁵ is a group selected from [(trifluoromethyl)sulfonyl]oxy, [(nonafluorobutyl)sulfonyl ]oxy, (methylsulfonyl)oxy, (p-toluenesulfonyl)oxy, (phenylsulfonyl)oxy, [(4-bromophenyl)sulfonyl]oxy, [(4-nitrophenyl)sulfonyl]oxy, [(2-nitrophenyl)sulfonyl]oxy, [(4-isopropylphenyl)sulfonyl]oxy, [(2,4,6-triisopropylphenyl)sulfonyl]oxy, [(2,4,6-trimethylphenyl)sulfonyl]oxy, [(4-tert-butylphenyl)sulfonyl]oxy and [(4-methoxyphenyl)sulfonyl]oxy, preferably [(trifluoromethyl)sulfonyl]oxy groups.

The compound of formula (VIIIa), where R ¹ represents a chlorine atom and where R ⁵ represents a [(trifluoromethyl)sulfonyl]oxy group, is (R)-8-chloro-2-(3-methylmorpholino)-1,7- naphthyridin-4-yl trifluoromethanesulfonate, which is the preferred compound of formula (VIIIb):

In another embodiment of the present invention, R ² and R ³ of the compounds of formula (VIa) represent, independently of each other, a hydrogen atom or a C ₁ -C ₃ alkyl group, in particular a methyl or ethyl group.

In another embodiment of the present invention, R ² and R ³ compounds of formula (VIa) together represent a -CH ₂ -CH ₂ - group or -CH ₂ -CH ₂ -CH ₂ - group, wherein said -CH ₂ -CH ₂ - group or -CH ₂ -CH ₂ -CH ₂ - the group is optionally substituted one, two, three or four times with a group selected from methyl and ethyl.

If R ² and R ³ of the compounds of formula (VIa) together represent a -CH ₂ -CH ₂ - group or -CH ₂ -CH ₂ -CH ₂ - group indicated by -CH ₂ -CH ₂ - group or indicated -CH ₂ - CH ₂ -CH ₂ - the group, together with the boron atom and oxygen atoms to which this group is attached, forms a 5- or 6-membered ring.

In another embodiment of the present invention, R ² and R ³ of the compounds of formula (VIa) together represent the group

where "*" represents the site of attachment to the rest of the molecule.

In another embodiment of the present invention, R ² and R ³ compounds of formula (VIa) together represent a -C(CH ₃ ) ₂ -C(CH ₃ ) ₂ - or -CH ₂ -C(CH ₃ ) ₂ -CH ₂ group .

In a preferred embodiment of the present invention, R ² and R ³ of the compounds of formula (VIa) together represent a -C(CH ₃ ) ₂ -C(CH ₃ ) ₂ group.

In another embodiment of the present invention, the compound of formula (VIa) is 1-methyl-1H-pyrazole-5-boronic acid.

In a preferred embodiment of the present invention, the compound of formula (VIa) is 1-methyl-1H-pyrazole-5-boronic acid pinacol ester (formula VIb):

Compounds of formula (VIa) or (VIb) are commercially available or can be synthesized by methods known to one skilled in the art.

In a preferred embodiment of the present invention, the compound of formula (VIIIa) is (R)-8-chloro-2-(3-methylmorpholino)-1,7-naphthyridin-4-yl trifluoromethanesulfonate (VIIIb) and the compound of formula (VIa) is 1-methyl-1H-pyrazole-5-boronic acid pinacol ester (VIb).

In another embodiment of the process according to the present invention, an intermediate of formula (VIIIa) is reacted with 0.7-2.0 molar equivalents of a compound of formula (VIa), preferably with 0.8-1.5 molar equivalents of a compound of formula (VIa), most preferably with 0.9-1.2 molar equivalents of a compound of formula (VIa).

In another embodiment of the process according to the present invention, the intermediate of formula (VIIIb) is reacted with 0.7-2.0 molar equivalents of a compound of formula (VIb), preferably with 0.8-1.5 molar equivalents of a compound of formula (VIb), most preferably with 0.9-1.2 molar equivalents of a compound of formula (VIb).

In another embodiment of the method according to the present invention, a compound of formula (VIa) or (VIb), in particular 1-methyl-1H-pyrazole-5-boronic acid pinacol ester (VIb), is dissolved in a solvent, for example isopropyl acetate , ethyl acetate, 1,2-dimethoxyethane, dioxane, N,N-dimethylformamide (=DMF), 1,2-dimethoxyethane (=DME), tetrahydrofuran (=THF), 2-methyltetrahydrofuran (=2-Me-THF) or isopropanol .

In a preferred embodiment of the method according to the present invention, a compound of formula (VIa) or (VIb), in particular 1-methyl-1H-pyrazole-5-boronic acid pinacol ester (VIb), is dissolved in isopropyl acetate or ethyl acetate, most preferably in ethyl acetate.

In another embodiment of the method according to the present invention, a compound of formula (VIIIa) or (VIIIb) is dissolved in a solvent, for example isopropyl acetate, ethyl acetate, 1,2-dimethoxyethane, dioxane, N,N-dimethylformamide (=DMF), 1, 2-dimethoxyethane (=DME), tetrahydrofuran (=THF), 2-methyltetrahydrofuran (=2-Me-THF) or isopropanol.

In a preferred embodiment of the method according to the present invention, a compound of formula (VIIIa) or (VIIIb), in particular (VIIIa), is dissolved in isopropyl acetate or ethyl acetate, most preferably ethyl acetate.

In another embodiment of the method according to the present invention, the reaction of an intermediate of formula (VIIIa) or (VIIIb), in particular (R)-8-chloro-2-(3-methylmorpholino)-1,7-naphthyridin-4-yl trifluoromethanesulfonate (VIIIb), with a compound of formula (VIa) or (VIb), in particular 1-methyl-1H-pyrazole-5-boronic acid pinacol ester (VIb), is carried out in an organic solvent, including a solvent selected from the group , consisting of isopropylacetate, ethyl acetate, 1,2-dimethoxyethane, 1,4-dioxane, dimethylformamide, tetrahydrofuran, 2-methyltetrahydrofuran and isopropanol; or in a solvent mixture comprising one or more of the above organic solvents and water.

In a preferred embodiment of the process according to the present invention, the reaction of an intermediate of formula (VIIIa) or (VIIIb), in particular (R)-8-chloro-2-(3-methylmorpholino)-1,7-naphthyridin-4-yl trifluoromethanesulfonate (VIIIb), with a compound of formula (VIa) or (VIb), in particular with 1-methyl-1H-pyrazole-5-boronic acid pinacol ester (VIb), is carried out in a solvent comprising ethyl acetate or isopropyl acetate, or in a solvent mixture comprising ethyl acetate and water or isopropyl acetate and water, most preferably a solvent mixture comprising ethyl acetate and water.

In another embodiment of the method according to the present invention, the reaction of an intermediate of formula (VIIIa) or (VIIIb), in particular (R)-8-chloro-2-(3-methylmorpholino)-1,7-naphthyridin-4-yl trifluoromethanesulfonate (VIIIb), with a compound of formula (VIa) or (VIb), in particular 1-methyl-1H-pyrazole-5-boronic acid pinacol ester (VIb), is carried out for 1-12 hours, in particular in within 1-5 hours, preferably within 1-3 hours, most preferably within 60-90 minutes.

In another embodiment of the method according to the present invention, the reaction of an intermediate of formula (VIIIa) or (VIIIb), in particular (R)-8-chloro-2-(3-methylmorpholino)-1,7-naphthyridin-4-yl trifluoromethanesulfonate (VIIIb), with a compound of formula (VIa) or (VIb), in particular with 1-methyl-1H-pyrazole-5-boronic acid pinacol ester (VIb), is carried out in the presence of a suitable catalyst system, such as, for example , palladium catalyst.

In another embodiment of the method according to the present invention, the palladium catalyst is selected from the group consisting of [1,1'-bis(diphenylphosphino)ferrocene]palladium(II)dichloro, palladium(II) acetate, bis(triphenylphosphine)palladium(II) dichloride ), dichlorobis(tricyclohexylphosphine)palladium(II), (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2-aminoethyl)phenyl)]palladium(II) chloride , chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II), tetrakis(triphenylphosphine )palladium(0), bis(tri-tert-butylphosphine)palladium(0), bis[tris(2-methylphenyl)phosphine]palladium(0), tris(dibenzylideneacetone)dipalladium(0).

In a preferred embodiment of the process according to the present invention, the palladium catalyst is [1,1'-bis(diphenylphosphino)ferrocene]dichloro palladium(II).

In another embodiment of the method according to the present invention, the reaction of an intermediate of formula (VIIIa) or (VIIIb), in particular (R)-8-chloro-2-(3-methylmorpholino)-1,7-naphthyridin-4-yl trifluoromethanesulfonate (VIIIb), with a compound of formula (VIa) or (VIb), in particular with 1-methyl-1H-pyrazole-5-boronic acid pinacol ester (VIb), is carried out in the presence of 0.001-0.1 molar equivalents, preferably 0.005 -0.05 molar equivalents, most preferably 0.0-0.03 molar equivalents, of palladium catalyst, preferably [1,1'-bis(diphenylphosphino)ferrocene]palladium(II)dichloro.

In another embodiment of the method according to the present invention, the reaction of an intermediate of formula (VIIIa) or (VIIIb), in particular (R)-8-chloro-2-(3-methylmorpholino)-1,7-naphthyridin-4-yl trifluoromethanesulfonate (VIIIb), with a compound of formula (VIa) or (VIb), in particular with 1-methyl-1H-pyrazole-5-boronic acid pinacol ester (VIb), is carried out in the presence of a base. Bases such as potassium phosphate, potassium carbonate, potassium bicarbonate, sodium phosphate, sodium carbonate, sodium bicarbonate, barium hydroxide, barium carbonate, cesium carbonate or lithium carbonate can be used. Potassium carbonate or potassium bicarbonate is preferred, potassium bicarbonate being most preferred.

In another embodiment of the method according to the present invention, the reaction of an intermediate of formula (VIIIa) or (VIIIb), in particular (R)-8-chloro-2-(3-methylmorpholino)-1,7-naphthyridin-4-yl trifluoromethanesulfonate (VIIIb), with a compound of formula (VIa) or (VIb), in particular with 1-methyl-1H-pyrazole-5-boronic acid pinacol ester (VIb), is carried out in the presence of 1-15 molar equivalents, preferably 2 -8 molar equivalents, most preferably 3-5 or 3.5-4.5 molar equivalents of base.

In another embodiment of the method according to the present invention, the reaction of an intermediate of formula (VIIIa) or (VIIIb), in particular (R)-8-chloro-2-(3-methylmorpholino)-1,7-naphthyridin-4-yl trifluoromethanesulfonate (VIIIb), with a compound of formula (VIa) or (VIb), in particular with 1-methyl-1H-pyrazole-5-boronic acid pinacol ester (VIb), is carried out at temperatures ranging from room temperature to boiling point solvent.

In another embodiment of the method according to the present invention, the reaction of an intermediate of formula (VIIIa) or (VIIIb), in particular (R)-8-chloro-2-(3-methylmorpholino)-1,7-naphthyridin-4-yl trifluoromethanesulfonate (VIIIb), with a compound of formula (VIa) or (VIb), in particular with 1-methyl-1H-pyrazole-5-boronic acid pinacol ester (VIb), is carried out under pressure at temperatures above the boiling point.

In another embodiment of the method according to the present invention, the reaction of an intermediate of formula (VIIIa) or (VIIIb), in particular (R)-8-chloro-2-(3-methylmorpholino)-1,7-naphthyridin-4-yl trifluoromethanesulfonate (VIIIb), with a compound of formula (VIa) or (VIb), in particular with 1-methyl-1H-pyrazole-5-boronic acid pinacol ester (VIb), carried out in isopropyl acetate or in isopropyl acetate and water at a temperature of 35 -75°C, preferably at 40-60°C, most preferably at 45-55°C.

In another embodiment of the method according to the present invention, the reaction of an intermediate of formula (VIIIa) or (VIIIb), in particular (R)-8-chloro-2-(3-methylmorpholino)-1,7-naphthyridin-4-yl trifluoromethanesulfonate (VIIIb), with a compound of formula (VIa) or (VIb), in particular with 1-methyl-1H-pyrazole-5-boronic acid pinacol ester (VIb), carried out in ethyl acetate or in ethyl acetate and water, preferably in ethyl acetate and water, at a temperature of 30-60°C, preferably at 35-50°C, most preferably at 38-45°C.

In another embodiment of the method according to the present invention, the reaction of an intermediate of formula (VIIIa) or (VIIIb), in particular (R)-8-chloro-2-(3-methylmorpholino)-1,7-naphthyridin-4-yl trifluoromethanesulfonate (VIIIb), with a compound of formula (VIa) or (VIb), in particular with 1-methyl-1H-pyrazole-5-boronic acid pinacol ester (VIb), is carried out under an inert gas atmosphere, where the inert gas is nitrogen or argon, preferably nitrogen.

2.1 Further processing of the crude compound of formula (IXa) or (IXb) and crystallization of the compound of formula (IXa) or (IXb)

In another embodiment of the method according to the present invention, in the case of the reaction of an intermediate of formula (VIIIa) or (VIIIb), in particular (R)-8-chloro-2-(3-methylmorpholino)-1,7-naphthyridine-4 -yl trifluoromethanesulfonate (VIIIb), with a compound of formula (VIa) or (VIb), in particular with 1-methyl-1H-pyrazole-5-boronic acid pinacol ester (VIb), an organic solvent or mixture of solvents, in particular ethyl acetate with/without water, or isopropyl acetate with/without water, optional

a) washed with an aqueous solution of a base selected from potassium hydroxide, potassium carbonate, potassium bicarbonate, potassium hydroxide, potassium tert-butoxide, sodium hydroxide, sodium phosphate, sodium carbonate, sodium hydroxide, sodium tert-butoxide, barium hydroxide, cesium carbonate, triethylamine ; preferably potassium hydroxide; and/or, optionally,

b) washed with water; and/or, optional

c) treated with an adsorbent; preferably the adsorbent is activated carbon; and/or optional

d) the adsorbent, in particular activated carbon, is filtered off;

to obtain a solution of a compound of formula (IXa) or (IXb) in said organic solvent or mixture of solvents, preferably a solution of a compound of formula (IXa) or (IXb) in ethyl acetate or isopropyl acetate, most preferably ethyl acetate.

In another embodiment of the method according to the present invention, the solvent or mixture of solvents of said solution of the compound of formula (IXa) or (IXb), preferably ethyl acetate or isopropyl acetate, most preferably ethyl acetate, is replaced by another solvent (solvent C hereinafter). Solvent C includes a solvent selected from methanol, ethanol, n-propanol, n-butanol, 2-butanol, isopropanol, preferably the solvent is replaced by isopropanol.

Crystallization of the compound of formula (IXa) or (IXb) is preferably carried out in solvent C, preferably in isopropanol.

Crystallization of a compound of formula (IXa) or (IXb) in solvent C, preferably isopropanol, is carried out using 2-20 kg per kg of compound of formula (IXa) or (IXb), preferably 2.5-10 kg, most preferably 2.5-6 kg, solvent C, preferably isopropanol, and the product can then be isolated.

The isolated compound of formula (IXa) or (IXb) can be dried at a temperature of 35-75°C, preferably at 40-65°C, most preferably at 45-55°C.

The isolated compound of formula (IXa) or (IXb) can be dried in vacuum at 20-100 mbar, preferably at 30-50 mbar, and in vacuum at 20-100 mbar, preferably at 30-50 mbar, and at temperatures of 35-75° C, preferably in vacuum at 20-100 mbar, preferably at 30-50 mbar, and at temperatures of 50-75 ° C, most preferably in vacuum at 20-100 mbar, preferably at 30-50 mbar, and at temperatures 40-60 °C.

3. Synthesis of an intermediate of formula (VIIIa) or (VIIIb) starting from a compound of formula (II) or (IIa)

According to another aspect, the present invention provides a process for preparing a compound of formula (VIIIa), comprising the step of reacting an intermediate of formula (II)

Where

R ¹ represents a chlorine, bromine or iodine atom or represents a group selected from [(trifluoromethyl)sulfonyl]oxy, [(nonafluorobutyl)sulfonyl]oxy, (methylsulfonyl)oxy, (p-toluenesulfonyl)oxy, (phenylsulfonyl)oxy, [(4-bromophenyl)sulfonyl]oxy, [(4-nitrophenyl)sulfonyl]oxy, [(2-nitrophenyl)sulfonyl]oxy, [(4-isopropylphenyl)sulfonyl]oxy, [(2,4,6-triisopropylphenyl) sulfonyl]oxy, [(2,4,6-trimethylphenyl)sulfonyl]oxy, [(4-tert-butylphenyl)sulfonyl]oxy and [(4-methoxyphenyl)sulfonyl]oxy;

with a compound selected from N-phenyl-bis(trifluoromethanesulfonimide), trifluoromethanesulfonic anhydride, methanesulfonic acid chloride, p-toluenesulfonyl chloride, nonafluorobutanesulfonyl chloride, nonafluorobutanesulfonyl fluoride, benzenesulfonyl chloride, 4-bromobenzenesulfonyl chloride, 4-nitrobenzenesulfonyl chloride , 2-nitrobenzenesulfonyl chloride, 4-isopropylbenzenesulfonyl chloride, 2,4 ,6-triisopropylbenzenesulfonyl chloride, 2-mesitylenesulfonyl chloride (=2,4,6-trimethylbenzenesulfonyl chloride), 4-tert-butylbenzenesulfonyl chloride and 4-methoxybenzenesulfonyl chloride;

to obtain intermediate compound of formula (VIIIa)

Where

R ¹ represents a chlorine, bromine or iodine atom or represents a group selected from [(trifluoromethyl)sulfonyl]oxy, [(nonafluorobutyl)sulfonyl]oxy, (methylsulfonyl)oxy, (p-toluenesulfonyl)oxy, (phenylsulfonyl)oxy, [(4-bromophenyl)sulfonyl]oxy, [(4-nitrophenyl)sulfonyl]oxy, [(2-nitrophenyl)sulfonyl]oxy, [(4-isopropylphenyl)sulfonyl]oxy, [(2,4,6-triisopropylphenyl) sulfonyl]oxy, [(2,4,6-trimethylphenyl)sulfonyl]oxy, [(4-tert-butylphenyl)sulfonyl]oxy and [(4-methoxyphenyl)sulfonyl]oxy;

R ⁵ represents a chlorine, bromine or iodine atom or represents a group selected from [(trifluoromethyl)sulfonyl]oxy, [(nonafluorobutyl)sulfonyl]oxy, (methylsulfonyl)oxy, (p-toluenesulfonyl)oxy, (phenylsulfonyl)oxy, [(4-bromophenyl)sulfonyl]oxy, [(4-nitrophenyl)sulfonyl]oxy, [(2-nitrophenyl)sulfonyl]oxy, [(4-isopropylphenyl)sulfonyl]oxy, [(2,4,6-triisopropylphenyl) sulfonyl]oxy, [(2,4,6-trimethylphenyl)sulfonyl]oxy, [(4-tert-butylphenyl)sulfonyl]oxy and [(4-methoxyphenyl)sulfonyl]oxy.

In another embodiment of the method according to the present invention for producing a compound of formula (I), the method further includes (before reacting an intermediate of formula (VIIIa) or (VIIIb) with a compound of formula (VIa) or (VIb)) the step of reacting the intermediate of formula (II)

Where

R ¹ represents a chlorine, bromine or iodine atom or represents a group selected from [(trifluoromethyl)sulfonyl]oxy, [(nonafluorobutyl)sulfonyl]oxy, (methylsulfonyl)oxy, (p-toluenesulfonyl)oxy, (phenylsulfonyl)oxy, [(4-bromophenyl)sulfonyl]oxy, [(4-nitrophenyl)sulfonyl]oxy, [(2-nitrophenyl)sulfonyl]oxy, [(4-isopropylphenyl)sulfonyl]oxy, [(2,4,6-triisopropylphenyl) sulfonyl]oxy, [(2,4,6-trimethylphenyl)sulfonyl]oxy, [(4-tert-butylphenyl)sulfonyl]oxy and [(4-methoxyphenyl)sulfonyl]oxy;

with a compound selected from N-phenyl-bis(trifluoromethanesulfonimide), trifluoromethanesulfonic anhydride, methanesulfonic acid chloride, p-toluenesulfonyl chloride, nonafluorobutanesulfonyl chloride, nonafluorobutanesulfonyl fluoride, benzenesulfonyl chloride, 4-bromobenzenesulfonyl chloride, 4-nitrobenzenesulfonyl chloride , 2-nitrobenzenesulfonyl chloride, 4-isopropylbenzenesulfonyl chloride, 2,4 ,6-triisopropylbenzenesulfonyl chloride, 2-mesitylenesulfonyl chloride (=2,4,6-trimethylbenzenesulfonyl chloride), 4-tert-butylbenzenesulfonyl chloride and 4-methoxybenzenesulfonyl chloride;

to obtain intermediate compound of formula (VIIIa)

Where

R ¹ represents a chlorine, bromine or iodine atom or represents a group selected from [(trifluoromethyl)sulfonyl]oxy, [(nonafluorobutyl)sulfonyl]oxy, (methylsulfonyl)oxy, (p-toluenesulfonyl)oxy, (phenylsulfonyl)oxy, [(4-bromophenyl)sulfonyl]oxy, [(4-nitrophenyl)sulfonyl]oxy, [(2-nitrophenyl)sulfonyl]oxy, [(4-isopropylphenyl)sulfonyl]oxy, [(2,4,6-triisopropylphenyl) sulfonyl]oxy, [(2,4,6-trimethylphenyl)sulfonyl]oxy, [(4-tert-butylphenyl)sulfonyl]oxy and [(4-methoxyphenyl)sulfonyl]oxy;

R ⁵ represents a chlorine, bromine or iodine atom or represents a group selected from [(trifluoromethyl)sulfonyl]oxy, [(nonafluorobutyl)sulfonyl]oxy, (methylsulfonyl)oxy, (p-toluenesulfonyl)oxy, (phenylsulfonyl)oxy, [(4-bromophenyl)sulfonyl]oxy, [(4-nitrophenyl)sulfonyl]oxy, [(2-nitrophenyl)sulfonyl]oxy, [(4-isopropylphenyl)sulfonyl]oxy, [(2,4,6-triisopropylphenyl) sulfonyl]oxy, [(2,4,6-trimethylphenyl)sulfonyl]oxy, [(4-tert-butylphenyl)sulfonyl]oxy and [(4-methoxyphenyl)sulfonyl]oxy.

In another embodiment of the method according to the present invention, R ¹ of the compound of formula (II) is a chlorine or bromine atom, preferably a chlorine atom. The compound of formula (II) wherein R ¹ represents a chlorine atom is a preferred compound of formula (IIa) (=(R)-8-chloro-2-(3-methylmorpholino)-1,7-naphthyridin-4-ol):

In another embodiment of the method according to the present invention, R ¹ of the compound of formula (II) is a group selected from [(trifluoromethyl)sulfonyl]oxy, [(nonafluorobutyl)sulfonyl]oxy, (methylsulfonyl)oxy, (p-toluenesulfonyl)oxy , (phenylsulfonyl)oxy, [(4-bromophenyl)sulfonyl]oxy, [(4-nitrophenyl)sulfonyl]oxy, [(2-nitrophenyl)sulfonyl]oxy, [(4-isopropylphenyl)sulfonyl]oxy, [(2, 4,6-triisopropylphenyl)sulfonyl]oxy, [(2,4,6-trimethylphenyl)sulfonyl]oxy, [(4-tert-butylphenyl)sulfonyl]oxy and [(4-methoxyphenyl)sulfonyl]oxy.

In another embodiment of the method according to the present invention, R ¹ of the compound of formula (II) is a group selected from [(trifluoromethyl)sulfonyl]oxy, [(nonafluorobutyl)sulfonyl]oxy, (methylsulfonyl)oxy and (p-toluenesulfonyl)oxy .

In another embodiment of the method according to the present invention, R ¹ of the compound of formula (VIIIa) is a chlorine or bromine atom, preferably a chlorine atom.

In another embodiment of the method according to the present invention, R ¹ of the compound of formula (VIIIa) is a group selected from [(trifluoromethyl)sulfonyl]oxy, [(nonafluorobutyl)sulfonyl]oxy, (methylsulfonyl)oxy, (p-toluenesulfonyl)oxy , (phenylsulfonyl)oxy, [(4-bromophenyl)sulfonyl]oxy, [(4-nitrophenyl)sulfonyl]oxy, [(2-nitrophenyl)sulfonyl]oxy, [(4-isopropylphenyl)sulfonyl]oxy, [(2, 4,6-triisopropylphenyl)sulfonyl]oxy, [(2,4,6-trimethylphenyl)sulfonyl]oxy, [(4-tert-butylphenyl)sulfonyl]oxy and [(4-methoxyphenyl)sulfonyl]oxy.

In another embodiment of the method according to the present invention, R ¹ of the compound of formula (VIIIa) is a group selected from [(trifluoromethyl)sulfonyl]oxy, [(nonafluorobutyl)sulfonyl]oxy, (methylsulfonyl)oxy and (p-toluenesulfonyl)oxy .

In another embodiment of the method according to the present invention, R ⁵ of the compound of formula (VIIIa) represents a chlorine, bromine or iodine atom.

In another embodiment of the method according to the present invention, R ⁵ of the compound of formula (IXa) is a group selected from [(trifluoromethyl)sulfonyl]oxy, [(nonafluorobutyl)sulfonyl]oxy, (methylsulfonyl)oxy, (p-toluenesulfonyl)oxy , (phenylsulfonyl)oxy, [(4-bromophenyl)sulfonyl]oxy, [(4-nitrophenyl)sulfonyl]oxy, [(2-nitrophenyl)sulfonyl]oxy, [(4-isopropylphenyl)sulfonyl]oxy, [(2, 4,6-triisopropylphenyl)sulfonyl]oxy, [(2,4,6-trimethylphenyl)sulfonyl]oxy, [(4-tert-butylphenyl)sulfonyl]oxy and [(4-methoxyphenyl)sulfonyl]oxy.

In a preferred embodiment of the method according to the present invention, R ⁵ of the compound of formula (VIIIa) is a [(trifluoromethyl)sulfonyl]oxy group.

In another embodiment of the method according to the present invention, R ¹ of the compound of formula (VIIIa) is a chlorine or bromine atom, preferably a chlorine atom, and R ⁵ is a group selected from [(trifluoromethyl)sulfonyl]oxy, [(nonafluorobutyl)sulfonyl ]oxy, (methylsulfonyl)oxy, (p-toluenesulfonyl)oxy, (phenylsulfonyl)oxy, [(4-bromophenyl)sulfonyl]oxy, [(4-nitrophenyl)sulfonyl]oxy, [(2-nitrophenyl)sulfonyl]oxy, [(4-isopropylphenyl)sulfonyl]oxy, [(2,4,6-triisopropylphenyl)sulfonyl]oxy, [(2,4,6-trimethylphenyl)sulfonyl]oxy, [(4-tert-butylphenyl)sulfonyl]oxy and [(4-methoxyphenyl)sulfonyl]oxy, preferably the [(trifluoromethyl)sulfonyl]oxy group.

The compound of formula (VIIIa) wherein R ¹ represents a chlorine atom and where R ⁵ represents a [(trifluoromethyl)sulfonyl]oxy group is (R)-8-chloro-2-(3-methylmorpholino)-1,7 -naphthyridin-4-yl trifluoromethanesulfonate, which is the preferred compound of formula (VIIIb):

In a preferred embodiment of the present invention, the compound of formula (II) is ^)-8-chloro-2-(3-methylmorpholino)-1,7-naphthyridin-4-ol (IIa) and the compound of formula (VIIIa) is (R )-8-chloro-2-(3-methylmorpholino)-1,7-naphthyridin-4-yl trifluoromethanesulfonate (VIIIb).

In another embodiment of the process according to the present invention, an intermediate of formula (II), preferably a compound of formula (IIa), is reacted with 0.8-2.0, preferably 0.9-1.7, most preferably 1.0-1.5, molar equivalents of a compound selected from N-phenyl-bis(trifluoromethanesulfonimide), trifluoromethanesulfonic anhydride, methanesulfonic acid chloride, p-toluenesulfonyl chloride, nonafluorobutanesulfonyl chloride, nonafluorobutanesulfonyl fluoride, benzenesulfonyl chloride, 4-bromobenzenesulfonyl chloride, 4-nitrobenzenesulfonyl chloride, 2-nitrobene zolsulfonyl chloride, 4-isopropylbenzenesulfonyl chloride, 2,4,6-triisopropylbenzenesulfonyl chloride, 2-mesitylenesulfonyl chloride (=2,4,6-trimethylbenzenesulfonyl chloride), 4-tert-butylbenzenesulfonyl chloride and 4-methoxybenzenesulfonyl chloride.

Preferably, the compound of formula (IIa) is reacted with 0.8-2.0, preferably 0.9-1.7, most preferably 1.0-1.5, molar equivalents of trifluoromethanesulfonic anhydride or N-phenyl-bis(trifluoromethanesulfonimide), most preferably 0.8-2.0, preferably 0.9 -1.7, most preferably with 1.0-1.5 molar equivalents of trifluoromethanesulfonic anhydride.

In another embodiment of the method, the above reaction is carried out in an aprotic solvent such as dichloromethane, tetrahydrofuran, pyridine, ethyl acetate, isopropyl acetate, acetonitrile, 2-methyltetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, acetone, 2-butanone, butyl acetate , cyclopentyl methyl ether, methyl tert-butyl ether, toluene, propionitrile, chlorobenzene, anisole, chloroform, the preferred solvent is dichloromethane.

Per kg of compound of formula (II) or (IIa) 4-20 kg of solvent is used, preferably 6-15 kg of solvent, most preferably 7-9 kg of solvent, preferably dichloromethane.

In another embodiment, reacting an intermediate of formula (II) with a compound selected from N-phenyl-bis(trifluoromethanesulfonimide), trifluoromethanesulfonic anhydride, methanesulfonic acid chloride, p-toluenesulfonyl chloride, nonafluorobutanesulfonyl chloride, nonafluorobutanesulfonyl fluoride, benzenesulfonyl chloride, 4-bromobenzenesulfonyl chloride ida, 4-nitrobenzenesulfonyl chloride, 2-nitrobenzenesulfonyl chloride, 4-isopropylbenzenesulfonyl chloride, 2,4,6-triisopropylbenzenesulfonyl chloride, 2-mesitylenesulfonyl chloride (=2,4,6-trimethylbenzenesulfonyl chloride), 4-tert-butylbenzenesulfonyl chloride and 4-methoxybenzenesulfonyl chloride, preferably with trifluoromethanesulfone omic anhydride or N-phenyl-bis (trifluoromethanesulfonimide) is carried out in the presence of a base, in particular an organic base or an inorganic base or mixtures of one or more organic bases with one or more inorganic bases.

For the above reaction, organic bases such as pyridine, N,N-diethylethanamine (=triethylamine), N,N-di(propan-2-yl)propan-2-amine (=triisopropylamine), N,N-dibutylbutan- 1-amine (=tributylamine), 2,6-dimethylpyridine (=2,6-lutidine), N-ethyl-N-(propan-2-yl)propan-2-amine (=N,N-diisopropylethylamine or Huenig's bases ), N-methylmorpholine, the preferred bases are N,N-diethylethanamine (=triethylamine) and pyridine, most preferred is pyridine.

The use of pyridine is in particular preferred in order to avoid undesirable color changes of the compound of formula (VIIIa) or (VIIIb).

Inorganic bases that can be used for the above reaction are, for example, potassium carbonate, potassium hydrogen carbonate, sodium phosphate, sodium carbonate, sodium hydrogen carbonate, calcium carbonate, calcium hydrogen carbonate or cesium carbonate.

In another embodiment of the method according to the present invention, an intermediate of formula (II), preferably a compound of formula (IIa), is reacted with a compound selected from N-phenyl-bis(trifluoromethanesulfonimide), trifluoromethanesulfonic anhydride, methanesulfonic acid chloride, p-toluenesulfonyl chloride , nonafluorobutanesulfonyl chloride, nonafluorobutanesulfonyl fluoride, benzenesulfonyl chloride, 4-bromobenzenesulfonyl chloride, 4-nitrobenzenesulfonyl chloride, 2-nitrobenzenesulfonyl chloride, 4-isopropylbenzenesulfonyl chloride, 2,4,6-triisopropylbenzenesulfonyl chloride, 2-mesitylensulfonyl chloride onyl chloride (=2,4,6-trimethylbenzenesulfonyl chloride), 4-tert-butylbenzenesulfonyl chloride and 4-methoxybenzenesulfonyl chloride, preferably with trifluoromethanesulfonic anhydride or N-phenyl-bis(trifluoromethanesulfonimide), in the presence of 0.7-4.0, preferably 0.9-3.0, most preferably 1.0-2.0, molar equivalents of base, preferably N,N-diethylethanamine or pyridine, most preferably pyridine.

In a preferred embodiment of the process according to the present invention, an intermediate of formula (II), preferably a compound of formula (IIa), is reacted with trifluoromethanesulfonic anhydride in the presence of 0.7-4.0, preferably 0.9-3.0, most preferably 1.0-2.0 molar equivalents of pyridine.

In another embodiment of the method according to the present invention, the reaction of an intermediate of formula (II) with a compound selected from ^-phenyl-bis(trifluoromethanesulfonimide), trifluoromethanesulfonic anhydride, methanesulfonic acid chloride, p-toluenesulfonyl chloride, nonafluorobutanesulfonyl chloride, nonafluorobutanesulfonyl fluoride, benzenesulfonyl chloride, 4 -bromobenzenesulfonyl chloride, 4-nitrobenzenesulfonyl chloride, 2-nitrobenzenesulfonyl chloride, 4-isopropylbenzenesulfonyl chloride, 2,4,6-triisopropylbenzenesulfonyl chloride, 2-mesitylenesulfonyl chloride (=2,4,6-trimethylbenzenesulfonyl chloride), 4-tert-butylbenzenesulfonyl chloride ide and 4-methoxybenzenesulfonyl chloride, preferably with trifluoromethanesulfonic acid anhydride or N-phenyl-bis(trifluoromethanesulfonimide), is carried out at temperatures of -30-30°C, preferably -20-20°C, most preferably at -15-0°C. The reaction time can be from 1 to 24 hours, the preferred time being 1-4 hours.

In a preferred embodiment of the process according to the present invention, an intermediate of formula (II), preferably a compound of formula (IIa), is reacted with trifluoromethanesulfonic anhydride in the presence of 0.7-4.0, preferably 0.9-3.0, most preferably 1.0-2.0 molar equivalents of pyridine at temperatures -30-30°C, preferably -20-5°C, most preferably -15 to -5°C. The reaction time can be from 1 to 24 hours, the preferred time being 1-4 hours.

3.1 Further processing of the crude compound of formula (VIIIa) or (VIIIb) and crystallization of the compound of formula (VIIIa) or (VIIIb)

In another embodiment of the method according to the present invention, in the case of reacting an intermediate of formula (II) with a compound selected from N-phenyl-bis(trifluoromethanesulfonimide), trifluoromethanesulfonic anhydride, methanesulfonic acid chloride, p-toluenesulfonyl chloride, nonafluorobutanesulfonyl chloride, nonafluorobutanesulfonyl fluoride, benzenesulfonyl chloride, 4-bromobenzenesulfonyl chloride, 4-nitrobenzenesulfonyl chloride, 2-nitrobenzenesulfonyl chloride, 4-isopropylbenzenesulfonyl chloride, 2,4,6-triisopropylbenzenesulfonyl chloride, 2-mesitylenesulfonyl chloride (=2,4,6-trimethylbenzenesulfonyl chloride), 4-tert-butylbenzenesulfonyl chloride and 4-methoxybenzenesulfonyl chloride, preferably with trifluoromethanesulfonic anhydride or N-phenyl-bis(trifluoromethanesulfonimide), organic solvent or mixture of solvents, in particular dichloromethane, optional

a) washed with water; and/or, optional

b) washed with an aqueous solution of a base selected from potassium hydroxide, potassium carbonate, potassium bicarbonate, potassium hydroxide, potassium tert-butoxide, sodium hydroxide, sodium phosphate, sodium carbonate, sodium hydroxide, sodium tert-butoxide, barium hydroxide, cesium carbonate, triethylamine ; preferably an aqueous solution of potassium carbonate; and/or, optionally,

c) after washing with an aqueous solution, the bases are washed again with water;

d) treated with an adsorbent; preferably the adsorbent is activated carbon; and/or optional

e) the adsorbent, in particular activated carbon, is filtered off;

to obtain a solution of a compound of formula (VIIIa) or (VIIIb) in said organic solvent or mixture of solvents, preferably a solution of a compound of formula (VIIIa) or (VIIIb) in dichloromethane.

The sequence of further processing of the crude compound of formula (VIIIa) or (VIIIb) according to steps a) (washing with water), b) (washing with an aqueous base solution), c) (washing with water after washing with an aqueous base solution), d) ( treatment with adsorbent) and/or e) (filtration of adsorbent) as described above may be modified. For example, steps d) and e) can be performed before steps a), b) and c).

In another embodiment of the method according to the present invention, the solvent or mixture of solvents of said solution of a compound of formula (VIIIa) or (VIIIb), preferably dichloromethane, is replaced by another solvent (solvent D hereinafter). Solvent D includes a solvent selected from methanol, ethanol, n-propanol, n-butanol, 2-butanol, isopropanol, preferably the solvent is replaced by isopropanol.

In the preferred version of the method, in accordance with the present invention, the reaction of the intermediate connection of formula (II) with a compound selected from N-phenyl-bis (triformettan sulfonymide), triformomethane sulfone anhydride, methane sulaic acid, n-toporbuncholoride, nonaftorbutan chloride, non-orefronyloride, non-orefronylorid Torbutan sulfunnilfluoride, benzolsulfuncholoride, 4- bromobenzenesulfonyl chloride, 4-nitrobenzenesulfonyl chloride, 2-nitrobenzenesulfonyl chloride, 4-isopropylbenzenesulfonyl chloride, 2,4,6-triisopropylbenzenesulfonyl chloride, 2-mesitylenesulfonyl chloride (=2,4,6-trimethylbenzenesulfonyl chloride), 4-tert-butylbenzenesulfonyl chloride and 4-methoxybenzenesulfonyl chloride is carried out in an inert gas atmosphere wherein the inert gas is nitrogen or argon, preferably nitrogen.

Crystallization of the compound of formula (VIIIa) or (VIIIb) is preferably carried out in solvent D, preferably isopropanol.

Per kg of compound of formula (VIIIa) or (VIIIb) 2 to 6 kg of organic solvent is used, preferably 3 to 5 kg of organic solvent, most preferably 3 to 4 kg of organic solvent, preferably isopropanol.

For example, the product can be isolated by filtration or by centrifugation. It can be dried at a temperature of 25 - 60°C, preferably at 40 - 50°C. It can be dried for 1-24 hours, preferably 8-15 hours, most preferably 10-14 hours.

Treatment of the crude compound of formula (VIIIa) or (VIIIb) and its subsequent crystallization from isopropanol gives the compound of formula (VIIIa) or (VIIIb) in high purity and yield of 64 - 87.7% of theory without the use of any chromatographic purification step.

The reaction to produce a compound of formula (VIIIa) or (VIIIb) can be performed on a large scale (eg, multi-kilogram scale). The purity of the resulting product was very high (eg, >98% (UHPLC area %)).

4. Intermediates of formula (IXa) or (IXb)

According to another aspect, the present invention provides an intermediate of formula (IXa)

Where

R ¹ represents a chlorine, bromine or iodine atom or represents a group selected from [(trifluoromethyl)sulfonyl]oxy, [(nonafluorobutyl)sulfonyl]oxy, (methylsulfonyl)oxy, (n-toluenesulfonyl)oxy, (phenylsulfonyl)oxy, [(4-bromophenyl)sulfonyl]oxy, [(4-nitrophenyl)sulfonyl]oxy, [(2-nitrophenyl)sulfonyl]oxy, [(4-isopropylphenyl)sulfonyl]oxy, [(2,4,6-triisopropylphenyl) sulfonyl]oxy, [(2,4,6-trimethylphenyl)sulfonyl]oxy, [(4-tert-butylphenyl)sulfonyl]oxy and [(4-methoxyphenyl)sulfonyl]oxy.

In another embodiment, the present invention provides an intermediate of formula (IXa) wherein R ¹ is a chlorine or bromine atom, preferably a chlorine atom.

In another embodiment, the present invention provides an intermediate of formula (IXa) wherein R ¹ is a group selected from [(trifluoromethyl)sulfonyl]oxy, [(nonafluorobutyl)sulfonyl]oxy, (methylsulfonyl)oxy, (n-toluenesulfonyl) oxy, (phenylsulfonyl)oxy, [(4-bromophenyl)sulfonyl]oxy, [(4-nitrophenyl)sulfonyl]oxy, [(2-nitrophenyl)sulfonyl]oxy, [(4-isopropylphenyl)sulfonyl]oxy, [(2 ,4,6-triisopropylphenyl)sulfonyl]oxy, [(2,4,6-trimethylphenyl)sulfonyl]oxy, [(4-tert-butylphenyl)sulfonyl]oxy and [(4-methoxyphenyl)sulfonyl]oxy.

In another embodiment, the present invention provides an intermediate of formula (IXa) wherein R ¹ is a group selected from [(trifluoromethyl)sulfonyl]oxy, [(nonafluorobutyl)sulfonyl]oxy, (methylsulfonyl)oxy and (n-toluenesulfonyl) oxy.

In a preferred embodiment, the present invention relates to a compound of formula (IXb):

5. Intermediates of Formula (VIIIa) or (VIIIb) In another aspect, the present invention covers an intermediate of Formula (VIIIa)

Where

R ¹ represents a chlorine, bromine or iodine atom or represents a group selected from [(trifluoromethyl)sulfonyl]oxy, [(nonafluorobutyl)sulfonyl]oxy, (methylsulfonyl)oxy, (n-toluenesulfonyl)oxy, (phenylsulfonyl)oxy, [(4-bromophenyl)sulfonyl]oxy, [(4-nitrophenyl)sulfonyl]oxy, [(2-nitrophenyl)sulfonyl]oxy, [(4-isopropylphenyl)sulfonyl]oxy, [(2,4,6-triisopropylphenyl) sulfonyl]oxy, [(2,4,6-trimethylphenyl)sulfonyl]oxy, [(4-tert-butylphenyl)sulfonyl]oxy and [(4-methoxyphenyl)sulfonyl]oxy; And

R ⁵ represents a chlorine, bromine or iodine atom or represents a group selected from [(trifluoromethyl)sulfonyl]oxy, [(nonafluorobutyl)sulfonyl]oxy, (methylsulfonyl)oxy, (n-toluenesulfonyl)oxy, (phenylsulfonyl)oxy, [(4-bromophenyl)sulfonyl]oxy, [(4-nitrophenyl)sulfonyl]oxy, [(2-nitrophenyl)sulfonyl]oxy, [(4-isopropylphenyl)sulfonyl]oxy, [(2,4,6-triisopropylphenyl) sulfonyl]oxy, [(2,4,6-trimethylphenyl)sulfonyl]oxy, [(4-tert-butylphenyl)sulfonyl]oxy and [(4-methoxyphenyl)sulfonyl]oxy.

In another embodiment, the present invention provides an intermediate of formula (VIIIa), wherein R ¹ represents a chlorine or bromine atom, preferably a chlorine atom.

In another embodiment, the present invention provides an intermediate of formula (VIIIa) wherein R ¹ is a group selected from [(trifluoromethyl)sulfonyl]oxy, [(nonafluorobutyl)sulfonyl]oxy, (methylsulfonyl)oxy, (n-toluenesulfonyl) oxy, (phenylsulfonyl)oxy, [(4-bromophenyl)sulfonyl]oxy, [(4-nitrophenyl)sulfonyl]oxy, [(2-nitrophenyl)sulfonyl]oxy, [(4-isopropylphenyl)sulfonyl]oxy, [(2 ,4,6-triisopropylphenyl)sulfonyl]oxy, [(2,4,6-trimethylphenyl)sulfonyl]oxy, [(4-tert-butylphenyl)sulfonyl]oxy and [(4-methoxyphenyl)sulfonyl]oxy.

In another embodiment, the present invention provides an intermediate of formula (VIIIa) wherein R ¹ is a group selected from [(trifluoromethyl)sulfonyl]oxy, [(nonafluorobutyl)sulfonyl]oxy, (methylsulfonyl)oxy and (n-toluenesulfonyl) oxy.

In another embodiment, the present invention provides an intermediate of formula (VIIIa) wherein R ⁵ represents a chlorine, bromine or iodine atom.

In another embodiment, the present invention provides an intermediate of formula (VIIIa) wherein R ⁵ is a group selected from [(trifluoromethyl)sulfonyl]oxy, [(nonafluorobutyl)sulfonyl]oxy, (methylsulfonyl)oxy, (n-toluenesulfonyl) oxy, (phenylsulfonyl)oxy, [(4-bromophenyl)sulfonyl]oxy, [(4-nitrophenyl)sulfonyl]oxy, [(2-nitrophenyl)sulfonyl]oxy, [(4-isopropylphenyl)sulfonyl]oxy, [(2 ,4,6-triisopropylphenyl)sulfonyl]oxy, [(2,4,6-trimethylphenyl)sulfonyl]oxy, [(4-tert-butylphenyl)sulfonyl]oxy and [(4-methoxyphenyl)sulfonyl]oxy.

In a preferred embodiment, the present invention provides an intermediate of formula (VIIIa) wherein R ⁵ is a [(trifluoromethyl)sulfonyl]oxy group.

In another embodiment, the present invention provides an intermediate of formula (VIIIa) wherein R ¹ represents a chlorine or bromine atom, preferably a chlorine atom, and where R ⁵ represents a group selected from [(trifluoromethyl)sulfonyl]oxy, [(nonafluorobutyl )sulfonyl]oxy, (methylsulfonyl)oxy, (n-toluenesulfonyl)oxy, (phenylsulfonyl)oxy, [(4-bromophenyl)sulfonyl]oxy, [(4-nitrophenyl)sulfonyl]oxy, [(2-nitrophenyl)sulfonyl] oxy, [(4-isopropylphenyl)sulfonyl]oxy, [(2,4,6-triisopropylphenyl)sulfonyl]oxy, [(2,4,6-trimethylphenyl)sulfonyl]oxy, [(4-tert-butylphenyl)sulfonyl] oxy and [(4-methoxyphenyl)sulfonyl]oxy, preferably [(trifluoromethyl)sulfonyl]oxy groups.

In a most preferred embodiment, the present invention provides an intermediate of formula (VIIIa) wherein R ¹ is a chlorine atom and where R ⁵ is a [(trifluoromethyl)sulfonyl]oxy group, yielding a compound of formula (VIIIb) (=(R) -8-chloro-2-(3-methylmorpholino)-1,7-naphthyridin-4-yl trifluoromethanesulfonate):

6. Polymorph Form B of the compound of formula (I) with high purity

The process for preparing the compound of formula (I) described in WO2016020320 A1 leads to polymorph Form B of the compound of formula (I). However, several attempts to scale up this method to obtain polymorph Form B of the compound of formula (I) at a level of purity that is acceptable for pharmaceutical use have not been successful. In addition, when attempting to scale up the process described in WO2016020320 A1, the result was a product of a compound of formula (I) that contained more than 0.15% of one or more by-products, for example, it contained more than 0.15% of the following compound:

In contrast, the process for preparing the compound of formula (I) in accordance with the present invention now provides the Form B polymorph of the compound of formula (I) with a sufficiently high degree of purity. The purity of the resulting batches (lab scale, kilogram scale and pilot scale) is very high. All individual by-products are known, precisely identified and toxicologically characterized. It was found that the palladium (Pd) content of the finished drug substance was always <10 ppm. The boron content (B) was also less than 10 ppm.

Thus, in accordance with a further aspect, the present invention covers polymorphic Form B of the compound of formula (I), which can be obtained by the process for preparing the compound of formula (I) in accordance with the invention, in particular using the processing method described in section 1.3. (“Further processing of the crude compound of formula (I)”) in combination with the crystallization method described in section 1.4. (“Crystallization of the crude compound of formula (I) to obtain its polymorphic form B”).

In another embodiment, polymorphic Form B of a compound of formula (I) according to the present invention is characterized by a purity of at least 99.6% (= area %), in particular at least 99.7% (= area %), preferably at least 99.8% (= area %), most preferably at least 99.9% (= area %) determined by UHPLC.

In another embodiment, the present invention covers polymorph Form B of the compound of formula (I) (=2-[(3R)-3-methylmorpholin-4-yl]-4-(1-methyl-1H-pyrazol-5-yl)-8 -(1H-pyrazol-5-yl)-1,7-naphthyridine), which is characterized by a purity of at least 99.6% (= area %), in particular at least 99.7% (= area %), preferably in at least 99.8% (= area %), most preferably at least 99.9% (= area %) determined by UHPLC.

The purity of polymorph Form B of the compound of formula (I) is determined by UHPLC, preferably using the method described in the Experimental Section - General Section ("UHPLC - method for determining the chemical purity and analysis of the compound of formula (I)").

Purity in "area %" is calculated as the percentage of UHPLC peak area under the UHPLC peak of polymorph Form B of the compound of formula (I) relative to the total peak area of all UHPLC peaks.

Polymorph Form B of the compound of formula (I) is further characterized by an X-ray powder diffraction (XRD) pattern that displays at least 3, in particular at least 5, preferably at least 7, more preferably at least 10, most preferably at least 12 of the following reflections, given as 2θ values: 8.3, 9.3, 13.8, 14.0, 18.0, 18.7, 19.6, 19.9, 20.1, 22.1, 23.9, 27.4.

In another embodiment, polymorph Form B of the compound of formula (I) is further characterized by an X-ray powder diffraction (XPD) pattern including the following reflectances, reported as 2θ values: 8.3, 18.0, 19.9.

In another embodiment, polymorph Form B of the compound of formula (I) is further characterized by an X-ray powder diffraction (XPD) pattern including the following reflectances, reported as 2θ values: 8.3, 9.3, 18.0, 19.9, 20.1.

In another embodiment, polymorph Form B of the compound of formula (I) is further characterized by an X-ray powder diffraction (XPD) pattern including the following reflectances, reported as 2θ values: 8.3, 9.3, 13.8, 14.0, 18.0, 19.9, 20.1.

In another embodiment, polymorph Form B of the compound of formula (I) is further characterized by an X-ray powder diffraction (XPD) pattern substantially as shown in Figure 1.

In another embodiment, polymorph Form B of the compound of formula (I) is characterized by the X-ray powder diffraction (XRD) pattern described in Table A1 (see Experimental Section - General).

In another embodiment, the present invention covers polymorph Form B of a compound of formula (I), which is characterized by an X-ray powder diffraction (XPD) pattern including the reflections defined above, given as 2θ values, and which is further characterized by a purity of at least 99.6% (= % area), in particular at least 99.7% (= area %), preferably at least 99.8% (= area %), most preferably at least 99.9% (= area %), determined by UHPLC.

In another embodiment, the present invention covers polymorphic Form B of a compound of formula (I) which is characterized by a purity of at least 99.6% (= area %), in particular at least 99.7% (= area %), preferably at least 99.8% (= area %), most preferably at least 99.9% (= area %) determined by UHPLC, wherein polymorph Form B of the compound of formula (I) contains

a) less than 15 mg boron, determined by ICP-MS, preferably less than 10 mg boron, per kg polymorph Form B of the compound of formula (I); and/or

b) less than 0.4 mg palladium determined by ICP-MS, preferably 0.3 mg palladium or less than 0.3 mg palladium; and/or

c) less than 0.05% (= area %) of the compound of formula (IXb), determined by UHPLC; and/or

d) less than 0.05% (= area %) of the compound of formula (VIb), determined by UHPLC; and/or

e) less than 0.05% (= area %) of dihydropyran, determined by UHPLC; and/or

f) less than 0.05% (= area %) of the compound of formula (IIIc) determined by UHPLC; and/or

g) less than 0.05% (= area %) of pinacol as determined by IX; and/or

h) less than 0.05% (=area %) of the compound of formula (VIIc/VIId), determined by UHPLC; and/or

i) less than 0.05% (= area %) of a compound of formula

determined by UHPLC; and/or

j) less than 0.05% (= area %) of a compound of formula

determined by UHPLC.

The content of boron and/or palladium in a compound of formula (I) is determined using ICP-MS, preferably using the method described in the Experimental Section - General Part ("ICP-MS - method for determining the sum of the elements, boron, palladium, iron, potassium, sodium").

Content of compounds of formulas (IXb), (VIb), (IIIc), (VIIc/VIId), dihydropyran,

determined by UHPLC, preferably using the method described in the Experimental Section - General Part ("UHPLC - method for determining the chemical purity and analysis of the compound of formula (I)").

The content of pinacol is determined using GC, preferably using the method described in the Experimental Section - General Part ("GC - method for determination of pinacol").

According to a further aspect, the present invention covers a pharmaceutical composition, in particular a medicinal product, containing polymorph Form B of a compound of formula (I) according to the present invention, which is characterized by a purity of at least 99.6% (=% area), in particular at least 99.7% (= area %), preferably at least 99.8% (= area %), most preferably at least 99.9% (= area %) determined by UHPLC, and one or several excipients, in particular one or more pharmaceutically suitable excipients.

Conventional techniques for preparing such pharmaceutical compositions in suitable dosage forms may be used.

The compound of formula (I) according to the invention may exhibit systemic and/or local activity. For this purpose, it can be administered in a suitable manner, such as by oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, vaginal, dermal, transdermal, conjunctival, auricular route or as an implant or stent.

For these routes of administration, the compound of formula (I) according to the invention can be administered in suitable dosage forms.

For oral administration, the compound of formula (I) according to the invention can be administered in dosage forms known in the art that deliver the compound of the invention rapidly and/or in a modified manner, such as, for example, tablets (uncoated or coated tablets, e.g. gastric acid-resistant or controlled-release coatings that are delayed or insoluble), orodissolving tablets, films/wafers, films/lyophilisates, capsules (e.g. hard or soft gelatin capsules), sugar-coated tablets, granules , pellets, powders, emulsions, suspensions, aerosols or solutions. In said dosage forms, the compound of formula (I) according to the invention can be included in crystalline and/or amorphized and/or dissolved form.

Parenteral administration can be performed by omitting the absorption step (eg, intravenous, intraarterial, intracardiac, intraspinal, or intralumbar) or including absorption (eg, intramuscular, subcutaneous, intradermal, transdermal, or intraperitoneal). Dosage forms that are suitable for parenteral administration include, inter alia, preparations for injection and infusion in the form of solutions, suspensions, emulsions, lyophilisates or sterile powders.

Examples that are suitable for other routes of administration are pharmaceutical forms for inhalation [including the use of dry powder inhalers, nebulizers, among others], nasal drops, nasal solutions, nasal sprays, tablets/films/wafers/capsules for lingual, sublingual or buccal administration, suppositories, eye drops, eye ointments, eye baths, eye inserts, ear drops, ear sprays, ear powders, ear washes, ear swabs; vaginal capsules, aqueous suspensions (lotions, shakes), lipophilic suspensions, emulsions, ointments, creams, transdermal therapeutic systems (such as patches), milks, pastes, foams, powders, implants or stents.

The compound of formula (I) in accordance with the invention can be included in these dosage forms. This can be accomplished in a manner known per se by mixing with pharmaceutically suitable excipients. Pharmaceutically suitable excipients include, but are not limited to:

fillers and carriers (such as, for example, cellulose, microcrystalline cellulose (such as, for example, Avicel®), lactose, mannitol, starch, calcium phosphate (such as, for example, Di-Cafos®)),

ointment bases (such as, for example, petroleum jelly, paraffins, triglycerides, waxes, wool wax, wool wax alcohols, lanolin, hydrophilic ointment, polyethylene glycols),

suppository bases (such as, for example, polyethylene glycols, cocoa butter, tallow),

solvents (such as, for example, water, ethanol, isopropanol, glycerin, propylene glycol, medium chain triglycerides, fatty oils, liquid polyethylene glycols, paraffins),

surfactants, emulsifiers, dispersants or wetting agents (such as, for example, sodium dodecyl sulfate, lecithin, phospholipids, fatty alcohols (such as, for example, Lanette®), sorbitol esters of fatty acids (such as, for example, Span®) , polyoxyethylene sorbitol fatty acid esters (such as, for example, Tween®), polyoxyethylene fatty acid glycerides (such as, for example, Cremophor®), polyoxyethylene fatty acid esters, polyoxyethylene fatty alcohol ethers, glycerol fatty acid esters , poloxamers (such as, for example, Pluronic®),

buffers, acids and bases (such as, for example, phosphates, carbonates, citric acid, acetic acid, hydrochloric acid, sodium hydroxide solution, ammonium carbonate, trometamol, triethanolamine),

isotonic agents (such as, for example, glucose, sodium chloride),

adsorbents (such as, for example, highly dispersed silica gel),

viscosity-increasing agents, gelling agents, thickeners and/or binders (such as, for example, polyvinylpyrrolidone, methylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, sodium carboxymethylcellulose, starch, carbomers, polyacrylic acids (such as, for example, Carbopol®), alginates, gelatin),

disintegrating agents (such as, for example, modified starch, sodium carboxymethylcellulose, sodium starch glycolate (such as, for example, Explotab®), cross-linked polyvinylpyrrolidone, croscarmellose sodium (such as, for example, AcDiSol®)),

flow regulators, lubricants, glidants and mold release agents (such as magnesium stearate, stearic acid, talc, highly dispersed silica gel (such as Aerosil®)),

coating agents (such as, for example, sugar, shellac) and film formers for films or diffusion membranes that dissolve quickly or in a modified manner (for example, polyvinylpyrrolidones (such as, for example, Kollidon®), polyvinyl alcohol, hydroxypropyl methylcellulose, hydroxypropylcellulose, ethylcellulose, phthalate hydroxypropyl methylcelluloses, cellulose acetate, cellulose acetate phthalate, polyacrylates, polymethacrylates, such as, for example, Eudragit®)),

capsule substances (such as gelatin, hydroxypropyl methylcellulose),

synthetic polymers (such as, for example, polylactides, polyglycolides, polyacrylates, polymethacrylates (such as, for example, Eudragit®), polyvinylpyrrolidones (such as, for example, Kollidon®), polyvinyl alcohols, polyvinyl acetates, polyethylene oxides, polyethylene glycols and their copolymers and block copolymers),

plasticizers (such as, for example, polyethylene glycols, propylene glycol, glycerin, triacetin, triacetyl citrate, dibutyl phthalate),

substances that promote penetration

stabilizers (such as, for example, antioxidants such as ascorbic acid, ascorbyl palmitate, sodium ascorbate, butylated hydroxyanisole, butylated hydroxytoluene, propyl gallate),

preservatives (such as, for example, parabens, sorbic acid, thiomersal, benzalkonium chloride, chlorhexidine acetate, sodium benzoate),

dyes (such as, for example, inorganic pigments such as iron oxides, titanium dioxide),

flavoring agents, sweeteners, taste and/or odor correcting substances.

EXPERIMENTAL SECTION

NMR peak shapes are given as they appear in the spectra; possible higher order effects have not been considered.

Chemical names were generated using ACD/Name software from ACD/Labs. In some cases, the common names of commercially available reagents were used instead of the names generated by ACD/Name.

The following Table 1 lists the abbreviations used in this paragraph and in the Examples section because they are not explained in the main text. Other abbreviations have meanings substantially common to one skilled in the art.

Other abbreviations have meanings substantially common to one skilled in the art.

Various aspects of the invention described in this application are illustrated by the following examples, which are not intended to limit the invention in any way.

The exemplary test experiments described in this application serve to illustrate the present invention and the invention is not limited to the examples given.

EXPERIMENTAL SECTION - GENERAL PART

All reagents for which the synthesis is not described in the experimental part are either commercially available, are known compounds, or can be formed by known methods from known compounds by a person skilled in the art.

Analytical methods and equipment

¹ H-NMR spectra were recorded in CDCl ₃ , DMSO-d6 or D ₂ O using a Bruker Biospin NMR instrument with a 400 MHz magnet, chemical shift (8) is presented in comparison with TMS as an internal standard.

HPLC chromatograms

HPLC Method - Scan. base: Agilent system (binary pump 1260, G1312B, degasser; autosampler, ColCom, DMD detector: Agilent G1315C, 220-320 nm); Column: Waters XSelect™ CSH (50×2.1 mm, 3.5 µm); Pace. columns: 3 5°C; Flow: 0.8 ml/min; Injected volume: 1 µl; Gradient: t- _{0 min} = 2% B, t _{3.5 min} = 98% B, t _{6 min} = 98% B, Break time: 3 min, 2% B. Eluent A: 10 mM ammonium bicarbonate in water, pH 9.5; Eluent B: 95% acetonitrile +5% 10 mM ammonium bicarbonate in water (pH 9.5);

HPLC Method - Scan. acid: Agilent system (1100, binary pump, G1312A, degasser; autosampler, ColCom, DMD detector: Agilent G1315B, 220-320 nm); Column: Waters XSelect™ CSH (50×2.1 mm, 3.5 µm); Pace. columns: 35°C; Flow: 0.8 ml/min; Injected volume: 1 µl; Gradient: t ₀ =2% V, t _3.5min =98% V, t _6min =98% V, Break time: 3 min; Eluent A: 0.1% formic acid in water. Eluent B: 0.1% formic acid in acetonitrile.

HPLC Method - Scan. acid: Agilent system (1100, binary pump, G1312A, degasser; autosampler, ColCom, DMD detector: Agilent G1315B, 220-320 nm); Column: Phenomex Kinetex C18 100A (100*4.6 mm 2.6 µm); Temp, columns: 35°C; Flow: 1.5 ml/min; Injected volume: 1 µl; Gradient: t ₀ =2% D, t _8min =98%) D, t _11min =98%) D, Break time: 3 min.; Eluent C: 0.1% formic acid in water. Eluent D: 0.1% formic acid in acetonitrile.

LC-MS chromatograms

LC-MS Method - Scan. base

Agilent 1100 bin. pump: G1312A, degasser; autosampler, ColCom, DMD: Agilent G1315B, 220-320 nm, MSD: Agilent LC/MSD G6130B, ERI, positive, /negative 100-800; Column: Waters XSelect™ C18, 30×2.1 mm, 3.5 μm, Temp: 25°C, Flow: 1 ml/min, Gradient: t ₀ =2% A, t _{1.6 min} =98% A, t _{3 min} =98% A, Break time: 1.3 min, Eluent A: 95% acetonitrile + 5% 10 mM ammonium bicarbonate in water in acetonitrile, Eluent B: 10 mM ammonium bicarbonate in water (pH = 9.5).

LC-MS Method - Scan. acid

Instrument: Agilent 1260 bin. pump: G1312B, degasser; autosampler, ColCom, DMD: Agilent G1315C, 220-320 nm, MSD: Agilent LC/MSD G6130B, ERI, positive/negative 100-800, Column: Waters XSelect™ CSH C18, 30×2.1 mm, 3.5 μm, Temp : 35°C, Flow: 1 ml/min, Gradient: t ₀ =5% A, t _{1.6 min} =98% A, t _{3 min} =98% A, Break time: 1.3 min, Eluent A: 0.1% formic acid in acetonitrile, Eluent B: 0.1% formic acid in water.

GC - method for determination of 1-butanol, dichloromethane, ethyl acetate, isopropanol, methanol: Headspace GC - USP, version 41, chapter <467>"residualsolvents".

Ion chromatography (IC) - method for the determination of chloride, phosphate, sulfate: USP, version 41, chapter <1065> "ion chromatography".

ICP-MS - method for determining the sum of elements, boron, palladium, iron, potassium, sodium: USP, version 41, chapter <233>"elementalimpurities", or Ph. Eur. ( ^9th edition with additions 9.1 - 9.5), chapter 2.2.58.

Coulometric titration for the determination of water: Karl Fischer, coulometric titration, Ph. Eur. ( ^9th edition with additions 9.1 - 9.5), chapter 2.5.32.

X-ray powder diffractometry (RPD):

RPD analyzes were performed using a diffractometer "X'Pert Pro" from PANalytical BV, the Netherlands, equipped with a Cu-emitting X-ray tube (Cu K alpha 1 radiation, wavelength 1.5406 ) and the Pixcel detector system. Samples were analyzed at 25°C in transmission mode and placed between films of low-density polyethylene. HighScore Plus software, version 2.2 s, from PANalytical BV was used, using the following parameters: range 3 - 40° 2θ, step size 0.013°, counting time 99 s, analysis time ~ 22 min. All X-ray reflections are reported as °2θ (theta) values with a resolution of ±0.1°.

List of RPD reflections (2θ values) of Polymorphic form B (=Mod B) of the compound of formula (I)

EXPERIMENTAL SECTION - EXAMPLES

Unless otherwise stated, reactions were carried out under nitrogen atmosphere.

Example 1a

(R)-8-chloro-2-(3-methylmorpholino)-1,7-naphthyridin-4-yl trifluoromethanesulfonate (VIIIb)

To a mixture of (R)-8-chloro-2-(3-methylmorpholino)-1,7-naphthyridin-4-ol (IIa) (20 g, 71.5 mmol) and triethylamine (19.88 ml, 143 mmol, 2 eq.) in dichloromethane (100 ml), a solution of N-phenyl-bis(trifluoromethanesulfonimide) (25.5 g, 71.5 mmol, 1 eq.) in dichloromethane (160 ml) was added dropwise. The resulting reaction mixture was stirred at room temperature overnight, after which HPLC analysis of the sample indicated that all starting material had been consumed. The reaction mixture was poured into water (200 ml) and the resulting mixture was acidified with acetic acid (110 ml) to pH ~ 3.5. After separation, the organic layer was stirred with an aqueous solution of acetic acid (100 ml, pH~3) for 5 min. The organic layer was separated, washed with water (200 ml) and then with 2M potassium carbonate solution (5 x 200 ml) until LCMS analysis of the organic layer indicated that all sulfonamide had been removed. The organic layer was then washed successively with water (200 ml) and brine (200 ml), dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue (23 g) was recrystallized from hot 2-propanol (2 volumes, 46 ml). The next morning, the solids were filtered and washed with 2-propanol (5 ml) to give (R)-8-chloro-2-(3-methylmorpholino)-1,7-naphthyridin-4-yltrifluoromethanesulfonate (VIIIb). 18.91 g (64% yield from theory) as a yellow solid.

^1H NMR (Chloroform-d) δ: 8.17 (d, J=5.5 Hz, 1H), 7.53 (d, J=5.5 Hz, 1H), 7.08 (s, 1H), 4.54 - 4.36 (m, 1H), 4.27 (d, J=12.0 Hz, 1H), 4.11 (dd, J=11.5, 3.8 Hz, 1H), 3.89 (d, J=11.5 Hz, 1H), 3.80 (dd, J=11.6, 3.1 Hz, 1H ), 3.66 (td, J=12.0, 3.0 Hz, 1H), 3.42 (td, J=12.9, 3.9 Hz, 1H), 1.39 (d, J=6.8 Hz, 3H).

LC-MS (method: Scan base): Rt 2.33 min;

MS (ERI positive) m/z=412.1 [M+H] ⁺ .

HPLC (method: Scan base): Rt 3.88 min.

Example 1b

(R)-4-(8-chloro-4-(1-methyl-1H-pyrazol-5-yl)-1,7-naphthyridin-2-yl)-3-methylmorpholine (IXb)

PdCl ₂ (dppf) ( 6.66 g, 9.1 mmol, 3 mol.%). The mixture was heated to 50°C, after which a degassed solution of potassium hydrogen carbonate (122 g, 4 eq.) in water (750 ml) was added to the reaction mixture at 50°C. Immediately thereafter, a solution of 1-methyl-1H-pyrazole-5-boronic acid pinacol ester (VIb) (63.2 g, 304 mmol, 1.0 eq.) in 750 ml of degassed isopropyl acetate was added over 1.5 h. After stirring for an additional hours at 50°C, HPLC analysis indicated complete conversion.

The reaction mixture was filtered through diatomaceous earth and the filter cake was washed with isopropyl acetate (300 ml). After this filtration was performed, the two layers were separated. The aqueous phase was extracted with isopropyl acetate (1×600 ml). The combined organic phases were washed with aqueous 1N. sodium hydroxide solution (4 x 600 ml) to remove traces of hydrolyzed triflate (only ~1% area was formed according to HPLC). The organic phase was washed successively with water (600 ml) and brine (600 ml), and dried over sodium sulfate. After forty minutes, activated carbon (~10 g per 100 g of starting material) was added and the resulting suspension was stirred overnight. The next morning, the solids were filtered off over diatomaceous earth, the filter cake was washed with isopropyl acetate (200 ml) and the filtrate was concentrated to give crude (R)-4-(8-chloro-4-(1-methyl-1H-pyrazol-5-yl )-1,7-naphthyridin-2-yl)-3-methylmorpholine (intermediate (IXb)) as a brown foam (100.5 g, 96%). The crude product was purified by crystallization:

Crude (R)-4-(8-chloro-4-(1-methyl-1H-pyrazol-5-yl)-1,7-naphthyridin-2-yl)-3-methylmorpholine (IXb) was loaded into a 2 L round bottom flask ) (98 g, 268 mmol) and isopropanol (500 ml). When heated to 82°C, a clear brown solution formed. Activated carbon (10 g, 833 mmol) was added and the black suspension was stirred at 82°C for 3 hours. The carbon was removed by filtration through diatomaceous earth using a preheated filtration unit. The filter was washed with 50 ml of isopropanol and the filtrate was concentrated under reduced pressure to obtain 92.87 g of a light brown solid. The filter used to remove the activated carbon was washed with DCM and the yellow filtrate was concentrated in vacuo. The substance was redissolved in 400 ml of isopropanol at 83°C, resulting in a clear dark brown solution. Upon cooling, a light brown solid precipitated. The suspension was stirred for 3 hours at room temperature. The solid was collected by filtration and washed on the filter with isopropanol (2 x 30 ml). After drying, 72.5 g of purified (R)-4-(8-chloro-4-(1-methyl-1H-pyrazol-5-yl)-1,7-naphthyridin-2-yl)-3-methylmorpholine (intermediate (IXb)) (72.5 g, yield from theory 79%).

The mother liquor, which still contained large quantities of expected product, was concentrated in vacuo to give 20.8 g of a brown solid.

¹ H NMR (Chloroform-d) δ: 8.06 (d, J=5.5 Hz, 1H), 7.65 (d, J=1.9 Hz, 1H), 7.15 (d, J=5.4 Hz, 1H), 7.07 (s, 1H), 6.43 (d, J=1.9 Hz, 1H), 4.51 (dt, J=9.3, 4.5 Hz, 1H), 4.34 (dd, J=13.4, 2.8 Hz, 1H), 4.11 (dd, J=11.5 , 3.8 Hz, 1H), 3.88 (d, J=11.4 Hz, 1H), 3.81 (dd, J=11.5, 3.2 Hz, 1H), 3.71 (s, 3H), 3.67 (td, J=11.8, 3.0 Hz , 1H), 3.42 (ddd, J=13.6, 12.4, 4.0 Hz, 1H), 1.40 (d, J=6.8 Hz, 3H).

LC-MS (method: Scan base): Rt 2.02 min; MS (ERI positive) m/z=344.2 [M+H] ⁺ .

HPLC (method: Scan base): Rt 3.24 min.

Example 1c

(3R)-3-methyl-4-(4-(1-methyl-1H-pyrazol-5-yl)-8-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5- yl)-1,7-naphthyridin-2-yl)morpholine (VIIc/VIId)

Intermediate (IXb) (3.0 g, 8.73 mmol) and PdCl ₂ (dppf) (0.192 g, 0.262 mmol) were charged into a 100 ml three-neck round bottom flask. Degassed ethyl acetate (12 mL) was added followed by degassed water (6.0 mL) and anhydrous potassium phosphate (5.56 g, 26.2 mmol). The resulting two-phase reaction mixture was heated to 65°C, after which a solution of 1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-5-boronic acid pinacol ester (IIIc) was added dropwise to the reaction mixture ( 2.91 g, 10.5 mmol) in degassed ethyl acetate (15 ml) for 1 hour (a syringe pump was used for addition). Almost complete conversion was achieved immediately after adding the entire amount of boronic acid ester. The reaction mixture was cooled and concentrated to remove ethyl acetate. Dichloromethane (30 ml) was added followed by water (30 ml, 10.0 volumes). The layers were separated and the organic phase was washed with 2 M potassium carbonate solution (30 ml). The organic phase was then washed with water (4 x 30 ml), dried over sodium sulfate, filtered and concentrated. This resulted in 4.16 g of crude (3R)-3-methyl-4-(4-(1-methyl-1H-pyrazol-5-yl)-8-(1-(tetrahydro-2H-pyran-2-yl)- 1H-pyrazol-5-yl)-1,7-naphthyridin-2-yl)morpholine (intermediate VIIc/VIId) as a brown solid.

According to ¹ H-NMR, the crude product consisted of a 1:1 mixture of diastereoisomers VIIc and VIId.

^1H NMR (Chloroform-d) δ: 8.41 (dd, J=5.5, 2.2 Hz, 1H), 7.71 (d, J=1.8 Hz, 1H), 7.67 (d, J=1.9 Hz, 1H), 7.22 ( dd, J=5.4, 1.4 Hz, 1H), 7.06 (d, J=3.8 Hz, 1H), 7.00 (dd, J=13.3, 1.8 Hz, 1H), 6.45 (t, J=1.7 Hz, 1H), 6.11 (dt, J=9.8, 2.7 Hz, 1H), 4.55 - 4.42 (m, 0.5H), 4.34 (dd, J=7.4, 2.7 Hz, 0.5H), 4.23 (dd, J=13.4, 2.8 Hz, 0.5H), 4.09 - 4.01 (m, 1.5H), 4.01 - 3.91 (m, 1H), 3.83 (dd, J=11.5, 5.7 Hz, 1H), 3.76 (s, 4H), 3.59 (tdd, J= 11.5, 7.9, 2.9 Hz, 1H), 3.47 (tdd, J=11.1, 7.7, 2.5 Hz, 1H), 3.34 (dtd, J=21.7, 12.9, 3.9 Hz, 1H), 2.63 - 2.48 (m, 1H) , 2.11 (td, J=12.9, 3.3 Hz, 2H), 1.81 - 1.58 (m, 3H), 1.35 (dd, J=6.8, 3.3 Hz, 3H).

LC-MS (method: Scan base): Rt 1.98 min;

MS (ERI positive) m/z=460.3 [M+H] ⁺ .

HPLC (method: Scan base): Rt 3.16 min.

The crude mixture of diastereoisomers VIIc and VIId was directly converted into the title compound (I) (see Example Id). Example 1d

2-[(3R)-3-methylmorpholin-4-yl]-4-(1-methyl-1H-pyrazol-5-yl)-8-(1H-pyrazol-5-yl)-1,7-naphthyridine ( I)

To a solution of crude intermediate (VIIc/VIId) (503 mg, 1.095 mmol) in a mixture of dichloromethane (1.50 ml) and methanol (0.15 ml) was added an aqueous solution of hydrochloric acid (1 N, 1.50 ml, 1.5 mmol). The resulting dark brown biphasic mixture was stirred at room temperature for 30 minutes, after which HPLC analysis of the organic and aqueous phases indicated that complete conversion had been achieved. The two-phase mixture was transferred to a separatory funnel using aqueous hydrochloric acid (1 N, 10 ml) and dichloromethane (10 ml). After vigorous shaking, the aqueous layer was separated. The organic phase was further extracted with an aqueous solution of hydrochloric acid (1 N, 10 ml). The combined aqueous phases were washed with dichloromethane (3×10 ml) and then poured into 25 ml of 10% potassium carbonate solution, which resulted in the formation of a blue-green suspension. The suspension was extracted with dichloromethane (4×10 ml). The combined organic layers were washed with brine, dried over sodium sulfate and concentrated under reduced pressure to give 337 mg of a bright yellow brittle foam. This material was transferred to dichloromethane (~8 ml), n-butanol (10 ml) was added and the resulting solution was concentrated under reduced pressure at 40°C to remove the low boiling dichloromethane, leaving approximately 6 ml of a greenish-yellow solution in the flask. The remaining solution was stirred at room temperature overnight. The next morning, the crystallized product was filtered using a glass filter, the bright yellow solid was washed with 1-butanol (3 x 2 ml) and dried under a stream of air to obtain 203 mg of 2-[(3R)-3-methylmorpholin-4-yl] -4-(1-methyl-1H-pyrazol-5-yl)-8-(1H-pyrazol-5-yl)-1,7-naphthyridine (compound (I)) as a bright yellow (micro)-crystalline powder. Concentration of the filtrate gave a further 67 mg of compound (I) as a tan powder.

Yield: 203 mg + 67 mg = 270 mg (total 65.70% of theory).

^1H NMR (Chloroform-d) δ: 12.81 (s, 1H, broad signal), 8.41 (d, J=5.5 Hz, 1H), 7.73 (d, J=1.9 Hz, 1H), 7.67 (d, J= 1.9 Hz, 1H), 7.34 (d, J=1.8 Hz, 1H), 7.17 (t, J=2.7 Hz, 2H), 6.46 (d, J=1.9 Hz, 1H), 4.43 (tt, J=9.2, 4.4 Hz, 1H), 4.19 (dd, J=11.4, 3.9 Hz, 1H), 4.04 (dd, J=12.8, 2.8 Hz, 1H), 3.93 (d, J=11.6 Hz, 1H), 3.86 (dd, J=11.5, 3.1 Hz, 1H), 3.74 (s, 4H), 3.57 (td, J=12.4, 3.9 Hz, 1H), 1.47 (d, J=6.8 Hz, 3H).

LC-MS (method: Scan base): Rt 1.88 min;

MS (ERI positive) m/z=376.2 [M+H] ⁺ .

LC-MS (method: Scan. acid): Rt 1.65 min;

MS (ERI positive) m/z=376.2 [M+H] ⁺ .

HPLC (method: Scan. acid): Rt 2.46 min.

HPLC (method: Scan. acid): Rt 3.41 min.

Example 1e

(3R)-3-methyl-4-(4-0-methyl-1H-pyrazol-5-yl)-8-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl )-1,7-naphthyridin-2-yl)morpholine (VIIc/VIId)

Intermediate (IXb) (3.0 g, 8.73 mmol) and PdCl ₂ (dppf) (0.192 g, 0.262 mmol) were charged into a 100 ml three-neck round bottom flask. Degassed isopropyl acetate (12 mL) was added followed by degassed water (6.0 mL) and anhydrous potassium phosphate (2.86 g, 17.5 mmol). The resulting two-phase reaction mixture was heated to 55°C, after which a solution of 1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-5-boronic acid pinacol ester (IIIc) was added dropwise to the reaction mixture ( 2.91 g, 10.5 mmol) in degassed isopropyl acetate (15 ml) over 1 hour (a syringe pump was used for addition). After addition was complete, the reaction mixture was continued to stir at 55°C overnight (16 hours). The reaction mixture was sequentially cooled to room temperature and filtered through a celite pad to remove interfacial material. The layers were separated and the organic phase was washed with 2 M potassium carbonate solution (30 ml). Water (30 ml) was added to the organic phase and the layers were allowed to separate. Before complete separation of the two phases, the mixture was filtered through a celite pad to remove interfacial material. The organic phase was washed 3 more times with water (3 x 30 ml), dried over sodium sulfate, filtered and concentrated. This resulted in 2.88 g of crude (3R)-3-methyl-4-(4-(1-methyl-1H-pyrazol-5-yl)-8-(1-(tetrahydro-2H-pyran-2-yl)- 1H-pyrazol-5-yl)-1,7-naphthyridin-2-yl)morpholine (intermediate VIIc/VIId) as a brown solid. According to ¹ H-NMR, the crude product consisted of a 1:1 mixture of diastereoisomers.

Example 2a

(R)-8-chloro-2-(3-methylmorpholino)-1,7-naphthyridin-4-yl trifluoromethanesulfonate (VIIIb)

100 g (357.49 mmol) (R)-8-chloro-2-(3-methylmorpholino)-1,7-naphthyridin-4-ol (IIa) was suspended in 800 ml of dichloromethane at room temperature (~22°C). Then 40.48 ml (500.485 mmol) of pyridine was added and the mixture was cooled to -10°C. At -10°C, 84.2 ml (500.485 mmol) of trifluoromethanesulfonic anhydride dissolved in 250 ml of dichloromethane was added to the mixture (30 min, temperature increased to -6°C). After addition was complete, the mixture was stirred for 1 hour at -10°C. 400 ml of water was slowly added, maintaining the temperature between 0 and 4°C. The phases were separated. The organic phase was washed with 400 ml of water. The organic phase was washed twice with 0.5 M aqueous potassium carbonate solution, each time with a portion of 200 ml, and once with 150 ml of water. The organic phase was filtered through an activated carbon filter and the volume of the filtrate was reduced to -100 ml by distilling off the dichloromethane under reduced pressure. 400 ml of isopropanol were added and again distilled under reduced pressure to a volume of ~ 100 ml (at 50°C). This operation was performed again. Finally, 240 ml of isopropanol was added and heated to 50°C. The mixture was stirred over the weekend and finally cooled to 0-3°C. The crystals were collected by filtration and washed with 100 ml of isopropanol. The product was dried under vacuum (20 mbar) at 45°C overnight. Yield: 113.87 g (77.35% of theory) yellow crystals.

HPLC: 100% (% area) for 7.4 min.

Example 2b

(R)-4-(8-chloro-4-(1-methyl-1H-pyrazol-5-yl)-1,7-naphthyridin-2-yl)-3-methylmorpholine (IXb)

100 g (242.842 mmol) (L)-8-chloro-2-(3-methylmorpholino)-1,7-naphthyridin-4-yl trifluoromethanesulfonate (VHIb) and 5.3 g (7.285 mmol) PdCl ₂ (dppf) were dissolved in 400 ml of ethyl acetate and heated to 50°C. To this mixture was added a solution of 97.2 g (971.370 mmol) of potassium hydrogen carbonate in 600 ml of water, and the temperature was maintained at 40°C. To this mixture was added a solution of 48.00 g (230.70 mmol) of 1-methyl-1H-pyrazole-5-boronic acid pinacol ester (VIb) in 300 ml of ethyl acetate over 3 h (at an internal temperature of 40°C). The reaction mixture was cooled to room temperature (+22°C) and the phases were separated. The aqueous phase was extracted with 300 ml ethyl acetate and the combined organic phases were washed twice with 1 N. an aqueous solution of potassium hydroxide, each time with a portion of 750 ml, and twice with water, each time with a portion of 500 ml. During the last wash, 10 ml of brine was added for better phase separation. The organic phase was dried over 100 g of sodium sulfate, filtered and the filter cake was washed with 200 ml of ethyl acetate. Then 70 g of activated carbon was added to the filtrate and the suspension was stirred for 2 hours at room temperature. The carbon was removed by filtration through diatomaceous earth (50 g) and the filter was washed with 100 ml ethyl acetate. Solvent replacement was performed by adding isopropanol and distilling off ethyl acetate at 85°C. When the volume of isopropyl acetate reached ~200 ml (internal temperature 85°C), the mixture was cooled to room temperature (by stirring overnight). The crystals were separated by filtration and washed with 20 ml of isopropanol. The product was dried under vacuum (20 mbar) at 45°C overnight. Yield: 63.2 g (75.7% of theory) yellow crystals.

HPLC: 99.7% (% area) at 11.9 min

Example 2 with

2-[(3R-3-methylmorpholin-4-yl]-4-(1-methyl-1H-pyrazol-5-yl)-8-(1H-pyrazol-5-yl)-1,7-naphthyridine (I )

120 g crude (3R)-3-methyl-4-(4-(1-methyl-1H-pyrazol-5-yl)-8-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole -5-yl)-1,7-naphthyridin-2-yl)morpholine (VIIc/VIId) was dissolved in 480 ml of dichloromethane and 480 ml of methanol and cooled to 0-5°C. Then 1200 ml of 1 N was added. an aqueous solution of hydrochloric acid, during which the temperature increased to 20°C. The mixture was stirred for 5 minutes at 20° C. and then the phases were separated and the aqueous phase was extracted twice with dichloromethane, each time with a portion of 480 ml. 46.6 g of N-acetylcysteine was added to the aqueous phase and the solution was stirred at room temperature overnight. 960 ml of dichloromethane were then added and the mixture was cooled to 10°C. The pH value was adjusted to pH=13 by adding 480 ml of 5 N. aqueous solution of potassium hydroxide. The solution was stirred for 30 minutes. The phases were separated and the aqueous phase was extracted with 252 ml of dichloromethane. The organic phases were combined and the solvent, dichloromethane, was replaced with n-butanol: the filtrate was slowly added to 631.5 ml of n-butanol at 110°C, and dichloromethane was distilled off. The mixture was cooled to 22°C and stirred overnight, then cooled to 0-3°C and stirred for 1 hour at this temperature. The product was isolated by filtration and the crystals were washed twice with cold n-butanol, each time with a portion of 160 ml. The product was dried under vacuum (20 mbar) at 45°C overnight. Yield: 62.87 g (64.13% of theory) yellow crystals.

HPLC: 99.48% (area%) at 4.3 min.

Example 2d

2-[(3R)-3-methylmorpholin-4-yl]-4-(1-methyl-1H-pyrazol-5-yl)-8-(1H-pyrazol-5-yl)-1,7-naphthyridine ( I)

Under nitrogen atmosphere 30 g (87.255 mmol) (R)-4-(8-chloro-4-(1-methyl-1H-pyrazol-5-yl)-1,7-naphthyridin-2-yl)-3-methylmorpholine (IXb) was dissolved in 105.8 ml of ethyl acetate and 1.91 g (2.618 mmol) of PdCl ₂ (dppf) was added. Then 53.1 ml of water and 55.56 g of potassium phosphate were added. This mixture was stirred for 30 minutes at 22°C. The internal temperature was raised to 55°C. At 5°C, a solution of 31.55 g (113.43 mmol) of 1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-boronic acid (IIIc) pinacol ester in 162.2 ml of ethyl acetate was added over 120 min, maintaining constant temperature at 55°C. The mixture was cooled to 35°C and ethyl acetate was distilled off in vacuum (at 110 mbar, ~100 ml ethyl acetate). Then 164.4 ml of dichloromethane and 255.6 ml of water were added. The phases were separated and the aqueous phase was extracted with 84.5 ml of dichloromethane. The combined organic phases were extracted twice with 1 N. an aqueous solution of potassium hydroxide, each time in a portion of 147 ml. The phases were separated and the organic phase was treated with activated carbon (21 g of activated carbon was added and the suspension was stirred overnight at 22°C). The carbon was removed by filtration through diatomaceous earth and the filter cake was washed with 40 ml of dichloromethane. A mixture of 14.23 g of N-acetylcysteine and 7.8 g of potassium hydroxide dissolved in 217.1 ml of water (pH=9) was added to the filtrate. The two-phase mixture was stirred for 8 hours at 20°C. The phases were separated and the organic phase was dried over 35.3 g of sodium sulfate, which was then filtered and washed twice with dichloromethane, each time with a portion of 35 ml. The solution was stored in the refrigerator and then used in the next stage of the method. To this solution (~350 ml) 160 ml of methanol was added and the solution was cooled to 0-5°C. Then 400 ml of 1 N was added. aqueous solution of hydrochloric acid and stirred for 30 minutes at room temperature. The phases were separated and the aqueous phase was extracted twice with dichloromethane, each time with a portion of 160 ml. 14.2 g of N-acetylcysteine was added to the aqueous phase (pH=1) and the solution was stirred overnight at 20°C. Then 320 ml of dichloromethane was added and the pH was adjusted to pH=13 by adding 160 ml of 5N. aqueous solution of potassium hydroxide. The solution was stirred for 30 minutes. The phases were separated and the aqueous phase was washed with 84 ml of dichloromethane. The dichloromethane solvent was replaced with n-butanol: the filtrate was slowly added to 212 ml of n-butanol at 110°C and dichloromethane was distilled off. The mixture was cooled overnight to 22°C, then cooled to 0-3°C and stirred for 1 hour at this temperature. The product was isolated by filtration and the crystals were washed with 20 ml of cold n-butanol. The product was dried under vacuum (20 mbar) at 45°C overnight. Yield: 25.60 g (78.34% of theory) yellow crystals.

HPLC: 99.48% (area%) at 4.3 min.

Example 2 e

2-[(3R)-3-methylmorpholin-4-yl]-4-(1-methyl-1H-pyrazol-5-yl)-8-(1H-pyrazol-5-yl)-1,7-naphthyridine ( I)

22.5 g (59.93 mmol) 2-[(3R)-3-methylmorpholin-4-yl]-4-(1-methyl-1H-pyrazol-5-yl)-8-(1H-pyrazol-5-yl)- 1,7-naphthyridine (I) from example 2d was dissolved in 156.4 ml of dichloromethane, 6.75 g of quadrasyl-mercaptopropyl (Pd absorber from Johnson Matthey, CAS number 1225327-73-0) and 6.75 g of Si-TMT isolute (silica gel-bound equivalent of 2,4,6-trimercaptotriazine (TMT), Pd absorbent from Biotage AB, Sweden, catalog no. 9538-1000) and the suspension was stirred for 22 hours at 20°C. The suspension was filtered and the filter cake was washed twice with dichloromethane, each time with a portion of 46.8 ml. The solvent, dichloromethane, was replaced with n-butanol: the filtrate was slowly added to 85 ml of n-butanol at 105°C, and dichloromethane was distilled off. Finally, the temperature was raised to 105° C. (internal temperature) and then all dichloromethane was removed. The mixture was cooled overnight to 22°C, then cooled to 0-3°C and stirred for 1 hour at this temperature. The product was isolated by filtration and the crystals were washed with 24 ml of cold n-butanol. The product was dried under vacuum (20 mbar) at 45°C overnight. Yield: 19.50 g (86.67% of theory) yellow crystals.

HPLC: 99.97% (area %).

Boron content: <1 ppm

Palladium content: <1 ppm

Polymorphic form of compound (I): B.

Example 3a

(R)-8-chloro-2-(3-methylmorpholino)-1,7-naphthyridin-4-yl trifluoromethanesulfonate (VIIIb)

To a suspension of (R)-8-chloro-2-(3-methylmorpholino)-1,7-naphthyridin-4-ol (IIa) (100 g, based on cNMR purity 90 wt. %) in dichloromethane (1.00 l ) triethylamine (63 mL, 450 mmol) was added at room temperature, resulting in the formation of a clear brown solution. The reaction mixture was cooled to 0°C (internal temperature) using an ice-salt bath. With vigorous stirring, trifluoromethanesulfonic anhydride (0.076 L, 450 mmol) was added dropwise over 10 min, resulting in a temperature increase of 10°C. By the time the last amount of trifluoromethanesulfonic anhydride was added, the internal temperature had already dropped. A sample (s1, taken 5 minutes after completion of the addition of trifluoromethanesulfonic anhydride) was analyzed by HPLC, which indicated that almost complete conversion of the starting material had occurred. The ice and salt bath was removed and water (500 ml) was added. The resulting two-phase mixture was stirred vigorously for 1 minute. The aqueous phase was separated and the organic phase was further washed with water (2×500 ml) to remove any residual triethylamine and trifluoromethanesulfonic anhydride. Then the organic layer was washed with saturated aq. potassium carbonate solution (500 ml), dried over sodium sulfate, filtered and concentrated under reduced pressure to a volume of 250 ml. Isopropanol (300 ml) was added and the mixture was further concentrated to a volume of -300 ml (290 g of product solution was weighed out). Additional isopropanol (100 ml, up to the planned 2 volumes) was added and the resulting mixture was left to stand overnight to allow the product to crystallize.

The next morning a solid precipitate of crystalline substance formed. The solid was loosened by scraping it with a spatula, after which the mixture was stirred with a magnetic stirrer to break large lumps into smaller particles (2 hours). The solids were filtered and dried in a stream of air to obtain 110.3 g (83%) (R)-8-chloro-2-(3-methylmorpholino)-1,7-naphthyridin-4-yl trifluoromethanesulfonate (intermediate (VIIIb)) in as a dark yellow crystalline powder that still contained a few large clumps. HPLC purity 98% area. The mother liquor was concentrated until 80 g of solution remained in the flask, which made it possible to isolate a second portion of the product weighing 6.26 g (4.7%).

Example 3b

(R)-4-(8-chloro-4-(1-methyl-1H-pyrazol-5-yl)-1,7-naphthyridin-2-yl)-3-methylmorpholine (IXb)

PdCl ₂ (dppf) ( 6.66 g, 9.1 mmol, 3 mol.%). The mixture was heated to 50°C, after which a degassed solution of potassium hydrogen carbonate (122 g, 4 eq.) in water (750 ml) was added to the reaction mixture at 50°C. Immediately thereafter, a solution of 1-methyl-1H-pyrazole-5-boronic acid pinacol ester (VIb) (63.2 g, 304 mmol, 1.0 eq.) in 750 ml of degassed isopropyl acetate was added over 1.5 hours. After stirring for an additional hour at 50°C, HPLC analysis indicated complete conversion.

The reaction mixture was filtered through diatomaceous earth and the filter cake was washed with isopropyl acetate (300 ml). After this filtration was performed, the two layers were separated. The aqueous phase was extracted with isopropyl acetate (1*600 ml). The combined organic phases were washed with 1 N. aqueous sodium hydroxide solution (4 × 600 ml) to remove traces of hydrolyzed triflate (according to HPLC, only ~1% area was formed). The organic phase was washed successively with water (600 ml) and brine (600 ml) and dried over sodium sulfate. After forty minutes, activated carbon (~10 g per 100 g of starting material) was added and the resulting suspension was stirred overnight. The next morning, the solids were filtered off with diatomaceous earth, the filter cake was washed with isopropyl acetate (200 ml) and the filtrate was concentrated to give crude (R)-4-(8-chloro-4-(1-methyl-1H-pyrazol-5-yl )-1,7-naphthyridin-2-yl)-3-methylmorpholine (IXb) as a brown foam (100.5 g, 96%).

Purification of crude intermediate (IXb)

Crude (R)-4-(8-chloro-4-(1-methyl-1H-pyrazol-5-yl)-1,7-naphthyridin-2-yl)-3-methylmorpholine (IXb) was loaded into a 2 L round bottom flask ) (98 g, 268 mmol) and isopropanol (500 ml). When heated to 82°C, a clear brown solution formed. Activated carbon (10 g, 833 mmol) was added and the black suspension was stirred at 82°C for 3 hours. The carbon was removed by filtration through diatomaceous earth using a preheated filtration unit. The filter was washed with 50 ml of isopropanol and the filtrate was concentrated under reduced pressure to obtain 92.87 g of a light brown solid. The filter used to remove the activated carbon was washed with dichloromethane and the yellow filtrate was concentrated in vacuo. The substance was redissolved in 400 ml of isopropanol at 83°C, resulting in a clear dark brown solution. Upon cooling, a light brown solid precipitated. The suspension was stirred for 3 hours at room temperature. The solid was collected by filtration and washed on the filter with isopropanol (2 x 30 ml). After drying, 72.5 g of purified (R)-4-(8-chloro-4-(1-methyl-1H-pyrazol-5-yl)-1,7-naphthyridin-2-yl)-3-methylmorpholine (IXb) was collected (72.5 g, yield 79%). The mother liquor, which still contained large quantities of expected product, was concentrated in vacuo to give 20.8 g of a brown solid.

Example 4a

(R)-8-chloro-2-(3-methylmorpholino)-1,7-naphthyridin-4-yl-trifluoromethanesulfonate (VIIIb)

3.00 kg of (R)-8-chloro-2-(3-methylmorpholino)-1,7-naphthyridin-4-ol (IIa) was dissolved in 31.9 kg of dichloromethane at 20°C. 1190 g of pyridine were then added. The solution was cooled to -10°C (internal temperature) and a solution of 4.236 kg bis(trifluoromethanesulfonic anhydride) in 10 kg dichloromethane was added, maintaining the internal temperature at -10°C. The addition time was approximately 1 hour. After completion of the reaction, 12.0 kg of water was added, maintaining the internal temperature in the range of 0°C - 15°C. After addition, the mixture was stirred for 5 minutes. The organic phase was separated and washed with 12.0 kg of water. The organic phase was washed 2 times with 0.5 N. an aqueous solution of potassium carbonate, each time in a portion of 6 kg, and finally 4.5 kg of water. The organic phase was filtered through activated carbon (Seitz activated carbon filter plates) and the filtrate was distilled to isopropanol (solvent exchange). First, dichloromethane was distilled off in vacuum (100 mbar) to obtain a concentrated solution (until it was stirrable), then 9.5 kg of isopropanol was added and distilled again (100 mbar) (until the solution was stirrable). Another 9.5 kg of isopropanol was added and distilled again (until the solution was stirrable), and finally 1 kg of isopropanol was added (total ~ 8-9 kg of isopropanol).

For crystallization, the temperature was reduced from 50°C to 18°C over 90 min (linear). The mixture was stirred for 12 min at 18°C and then cooled to 0°C (linear over 180 min). The mixture was then stirred for 60 minutes at 0°C. The crystals were separated by filtration and washed with 2.4 kg of cold isopropanol. The product was dried in vacuum at 45°C for at least 12 hours (to constant weight).

Four batches were prepared according to this protocol:

Example 4b

(R)-4-(8-chloro-4-(1-methyl-1H-pyrazol-5-yl)-1,7-naphthyridin-2-yl)-3-methylmorpholine (IXb)

Under a nitrogen atmosphere, 2.1 kg of (R)-8-chloro-2-(3-methylmorpholino)-1,7-naphthyridin-4-yltrifluoromethanesulfonate (VIIIb) was dissolved in 8.4 L of ethyl acetate and 112 g of PdCl ₂ (dppf) was added. The solution was heated to 50°C (internal temperature) and then 2.042 kg of potassium bicarbonate (KHCO ₃ ) dissolved in 11.0 L of water was added, followed by the addition of 1.6 L of water (to clean the tubes). The internal temperature was set to 43°C and then 1.061 kg of 1-methyl-1H-pyrazole-5-boronic acid pinacol ester dissolved in 6.0 L of ethyl acetate was added over 3 hours, maintaining the internal temperature at 43°C. After addition was complete, the mixture was stirred for 75 minutes at 43°C.

Isolation of the reaction product: the mixture was cooled to 22°C and the organic phase was separated (~15.4 L). The aqueous phase was extracted with 6.3 L of ethyl acetate. The organic phases were combined and cooled to 10°C and then washed with 15.75 L of 5.3% aqueous potassium hydroxide solution (stirring was performed for 15 min at 10°C). The phases were separated and the organic phase was washed again at 10°C with 15.75 L of 5.3% aqueous potassium hydroxide solution. After this, the organic phase was separated and washed twice with water, each time with a portion of 10.5 l. 2.10 kg of magnesium sulfate was added to the organic phase and stirred for 70 min at 22°C. Then the magnesium sulfate was filtered off and washed twice with ethyl acetate, each time with a portion of 4.2 liters. 1.47 kg of activated carbon was added to the filtrate and the suspension was stirred for 2.5 hours at 22°C. The activated carbon was removed by filtration through diatomaceous earth and washed with ethyl acetate (twice, each time with a portion of 4.2 L). 27.0 kg of filtrate (product in ethyl acetate) was obtained.

In accordance with this protocol, five batches were obtained:

Crystallization from isopropanol:

27.0 kg (administration 1) and 32.0 kg (administration 2) (R)-4-(8-chloro-4-(1-methyl-1H-pyrazol-5-yl)-1,7-naphthyridin-2-yl) -3-methylmorpholine (IXb) in ethyl acetate (total: 59.0 kg) was combined and solvent exchanged to isopropanol. Ethyl acetate was distilled off at normal pressure (internal temperature: 73°C at the beginning, 78°C at the end). When 57.5 L had been distilled, 10.5 kg of isopropanol was added and 13.5 L of liquid was distilled (at normal pressure, internal temperature: 81°C at the beginning, 83°C at the end). Another 10.5 kg of isopropanol was added and 13.5 L of liquid was distilled (at normal pressure, internal temperature: 80°C at the beginning 83°C at the end). Then another 10.5 kg of isopropanol was added and 14.0 L of liquid was distilled (at normal pressure, internal temperature: 82°C at the beginning, 84-85°C at the end). The solution was cooled to 18°C (linearly over 420 min). The suspension was stirred for 1 hour at 20°C. The product was isolated by filtration and washed with isopropanol (total 2.4 kg). The product was dried in vacuum at 50°C for at least 12 hours (to constant weight). Yield: 2.69 kg (77% of theory)

Similarly, injection batches 3-5 were combined (78.2 kg total) and the same solvent exchange was performed to yield 4.042 kg (77% of theory) of product.

The following table summarizes the results:

The following table summarizes the analytical results of two batches (2.69 kg batch IXb and 4.042 kg batch IXb):

Example 4c

2-[(3R)-3-methylmorpholin-4-yl]-4-(1-methyl-1H-pyrazol-5-yl)-8-(1H-pyrazol-5-yl)-1,7-naphthyridine ( I)

Under a nitrogen atmosphere, 3.40 kg of (R)-4-(8-chloro-4-(1-methyl-1H-pyrazol-5-yl)-1,7-naphthyridin-2-yl)-3-methylmorpholine (IXb) was dissolved in 10.8 kg of ethyl acetate and 221 g of PdCl ₂ (dppf) was added. Then 6.0 kg of water and 6.2 kg of potassium phosphate were added. This mixture was stirred for 30 minutes at 22°C. The internal temperature was raised to 55°C. At 55°C, a solution of 3.58 kg of 1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-boronic acid pinacol ester (IIIc) in 16.4 kg of ethyl acetate was added over 120 min, maintaining a constant temperature at 55°C, and the resulting mixture was stirred at 200 rpm. 2 kg of ethyl acetate was added (used to rinse the tubes). After addition, the mixture was stirred for 10 minutes at 55°C.

To isolate the reaction product, the temperature was reduced to 35°C and 26.6 kg of ethyl acetate was distilled off in vacuum. The mixture was cooled to 20°C and 24.7 kg of dichloromethane and 29.0 kg of water were added. The mixture was stirred for 10 minutes. The organic phase was separated and the aqueous phase was extracted with 12.8 kg of dichloromethane. The combined organic phases were washed with 17.7 kg 1 N. aqueous solution of potassium hydroxide (stirring was performed for 10 minutes). The phases were separated and the organic phase was again washed with 17.7 kg 1N. aqueous solution of potassium hydroxide (stirring for 10 minutes). The organic phase was separated and filtered through activated carbon (Seitz activated carbon filter plates) for 3 hours (circulating the filtrate). The activated carbon was washed twice with dichloromethane, each time with a portion of 13.3 kg, and once with 6.6 kg of dichloromethane. The combined filtrates were added to a solution of 1.61 N-acetylcysteine in 9.0 kg aqueous potassium hydroxide solution (1099 g potassium hydroxide dissolved in 8.0 kg water). The mixture was stirred for 18 hours at 20°C. The phases were separated. 35.72 kg of organic phase was obtained.

Similarly, a total of 3 batches, based on 3.40 kg of (R)-4-(8-chloro-4-(1-methyl-1H-pyrazol-5-yl)-1,7-naphthyridin-2-yl)-3- methylmorpholine (IXb) was converted to (3R)-3-methyl-4-(4-(1-methyl-1H-pyrazol-5-yl)-8-(1-(tetrahydro-2H-pyran-2-yl) -1H-pyrazol-5-yl)-1,7-naphthyridin-2-yl)morpholine (VIIc/VIId) in dichloromethane:

Three batches were divided into 6 portions (half of each batch) and each batch was processed into the next reaction step.

The approach is described for a split batch of 17.8 kg (VIIc/VIId) in dichloromethane.

17.8 kg (VIIc/VIId) in dichloromethane was taken from the barrel and the barrel was washed with 800 g of dichloromethane. Then 9 liters of dichloromethane were distilled off at normal pressure (60°C). The solution was cooled to 22°C and 3.3 kg of dichloromethane and 7.2 kg of methanol were added. The mixture was cooled to 0-5°C and 16.8 kg of aqueous hydrochloric acid solution was added, maintaining the temperature between 0 and 20°C. The mixture was stirred for 10 minutes at 20-22°C. The phases were separated and the aqueous phase was extracted twice with dichloromethane, each time with a portion of 8.8 kg. The aqueous phase was separated and 800 g of N-acetylcysteine was added and the solution was stirred for 12 hours at 20°C. Then 17.6 kg of dichloromethane was added and 8246 g of 5N were added. aqueous potassium hydroxide solution, and the mixture was stirred for 30 minutes. The final pH value of the aqueous phase was pH=13.6 (at this point the pH should be 12-14). The phases were separated, the aqueous phase was extracted with 5.2 kg of dichloromethane and the organic phases were combined. 22.7 kg of compound (I) were obtained in dichloromethane.

The following table summarizes the results of 6 batches obtained using the described method:

For the next step of the process, twice 3 batches of the previous batches obtained were combined and converted into the final product:

Changing the dichloromethane solvent to n-butanol: combine 23.9 kg, 23.6 kg and 23.0 kg of compound (I) (total 70.5 kg + 5.0 kg wash) and slowly add to 16.6 kg n-butanol, which was preheated to 98°C. At normal pressure, 59 liters of dichloromethane were distilled off. The internal temperature during distillation was 81 - 90°C. Then 5.0 kg of dichloromethane, which was used to clean the tubes, was also distilled off (5 L). 15.5 kg of n-butanol was added and 10 liters of liquid were distilled off at normal pressure (88 - 93°C). The temperature was raised to 108°C (internal temperature, 100 ml of n-butanol was distilled off). At this point there was no more dichloromethane left. The solution was cooled to 20-22°C (over 7 hours (linear)). The suspension was stirred for 1 hour at 20°C, then cooled to 2-3°C, and stirred for 1 hour at this temperature. The crystals were separated by filtration and washed with 8.0 kg of cold n-butanol. The crude filter cake containing product (I) was dissolved directly on the filter (without isolation) using 47.5 kg of warm 30°C dichloromethane (if this amount is not enough, more dichloromethane can be used and then distilled off). The solution was cooled to 20°C and 1020 g of quadrasyl mercaptopropyl (Pd absorbent from Johnson Matthey, CAS number 1225327-73-0) and 1020 g of Si-TMT isolute (silica gel-bound equivalent of 2,4,6-trimercaptotriazine (TMT)) were added ), Pd absorber from Biotage AB, Sweden, catalog no. 9538-1000). The suspension was stirred for 12 hours at 20-21°C. The suspension was filtered and the filter cake was washed with dichloromethane twice, each time with a portion of 13.3 kg. The filtrate was filtered again (particle filtration according to GMP).

Final crystallization method

Replacing the solvent - dichloromethane with n-butanol: the filtrate of compound (I) was slowly added to 16.5 kg of n-butanol, which was preheated to 98°C. At normal pressure, 53 liters of dichloromethane were distilled off. The internal temperature during distillation was 93 - 98°C. Then 5.0 kg of dichloromethane, which was used to clean the tubes, was also distilled off (4 L). 9.0 kg of n-butanol was added and 10.5 liters were distilled off at normal pressure (90 - 91°C). The temperature was raised to 109°C (internal temperature, 100 ml of n-butanol was distilled off). At this point there was no more dichloromethane left. The solution was cooled to 20-22°C (over 7 hours (linear)). The suspension was stirred for 1 hour at 20°C, then cooled to 2-3°C, and stirred for 1 hour at this temperature. The crystals were separated by filtration and washed with 8.0 kg of cold n-butanol. The product was dried under vacuum (30 mbar) at 50°C for at least 12 hours (to constant weight).

3.753 kg (67% of theory) of yellow crystals were obtained.

Example 5

Production cycle of the pilot plant

We carried out the production cycle of a pilot plant. Six batches (each 16.3 kg) were converted in the same manner as described in example 4c (without cleaning the reactors and filtration units during the production run). A total of 97.8 kg (HCL) gave 75.4 kg of the target compound (I)

Two of these batches (administration 1 - 10.40 kg I and injection 2 - 13.50 kg I) were combined and analyzed.

Example 6

2-[(3R-3-methylmorpholin-4-yl1-4-(1-methyl-1H-pyrazol-5-yl)-8-(1H-pyrazol-5-yl)-1,7-naphthyridine (I)

Under nitrogen atmosphere 30 g (87.255 mmol) (R)-4-(8-chloro-4-(1-methyl-1H-pyrazol-5-yl)-1,7-naphthyridin-2-yl)-3-methylmorpholine (IXb) was dissolved in 105.8 ml of ethyl acetate and 1.91 g (2.618 mmol) of PdCl ₂ (dppf) was added. Then 53.1 ml of water and 55.56 g of potassium phosphate were added. This mixture was stirred for 30 minutes at 22°C. The internal temperature was raised to 55°C. At 55°C, a solution of 31.55 g (113.43 mmol) of 1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-boronic acid (IIIc) pinacol ester in 162.2 ml of ethyl acetate was added over 120 min, maintaining constant temperature at 55°C. The mixture was cooled to room temperature (~22°C) and 150 ml of water was added. The phases were separated and the aqueous phase was extracted with 100 ml of ethyl acetate. The combined organic phases were treated with activated carbon (21 g of activated carbon was added and the suspension was stirred overnight at 22°C). The carbon was removed by filtration through diatomaceous earth and the filter cake was washed with 30 ml of ethyl acetate. 100 ml of methanol and 300 ml of 1 N were added to the filtrate. aqueous solution of hydrochloric acid and stirred for 30 minutes at room temperature. The phases were separated and the aqueous phase was extracted with 100 ml of ethyl acetate. 14.82 g of N-acetylcysteine was added to the aqueous phase (pH=1) and the solution was stirred overnight at 20°C. 300 ml of dichloromethane was added and the pH was adjusted to pH=13 by adding 190 ml of 5N. aqueous solution of potassium hydroxide. The solution was stirred for 30 minutes.

The phases were separated and the organic phase was washed with 150 ml of water. To the organic phase were added 6 g of quadrasyl mercaptopropyl (Pd scavenger from Johnson Matthey, CAS number 1225327-73-0) and 6 g of Si-TMT isolute (silica gel-bound equivalent of 2,4,6-trimercaptotriazine (TMT), Pd scavenger from Biotage AB, Sweden, catalog no. 9538-1000), and the suspension was stirred overnight at 20°C. The suspension was filtered and the filter cake was washed twice with dichloromethane, each time with a portion of 25 ml. The solvent - dichloromethane was replaced with n-butanol: the filtrate was slowly added to 60 ml of n-butanol at 85°C and dichloromethane was distilled off. Finally, the temperature was raised to 105° C. (internal temperature) and then all dichloromethane was removed. The mixture was cooled overnight to 22°C, then cooled to 0-3°C, and stirred for 1 hour at this temperature. The product was isolated by filtration and the crystals were washed with 20 ml of cold n-butanol. The product was dried under vacuum (20 mbar) at 45°C overnight. Yield: 21.27 g (64.93% of theory) yellow crystals.

HPLC: 99.19% (area %).

Boron content: <1 ppm

Palladium content: <1 ppm

Modification (Mod.): V.

Claims (95)

1. Method for preparing the compound of formula (I) or its tautomer of formula (Ia) or mixtures thereof, wherein said method includes the following sequential steps: (a) carrying out the reaction of the intermediate compound of formula (IXa) Where R ¹ represents a chlorine, bromine or iodine atom; with a compound of formula (IIIa) or (IIIb) or a mixture thereof, where R ² and R ³ represent, independently of each other, a hydrogen atom or a C ₁ -C ₆ alkyl group; or R ² and R ³ together represent a -CH ₂ -CH ₂ - group or -CH ₂ -CH ₂ -CH _{2 -} group, wherein said -CH ₂ -CH ₂ - group or -CH ₂ -CH ₂ -CH ₂ - the group is optionally substituted one, two, three or four times with a group selected from methyl and ethyl; or R ² and R ³ together represent the group where "*" represents the site of attachment to the rest of the molecule; And R ⁴ represents a tetrahydro-2H-pyran-2-yl group; to obtain an intermediate of formula (VIIa) or (VIIb) or mixtures thereof, where R ⁴ represents a tetrahydro-2H-pyran-2-yl group; And (b) removing the R ⁴ group from the intermediate of formula (VIIa) or (VIIb), thereby providing a compound of formula (I), or a tautomer of formula (Ia), or a mixture thereof. 2. Method according to claim 1, wherein the compound of formula (IXa) is (R)-4-(8-chloro-4-(1-methyl-1H-pyrazol-5-yl)-1,7-naphthyridin-2-yl)-3-methylmorpholine; and/or wherein the compound of formula (IIIa) is 1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-5-boronic acid pinacol ester; and/or wherein the compound of formula (VIIa) is (3R)-3-methyl-4-(4-(1-methyl-1H-pyrazol-5-yl)-8-(1-(tetrahydro-2H-pyran-2-yl )-1H-pyrazol-5-yl)-1,7-naphthyridin-2-yl)morpholine. 3. Method according to claim 1 or 2, wherein the reaction of an intermediate of formula (IXa) with a compound of formula (IIIa) or formula (IIIb) is carried out in the presence of a palladium catalyst and/or a base. 4. Method according to any one of paragraphs. 1-3, wherein the reaction of an intermediate of formula (IXa) with a compound of formula (IIIa) or (IIIb) is carried out in an organic solvent, where the solvent includes isopropyl acetate, ethyl acetate, 1,2-dimethoxyethane, 1,4-dioxane, dimethylformamide, tetrahydrofuran, 2-methyltetrahydrofuran, methanol, ethanol, 1-propanol, isopropanol, 1-butanol or 2-butanol; or wherein said reaction is carried out in a solvent mixture comprising one or more of said solvents and water. 5. Method according to any one of paragraphs. 1-4, wherein the R ⁴ group is removed from the intermediate of formula (VIIa) or (VIIb) by reacting the intermediate of formula (VIIa) or (VIIb) with an acid in a solvent or mixture of solvents. 6. Method according to any one of paragraphs. 1-5, wherein the intermediate of formula (VIIa) or (VIIb) is a compound of formula 7. Method according to any one of paragraphs. 1-6, wherein the intermediate of formula (VIIa), (VIIb), (VIIc), (VIId) or (VIIc/VIId) is not isolated and/or purified before the step of removing the R ⁴ group from the intermediate of formula (VIIa), VII(b), (VIIc), (VIId) or (VIIc/VIId). 8. Method according to any one of paragraphs. 1-7, wherein the R ⁴ group is removed from the intermediate of formula (VIIa) or (VIIb) by reacting the intermediate of formula (VIIa) or (VIIb) with an aqueous solution of hydrochloric acid in a solvent mixture comprising dichloromethane, methanol and water, with by obtaining a crude compound of formula (I) dissolved in an acidified aqueous phase, wherein the pH of the resulting acidified aqueous solution is less than 3 (pH<3). 9. Method according to claim 8, where (a) an acidified aqueous solution of the crude compound of formula (I) is extracted one or more times with solvent A, where solvent A includes dichloromethane, ethyl acetate, isopropyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran, toluene or chloroform; and/or an acidified aqueous solution of the crude compound of formula (I) is treated one or more times with a Pd scavenger; (b) the acidified aqueous solution of the crude compound of formula (I) obtained in the previous step (a) is treated with solvent A and an aqueous base solution to obtain a two-phase system, wherein the aqueous phase of said two-phase system has a pH>12; (c) the aqueous phase with pH>12 obtained in step (b) is separated from the two-phase system to obtain a solution of the crude compound of formula (I) in solvent A; and, optionally, (d) replacing solvent A of the solution of the crude compound of formula (I) in solvent A with solvent B, where solvent B includes ethanol, n-propanol, n-butanol, 2-butanol or isopropanol; to obtain a solution of the crude compound of formula (I) in solvent B. 10. The method of claim 9, wherein solvent A includes dichloromethane, and where the aqueous base solution includes an aqueous solution of potassium hydroxide, and wherein solvent B includes n-butanol. 11. Method according to any one of paragraphs. 8-10, wherein the crude compound of formula (I) is crystallized in solvent B, preferably n-butanol, to obtain polymorph Form B of the compound of formula (I). 12. Method according to any one of paragraphs. 1-11, which before stage (a) in accordance with paragraph 1 additionally includes the following stage: (a) carrying out the reaction of the intermediate compound of formula (VIIIa) Where R ¹ represents a chlorine, bromine or iodine atom; And R ⁵ represents a [(trifluoromethyl)sulfonyl]oxy group; with a compound of formula (VIa) Where R ² and R ³ represent, independently of each other, a hydrogen atom or a C ₁ -C ₆ alkyl group; or R ² and R ³ together represent a -CH ₂ -CH ₂ - group or -CH ₂ -CH ₂ -CH _{2 -} group, wherein said -CH ₂ -CH ₂ - group or -CH ₂ -CH ₂ -CH ₂ - the group is optionally substituted one, two, three or four times with a group selected from methyl and ethyl; or R ² and R ³ together represent the group where "*" represents the site of attachment to the rest of the molecule; to obtain intermediate compound of formula (IXa) Where R ¹ represents a chlorine, bromine or iodine atom. 13. The method according to claim 12, where the compound of formula (VIIIa) is (R)-8-chloro-2-(3-methylmorpholino)-1,7-naphthyridin-4-yl trifluoromethanesulfonate; and/or wherein the compound of formula (VIa) is 1-methyl-1H-pyrazole-5-boronic acid pinacol ester. 14. Method according to any one of paragraphs. 1-13, wherein the reaction of an intermediate of formula (VIIIa) with a compound of formula (VIa) is carried out in the presence of a palladium catalyst and/or a base. 15. Intermediate of formula (IXa) Where R ¹ represents a chlorine, bromine or iodine atom. 16. An intermediate according to claim 15, which is a compound of formula (IXb) 17. Intermediate of formula (VIIIa) Where R ¹ represents a chlorine or bromine atom, preferably a chlorine atom, And R ⁵ represents a [(trifluoromethyl)sulfonyl]oxy group. 18. An intermediate according to claim 17, which is a compound of formula (VIIIb) 19. Method according to any one of paragraphs. 1-14, which before step (a) in accordance with paragraph 12 further includes the step of carrying out the reaction of the intermediate compound of formula (II) Where R ¹ represents a chlorine, bromine or iodine atom; with a trifluoromethanesulfonic anhydride compound; to obtain intermediate compound of formula (VIIIa) Where R ¹ represents a chlorine, bromine or iodine atom; R ⁵ represents a [(trifluoromethyl)sulfonyl]oxy group. 20. The method according to claim 19, wherein the compound of formula (II) is (R)-8-chloro-2-(3-methylmorpholino)-1,7-naphthyridin-4-ol, which is reacted with trifluoromethanesulfonic anhydride to obtain intermediate of formula (VIIIb)

Images